EA040841B1 - ANTIBACTERIAL DERIVATIVES OF QUINOLINE - Google Patents

Description

The present invention relates to new substituted quinoline derivatives useful for the treatment of bacterial diseases, including, but not limited to, diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis, M. bovis, M. leprae, M. avium and M. marinum, or pathogenic staphylococci or streptococci.

State of the art

Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), a serious and potentially fatal infection worldwide. World Health Organization estimates indicate that more than 8 million people become infected with TB each year and 2 million people die from TB each year. In the past decade, TV cases have grown by 20% worldwide, with the largest share in the poorest countries. If this trend continues, the incidence of TB will increase by 41% in the next twenty years. Fifty years after the introduction of effective chemotherapy, TB remains the world's leading infectious cause of adult death after AIDS. Complicating the TB epidemic is a rising tide of multidrug-resistant strains and a devastating symbiosis with HIV. HIV-positive subjects infected with TB are 30 times more likely to develop active TB than HIV-negative subjects, and TB causes the death of one in three people with HIV/AIDS worldwide.

All existing approaches to the treatment of tuberculosis involve a combination of multiple agents. For example, the regimen recommended by the US Department of Health is a combination of isoniazid, rifampicin, and pyrazinamide for 2 months, followed by isoniazid and rifampicin for the next four months. These drugs continue to be administered for another seven months in HIV-infected patients. For patients infected with multidrug-resistant strains of M. tuberculosis, agents such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin, and ofloxacin are added to combination therapy. There is no single agent that is effective in the clinical treatment of tuberculosis, just as there is no combination of agents that suggests the possibility of therapy of less than six months.

There is a great medical need for new drugs that will improve current treatment by allowing regimens that are easier on the patient and ensure adherence to treatment. Shorter modes and those requiring less supervision are the best way to achieve this. Most of the benefit of treatment occurs in the first 2 months during the intensive or bactericidal phase when the four drugs are administered together; the bacterial load is greatly reduced and patients become non-infectious. A 4- or 6-month extension or sterilization phase is required to eliminate persistent bacilli and minimize the risk of recurrence. A powerful sterilizing drug that shortens the treatment to 2 months or less will be extremely helpful. Medications that improve treatment adherence by requiring less intensive follow-up are also needed. Clearly, a compound that reduces both overall duration of treatment and frequency of drug administration will provide the greatest benefit.

A complication of the TB epidemic is an increase in the incidence of multidrug-resistant strains or MDR-TB. Up to 4% of all cases in the world are considered MDR-TB, i.e. who are resistant to the most effective four-drug standard drugs, isoniazid and rifampin. MDR-TB is fatal if left untreated and cannot be adequately treated with standard therapy, so treatment requires up to 2 years of second-line therapy. These drugs are often toxic, expensive, and ineffective. In the absence of effective therapy, infectious MDR-TB patients continue to spread the disease, causing new infections with MDR-TB strains. There is a great medical need for a new drug with a new mechanism of action, which is able to show activity against drug-resistant strains, in particular MDR.

The term drug resistant as used above and below in this document is a term well understood by a person skilled in microbiology. A drug-resistant mycobacterium is a mycobacterium that is no longer sensitive to at least one previously effective drug; which has developed the ability to resist the antibacterial effects of at least one previously effective drug. A drug-resistant strain can pass on this ability of resistance to its offspring. Said resistance may be due to random genetic mutations in the bacterial cell that change its sensitivity to one drug or to different drugs. MDR tuberculosis is a specific form of drug-resistant tuberculosis due to bacteria resistant to at least isoniazid and rifampicin (with or without resistance to other drugs), which are currently the two most potent anti-tuberculosis drugs. Thus, as used below or above herein, drug-resistant includes multidrug-resistant.

Another factor in controlling the TV epidemic is the problem of latent TV. Despite dozens

- 1 040841 tuberculosis control programs (TB), about 2 million people are infected with M. tuberculosis, even if they are asymptomatic. About 10% of these people are at risk of developing active TV during their lifetime. The global TB epidemic is fueled by the infection of TB patients with HIV and the rise of multidrug-resistant TB strains (MDR-TB). Latent TB reactivation is a high risk factor for the development of the disease and is responsible for 32% of deaths in HIV-infected people. To control the TB epidemic, new drugs must be discovered that can kill dormant or latent bacilli. Dormant TB can be reactivated and cause disease through several factors, such as suppression of the patient's immune system through the use of immunosuppressants such as antibodies to tumor necrosis factor alpha or interferon gamma. In the case of HIV positive patients, the only prophylactic treatment suitable for latent TB is 2-3 month regimens of rifampicin, pyrazinamide. The effectiveness of the treatment regimen is still not clear and, moreover, the duration of treatment is very limited in resource-limited settings. Thus, there is a strong need to discover new drugs that can act as chemopreventive agents for individuals carrying latent TB bacilli.

Tuberculosis bacilli enter the body of healthy people with inhaled air; they are phagocytosed by alveolar macrophages of the lungs. This leads to a powerful immune response and the formation of granulomas, which consist of macrophages infected with M. tuberculosis and surrounded by T cells. After 6-8 weeks, the host's immune response causes the death of infected cells by necrosis and the accumulation of caseous matter with some extracellular bacilli surrounded by macrophages, epithelioid cells and layers of lymphoid tissue in the periphery. In the case of healthy individuals, most mycobacteria are killed under these conditions, but a small proportion of bacilli survive and are believed to exist in a non-dividing, hypometabolic state and are tolerant of killing by anti-TB drugs such as isoniazid. These bacilli can remain in altered physiological conditions even throughout the life of an individual without showing any clinical symptoms of the disease. However, in 10% of cases, these latent bacilli can reactivate, causing disease. One of the hypotheses for the development of these persistent bacteria lies in the pathophysiological conditions of pathological foci in the human body, namely, reduced oxygen tension, lack of nutrients and acidic pH. These factors are thought to confer phenotypic tolerance on these bacteria to major antimycobacterial drugs.

Along with the control of the TB epidemic, there is a new problem of resistance to first-line antibacterial agents. Some important examples include penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, multidrug-resistant Salmonella.

The consequences of resistance to antibacterial agents are severe. Infections caused by resistant microbes do not respond to treatment, leading to prolonged illness and a higher risk of death. Ineffective treatment also leads to a longer period of contagiousness, which increases the number of infected people in the community, and thus exposes the general population to the risk of infection with a resistant strain. Hospitals are a key component in the fight against germs around the world. The combination of highly susceptible patients, intensive and prolonged use of antimicrobials, and cross-infection lead to infections with highly resistant bacterial pathogens.

Self-medication with antimicrobials is another major factor contributing to resistance.

Self-administered antimicrobials may not be appropriate, are often taken in inadequate doses, or may not contain an adequate amount of active drug.

Patient adherence to recommended treatment is another big problem. Patients forget to take their medication, stop their treatment when they feel better, or may not be able to take the full course, thus creating ideal conditions for microbes to adapt rather than die.

Due to emerging resistance to multiple antibiotics, clinicians are faced with infections for which no effective treatment exists. The morbidity, mortality and financial cost of such infections are becoming a growing health burden worldwide.

Thus, there is a great need for new compounds for the treatment of bacterial infections, especially mycobacterial infections, including drug-resistant and latent mycobacterial infections, as well as other bacterial infections, especially those caused by resistant bacterial strains.

WO 2004/011436, WO 2005/070924, WO 2005/070430 and WO 2005/075428 disclose certain substituted quinoline derivatives with activity against mycobacteria, in particular against Mycobacterium tuberculosis.

WO 2005/117875 describes substituted quinoline derivatives having activity against

- 2 040841 for the treatment of resistant strains of mycobacteria. WO 2006/067048 discloses substituted quinoline derivatives with activity against latent tuberculosis. One particular compound of these substituted quinoline derivatives is described in Science (2005), 307, 223-227 and its mode of action is described in WO 2006/035051.

Other substituted quinolines are disclosed in US-5965572 (US) for the treatment of antibiotic-resistant infections and in WO 00/34265 for inhibiting the growth of bacterial microorganisms.

The purpose of the present invention is to provide new compounds, in particular substituted quinoline derivatives, having the property of inhibiting bacterial growth, especially streptococci, staphylococci or mycobacteria, and therefore of use in the treatment of bacterial diseases, in particular diseases caused by pathogenic bacteria such as Streptococcus pneumonia, Staphylococcus aureus or Mycobacterium tuberculosis (including latent disease and including drug resistant strains of M. tuberculosis), M. bovis, M. leprae, M. avium and M. marinum.

The compounds of the present invention are characterized by having an unsaturated carbon chain attached at position 3 to the quinoline core, and thus have a different basic structure compared to the quinoline derivatives described in the aforementioned level. The compounds of the present invention therefore have the advantage of being able to form fewer enantiomers. The compounds of the present invention show not only activity against strains of mycobacteria, but they also have improved activity against other bacterial strains, especially against streptococci and/or staphylococci.

The essence of the invention

The present invention relates to new substituted quinoline derivatives according to formula (Ia)

including any stereochemically isomeric form thereof, where Q is a radical of the formula

(a-1) (a-2) (θ' ³ ) p is an integer equal to 1;

q is an integer equal to zero, 1, 2, 3;

R ¹ represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, C1. ₆ alkyloxy, phenyl or Het selected from furanyl, benzothienyl and pyridyl;

R ² is hydrogen, C1. ₆ alkyloxy, C1. ₆ alkylthio;

R ³ is alkyl containing 1-6 carbon atoms, arylC1. ₆ alkyl, aryl, where aryl is selected from phenyl or naphthyl optionally substituted with halogen or C1. ₆ alkyloxy;

R ^3a is hydrogen, cyano;

R ⁴ and R ⁵ each independently represents alkyl containing 1-6 carbon atoms; or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidino, piperidino, piperazino, morpholino, hexahydro-1H-1,4-diazepinyl, 2,5diazabicyclo[2.2.1] heptyl, triazolyl, each radical is optionally substituted with 1, 2, 3 or 4 substituents, each substituent is independently selected from alkyl having 1-6 carbon atoms;

R ⁶ is phenyl optionally substituted with halo or C ₁ . ₆ alkyloxy;

R ⁷ is hydrogen;

or their pharmaceutically acceptable salts.

Whenever the term "compounds of formula (Ia)" or "compounds of the invention" is used in the present specification, this means that the pharmaceutically acceptable salts thereof are also included.

Aryl, or Het, as defined in the substituent definitions of compounds of formula (Ia) (see e.g. R ³ ) as mentioned above or below, may be attached to the remainder of the molecule of a compound of formula (Ia) via any ring carbon or heteroatom, as appropriate, unless otherwise specified.

The lines from the substituents to the ring systems indicate that the bond can be made to any suitable ring atom.

The pharmaceutically acceptable salts as mentioned above or below are intended to include the therapeutically active non-toxic acid addition salt forms which the compounds according to formula (Ia) are able to form. Said acid addition salts can be prepared by treating the base form of the compounds according to formula (Ia) suitable acids, for example inorganic acids, for example hydrohalic acid, particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid

- 3 040841 slot and phosphoric acid; organic acids, e.g. acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, para-aminosalicylic acid and pamoic acid.

Compounds of formula (Ia) containing acidic protons may be converted into their therapeutically active non-toxic metal and amino addition salt forms by treatment with suitable organic and inorganic bases. The pharmaceutically acceptable salts as mentioned above or below are intended to also include the therapeutically active non-toxic metal and amino addition salt forms (base addition salt forms) that the compounds of formula (Ia) are able to form. Suitable base addition salt forms include, for example, ammonium salts, alkali and alkaline earth salts, for example, lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example, primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, tetrabutylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, benzathine, N-methyl-D-glucamine, 2-amino-2(hydroxymethyl)-1,3-propanediol, hydrabamine salts and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely, said acid or base addition salt forms may be converted to their free forms by treatment with a suitable base or acid.

The term pharmaceutically acceptable salt also includes the quaternary ammonium salts (quaternary amines) which the compounds of formula (Ia) are able to form by reaction between the basic nitrogen of the compound of formula (Ia) and a suitable quaternizing agent such as, for example, an optionally substituted _{C1_6} alkyl halide, arylC1_ ₆ alkyl halide, C1_ ₆ alkyl carbonyl halide, aryl carbonyl halide, HetC ₁ . ₆ -alkyl halide or Het-carbonyl halide, for example methyl iodide or benzyl iodide. Preferably Het is a monocyclic heterocycle selected from furanyl, pyridyl or benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted with 1, 2 or 3 substituents, each substituent independently selected from halo, alkyl and aryl. Preferably the quaternizing agent is a _{C1_6} alkyl halide. Other reagents with easy leaving groups may also be used, such as C1_balkyl trifluoromethanesulfonates, _{C1_6} alkyl methanesulfonates, and _{C1_6} alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen atom. Pharmaceutically acceptable counterions include chlorine, bromine, iodine, trifluoroacetate, acetate, triflate, sulfate, sulfonate. Preferably the counterion is iodine. The selected counterion can be incorporated using ion exchange resins.

Within the scope of this application, the compound of the invention is expressly intended to include all their stereochemically isomeric forms. The term stereochemically isomeric forms, as used above or below, defines all possible stereoisomeric forms that compounds of formula (Ia), pharmaceutically acceptable salts, or physiologically functional derivatives may have. Unless otherwise mentioned or shown, the chemical designation of compounds means a mixture of all possible stereochemically isomeric forms.

In particular, stereogenic centers may be in the R or S configuration; substituents on divalent cyclic (partially) saturated radicals may have either the cis or trans configuration. Compounds spanned by double bonds may have E (entgegen) or Z (zusammen) stereochemistry at said double bond. The terms cis, trans, R, S, E, and Z are well known to those of ordinary skill in the art.

The stereochemically isomeric forms of the compounds of formula (Ia) are obviously intended to be embraced within the scope of the present invention. Of particular interest are those compounds of formula (Ia) which are stereochemically pure.

Following the rules of CAS nomenclature, when two stereogenic centers of known absolute configuration are present in a molecule, the designator R or S is assigned (based on the Cahn-Ingold-Prelog order rule) to the lowest numbered chiral center, the reference center. The configuration of the second stereogenic center is indicated using the relative designators [R*,R*] or [R*,S*], where R* is always defined as the reference center, and [R*,R*] indicates centers with the same chirality, and [ R*,S*] indicates centers with different chirality. For example, if the lowest numbered chiral center in the molecule has an S configuration and the second center has an R configuration, then the stereo index would be defined as S-[R*,S*]. If α and β are used: the position of the highest priority substituent on the asymmetric carbon atom of the ring system having the lowest number of rings is arbitrarily set to the α position of the median plane defined by the ring system. The position of the deputy with the highest priority on

- 4 040841 another asymmetric carbon atom in the ring system relative to the position of the substituent with the highest priority on the reference atom is called α if it is on the same side of the median plane defined by the ring system, or β if it is on the other side of the median plane, certain ring system.

When a specific stereoisomeric form is indicated, it means that said form is substantially free, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, further preferably less than than 2% and most preferably less than 1% of the other isomer(s). Thus, when a compound of formula (Ia), for example, is defined as (E), this means that the compound is essentially not containing the (Z) isomer.

In particular, in view of the fact that the compounds of formula (Ia) contain at least 1 double bond in the Q substituent, the compounds may have an E configuration at this double bond, they may have a Z configuration at this double bond, or they may be a mixture The E and Z configurations of this double bond. Preferably, the compound of formula (Ia), as defined above or hereinafter, has a specific configuration at this double bond (generally no other configuration).

Compounds of formula (Ia) in which Q is a radical of formula (a-2) or (a-3) also contain at least one chiral center, ie a carbon atom which attaches a substituent Q to the quinoline group. These compounds may have an R configuration at this carbon atom, an S configuration at this carbon atom, or they may be a mixture of R and S at this carbon atom. Preferably, the compound of formula (Ia), as defined above or hereinafter, has a specific configuration at that carbon atom (generally no other configuration).

Compounds of any formula (Ia) can be synthesized as mixtures, in particular racemic mixtures, of enantiomers which can be separated from each other following separation techniques known in the art. The racemic compounds of formula (Ia) may be converted to the corresponding diastereomeric salt forms by reaction with an appropriate chiral acid. Said diastereomeric salt forms are subsequently separated, for example by selective or fractional crystallization, and the enantiomers are recovered from them with alkali. An alternative method for separating the enantiomeric forms of compounds of formula (Ia) 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 respective starting materials, provided that the reaction proceeds stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific preparation methods. It will be useful in these methods to use enantiomerically pure starting materials.

Tautomeric forms of compounds of formula (Ia) are intended to include compounds of formula (Ia) in which, for example, the enol group has been converted to a keto group (ketoenol tautomerism). Tautomeric forms of the compounds of formula (Ia) or intermediates of the present invention are intended to be within the scope of the present invention.

The N-oxide forms of the compounds of the present invention are intended to include compounds of formula (Ia) in which one or more tertiary nitrogen atoms are oxidized to the so-called Noxide.

Compounds of formula (Ia) may be converted to the corresponding N-oxide forms following art-known procedures for converting trivalent nitrogen to its N-oxide form. Said N-oxidation reaction can generally be carried out by reacting the starting material of formula (Ia) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides, eg sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxyacids such as, for example, benzenecarboperoxoic acid or halogenated benzenecarboperoxoic acid, such as 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, such as peroxoacetic acid, alkyl hydroperoxides, such as tert-butyl hydroperoxide.

Suitable solvents are, for example, water, lower alcohols, such as ethanol, and the like, hydrocarbons, such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons, such as dichloromethane, and mixtures of such solvents.

At the heart of the present application, a compound of the invention is inherently intended to include all isotopic combinations of its chemical elements. At the heart of this application, a chemical element, especially when a compound according to formula (Ia) is mentioned, includes all isotopes and isotopic mixtures of that element, whether natural or synthetically produced, or abundant in nature, or in isotopically enriched form. In particular, when hydrogen is mentioned, it will be understood to refer to 1H, ^2H , ^3H and mixtures thereof; when carbon is mentioned, it is clear that it refers to ^P C, ¹² C, ¹³ C, ¹⁴ C and mixtures thereof; when nitrogen is mentioned, it is clear that it refers to ¹³ N, ¹⁴ N, ¹⁵ N

- 5 040841 and mixtures thereof; when oxygen is mentioned, it is clear that it refers to ¹⁴ 0, ¹⁵ 0, ¹⁶ 0, ¹⁷ 0, ¹⁸ O and mixtures thereof; and when fluorine is mentioned it is understood to refer to ¹⁸ F, ¹⁹ F and mixtures thereof.

A compound of the invention therefore inherently includes a compound with one or more isotopes of one or more elements and mixtures thereof, including a radioactive compound, also referred to as a radiolabelled compound, in which one or more non-radioactive atoms are replaced by one of its radioactive isotopes. The term radiolabeled compound is intended to refer to any compound of formula (Ia), a pharmaceutically acceptable salt thereof, which contains at least one radioactive atom. For example, the compound may be labeled with a positron or a gamma emitting radioactive isotope. For radioligand binding techniques (membrane receptor assay), ^{the 3} H-atom or ¹²⁵ I-atom is the atom selected for substitution. For imaging, positron-active (PET) radioactive isotopes are more commonly used - ^PS , ¹⁸ F, ¹⁵ O and ¹³ N, all of which are accelerator-derived and have half-lives of 20, 100, 2 and 10 min, respectively. Because the half-lives of these radioactive isotopes are so short, it is only possible to use them in facilities that have an accelerator in place to produce them, thus limiting their use. The most widely used of these are ¹⁸ F, ^99m Tc, ²⁰¹ Tl and ¹²³ I. The handling, production, isolation and incorporation of these radioactive isotopes is known to those skilled in the art.

In particular, the radioactive atom is selected from the group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. Preferably, the radioactive atom is selected from the group of hydrogen, carbon and halogen.

In particular, the radioactive isotope is selected from the group ³ H, ⁿ C, ¹⁸ F, ¹²² I, ¹²³ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. Preferably the radioactive isotope is selected from the group ³ H, ¹¹ C and ¹⁸ F.

As used herein, alkyl is a straight or branched chain hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms attached to a straight or branched chain hydrocarbon radical having 1 to 6 carbon atoms; where each carbon atom may be optionally substituted with cyano, hydroxy, C _1-6 alkyloxy or oxo. Preferably, alkyl is a straight or branched chain hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms; where each carbon atom may be optionally substituted with hydroxyl or C _1-6 alkyloxy.

Preferably alkyl is methyl, ethyl or cyclohexylmethyl, more preferably methyl or ethyl. An interesting embodiment of alkyl in all definitions used above or below is C _1-6 alkyl, which is a straight or branched chain hydrocarbon radical having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, 2 -methylethyl, pentyl, hexyl and the like. A preferred subgroup of C _1-6 alkyl is C _1-4 alkyl which is a straight or branched chain hydrocarbon radical having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, 2-methylethyl and the like. .

As used herein, C _2-6 alkenyl is a straight or branched chain hydrocarbon radical having 2 to 6 carbon atoms containing a double bond, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like; C _2-6 alkynyl is a straight or branched chain hydrocarbon radical having 2 to 6 carbon atoms containing a triple bond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like; C ₃ - ₆ cycloalkyl is a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms and is basic in cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

Within the scope of this application, halogen is a substituent selected from the group of fluorine, chlorine, bromine and iodine, and haloalkyl is a straight or branched chain hydrocarbon radical having from 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon radical having from 3 up to 6 carbon atoms, or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms attached to a straight or branched chain hydrocarbon radical having 1 to 6 carbon atoms; where one or more carbon atoms are replaced by one or more halogen atoms. Preferably the halogen is bromine, fluorine or chlorine; especially preferably chlorine or bromine. Preferably haloalkyl is polyhaloC^alkyl, which is defined as mono- or polyhalo-substituted C _1-6 alkyl, eg methyl with one or more fluorine atoms, eg difluoromethyl or trifluoromethyl, 1,1-difluoroethyl and the like. In case more than one halogen atom is attached to an alkyl or C _1-6 alkyl group within the definition of haloalkyl or polyhaloC _1-6 alkyl, they may be the same or different.

The first embodiment of interest relates to a compound of formula (Ia) wherein Q is a radical of formula

- 6 040841

p is an integer equal to 1, 2, 3 or 4;

q is an integer equal to zero, 1, 2, 3 or 4;

R ¹ is hydrogen, cyano, formyl, carboxyl, halogen, alkyl, C _2-6 alkenyl, C _2-6 alkynyl, haloalkyl, hydroxy, alkyloxy, alkylthio, alkylthioalkyl, -C=N-OR ¹¹ , amino, mono- or di(alkyl)amino, aminoalkyl, mono- or di(alkyl)aminoalkyl, alkylcarbonylaminoalkyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, arylalkyl, arylcarbonyl, R ^5a R ^4a N alkyl, di(aryl) alkyl, aryl, R ^5a R ^4a N-, R ^5a R ^4a NC (=O) - or Het;

R ² is hydrogen, alkyloxy, aryl, aryloxy, hydroxy, mercapto, alkyloxyalkyloxy, alkylthio, mono- or di(alkyl)amino, pyrrolidino, or a radical of the formula

where Y represents CH2, O, S, NH or N-alkyl;

R ³ is alkyl, arylalkyl, aryl-O-alkyl, arylalkyl-O-alkyl, aryl, Het, Het-alkyl, Het-O-alkyl, Het-alkyl-O-alkyl, or ^> \__/ phenyl

R ^3a is hydrogen, cyano, alkyl, arylalkyl, aryl-O-alkyl, arylalkyl-O-alkyl, aryl, Het, Het-alkyl, Het-O-alkyl or Het-alkyl-O-alkyl;

R ⁴ and R ⁵ are each independently hydrogen, alkyl, alkyloxyalkyl, arylalkyl, Hetalkyl, mono- or dialkylaminoalkyl, Het, aryl, or -C(=NH)-NH ₂ ; or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-III-azepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazepinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2, 5diazabicyclo[2.2.1]heptyl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, each radical optionally substituted with 1, 2, 3 or 4 substituents each substituent is independently selected from alkyl, haloalkyl, alkylcarbonyl, halogen, arylalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkylthioalkyl, aryl, pyridyl, pyrimidinyl, piperidinyl, or pyrrolidinyl optionally substituted with arylalkyl;

R ^4a and R ^5a together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-III-azepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazepinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, each radical is optionally substituted with 1, 2, 3 or 4 substituents, each substituent is independently selected from alkyl, haloalkyl, halogen, arylalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkylthioalkyl, aryl, pyridyl or pyrimidinyl;

R ⁶ is aryl ¹ or Het;

R ⁷ is hydrogen, halogen, alkyl, aryl or Het;

R ⁸ is hydrogen or alkyl;

R ⁹ is oxo; or

R ⁸ and R ⁹ together form the radical -CH=CH-N=;

R ¹¹ is hydrogen or alkyl;

aryl is a homocycle selected from phenyl, naphthyl, acenaphthyl, or tetrahydronaphthyl, each optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy , haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl, or mono- or dialkylaminocarbonyl; aryl ¹ is a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from hydroxy, halogen, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, alkylthio, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl, Het or mono- or dialkylaminocarbonyl;

- 7 040841

Het is a monocyclic heterocycle selected from N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3dihydrobenzo[1,4]dioxinyl, or benzo[1,3]dioxolyl; each monocyclic and bicyclic heterocycle is optionally substituted with 1, 2 or 3 substituents, each substituent is independently selected from halo, hydroxy, alkyl or alkyloxy.

A second embodiment of interest relates to a compound of formula (Ia) wherein Q is a radical of formula

p is an integer equal to 1, 2, 3 or 4;

q is an integer equal to zero, 1, 2, 3 or 4;

R ¹ is hydrogen, cyano, formyl, carboxyl, halogen, C _1-6 alkyl, C _2-6 alkenyl,

C _2-6 alkynyl, haloC _1-6 alkyl, hydroxy, C _1-6 alkyloxy, C _1-6 alkylthio, C _1-6 alkylthioC _1-6 alkyl, -c=N-OR ¹¹ , amino, mono- or di (C1-6alkyl) amino, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonylaminoC1-6alkyl, aminocarbonyl, mono- or di(C1-6alkyl)aminocarbonyl, arylC1-6alkyl, arylcarbonyl, R ^5a R ^4a NC1-6-αkyl, di(aryl)C _1-6 alkyl, aryl, R ^5a R ^4a N-, R ^5a R ^4a NC (=O)- or Het;

R ² is hydrogen, C _1-6 alkyloxy, aryl, aryloxy, hydroxy, mercapto, C _1-6 alkyloxyC ₁₆ alkyloxy, C 1-6 alkylthio, mono- or di(C _1-6 αalkyl)amino, pyrrolidino, or a radical of the formula

where Y represents CH ₂ , O, S, NH or NC _1-6 alkyl;

R ³ is C _1-6 alkyl, arylC _1-6 alkyl, aryl-OC _1-6 alkyl, aryl-C _1-6 alkyl-O-C _1-6 alkyl, aryl, aryl-aryl, Het, Het- C _1-6 alkyl, Het-OC _1-6 alkyl, Het-C _1-6 alkyl-O-C _1-6 alkyl or ^> \__/ phenyl

R ^3a is hydrogen, cyano, C _1-6 alkyl, arylC _1-6 alkyl, aryl-OC _1-6 alkyl, aryl-C _1-6 alkylO-C _1-6 alkyl, aryl, aryl-aryl, Het, Het-C _1-6 alkyl, Het-OC _1-6 alkyl or Het-C _1-6 alkyl-O-C _1-6 alkyl;

R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkyloxyC _1-6 alkyl, arylC _1-6 alkyl, Het-C _1-6 alkyl. mono-or diC _1-6 alkylaminoC _1-6 alkyl.bicyclo[2.2.1]heptyl, Het, aryl or C(=NH)-NH ₂ ; or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 1,1-thiomorpholinyl dioxide, azetidinyl, 2,3-dihydroisoindole-1- yl, thiazolidin-3-yl, 1,2,3,6tetrahydropyridyl, hexahydro-1H-azepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4oxazepinyl, 1,2,3,4-tetrahydroisoquinoline-2- yl, 2,5-diazabicyclo[2.2.1]heptyl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, each radical is optionally substituted 1, 2, 3 or 4 substituents, each substituent independently selected from alkyl, haloC _1-6 alkyl, C _1-6 αalkylcarbonyl, halo, arylC _1-6 alkyl, hydroxy, C _1-6 alkyloxy, amino, mono or diC _{1- 6} alkylamino, aminoC _1-6 alkyl, mono- or diC _1-6 alkylaminoC _1-6 alkyl, C _1-6 alkylthio, C _1-6 αalkylthioC _1-6 αalkyl, aryl, pyridyl , pyrimidinyl, piperidinyl optionally substituted with C _1-6 alkyl, or pyrrolidinyl optionally substituted with arylC _1-6 alkyl;

R ^4a and R ^5a together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazepinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, each radical is optionally substituted with 1, 2, 3 or 4 substituents, each substituent is independently selected from C _{1 -6} αalkyl, haloC _1-6 alkyl, halogen, arylC _1-6 alkyl, hydroxy, C _1-6 alkyloxy, amino, mono- or diC _1-6 alkylamino, C _1-6 alkylthio, C _1-6 alkylthioC _{1- 6} alkyl, aryl, pyridyl or pyrimidinyl;

R ⁶ is aryl ¹ or Het;

- 8 040841

R ⁷ is hydrogen, halogen, C _1-6 alkyl, aryl or Het;

R ⁸ is hydrogen or C _1-6 alkyl;

R ⁹ is oxo; or

R ⁸ and R ⁹ together form the radical -CH=CH-N=;

R ¹¹ is hydrogen or C _1-6 alkyl;

aryl is a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from hydroxy, halo, cyano, nitro, amino, mono- or diC _1-6 alkylamino, C _1-6 αalkyl, C _2-6 alkenyl optionally substituted with phenyl, haloC _1-6 alkyl, C _1-6 alkyloxy, haloC _1-6 alkyloxy, carboxyl, C _1-6 αalkyloxycarbonyl, aminocarbonyl, morpholinyl, or mono- or diC _{1 -6} alkylaminocarbonyl;

aryl ¹ is a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from hydroxy, halo, cyano, nitro, amino, mono- or diC _1-6 alkylamino, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylthio, haloC _1-6 alkyloxy, carboxyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl, Het or mono-or diC _{1- 6} alkylaminocarbonyl;

Het is a monocyclic heterocycle selected from N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3dihydrobenzo[1,4]dioxinyl, or benzo[1,3]dioxolyl;

each monocyclic and bicyclic heterocycle is optionally substituted with 1, 2 or 3 substituents, each substituent is independently selected from halo, hydroxy, C _1-6 alkyl or C _1-6 alkyloxy.

A third embodiment of interest relates to a compound of formula (Ia) wherein Q is a radical of formula

p is an integer equal to 1, 2, 3 or 4; q is an integer equal to zero, 1, 2, 3 or 4;

R ¹ is hydrogen, cyano, formyl, carboxyl, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, polyhaloC1-6alkyl, hydroxy, C1-6alkyloxy, C1-6alkylthio, C1-6αalkyloxyC1-6alkyl, C1-6alkylthioC1- 6alkyl, hydroxyC1-6alkyl, -C=N-OR ¹¹ , amino, mono- or di (C1-6αkyl) amino, aminoC _1-6 alkyl, mono- or di(C _1-6 alkyl) aminoC _1-6 alkyl, C _1-6 alkylcarbonylamino C _1-6 alkyl, aminocarbonyl, mono- or di (C _1-6 αkyl) α minokα rbonyl, aryl C _1-6 alkyl, aryl carbonyl, R ^5a R ^4a NC _1-6 alkyl, di(aryl) C _{1- 6} alkyl, aryl, R ^5a R ^4a N-, R ^5a R ^4a NC (=O) - or Het;

R ² is hydrogen, C _1-6 alkyloxy, aryl, aryloxy, hydroxy, mercapto, C _1-6 alkyloxyC _1-6 alkyloxy, C _1-6 alkylthio, mono or di(C _1-6 alkyl)amino, pyrrolidino, or formula radical

where Y represents CH ₂ , O, S, NH or NC _1-6 alkyl;

R ³ is C _1-6 alkyl, C _3-6 cycloalkyl, arylC _1-6 alkyl, aryl-OC _1-6 αkyl, arylC _1-6 alkylO-C _1-6 alkyl, aryl, Het, Het-C _{1 -6} alkyl, Het-OC _1-6 alkyl or HetC _1-6 alkyl-O-C _1-6 alkyl or .O

phenyl

R ^3a is hydrogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, arylC _1-6 alkyl, aryl-OC _1-6 alkyl, arylC _1-6 αalkyl-OC _1-6 alkyl, aryl, Het, Het-C _1-6 alkyl, Het-OC _1-6 αlκyl or HetC _1-6 alkyl-O-C _1-6 alkyl;

R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkyloxyC _1-6 alkyl, arylC _1-6 alkyl, HetC _1-6 αalkyl, mono- or di (C _1-6 alkyl) aminoC _1-6 alkyl, Het, aryl or -C(=NH)-NH2; or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazepinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2, 5diazabicyclo[2.2.1]heptyl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, each radical optionally substituted with 1, 2, 3 or 4 substituents , each substituent is independently selected from C _1-6 alkyl, polyhaloC _1-6 alkyl,

- 9 040841

C1-balkylcarbonyl, halogen, _arylC1-6 alkyl, hydroxy, C ₁ . ₆ alkyloxy, C _1- balkyloxyC _1- balkyl, amino, mono- or di (C _1-6 alkyl) amino, C _1-6 alkylthio, C _1-6 alkyloxyC _1-6 alkyl, C _1-6 alkylthioC _1-6 alkyl, aryl, pyridyl, pyrimidinyl, piperidinyl or pyrrolidinyl optionally substituted with arylC _1-6 alkyl;

R ^4a and R ^5a together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazepinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, each radical is optionally substituted with 1, 2, 3 or 4 substituents, each substituent is independently selected from C ₁ . ₆ alkylα, _polyhaloC1-6 alkyl, halo, _arylC1-6 alkyl, hydroxy, _C1-6 alkyloxy, C ₁ . ₆ alkyloxyC ₁ . ₆ alkyl, amino, mono- or di(C ₁ _ ₆ alkyl) amino, C ₁ . ₆ alkylthio, C ₁ . ₆ alkyloxyC ₁ . ₆ alkyl, C ₁ . ₆ alkylthioC ₁ . ₆ alkyl, aryl, pyridyl or pyrimidinyl;

R ⁶ is aryl ¹ or Het;

R ⁷ is hydrogen, halogen, C ₁ _ ₆ alkyl, aryl or Het;

R ⁸ is hydrogen or C ₁ _ ₆ alkyl;

R ⁹ is oxo; or R ⁸ and R ⁹ together form the radical -CH=CH-N=;

R ¹¹ is hydrogen or C ₁ _ ₆ alkyl;

aryl is a homocycle selected from phenyl, naphthyl, acenaphthyl, or tetrahydronaphthyl, each optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from hydroxy, halo, cyano, nitro, amino, mono-, or di(C _{1 .6} alkyl ) amino, C ₁ . ₆ alkyl, _polyhaloC1-6 alkyl, _C1-6 alkyloxy, _haloC1-6 alkyloxy, carboxyl, _C1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono- or di(C _{1 .6} alkyl)aminocarbonyl;

aryl ¹ is a homocycle selected from phenyl, naphthyl, acenaphthyl, or tetrahydronaphthyl, each optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from hydroxy, halo, cyano, nitro, amino, mono-, or di(C ₁ _ ₆ alkyl)amino, C ₁ . ₆ alkyl, _polyhaloC1-6 alkyl, _C1-6 alkyloxy, _{C1_6} alkylthio _{, haloC1-6} alkyloxy, carboxyl, _C1-6 alkyloxycarbonyl _, aminocarbonyl, morpholinyl, Het or mono-or di( _{C1_6} alkyl)aminocarbonyl;

Het is a monocyclic heterocycle selected from N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo[1,4]dioxinyl, or benzo[1,3]dioxolyl;

each monocyclic and bicyclic heterocycle is optionally substituted with 1, 2 or 3 substituents, each substituent is independently selected from halo, hydroxy, C ₁ . ₆ alkyl or C ₁ . ₆ alkyloxy.

The fourth interesting embodiment relates to a compound of formula (Ia) or any subgroup thereof, as mentioned above, in the form of interest embodiment, where R ¹ represents hydrogen, cyano, halogen, alkyl, haloalkyl, hydroxy, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, arylalkyl , di(aryl)alkyl, aryl or Het; preferably R ¹ is hydrogen, halogen, aryl, Het, alkyl or alkyloxy; more preferably R ¹ is halogen. More preferably R ¹ is bromine. Or R ¹ is formyl, carboxyl, C2.6alkenyl, C2.6alkynyl, -C=N-OR ¹¹ , amino, mono- or di(alkyl)amino, aminoalkyl, mono- or di(alkyl)aminoalkyl, alkylcarbonylaminoalkyl, aminocarbonyl , mono- or di(alkyl)aminocarbonyl, arylcarbonyl, R ^5a R ^4a N alkyl, R ^5a R ^4a N-, R ^5a R ^4a NC (=O)-; more preferably C2. ₆ alkenyl, C ₂ - ₆ alkynyl, -C=N-OR ⁿ , amino, mono or di(alkyl)amino, aminoalkyl, mono- or di(alkyl)aminoalkyl, alkylcarbonylaminoalkyl, aminocarbonyl, mono or di(alkyl)aminocarbonyl, R ^5a R ^4a N alkyl, R ^5a R ^4a N-, R ^5a R ^4a NC(=O)-; even more preferably C2.6alkenyl, C2.6alkynyl, -C=N-OR ¹¹ , R ^5a R ^4a N alkyl, R ^5a R ^4a N-, R ^5a R ^4a NC (=O)-; even more especially _C2-6 alkenyl or -C=N-OR ¹¹ .

A fifth embodiment of interest relates to a compound of formula (Ia), or any subgroup thereof, as mentioned above, as an embodiment of interest, wherein p is 1.

A sixth embodiment of interest relates to a compound of formula (Ia) or any of its subgroups as mentioned above, in the form of interest embodiment, where R ² represents hydrogen, alkyloxy or alkylthio, especially preferably hydrogen, C1.6alkyloxy or C1.6alkylthio. More preferably R ² is C1. ₆ alkyloxy, preferably methyloxy.

The seventh interesting embodiment relates to a compound of formula (Ia) or any of its subgroups, as mentioned above, in the form of interesting embodiment, where R ³ represents alkyl, arylalkyl, aryl or Het; particularly preferably C1-6alkyl, arylC1-6alkyl, aryl or Het; more preferably C1-6alkyl, optionally substituted phenyl, optionally substituted naphthyl, arylC16alkyl, where aryl is optionally substituted phenyl or optionally substituted naphthyl, or Het; even more preferably C1.6alkyl, phenyl, naphthyl, arylC1-6alkyl, where aryl is phenyl or naphthyl or thienyl. Preferably R ³ is C1-6 alkyl, especially

- 10 040841 preferably methyl; phenyl; naphthyl; phenylC _1-6 alkyl or naphthylC _1-6 alkyl; more preferably R ³ is C _1-6 alkyl, particularly preferably methyl, phenyl, naphthyl or phenylC _1-6 alkyl.

An eighth embodiment of interest relates to a compound of formula (Ia) or any of its subgroups as mentioned above, in the form of interest embodiment, where R ³ represents hydrogen, cyano, C _1-6 αkyl, arylC _1-6 alkyl, aryl, Het or Het -C _1-6 alkyl; especially preferably cyano, C _1-6 alkyl or arylC _1-6 alkyl; more preferably phenylC _1-6 alkyl.

A ninth embodiment of interest relates to a compound of formula (Ia), or any subgroup thereof, as mentioned above, as an embodiment of interest, wherein q is 1, 2, or 3. More preferably, q is 1.

The tenth embodiment of interest relates to a compound of formula (Ia) or any of its subgroups as mentioned above, in the form of interest embodiment, where R ⁴ and R ⁵ each independently represents hydrogen or C _1-6 αkyl, particularly preferably C _1-6 alkyl , more preferably methyl or ethyl. Preferably R ⁴ and R ⁵ are methyl.

An eleventh embodiment of interest relates to a compound of formula (Ia) or any of its subgroups as mentioned above, in the form of an interesting embodiment, where R ⁴ and R ⁵ together with the nitrogen atom to which they are attached, form a radical selected from the group consisting of piperidino , piperazino, morpholino, imidazolyl, triazolyl, each of said rings optionally substituted with C16 alkyl; more preferably piperidino, piperazino or morpholino, each of said rings being optionally substituted with C1-4alkyl; even more preferably piperidino, piperazino optionally substituted with C1-4alkyl, or morpholino; or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a radical selected from the group consisting of 1,1-dioxidthiomorpholinyl, azetidinyl, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1 , 2, 3, 6-tetrahydropyridyl, hexahydro-Shazepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazepinyl, 1, 2, 3, 4-tetrahydroisoquinolin-2-yl, 2,5-diazabicyclo [2.2.1]heptyl, each of said rings optionally substituted with C16alkyl or arylC _[-6alkyl ; more preferably hexahydro-1H-1,4-diazepinyl or 2,5diazabicyclo[2.2.1]heptyl, each of said rings optionally substituted with Cl _-6 αkyl or arylC1-6alkyl.

The twelfth embodiment of interest relates to a compound of formula (Ia) or any subgroup thereof as mentioned above, in the form of interest embodiment, where R ⁶ represents phenyl, optionally substituted with halogen, cyano or C _1-6 alkyloxy; particularly preferably phenyl optionally substituted with halogen.

A thirteenth embodiment of interest relates to a compound of formula (Ia) or any of its subgroups as mentioned above, in the form of interest embodiment, where R ⁷ represents hydrogen.

A fourteenth embodiment of interest relates to a compound of formula (Ia), or any subgroup thereof, as mentioned above, as an interesting embodiment, wherein the compound is a compound of formula (Ia).

A seventeenth embodiment of interest relates to a compound of formula (Ia), or any subgroup thereof, as mentioned above, as an interesting embodiment, wherein Q is a radical of formula (a-1) or (a-2).

An eighteenth embodiment of interest is a compound of formula (Ia) or any of its subgroups as mentioned above, in the form of an interesting embodiment, where aryl is naphthyl or phenyl, more preferably phenyl, each optionally substituted with one or two substituents selected from halogen, for example, chlorine; cyano; alkyl, for example methyl; or alkyloxy, for example methyloxy.

A nineteenth embodiment of interest relates to a compound of formula (Ia) or any of its subgroups as mentioned above, in the form of interest embodiment, where R ¹ is located at the 6 position of the quinoline ring.

Within the scope of this application, the quinoline ring of the compounds of formula (Ia) is numbered as follows:

A twentieth interesting embodiment is the use of a compound of formula (Ia), or any subgroup thereof, as mentioned above, as an interesting embodiment, for the manufacture of a medicament for the treatment of a bacterial infection caused by a Gram-positive bacterium.

The twenty-first embodiment of interest is the use of a compound of formula (Ia), or any subgroup thereof, as mentioned above, as an interesting embodiment, for the manufacture of a medicament for the treatment of a bacterial infection, wherein the compound of formula (Ia) has

- 11 040841

IC ₉₀ <15 μl/ml against at least one bacterium, particularly preferably a Gram-positive bacterium; preferably IC ₉₀ <10 µl/ml; more preferably IC ₉₀ <5 µl/ml;

The IC ₉₀ value is determined as described below.

A twenty-second embodiment of interest refers to a compound of formula (Ia), or any subgroup thereof, as mentioned above, as an embodiment of interest, wherein one or more preferably all of the following definitions are used:

R ¹ is hydrogen, halogen, aryl, Het, alkyl or alkyloxy; especially preferably hydrogen, halogen, aryl, Het, C _1-6 alkyl or C _1-6 alkyloxy; more preferably halogen, preferably bromine;

R ² is hydrogen, alkyloxy or alkylthio, particularly preferably hydrogen, C _1-6 alkyloxy or C _1-6 alkylthio; more preferably C _1-6 alkyloxy, preferably methyloxy;

R ³ is alkyl, arylalkyl, aryl or Het; particularly preferably C _1-6 alkyl, arylC _1-6 alkyl, aryl or Het; more preferably C _1-6 alkyl, particularly preferably methyl, phenyl, naphthyl or phenylC _1-6 alkyl;

R ⁴ and R ⁵ is C1-6 alkyl; particularly preferably methyl; or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a radical selected from the group consisting of piperidino, piperazino, morpholino, imidazolyl, triazolyl, hexahydro-1H-1,4-diazepinyl or 2,5diazabicyclo[2.2 .1]heptyl, each of said rings being optionally substituted with C1-6αkyl or _{arylC1-6alkyl} ; more preferably piperidino, piperazino optionally substituted with C _1-4 alkyl, morpholino, hexahydro-1H-1,4-diazepinyl optionally substituted with C _1-6 alkyl, or 2,5-diazabicyclo[2.2.1]heptyl optionally substituted with aryl C _1-6 alkyl; especially preferably R ⁴ and R ⁵ is C _1-6 αkyl, preferably methyl;

R ⁶ is phenyl optionally substituted with halogen, cyano or C _1-6 alkyloxy; particularly preferably phenyl optionally substituted with halogen;

R ⁷ is hydrogen;

q is 1, 2, or 3;

p has a value of 1;

Q represents a radical of formula (a-1), (a-2) or (a-3); especially preferably (a-1) or (a-2).

Preferably in the compounds of formula (Ia) or any subgroup thereof as mentioned above, in the embodiment of interest, the term alkyl is C _1-6 alkyl, more preferably C _1-4 αalkyl, and the term haloalkyl is polyhaloC _1-6 alkyl.

More preferred compounds of formula (Ia) are compounds selected from

their pharmaceutically acceptable salt.

In addition, the invention also relates to a compound of the formula

(Sha) its pharmaceutically acceptable salt.

Pharmacology

The compounds of the present invention have unexpectedly demonstrated utility in the treatment of bacterial infection, including mycobacterial infection, in particular diseases

- 12 040841 called pathogenic mycobacteria such as Mycobacterium tuberculosis (including its latent and drug-resistant form), M. bovis, M. avium, M. leprae and M. marinum. The present invention thus also relates to compounds of formula (Ia) as described above, to their pharmaceutically acceptable salts, for use in medicine, in particular for use as a drug for the treatment of bacterial infection, including mycobacterial infection.

Further, the present invention also relates to the use of a compound of formula (Ia) as described above, to their pharmaceutically acceptable salts, as well as to any of their pharmaceutical compositions, as described below, for the manufacture of a medicament for the treatment of a bacterial infection, including mycobacterial infection. .

In addition to their activity against mycobacteria, the compounds of the invention are also active against other bacteria. Generally, bacterial pathogens can be classified as Gram-positive or Gram-negative pathogens. Antibiotics with activity against both Gram-positive and Gram-negative pathogens are generally considered to have a broad spectrum of activity. The compounds of the present invention are considered active against gram-positive and/or gram-negative bacterial pathogens, in particular against gram-positive bacterial pathogens. In particular, the present compounds are active against at least one gram-positive bacterium, preferably against several gram-positive bacteria, more preferably against one or more gram-positive bacteria and/or one or more gram-negative bacteria.

The present compounds have bactericidal or bacteriostatic activity.

Examples of Gram-positive and Gram-negative aerobic and anaerobic bacteria include Staphylococci, eg S. aureus; Enterococci, eg E. faecalis; Streptococci, eg S. pneumoniae, S. mutans, S. pyogens; Bacilli, for example Bacillus subtilis; Listeria, for example Listeria monocytogenes; Haemophilus, eg H. influenza; Moraxella, eg M. catarrhalis; Pseudomonas, such as Pseudomonas aeruginosa; and Escherichia, for example E. coll. Gram-positive pathogens, eg Staphylococci, Enterococci and Streptococci, are of particular importance due to the development of resistant strains that are both difficult to treat and difficult to eradicate completely, for example, in a hospital environment once they have been colonized. Examples of such strains are methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae, and multidrug-resistant Enterococcus faecium.

The compounds of the present invention have also shown activity against resistant bacterial strains.

The compounds of the present invention are particularly active against Streptococcus pneumoniae and Staphylococcus aureus, including resistant Staphylococcus aureus such as, for example, methicillin-resistant Staphylococcus aureus (MRSA).

Thus, the present invention also relates to the use of a compound of formula (Ia), their pharmaceutically acceptable salts as well as any of their pharmaceutical compositions as described below, for the manufacture of a medicament for the treatment of a bacterial infection, including infection caused by staphylococci and/or streptococci.

Without wishing to be bound by theory, it is believed that the activity of the present compounds is to inhibit the FIFO ATP synthetase, in particular the inhibition of the FO complex of the FIFO ATP synthetase, more specifically the inhibition of the c subunit c of the FO complex of the FIFO ATP synthetase, resulting in the death of bacteria by depletion of bacterial cellular levels of ATP. Therefore, in particular, the compounds of the present invention are active against those bacteria whose viability depends on the correct functioning of the FIFO ATP synthetase.

Bacterial infections which may be treated with the present compounds include, for example, infections of the central nervous system, infections of the external ear, infections of the middle ear such as acute otitis media, infections of the intracranial sinuses, infections of the eyes, infections of the oral cavity such as infections of the teeth, gums and mucous membranes, upper respiratory tract infections, lower respiratory tract infections, urinary tract infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, infections of the skin and skin structures, bacterial endocarditis, burns, antibiotic prophylaxis in surgery and antibacterial prophylaxis in immunocompromised patients, such as patients receiving chemotherapy for cancer or organ transplant patients.

If it is said in this document above or below that the compounds can treat a bacterial infection, this means that the compounds can treat an infection caused by one or more strains.

The invention also relates to a pharmaceutical composition containing a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound of the invention. The compounds of the invention may be formulated into various pharmaceutical forms for administration. As suitable compositions, all compositions commonly used for the systemic administration of drugs may be cited. For making headlights

- 13 040841 maceutical compositions according to this invention, an effective amount of a particular compound, optionally in the form of a salt, as an active ingredient, is combined in a homogeneous mixture with a pharmaceutically acceptable carrier, while the carrier may take many different forms, depending on the form of the preparation desired for introductions. These pharmaceutical compositions are preferably in a single dosage form, suitable in particular for administration orally or by parenteral injection. For example, during the preparation of compositions in oral dosage form, any of the usual pharmaceutical media can be used, such as, for example, water, glycols, oils, alcohols, and the like. in the case of liquid oral preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrants and the like, in the case of powders, pills, capsules and tablets. Due to their ease of administration, tablets and capsules are the most preferred oral dosage forms, in which case solid pharmaceutical carriers are undoubtedly used. For parenteral compositions, the carrier will usually comprise sterile water, at least to a large extent, although other ingredients, for example, to enhance solubility, may be added. Injectable solutions, for example, may be prepared wherein the carrier comprises saline solution, glucose solution, or a mixture of saline and glucose solution. Suspensions for injection may also be prepared, in which case suitable liquid carriers, suspending agents, and the like. may apply. Solid form preparations are also contemplated which are intended to be converted, shortly before use, to liquid preparations.

Depending on the route of administration, the pharmaceutical composition will preferably contain from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1% to 50% by weight of the active ingredient(s) and from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of the pharmaceutically acceptable carrier, all percentages based on the total weight of the composition.

The pharmaceutical composition may further contain various other ingredients known in the art, such as a lubricant, stabilizer, buffering agent, emulsifier, viscosity adjusting agent, surfactant, preservative, flavoring agent or coloring agent.

It is particularly preferred to formulate the aforementioned pharmaceutical compositions in unit dosage forms for ease of administration and dosing versatility. Dosage form as used herein means physically separate units suitable as unit dosages, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored or coated tablets), capsules, pills, powder sachets, strips, suppositories, injectable solutions or suspensions, and the like. and their individual components. The daily dose of a compound of the invention will, of course, vary depending on the compound used, the route of administration, the desired effect of the treatment, and the mycobacterial disease being treated. However, in general, satisfactory results will be obtained when the compound of the invention is administered at a daily dose not exceeding 1 g, for example in the range of 10 to 50 mg/kg of body weight.

Given the fact that the compounds of formula (Ia) are active against bacterial infections, the present compounds can be combined with other antibacterial agents in order to effectively combat bacterial infections.

Thus, the present compound also refers to a pharmaceutical combination of (a) a compound of the invention and (b) one or more other antibacterial agents.

The present invention also relates to a combination of (a) a compound of the invention and (b) one or more other antibacterial agents for use as a medicine.

The present invention also relates to the use of a combination or pharmaceutical composition as defined immediately above for the treatment of a bacterial infection.

A pharmaceutical composition containing a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of (a) a compound of the invention and (b) one or more other antibacterial agents is also included in the present invention.

The weight ratio of (a) the compound of the invention and (b) the other antibacterial agent(s) when administered as a combination can be determined by one of skill in the art. The indicated ratio and the exact dosage and frequency of administration depend on the specific compound of the invention and other antibacterial agent(s), the specific disease being treated, the severity of the disease being treated, age, weight, sex, diet, time of administration. and the general health of the particular patient, the route of administration, as well as other drugs that the individual may be taking, as is well known to those skilled in the art. Moreover, it has been proven that the effective daily amount can be reduced

- 14 040841 or increased depending on the response of the subject under treatment and / or depending on the assessment of the attending physician who prescribed the compounds of this invention. The specific weight ratio of this compound of formula (Ia) and the other antibacterial agent may range from 1/10 to 10/1, more specifically 1/5 to 5/1, even more specifically 1/3 to 3/1.

The compounds of the invention and one or more other antibacterial agents may be combined in a single formulation, or they may be formulated in separate formulations such that they may be administered simultaneously, separately or sequentially. Thus, the present invention also relates to a product containing (a) a compound of the invention and (b) one or more other antibacterial agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.

Other antibacterial agents that can be combined with compounds of formula (Ia) are, for example, antibacterial agents known in the art. Other antibacterial agents include β-lactam antibiotics such as natural penicillins, semisynthetic penicillins, natural cephalosporins, semisynthetic cephalosporins, cephamycins, 1-oxacephems, clavulanic acid preparations, penems, carbapenems, nocardicins, monobactams; tetracyclines, anhydrotetracyclines, anthracyclines; aminoglycosides; nucleosides such as N-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin S; macrolides such as 12-membered ring macrolides, 14-membered ring macrolides, 16-membered ring macrolides; ansamycins; peptides such as bleomycins, gramicidins, polymyxins, bacitracins, large ring peptide antibiotics containing lactone bonds, actinomycins, amphomycin, capreomycin, distamycin, enduracidins, mikamycin, neocarzinostatin, stendomycin, BIOMYCIN, virginiamycin; cycloheximide; cycloserine; variotin; sarcomycin A; novobiocin; griseofulvin; chloramphenicol; mitomycins; fumagillin; monensins; pyrrolnitrin; fosfomycin; fusidic acid; D(β-hydroxyphenyl)glycine; D-phenylglycine; enediins.

Specific antibiotics that can be combined with the present compounds of formula (Ia) are, for example, benzylpenicillin (potassium, procaine, benzathine), phenoxymethylpenicillin (potassium), potassium fenticillin, propicillin, carbenicillin (disodium, sodium phenyl, sodium indanyl), sulbenicillin , ticarcillin disodium, methicillin sodium, oxacillin sodium, cloxacillin sodium, dicloxacillin, flucloxacillin, ampicillin, mezlocillin, piperacillin sodium, amoxicillin, cyclacillin, hectacillin, sulbactam sodium, talampicillin hydrochloride, bacampicillin hydrochloride, pivmecillin, cephalexin, cefacillin, cefaloglydin , cefroxadine, cefapirin sodium, cephalothin sodium, cefacetril sodium, cefsulodin sodium, cephaloridine, cefatrizine, cefoperazone sodium, cefamandol, vefotiam hydrochloride, cefazolin sodium, ceftizoxime sodium, cefotaxime sodium, cefmenoxime hydrochloride, cefuroxime, ceftriaxone sodium, ceftazidime, cefmetazole, cefotetan, latamoxef, clavulanova i acid, imipenem, aztreonam, tetracycline, chlortetracycline hydrochloride, demethylchlortetracycline, oxytetracycline, metacycline, doxycycline, roletetracycline, minocycline, daunorubicin hydrochloride, doxorubicin, aclarubicin, kanamycin sulfate, bekanamycin, tobramycin, gentamicin sulfate, dibekacin, amikacin, micronomycin, neamomycin, sulfate, paromomycin sulfate, streptomycin sulfate, dihydrostreptomycin, destomycin A, hygromycin B, apramycin, sisomycin, netilmicin sulfate, spectinomycin hydrochloride, astromycin sulfate, validamycin, kasugamycin, polyoxin, blasticidin S, erythromycin, erythromycin estolate, oleandomycin phosphate, tratycetylene phosphate yosamycin, spiramycin, tylosin, ivermectin, midecamycin, bleomycin sulfate, peplomycin sulfate, gramicidin S, polymyxin B, bacitracin, colistin sulfate, colistin methanesulfonate sodium, enramycin, mikamycin, virginiamycin, capreomycin sulfate, biomycin, enviomycin, vanmycinostatin, neomycin D, , bestatin, pepstatin, monensin, lasalocide, salinomycin, amphotericin B, nystatin, natamycin, trichomycin, mithramycin, lincomycin, clindamycin, clindamycin palmitate hydrochloride, flavophospholipol, cycloserine, pecilocin, griseofulvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, phosphoromycin C, phosphomirrol pyrol fusidic acid, bicosamycin, tiamulin, sikkanin.

Other antimycobacterial agents that can be combined with compounds of formula (Ia) are, for example, rifampicin (=rifampin); isoniazid; pyrazinamide; amikacin; ethionamide; ethambutol; streptomycin; para-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thioacetazone; RA-824; quinolones/fluoroquinolones such as, for example, moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin; macrolides such as, for example, clarithromycin, clofazimine, amoxicillin with clavulonic acid; rifamycins; rifabutin; rifapentine; compounds disclosed in WO 2004/011436.

General procedure for obtaining

The compounds of the invention can generally be prepared in a sequence of steps, each of which is known to the average person.

Compounds of formula (Ia) wherein Q is a radical of formula (a-1), (a-2) or (a-3), said compounds being represented by formula (Ia-1), (Ia-2), (Ia-3) can be prepared by reacting an intermediate of formula (II-a) or (II-c) with a suitable acid such as, for example, polyphosphoric acid.

Compounds of formula (Ia-1), (Ia-2) can also be prepared by reacting an intermediate of formula (II-a) with SOCl ₂ in the presence of a suitable solvent such as, for example, pyridine, triethylamine, diisopropylamine, diisopropylethylamine.

The reaction in the presence of a suitable acid, such as, for example, polyphosphoric acid, is preferred for the preparation of compounds of formula (Ia-1). The reaction in the presence of SOCl ₂ is preferred for the preparation of compounds of formula (Ia-2).

Instead of SOCl ₂ can also be used diethylaminosulfonate or other reagents, which are well known to the average specialist.

It is believed that one of ordinary skill in the art can set the appropriate temperatures, solvent, and reaction times in order to optimize the above reactions if the desired compound is obtained.

Compounds of formula (Ia-1) can also be prepared by reacting an intermediate of formula (IIIa) wherein W1 is a suitable leaving group such as, for example, a halogen group, for example chlorine, with an intermediate of formula (IV) in the presence of a suitable base such as, for example, Na ₂ CO ₃ ; and a suitable solvent, such as, for example, an alcohol, such as methanol.

Compounds of formula (Ia) where Q is a radical of formula (a-3) and where R ³ is

- 16 040841 is cyano, these compounds represented by formula (Ia-4) can be obtained by reacting an intermediate compound of formula (VII) with diethyl cyanomethyl acetate in the presence of sodium hydride and a suitable solvent such as, for example, tetrahydrofuran.

(1a-4) (VII)

Compounds of formula (Ia) can also be prepared by converting compounds of formula (Ia) into each other according to a series of rearrangement reactions known in the art.

Compounds of formula (Ia) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen atom to its N-oxide form. Said N-oxidation reaction can generally be carried out by reacting the starting product of formula (Ia) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, eg sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids such as, for example, benzenecarboperoxoic acid or halogenated benzenecarboperoxoic acid, for example, 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkyl hydroperoxides, for example, tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, eg ethanol and the like, hydrocarbons, eg toluene, ketones, eg 2-butanone, halogenated hydrocarbons, eg dichloromethane, and mixtures of such solvents.

Compounds of formula (Ia) where R ¹ is halogen, such as bromine, can be converted to a compound of formula (Ia) where R ¹ is Het by reacting with Het-B(OH) ₂ in the presence of a suitable catalyst such as , for example Pd(OAc) ₂ or Pd(PPh ₃ ) ₄ , in the presence of a suitable base, such as, for example, K ₃ PO ₄ or Na ₂ CO ₃ , and a suitable solvent, such as, for example, toluene or 1,2 -dimethoxyethane (DME).

Similarly, compounds of formula (Ia) in which R ¹ is halogen, eg bromine, can be converted to compounds of formula (Ia) in which R ¹ is alkyl, eg methyl, by treatment with a suitable alkylating agent such as as CH ₃ B(OH) ₂ or (CH ₃ ) ₄ Sn, in the presence of a suitable catalyst, such as, for example, Pd(PPh ₃ ) ₄ , in a suitable solvent, such as, for example, toluene or 1,2-dimethoxyethane ( DME).

Compounds of formula (Ia) where R ¹ is halogen, particularly preferably bromine, can be converted to a compound of formula (Ia) where R ¹ is hydrogen by reacting with HCOONH4 in the presence of a suitable catalyst such as, for example, palladium on charcoal, and in the presence of a suitable solvent such as, for example, an alcohol, such as methanol. Similar reaction conditions can be used to convert a compound of formula (Ia) where R ⁴ or R ⁵ is benzyl to a compound of formula (Ia) where R ⁴ or R ⁵ is hydrogen.

Compounds of formula (Ia) where R ¹ is halogen, particularly preferably bromine, can also be converted to a compound where R ¹ is formyl by reacting with N,N-dimethylformamide in the presence of nBuLi and a suitable solvent such as, for example, tetrahydrofuran. Said compounds may then be further converted to a compound of formula (Ia) wherein R ¹ is —CH ₂ —OH by reaction with a suitable reducing agent such as, for example, NaBH ₄ , and in the presence of a suitable solvent, such as, for example, an alcohol such as methanol and tetrahydrofuran.

Compounds of formula (Ia) where R ¹ is C2-6 alkenyl can be prepared by reacting a compound of formula (Ia) where R ¹ is halogen, e.g. bromine and the like, with tributyl( _C2.6 alkenyl)tin , such as, for example, tributyl(vinyl)tin, in the presence of a suitable catalyst, such as, for example, Pd(PPh3)4, in the presence of a suitable solvent, such as, for example, N,N-dimethylformamide. This reaction is preferably carried out at an elevated temperature.

Compounds of formula (Ia) where R ¹ is R ^5a R ^4a N- can be prepared from a compound of formula (Ia) where R ¹ is halogen, e.g. bromine and the like, by reaction with R ^5a R ^4a NH in the presence of a suitable catalyst such as, for example, tris(dibenzylideneacetone)palladium, a suitable ligand, such as, for example, 2-(di-tert-butylphosphino)biphenyl, a suitable base, such as, for example, sodium t-butoxide, and a suitable solvent such as, for example, toluene.

Compounds of formula (Ia) where R ¹ is -C=N-OR ⁿ can be prepared from a compound of formula (Ia) where R ¹ is formyl by reaction with hydroxylamine hydrochloride or C ₁ hydrochloride. ₆ alkoxylamine in the presence of a suitable solvent such as,

- 17 040841 for example, pyridine.

Compounds of formula (Ia) where R ¹ is -CH2-NH2 can be prepared from a compound of formula (Ia) where R ¹ is formyl by reduction in the presence of H2 with a suitable catalyst such as, for example, palladium on charcoal. , and a suitable solvent such as, for example, NH3/alcohol, for example, NH3/methanol. Compounds of formula (Ia) where R ¹ is CH2-NH2 can be converted to a compound of formula (Ia) where R ¹ is -CH2-N(C _{1 -6} alkyl) ₂ by reacting with a suitable aldehyde or ketone a reagent, such as, for example, paraformaldehyde or formaldehyde, in the presence of sodium cyanoborohydride, acetic acid and a suitable solvent, such as, for example, acetonitrile.

Compounds of formula (Ia) where R ¹ is R ^5a R ^4a N-CH ₂ - can be prepared by reacting a compound of formula (Ia) where R ¹ is formyl with a suitable reagent of formula R ^5a R ^4a NH in the presence of a suitable reducing agent such as, for example, BH3CN, a suitable solvent, such as, for example, acetonitrile and tetrahydrofuran, and a suitable acid, such as, for example, acetic acid.

Compounds of formula (Ia) where R ¹ is amino can be prepared by reacting a compound of formula (Ia) where R ¹ is carboxyl with a suitable azide such as, for example, diphenylphosphoryl azide (DPPA) and a suitable base such as such as, for example, triethylamine, in a suitable solvent, such as, for example, toluene. The resulting product is subjected to the Curtis reaction, and with the introduction of trimethylsilylethanol, an intermediate carbamate compound is formed. In the next step, this intermediate is reacted with tetrabutylammonium bromide (TBAB) in a suitable solvent such as, for example, tetrahydrofuran to give the amine derivative.

Compounds of formula (Ia) where R ¹ is aminocarbonyl, mono- or di(alkyl)aminocarbonyl or R ^5a R ^4a N-C(=O)- can be prepared by reacting a compound of formula (Ia) where R ¹ is is a carboxyl, with a suitable amine, a suitable coupling reagent such as, for example, hydroxybenzotriazole, a suitable activation reagent, such as, for example, 1,1'-carbonyldiimidazole or N,N'-dicyclohexylcarbodiimide or 1-(3dimethylaminopropyl)-3-ethylcarbodiimide , a suitable base such as, for example, triethylamine, and a suitable solvent, such as, for example, tetrahydrofuran and methylene chloride.

Compounds of formula (Ia) where R ¹ is arylcarbonyl can be prepared by reacting in the first step (a) a compound of formula (Ia) where R ¹ is halogen, e.g. bromine and the like, with a suitable arylaldehyde in the presence of nBuLi and in a suitable solvent such as, for example, tetrahydrofuran. This reaction is preferably carried out at a reduced temperature, such as, for example -70°C. In the next step (b), the product obtained in step (a) is oxidized with suitable oxidizing agents, such as, for example, manganese oxide, in the presence of a suitable solvent, such as, for example, methylene chloride.

Compounds of formula (Ia) wherein R ⁴ and R ⁵ is a ring moiety substituted with an alkyl carbonyl may be prepared from the corresponding compound where the ring moiety is unsubstituted by reaction with a suitable acyl chloride, for example acetyl chloride, in the presence of a suitable base such as, for example, triethylamine, and a suitable solvent such as, for example, methylene chloride.

Compounds of formula (Ia) wherein R ⁴ and R ⁵ represent an unsubstituted ring moiety can be prepared from the corresponding compound where the ring moiety is substituted with arylalkyl by reacting with ammonium formate in the presence of a suitable catalyst such as, for example, palladium on charcoal, and a suitable solvent such as, for example, an alcohol, such as methanol.

Compounds of formula (Ia) where R ⁶ is phenyl substituted with halogen can be converted to a compound of formula (Ia) where R ⁶ is phenyl substituted with Het by reacting with Het-B(OH) ₂ in the presence of a suitable catalyst , such as, for example, Pd(PPh ₃ ) ₄ , in the presence of a suitable base, such as, for example, Na ₂ CO ₃ , and a suitable solvent, such as, for example, toluene or 1,2-dimethoxyethane (DME), and an alcohol such as methanol.

Compounds of formula (Ia), where R ⁴ and R ⁵ taken together with the nitrogen atom to which they are attached to form 1,1-dioxidethiomorpholinyl, can be obtained from the corresponding thiomorpholine derivative by reaction with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, eg sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids such as, for example, benzenecarboperoxoic acid or a halogen substituted with benzenecarboperoxoic acid, for example, 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkyl hydroperoxides, for example, tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, eg ethanol and the like, hydrocarbons, eg toluene, ketones, eg 2-butanone, halogenated hydrocarbons, eg dichloromethane, and mixtures of such solvents.

- 18 040841

The compounds of formula (Ia) may also be converted to a quaternary amine by reaction with a suitable quaternization agent such as, for example, an optionally substituted C _1-6 alkyl halide, arylC1. ₆ alkyl halide, C ₁ . ₆ alkylcarbonyl halide, arylcarbonyl halide, Het ¹ C1.6 alkyl halide or Het ¹ carbonyl halide, for example methyl iodide or benzyl iodide, in the presence of a suitable solvent such as, for example, acetone, where Het ¹ is furanyl or thienyl; or a bicyclic heterocycle selected from benzofuranyl or benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted with 1, 2 or 3 substituents, each substituent independently selected from halo, C1. ₆ alkyl and aryl. Said quaternary amines are represented by the formula below wherein R ¹⁰ is C1.6 alkyl, C1-6 alkylcarbonyl, arylC16 alkyl, arylcarbonyl, Het ¹ C1.6 alkyl, or Het ¹ carbonyl, and where A- is a pharmaceutically acceptable counterion such as , for example, the iodine ion,

where Q is a radical of the formula

Obviously, in the upstream and downstream reactions, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to procedures generally known in the art, such as extraction, crystallization, and chromatography. Obviously, reaction products that exist in more than one enantiomeric form can be isolated from their mixtures by known techniques, especially preparative chromatography such as preparative HPLC, chiral chromatography. Individual diastereomers or individual enantiomers can also be obtained using supercritical fluid chromatography (SCF).

Starting materials and intermediates are compounds that are either commercially available or can be prepared according to conventional reaction procedures generally known in the art. For example, intermediates of formula (IIa) to (IId) can be prepared according to the procedures described in WO 2004/011436, WO 2005/070924, WO 2005/070430 or WO 2005/075428, the contents of which are incorporated herein by reference. .

In particular, intermediates of formula (IIa) and (IIc) can be prepared by reacting an intermediate of formula (V) with an intermediate of formula (VI-a) or (VI-b) according to the following reaction scheme (1).

Scheme 1

using nBuLi in a mixture of diisopropylamine and tetrahydrofuran, where all radicals are defined in formula (Ia). Stirring can increase the rate of the reaction. The reaction can easily be carried out in the temperature range between -20 and -70°C.

- 19 040841

Intermediate compounds of formula (V) can be obtained in accordance with the following reaction scheme (2).

Scheme 2

where all radicals are defined in formula (Ia). Reaction scheme (2) includes step (a) in which an appropriately substituted aniline is reacted with a suitable acyl chloride such as,

3-phenylpropionyl chloride, for example,

-fluorobenzenepropionyl chloride or pchlorobenzenepropionyl chloride in the presence of a suitable base such as triethylamine and a suitable reaction inert solvent such as methylene chloride or ethylene dichloride. The reaction can easily be carried out in the temperature range between room temperature and boiling point. In the next step (b), the adduct obtained in step (a) is reacted with phosphoryl chloride (POCl ₃ ) in the presence of N,N-dimethylformamide (Vilsmeier-Haack formylation followed by cyclization). The reaction can easily be carried out in the temperature range between room temperature and boiling point. In the next step (c-1), a particular R ² group, where R ² is, for example, a C1-6 alkyloxy radical, is introduced by reacting the intermediate from step (b) with O-C1-6 alkyl in the presence of a suitable a solvent such as, for example, HO-C1-6 alkyl. The intermediate obtained in step (b) may also be converted to an intermediate where R ² is, for example, a C1-6 alkylthio radical by reaction with S=C(NH ₂ ) ₂ in the presence of a suitable solvent such as, e.g. an alcohol, e.g. ethanol, or an alcohol/water mixture, optionally in the presence of a suitable base such as e.g. KOH (see step (c-2)) followed by reaction with C _1-6 alkyl-I in the presence of a suitable base , such as, for example, K2CO3, and a suitable solvent, such as, for example, 2-propanone (see step (d)). The intermediate from step (b) may also be converted to an intermediate where R ² is N(R ^2a ) (alkyl) where R ^2a is hydrogen or alkyl by reacting with the appropriate salt NH(R ^2a ) (alkyl) in the presence of a suitable base, such as, for example, potassium carbonate, and a suitable solvent, such as, for example, acetonitrile (step (c-3)). The intermediate obtained in step (b) may also be converted to an intermediate wherein R ² is C1-6alkyloxyC1-6alkyloxy optionally substituted with C1-6alkyloxy, indicated by ^R2 represented by ^R2b , by reacting with C1-6alkyloxyC _1-6alkylOH optionally substituted with C ₁₆ alkyloxy in the presence of NaH and a suitable solvent such as, for example, tetrahydrofuran (step (c-4)).

Intermediate compounds of formula (V), where R ² and R ⁷ represent hydrogen, these intermediate compounds represented by formula (Ve) can be obtained in accordance with the following reaction scheme (3), where in the first stage (a) substituted indole- 2,3-dione is reacted with optionally substituted 3-phenylpropionaldehyde in the presence of a suitable base,

- 20 040841 such as sodium hydroxide (Pfitzinger reaction), after which the carboxylic acid compound is decarboxylated in the next step (b) at high temperature in the presence of a suitable reaction inert solvent such as diphenyl ether.

Scheme 3

o (V-e)

Intermediates of formula (V) wherein R ⁶ is Het, said intermediates represented by formula (Vf) can be prepared according to the following reaction scheme 3a.

Scheme 3a

(V-f)

Reaction scheme (3a) includes step (a) in which a suitable quinoline residue is reacted with Het-C(=O)-H using nBuLi in admixture with a suitable base such as, for example, 2,2,6,6tetramethylpiperidine and a suitable solvent such as, for example, tetrahydrofuran.

Stirring can increase the rate of the reaction. The reaction can easily be carried out in the temperature range between -20 and -70°C. In the next step (b), the product obtained in step (a) is converted into an intermediate of formula (V-f) by reaction with a suitable acid such as, for example, trifluoroacetic acid and triisopropylsilane in the presence of a suitable solvent, such as, for example, methylene chloride .

Intermediates of formula (V), especially (V'-a) or (V'-b) can be prepared according to the following reaction scheme (4).

Scheme 4

(V'-b)

The reaction scheme (4) includes step (a) in which the quinoline residue is converted into a quinolinone residue by reaction with a suitable acid such as, for example, hydrochloric acid. In the next step (b), the R ⁸ substituent is introduced by reacting the intermediate obtained in step (a) with a suitable alkylating agent such as, for example, an alkyl iodide, such as methyl iodide, in the presence of a suitable base, such as, for example, NaOH or benzyltriethylammonium chloride, a suitable solvent such as, for example, tetrahydrofuran.

Intermediates of formula (V) wherein R ⁸ and R ⁹ are taken together to form a CH=CH-N= radical, said intermediates represented by formula (V'-c) can be prepared according to the following reaction scheme (5 ).

Scheme 5

Reaction scheme (5) includes step (a) in which the intermediate is reacted with NH2-CH2-CH(OCH ₃ )2. In the next step (b), a condensed imidazolyl residue is formed by reaction with acetic acid in the presence of a suitable solvent such as, for example, xylene.

- 21 040841

Intermediates of formula (VI-a) are compounds that are either commercially available or can be prepared according to conventional reaction procedures generally known in the art. For example, intermediate compounds of formula (VIa) can be obtained in accordance with the following reaction scheme (6).

Scheme 6

(Vl-a)

Reaction scheme (6) includes step (a) in which R ³ , in particular an appropriately substituted aryl, more preferably an appropriately substituted phenyl, is reacted by a Friedel-Crafts reaction with a suitable acyl chloride such as 3-chloropropionyl chloride or 4-chlorobutyryl chloride in the presence of a suitable Lewis acid such as, for example, AlCl ₃ , FeCl ₃ , SnCl ₄ , TiCl ₄ or ZnCl 2 , and a suitable reaction inert solvent such as methylene chloride or ethylene dichloride. The reaction can easily be carried out in the temperature range between room temperature and boiling point. In the next step (b), an amino group (-NR4R ⁵ ) is introduced by reacting the intermediate obtained in step (a) with a primary or secondary amine (HNR4R ⁵ ).

Intermediates of formula (VI-a) can also be prepared according to the following reaction scheme (7).

Scheme 7

Reaction scheme (7) includes step (a) in which R ³ -C(=O)-H, for example an appropriately substituted arylcarboxyaldehyde, more preferably an appropriately substituted phenyl or naphthylcarboxyaldehyde, is reacted with a suitable intermediate, such as, for example, , 1-bromo-4-chlorobutane, in the presence of a Grignard reagent and a suitable solvent such as, for example, diethyl ether, tetrahydrofuran. The reaction can easily be carried out at a low temperature, for example 5°C. In the next step (b), the oxidation is carried out in the presence of a Jones reagent in a suitable solvent such as, for example, acetone. In the next step (c), the amino group (-NR ⁴ R ⁵ ) is introduced by reacting the intermediate obtained in step (b) with the primary or secondary amine HNR ⁴ R ⁵ in the presence of a suitable solvent, such as, for example, acetonitrile, and a suitable a base such as, for example, K ₂ CO ₃ .

Alternatively, intermediates of formula (VI-a) can be prepared according to the following reaction scheme (8).

Scheme 8

Reaction scheme (8) includes step (a) in which, for example, a suitable acid is reacted with NH(CH ₃ ) (OCH ₃ ) in the presence of 1,1'-carbonyldiimidazole and a suitable solvent such as, for example, CH2Cl2. In the next step (b), the product obtained in step (a) is reacted with suitable Grignard reagents, for example 4-chlorobutylmagnesium bromide, in the presence of a suitable solvent, such as, for example, tetrahydrofuran. In the next step (c), the amino group (NR4R ⁵ ) is introduced by reacting the intermediate obtained in step (b) with the primary or secondary amine HNR4R ⁵ in the presence of a suitable solvent such as, for example, acetonitrile and a suitable base, such as, e.g. K2CO3.

Intermediates of formula (VI-b) are compounds that are either commercially available or can be prepared according to conventional reaction procedures generally known in the art. For example, intermediates of formula (VI-b) where q

- 22 040841 has a value of 1, these intermediate compounds represented by formula (VI-b-1) can be obtained in accordance with the following reaction scheme (9).

Scheme 9

(VI-b-1)

Reaction scheme (9) includes step (a) in which, for example, a suitable acid is reacted with NH(CH ₃ ) (OCH ₃ ) in the presence of 1,1'-carbonyldiimidazole and a suitable solvent such as, for example, CH2Cl2. In the next step (b), the product obtained in step (a) is reacted with Grignard reagents CH ₃ MgCl in the presence of a suitable solvent such as, for example, tetrahydrofuran. In the next step (c), the amino group (-NR4R ⁵ ) is introduced by reacting the intermediate obtained in step (b) with the primary or secondary amine HNR4R ⁵ in the presence of CH2 (=O), a suitable acid such as, for example, hydrochloric acid and the like, and a suitable solvent such as, for example, an alcohol, such as ethanol.

Intermediates of formula (VI-b) where R ^3a -CH ₂ -n is R ^3a ' -CH2-CH2- (which is possible for those intermediates of formula (VI-b) where R ^3a is alkyl, arylalkyl, aryl-O-alkyl or arylalkyl-O-alkyl, and R ^3a ' is the same as R ^3a but 1 carbon less in the alkyl chain attached to CH2), and where q is 1, said intermediates, represented by formula (VI-b-2) can be obtained according to the following reaction scheme (10).

Scheme 10

Reaction scheme 10 includes step (a) where a suitable aldehyde is reacted with acetone in the presence of a suitable base such as, for example, sodium hydroxide. In the next step (b), the product obtained in step (a) is reacted with the primary or secondary amine HNR4R ⁵ in the presence of CH ₂ (=O), a suitable acid such as, for example, hydrochloric acid and the like, and a suitable solvent, such as, for example, an alcohol, such as ethanol. In the next step (c), the product from step (b) is hydrogenated (H ₂ ) in the presence of a suitable catalyst such as, for example, palladium-carbon and a suitable solvent, such as, for example, water and an alcohol, such as ethanol.

Intermediates of formula (IV) wherein R ³ is halogenated phenyl may be converted to intermediates of formula (IV) where R ³ is phenyl substituted with aryl by reaction with an aryl boronic acid in the presence of a suitable base such as, for example , potassium phosphate, a suitable catalyst such as, for example, palladium acetate, and a suitable ligand, such as, for example, 2-dicyclohexylphosphino-2',6'dimethoxybiphenyl, in a suitable solvent, such as, for example, toluene.

Intermediates of formula (IV) wherein R ³ is halosubstituted phenyl may also be converted to intermediates of formula (IV) wherein R ³ is phenyl substituted with C _2-6 alkenyl optionally substituted with phenyl by reaction with the appropriate C _{2 -6} alkene, such as, for example, styrene, in the presence of a suitable base, such as, for example, triethylamine, a suitable catalyst, such as, for example, palladium acetate, and a suitable ligand, such as, for example, tri-o-tolylphosphine, in a suitable solvent such as, for example, DMF.

In the cases of the above reaction schemes, the suitable amine HNR4R ⁵ is a substituted 2,5-diazabicyclo[2.2.1]heptyl, said amine can be prepared according to the following reaction scheme (11).

Scheme 11

Reaction scheme (11) includes the step of reacting an appropriately protected 2,5-diazabicyclo[2.2.1]heptyl, where P is, for example, t-butyloxycarbonyl, with suitable reagents of the formula W-R', where W is a suitable leaving group, such such as halogen, eg bromine and the like, and where R' is a substituent introduced in the presence of a suitable base such as, for example, K ₂ CO ₃ , NaHCO ₃ or triethylamine, a suitable phase transfer reagent, such as, for example, tetra-n-butylammonium chloride, a suitable solvent such as, for example, acetonitrile, and optionally KI to increase the reaction rate. In the next step (b), the protecting group is removed by reaction with a suitable acid, such as, for example, trifluoroacetic acid, in the presence of a suitable solvent, such as, for example, methylene chloride.

Intermediate compounds of formula (III-a) can be obtained in accordance with the following reaction scheme (12).

Scheme 12

Reaction scheme (12) includes step (a) where a suitable quinoline derivative, where W ₂ is a suitable leaving group, such as, for example, halogen, for example, bromine, is reacted with a suitable alkyne derivative, where W 1 is a suitable leaving group, such as, for example, halogen, for example, chlorine, in the presence of a suitable catalyst, such as, for example, PdCl ₂ (PhCN) ₂ , a suitable ligand, such as, for example, X-PHOS, a suitable base, such as, for example, CS ₂ CO ₃ and a suitable solvent such as, for example, N,Ndimethylformamide. In the next step (b), the product obtained in step (a) is reacted with

R\

B(OH) ₂ in the presence of a suitable catalyst such as, for example, PdCl ₂ (PhCN) ₂ , a suitable base, such as, for example, KHCO ₃ , and a suitable solvent, such as, for example, 1-methyl-2-pyrrolidinone and water.

Intermediates of formula (VII) can be prepared according to Reaction Scheme 13.

Scheme 13

In reaction scheme 13, in step (a), an intermediate of formula (V) is reacted with an intermediate of formula (IX) where W' is a suitable leaving group such as, for example, 1H-benzotriazole and W is a suitable leaving group, such as, for example, halogen, for example chlorine, in the presence of nBuLi, a suitable base, such as, for example, N-(1-methylethyl)-2-propanamine, and a suitable solvent, such as, for example, tetrahydrofuran. The reaction can easily be carried out in the temperature range between -20 and -70°C. In the next step (b), the resulting intermediate of formula (VIII) is reacted with a primary or secondary amine HNR4R ⁵ in the presence of a suitable base such as, for example, potassium carbonate and a suitable solvent, such as, for example, acetonitrile.

The following examples illustrate the present invention without limiting it.

experimental part

For some compounds or intermediates in this regard, the absolute stereochemical configuration of the stereogenic carbon atom(s) or the configuration at the double bond has not been experimentally determined. In these cases, the stereochemical isomeric form that is isolated first is defined as A and the second as B, without further reference to the actual stereochemical configuration. However, said A and B isomeric forms can be unambiguously characterized by those of ordinary skill in the art using methods known in the art, such as, for example, X-ray diffraction or NMR. It is considered to be within the knowledge of the average person to recognize that the most appropriate method determines the actual stereochemical configuration. In case A and B are stereoisomeric mixtures, in specific mixtures of enantiomers, they can then be separated, whereby the respective first isolated fractions are defined as A1, respectively B1, and the second as A2, respectively B2, without further reference to the actual stereochemical configuration. . However, said A1, A2 and B1, B2 isomeric forms, in particular the A1, A2 and B1, B2 enantiomeric forms, can be unambiguously characterized by those of ordinary skill in the art using methods known in the art such as, for example, X-ray diffraction. For example, intermediates of formulas (II-a), (II-b), (II-c) or (II-d) are designated as a particular diastereoisomer (generally not containing other diastereoisomer(s)). If two chiral centers are present in said intermediates of formulas (II-a), (II-b), (II-c) or (II-d), this means that the intermediate is a mixture, in particular a racemic mixture (R,S) and (S,R) enantiomers or a racemic mixture of the (R,R) and (S,S) enantiomer. In the following, mixtures of two enantiomers are designated as diastereoisomer A or B. Whether a mixture is designated as A or B depends on whether it is isolated first in the synthetic procedure (i.e. A) or second (i.e. B). When a specified intermediate is designated as a specific enantiomer (essentially free of other enantiomers), it means that the intermediate is the (R,S), (S,R), (R,R) or (S,S) enantiomer. In the following, these specific enantiomers are referred to as A1, A2, B1 or B2. Whether an enantiomer is designated as A1, A2, B1 or B2 depends on whether it is isolated first or second (1 or 2) in the synthetic procedure and whether it is isolated from the A (A1, A2) or B (B1, B2) diastereoisomer.

In some cases, when an intermediate designated as a specific diastereoisomer or enantiomer is converted to another intermediate, the latter may inherit the designation from the previous diastereoisomer (A or B) or enantiomer (A1, A2, B1, B2). Whenever this applies, it also applies to the final connection.

Hereinafter, DMF is defined as N,N-dimethylformamide, THF is defined as tetrahydrofuran, DIPE is defined as diisopropyl ether, DCM is defined as dichloromethane, PPA is defined as polyphosphoric acid.

experimental part

A. Preparation of intermediates.

Example A1.

a) Obtaining intermediate compound 1.

4-Chlorobenzenepropanoyl chloride (0.466 mol) was added slowly at 5° C. to a solution of 4-bromobenzenamine (0.388 mol) in Et ₃ N (70 ml) and CH ₂ Cl ₂ (700 ml). The mixture is stirred at room temperature for one hour. H ₂ O is added. The precipitate is filtered off, washed with H ₂ O and dried. The residue is recrystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 110 g of intermediate 1 (83%) (melt temp. 194°C).

b) Preparation of intermediate 2.

POC13 (192.6 ml) was added slowly at 5°C to DMF (35.4 ml). Intermediate 1 (prepared according to the procedure described in step A1.a) (0.296 mol). The mixture is stirred at 80° C. for 12 hours, poured slowly onto ice and extracted with CH ₂ Cl ₂ . The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The product was used without further purification. Yield: 150 g of intermediate 2.

- 25 040841

c) Preparation of intermediate 3.

A mixture of intermediate 2 (prepared according to the procedure in step A1.b) (0.409 mol) in CH ₃ ONa (300 ml) and CH ₃ OH (300 ml) was stirred and heated at reflux for 15 am The mixture is poured onto ice and extracted with CH ₂ Cl ₂ . The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue (150 g) is purified by silica gel column chromatography (eluent: cyclohexane/CH ₂ Cl ₂ 90/10; 35-70 μm). Pure fractions are collected and the solvent is evaporated. The residue is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 27 g of intermediate 3 (18%) (melt temp. 100°C).

d) Preparation of intermediates 4 and 39.

nBuLi 1.6M (0.061 mol) was added slowly at -20°C to a solution of N-(1-methylethyl)-2-propanamine (0.061 mol) in THF (85 ml). The mixture is stirred at -20°C for 30 minutes and then cooled to -70°C. A solution of intermediate 3 (prepared according to the procedure in step A1.c) (0.055 mol) in THF (200 ml) was added slowly. The mixture is stirred at -70° C. for 30 minutes. A solution of 3-(dimethylamino)-1-phenyl-1-propanone (0.066 mol) in THF (120 ml) was added. The mixture is stirred at -70°C for one hour, then hydrolysed at -30°C with ice water and extracted with EtOAc. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated.

The residue (31 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 99.5/0.5/0.05; 20-40 μm). Three pure fractions are collected and their solvents are evaporated. Yield: 6.5 g of fraction 1, 2.4 g of fraction 2 and 2.4 g of fraction 3. Fraction 1 and fraction 2 (fraction 3 is a mixture) are crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 5.19 g of intermediate 4 (diastereomer A) (17%) and 1.8 g of intermediate 39 (diastereomer B) (6%).

The following intermediates were prepared according to the previous procedure and purified as shown.

Intermediates 40 and 41 The residue (4.7 g) is purified by silica gel column chromatography (eluent: CH ₂ C1 ₂ /CH ₃ OH/NH ₄ OH 92/8/0.2; 1540 μm). Two fractions are collected and the solvent is evaporated. Yield: 0.45 g of fraction 1 and 0.4 g of fraction 2. Fraction 1 and fraction 2 are crystallized from DIPE. The residue is filtered off and dried. Yield: 0.367 g of intermediate 40 (diastereomer A) (melting temp. 160°C) and 0.298 g of intermediate 41 (diastereomer B) (melting temp. 194°C). O CH ₃ 1 he 1 A । γ cn ₃ Br > O J1 cn ₃ C|1 dia A Intermediate 40 O he, OH 1 || ^1 cn ₃ n, > o J1 CH ₃ C|| dia V Intermediate 41

- 26 040841

Example A2.

a) Preparation of intermediate compound 5.

A mixture of 6-bromo-2-chloro-3-(phenylmethyl)-quinoline (prepared according to the procedures described in WO 2005/070924, the content of which is incorporated herein by reference) (0.045 mol) and thiourea (0.05 mol) in ethanol (150 ml) was stirred and heated at reflux for 8 hours and then brought to room temperature. A solution of KOH (0.068 mol) in H ₂ O (15 ml) is added. The mixture is stirred and heated at reflux for one hour and poured onto ice. The precipitate is filtered off, washed with H ₂ O and dried. Yield: 11 g of intermediate 5 (74%).

b) Preparation of intermediate 6.

CH ₃ I (0.037 mol) was added slowly at room temperature to a mixture of intermediate 5 (prepared according to the procedure in step A2.a) (0.033 mol) and K ₂ CO ₃ (0.037 mol) in 2-propanone (150 ml). The mixture is stirred at room temperature for 8 hours, poured into H ₂ O and extracted with CH ₂ Cl ₂ . The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. Yield: 11.2 g of the first fraction (97%). Part of this fraction (2 g) is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 1.45 g of intermediate 6 (70%) (temp, melt. 88°C).

c) Preparation of intermediates 7 and 8.

nBuLi 1.6M in hexane (0.027 mol) was added slowly at -20°C to a solution of N-(1methylethyl)-2-propanamine (0.027 mol) in THF (40 ml). The mixture is cooled again to a temperature of -70°C. A solution of intermediate 6 (0.024 mol) in THF (100 ml) was added slowly. The mixture is stirred at -70° C. for 30 minutes. A solution of 3-(dimethylamino)-1-phenyl-1-propanone (0.029 mol) in THF (60 ml) was added slowly. The mixture is stirred at -70°C for 2 hours, hydrolyzed at -20°C with ice water and extracted with EtOAc. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue (13.2 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 99.25/0.75/0.1; 20-45 µm). Two pure fractions are collected and their solvents are evaporated. Fraction 1 is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 1 g of intermediate 7 (8%) (mp. 208°C). Fraction 2 is crystallized from diethyl ether and DIPE. The precipitate is filtered off and dried. Yield: 1.75 g of intermediate 8 (13%) (melt temp. 196°C).

Example A3.

a) Preparation of intermediate compound 9.

A mixture of 6-bromo-2-chloro-3-(phenylmethyl)-quinoline (prepared according to the procedures described in WO 2005/070924, the content of which is incorporated herein by reference) (0.233 mol) in CH ₃ ONa 30% in CH 3 OH (222.32 ml) and CH 3 OH (776 ml) were stirred and heated at reflux overnight, then poured onto ice and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue is purified by silica gel column chromatography (eluent:

CH ₂ Cl ₂ /cyclohexane 20/80 and then 100/0; 20-45 µm). Pure fractions are collected and the solvent is evaporated. Yield: 25 g of intermediate 9 (33%).

b1) Preparation of intermediates 10 and 11.

dia A dia B

Intermediate 10 Intermediate 11 nBuLi 1.6 M in hexane (0.04 mol) was added slowly at -20°C to a solution of N-(1methylethyl)-2-propanamine (0.04 mol) in THF (60 ml) . The mixture is stirred at -20°C for 15 minutes and then cooled to -60°C. A solution of intermediate 9 (prepared according to the procedure in step A3.a) (0.037 mol) in THF (120 ml) was added slowly. The mixture is stirred at -60° C. for 30 minutes. A solution of 3-(1Himidazol-1-yl)-1-phenyl-1-propanone (0.044 mol) in THF (90 ml) was added. The mixture is stirred at -60°C for one hour, then hydrolyzed at -30°C with ice water and extracted with EtOAc. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated.

The residue (31 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 98/2/0.1; 20-45 μm). Two pure fractions are collected and their solvents are evaporated. Yield: 1.2 g of fraction 1 and 1.9 g of fraction 2. Fraction 1 is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 1.05 g of intermediate 10 (6%) (mp. 216°C). Fraction 2 is crystallized from 2-propanone and diethyl ether. The precipitate is filtered off and dried. Yield: 1.64 g of intermediate 11 (8.5%) (mp. 230°C).

The following intermediates were prepared according to the previous procedure and purified as shown.

- 28 040841

Intermediates 42 and 43 The residue (20 g) is purified by silica gel column chromatography (eluent: CH2CI2/CH3OH/NH4OH 99/1/0.1; 1540 µm). Two pure fractions are collected and the solvent is evaporated. Yield: 1.7 g of fraction 1 and 3.8 g of fraction 2. Fraction 1 is crystallized from DIPE. Sediment filtered and dried. Yield: 1.1 g of intermediate 42 (6%). Fraction 2 is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 2.2 g of intermediate 43 (12%). O sn, OH 1 11 ^CHz O G)> । M sn ₃ diaA Intermediate 42 O sn, OH 1 || 1 I ^dc 1 V dc, diaB Intermediate connection 43 Intermediates 44 and 45 The residue (20 g) is purified by silica gel column chromatography (eluent: CH2CI2/CH3OH/NH4OH 99.5/0.5/0.1; 15-40 µm). Three pure fractions are collected and their solvent is evaporated. Yield: 2.8 g of fraction 1, 3.4 g of fraction 2 and 2.7 g of fraction 3. Fraction 1 and fraction 2 are crystallized from DIPE. The precipitate is filtered off and dried. Yield: 1.45 g of intermediate 44 (7%) and 1.55 g of intermediate 45 (8%). O CH ₃ OH 1 ³ ΥΎΎ ^CH3 ϊόι dia A Intermediate 44 O 1^ CH ₃ 1 OH 1 CH/^^^F dia B Intermediate 45

b2) Preparation of intermediate 12.

nBuLi 1.6 M (0.007 mol) in hexane is added dropwise at -20°C to a solution of N-(1methylethyl)-2-propanamine (0.0069 mol) in THF (10 ml) in a stream of N2. The mixture is stirred at 80°C for 20 minutes, then cooled to -70°C. A solution of intermediate 9 (prepared according to the procedure in step A3.a) (0.006 mol) in THF (10 ml) was added. The mixture was stirred at -70° C. for 2 hours. A solution of 3-(4-morpholinyl)-1-phenyl-1-propanone (0.0091 mol) in THF (10 ml) was added. The mixture is stirred at 70°C for 2 hours, then brought to -30°C, poured into H ₂ O at 0°C and extracted with CH ₂ Cl ₂ . The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue (4.1 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ 100; 1540 μm). Pure fractions are collected and the solvent is evaporated. Yield: 0.9 g of intermediate 12 (27%).

- 29 040841 b3) Preparation of intermediates 17 and 18.

dia A dia B

Intermediate 17 Intermediate 18 nBuLi 1.6 M (0.008 mol) in hexane was added dropwise at -20°C to a solution of N-(1methylethyl)-2-propanamine (0.008 mol) in THF (16 ml) under a stream of N ₂ . The mixture is stirred at 20°C for 20 minutes, then cooled to -70°C. A solution of intermediate 9 (prepared according to the procedure in step A3.a) (0.0067 mol) in THF (25 ml) was added. The mixture is stirred for one hour and 30 minutes. A solution of 3-(diethylamino)-1-(2naphthalenyl)-1-propanone (0.008 mol) in THF (25 ml) was added. The mixture was stirred at -70°C for 3 hours, then poured onto ice at -30°C and extracted with EtOAc. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated.

The residue is purified by silica gel column chromatography (eluent: CH ₂ C1 ₂ /CH ₃ OH/NH ₄ OH 98/2/0.1; 15-40 μm). Two fractions are collected and the solvent is evaporated. Yield: 1.8 g of fraction 1 and 0.5 g of fraction 2. Both fractions are purified by silica gel column chromatography (eluent: cyclohexane/EtOAc 70/30; 15-40 μm). Two fractions are collected and the solvent is evaporated. Yield: 0.47 g of fraction A and 0.43 g of fraction B. Both fractions are crystallized from DIPE/diethyl ether. The precipitate is filtered off and dried. Yield: 0.32 g of intermediate 17 (8.2%) (melting temp.: 134°C) and 0.23 g of intermediate 18 (5%) (melting temp.: 184°C).

The following intermediates were prepared according to the previous procedure and purified as shown.

Intermediates 46 and 47 The residue (6 g) is purified by silica gel column chromatography (eluent: CH ₂ C1 ₂ /CH ₃ OH/NH ₄ OH 94/6/0.2; 15-40 μm). Two fractions are collected and the solvent is evaporated. Yield: 1.25 g of intermediate 46 (26%) and 0.9 g of intermediate 47 (19%). About | sn, (he 1 | ^SNz ΐί o A |] IU ¹ dia A Intermediate 46 O SS 1 OH 1 'ik 1LJI dia B Intermediate 47

Preparation of intermediate compound 19.

b4)

nBuLi 1.6 M (0.01 mol) in hexane is added dropwise at -20° C. to a solution of N-(1methylethyl)-2-propanamine (0.01 mol) in THF (15 ml) under N ₂ flow. The mixture is stirred at 20°C for 15 minutes, then cooled to -70°C. A solution of intermediate 9 (prepared according to the procedure in step A3.a) (0.0009 mol) in THF (30 ml) was added dropwise. The mixture is stirred at -70°C for 30 minutes. A solution of 1(dimethylamino)-5-phenyl-3-pentanone (0.0128 mol) in THF (15 ml) was added. The mixture is stirred at -70°C for 2 hours, poured at -30°C onto ice and extracted with CH ₂ Cl ₂ . The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated.

The residue (5.5 g) is purified by silica gel column chromatography (eluent: CH ₂ C1 ₂ /CH ₃ OH 98/2; 15-40 μm). Three fractions are collected and the solvent is evaporated. Yield: 0.8 g of fraction 1, 0.65 g of fraction 2 and 0.216 g of fraction 3.

Fraction 3 is crystallized from petroleum ether. The precipitate is filtered off and dried. Yield: 0.136 g of intermediate 19 (5%).

The following intermediate compounds are obtained in accordance with the previous method.

b5) Preparation of intermediates 25, 26 and 27.

Intermediate 48

The residue (350 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /iPrOH/NH ₄ OH 99.5/0.5/0.2; 20-45 μm). Three fractions are collected and the solvent is evaporated. Yield: 133 g of starting material A, 20.1 g of fraction B (dia B) and 33 g of fraction C (dia B). Fraction C is crystallized from DIPE. The precipitate is filtered off and dried. Yield: 25 g of intermediate 48 (B1) nBuLi 1.6 M (0.0686 mol) in hexane are added dropwise at -78°C in a stream of N2 to a solution of N-(1-methylethyl)-2-propanamine (0 .0686 mol) in THF (70 ml) and the mixture was allowed to warm to 0°C. Intermediate 9 (prepared according to the procedure in step A3.a) (0.624 mol) in THF (205 ml) was added dropwise at -78°C and the resulting mixture was stirred at -78°C for one hour. 3-(dimethylamino)-1-phenyl1-propanone (0.0748 mol) in THF (133 ml) was added, the mixture was stirred at -78°C for one hour and then allowed to warm to 0°C. The mixture was poured into saturated NH ₄ Cl solution and extracted with EtOAc. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 99/1/0.1; 15-40 μm). Two pure fractions are collected and their solvents are evaporated. Fraction 1 (3.56 g) is crystallized from 2-propanone and diethyl ether. The precipitate is filtered off and dried. Yield: 1.14 g of intermediate 25 (4%). Fraction 2 (7.67 g) is crystallized from 2-propanone and diethyl ether. The precipitate is filtered off and dried. Yield: 2.65 g of intermediate 26 (8%). The mother layers of fractions 1 and 2 are combined and the solvent is evaporated. Yield: 4.53 g of intermediate 27.

- 31 040841 b6) Preparation of intermediates 28 and 29.

dia A dia B

Intermediate 28 Intermediate 29 nBuLi 1.6 M (0.04 mol) in hexane was added dropwise at -78° C. under N ₂ flow to a solution of N-(1-methylethyl)-2-propanamine (0.04 mol ) in THF (70 ml). The temperature of the mixture is brought to 0°C and then cooled again to a temperature of -78°C. A solution of intermediate 9 (prepared according to the procedure in step A3.a) (0.0365 mol) in THF (70 ml) was added dropwise. The mixture is stirred at -78°C for one hour. A solution of 4-(dimethylamino)-2-butanone (0.0438 mol) in THF (70 ml) was added. The mixture was stirred at -78°C for one hour, brought to -30°C, poured onto ice and extracted with EtOAc.

The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated.

The residue (17 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 97/3/0.2; 15-40 μm). Two pure fractions are collected and their solvents are evaporated. The residue is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 1.2 g of intermediate 28 (9.2%) and 1 g of intermediate 29 (7.4%).

The following intermediates were prepared according to the previous procedure and purified as shown.

Intermediates 49 and 50

The residue (23 g) is purified by silica gel column chromatography (eluent: CH ₂ C1 ₂ /CH ₃ OH/NH ₄ OH 99/1/0.1). Two pure fractions are collected and the solvent is evaporated. Yield: 2.5 g of fraction 1 and 2 g of fraction 2. Fraction 1 is crystallized from DIPE. The precipitate is filtered off and dried. Yield: 1.93 g of intermediate 49 (13%) (melt temp. 180°C). Fraction 2 is crystallized from EtOAc. The precipitate is filtered off and dried. Yield: 1.23 g of intermediate 50 (10.6%) (melt temp. 142°C).

- 32 040841

Intermediates 51 and 52 The residue (20.8 g) is purified by silica gel column chromatography (eluent: CH2CI2/CH3OH/NH4OH 99/1/0.1). Two pure fractions are collected and their solvents are evaporated. Fraction 1 is crystallized from DIPE. Sediment filtered and dried. Yield: 1.21 g of intermediate 51 (7.3%) (temp. melt. 150°C). Fraction 2 is crystallized from EtOAc. The precipitate is filtered off and dried. Yield: 4.13 g of intermediate 52 (34%) (temp, melt 230°C). O (N' ³ he 1 | if T T Ύ ^Ν ιΟ dia A Intermediate 51 O ³ I he II Ύ T T Ύ g || IU ¹ CH ₃ -^ diaE Intermediate 52

Example A4.

a) Preparation of intermediate compound 13.

POCl ₃ (3.453 mol) was added slowly at 5° C. to DMF (120 ml). After the addition is complete, 4'-fluoro-hydrocinnamanilide (0.492 mol) is added. The mixture was stirred at 80° C. overnight, then brought to room temperature and poured onto ice. Add EtOAc. The mixture is stirred for one hour while ice is added and then extracted with EtOAc. The organic layer is separated, washed twice with H ₂ O, dried (MgSO ₄ ), filtered and the solvent is evaporated. Yield: 80.2 g of intermediate 13 (60%).

b) Preparation of intermediate 14.

A mixture of intermediate 13 (prepared according to the procedure described in step A4.a) (0.295 mol) in CH ₃ ONa 30% in CH ₃ OH (250 ml) and CH ₃ OH (250 ml) was stirred at 80°C during the night. The mixture was brought to room temperature, poured onto ice and extracted with EtOAc. The organic layer was separated, washed with H2O, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (57 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /cyclohexane 20/80; 20-45 μm). Pure fractions are collected and the solvent is evaporated. Yield: 27 g of intermediate 14 (34%).

c) Preparation of intermediates 15 and 16.

dia A dia B

Intermediate 15 Intermediate 16 nBuLi 1.6 M (0.0-67 mol) in hexane was added dropwise at -30°C under N2 flow to a solution of N-(1-methylethyl)-2-propanamine (0.067 mol) in THF (150 ml). The mixture is stirred at 20°C for 30 minutes and then cooled to -70°C. A solution of intermediate 14 (prepared according to the procedure in step A4.b) (0.044 mol) in THF (50 ml) was added dropwise. The mixture is stirred at -70°C for 45 minutes. Add drop by drop

- 33 040841 solution of 3-(dimethylamino)-1-phenyl-1-propanone (0.053 mol) in THF (50 ml). The mixture is stirred at -60°C for 2 hours, hydrolyzed with ice water and extracted with EtOAc. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue (22 g) is purified by silica gel column chromatography (eluent: CH ₂ C1 ₂ /CH ₃ OH/NH ₄ OH 99.25/0.75/0.1; 1540 μm). Three pure fractions are collected and their solvents are evaporated. Yield: 4 g of fraction 1, 3 g of fraction 2 and 1.3 g of fraction 3. Fraction 1 is crystallized from EtOAc and diethyl ether. The precipitate is filtered off and dried. Yield: 2.9 g of intermediate 15 (14.8%). Fraction 2 is crystallized from EtOAc and diethyl ether. The precipitate is filtered off and dried. Yield: 1.5 g of intermediate 16 (7.7%).

Example A5.

a) Preparation of intermediate 20.

Benzenepropanoyl chloride (0.53 mol) is slowly added at 5°C under N2 flow to a solution of [1,1'-biphenyl]-4-amine (0.443 mol) and Et ₃ N (0.719 mol) in CH ₂ Cl ₂ (750 ml). After completion of the addition, the mixture was stirred at 5° C. for one hour, at room temperature for 2 hours, and poured into HCl 3N and ice. Add CH2Cl ₂ . The mixture is stirred at room temperature for 30 minutes and extracted with CH2Cl ₂ . The organic layer was separated, washed with H2O, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue is taken up in diethyl ether, filtered off and dried. Yield: 112 g of intermediate 20 (84%).

b) Preparation of intermediate 21.

POCl ₃ (2.24 mol) was added dropwise at 5° C. to DMF (76.8 ml). Intermediate 20 (prepared according to the procedure in step A5.a) (0.32 mol) is added. The mixture was stirred at 80° C. overnight, then poured onto ice, stirred for 30 minutes and extracted with EtOAc.

The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue (136 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /cyclohexane 70/30; 2045 μm). The desired fractions are collected and the solvent is evaporated. Yield: 26 g of intermediate 21 (84%).

c) Preparation of intermediate 22.

A mixture of intermediate 21 (prepared according to the procedure in step A5/b) (0.0788 mol) in CH3ONa 30% in CH3OH (50 ml) and CH3OH (200 ml) was stirred at 80°C overnight. The mixture was brought to room temperature, poured into ice water and extracted with EtOAc. The organic layer was separated, washed with H2O, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (30 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /cyclohexane 70/30; 20-45 μm). Pure fractions are collected and the solvent is evaporated. Yield: 17 g of intermediate 22 (66%).

- 34 040841 d1) Preparation of intermediates 23 and 24.

dia A dia B

Intermediate 23 Intermediate 24 nBuLi 1.6 M (0.055 mol) in hexane was added dropwise at -30° C. under N ₂ flow to a solution of N-(1-methylethyl)-2-propanamine (0.055 mol) in THF ( 150 ml). The mixture is stirred at a temperature of 20°C for 30 minutes and then cooled to a temperature of -70°C. A solution of intermediate 22 (prepared according to the procedure in step A5.c) (0.036 mol) in THF (50 ml) was added dropwise. The mixture is stirred at -70°C for 45 minutes. A solution of 3-(dimethylamino)-1-phenyl-1-propanone (0.044 mol) in THF (50 ml) was added dropwise. The mixture was stirred at -70°C for 2 h, hydrolyzed with ice water and extracted with EtOAc. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated.

The residue (19 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 99.5/0.5/0.1; 15-40 μm). Two pure fractions are collected and their solvents are evaporated. Yield: 1.3 g of fraction 1 and 1.5 g of fraction 2. Fraction 1 is crystallized from EtOAc and diethyl ether. The precipitate is filtered off and dried. Yield: 0.85 g of intermediate 23 (4.7%) (melting point 174°C). Fraction 2 is crystallized from diethyl ether and DIPE. The precipitate is filtered off and dried. Yield: 1 g of intermediate 24 (5.5%) (melt temp. 192°C).

The following intermediates were prepared according to the previous procedure and purified as shown.

Intermediates 53 and 54 The residue (21 g) is purified by silica gel column chromatography (eluent: CH ₂ C1 ₂ /CH ₃ OH/NH ₄ OH 99.5/0.5/0.1; 20-45 μm). Two pure fractions are collected and the solvent is evaporated. Yield: 1.8 g of fraction 1 and 1.5 g of fraction 2. Fraction 1 is crystallized from DIPE. The precipitate is filtered off and dried. Yield: 1.7 g of intermediate 55 (8%) (temp, melt. 148°C). Fraction 2 is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 1.1 g of intermediate 54 (7%) (temp, melt. 165°C). O ^1 sc 1 OH 1 II CH ₃ ιό dia A Intermediate 53 O CH ₃ OH 1 H ₃ C. Il li CH ₃ \ O d|1 dia B Intermediate 54

- 35 040841

Intermediates 55 and 56 The residue (23 g) is purified by silica gel column chromatography (eluent: CH ₂ C1 ₂ /CH ₃ OH/NH ₄ OH 9.5/0.5/0.1; 20-45 μm). Two pure fractions are collected and their solvents are evaporated. Fraction 1 is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 1.8 g of intermediate 55 (8%) (melt temp. 165°C). Fraction 2 is crystallized from diethyl ether and DIPE. The precipitate is filtered off and dried. Yield: 1.6 g of intermediate 56 (7%) (melt temp. 165°C). O 1 SP, OH 1 H ₃ C 1) CH ₃ o ch । U ¹ <ΊΙ ₃ dia A Intermediate 55 O CH ₃ 1 he । A /g. n ₃ with γ । 1 d sn ₃ ιό cii ₃ dia V Intermediate 56

d2) Preparation of intermediate 36 and 37.

dia A dia B

Intermediate 36 Intermediate 37

A mixture of N-(1-methylethyl)-2-propanamine hydrochloride (1:1) (0.0102 mol) in THF (10 ml) was stirred at -20°C.

nBuLi 1.6 M in hexane (0.0102 mol) is added dropwise. The mixture is kept at this temperature for 15 minutes, then cooled to a temperature of -70°C. A solution of intermediate 22 (prepared according to the procedure in step A5.c) (0.0092 mol) in THF (10 ml) was added dropwise at -70°C. The mixture is stirred at this temperature for 30 minutes. A solution of 3-(dimethylamino)-1-(1-naphthalenyl)-1-propanone (0.0111 mol) in THF (10 ml) was added dropwise. The mixture was stirred at -70°C for 3 h, then poured into ice water, NaCl and extracted with EtOAc. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. Yield: 6 g. This fraction is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 99/1/0.1; 15-40 μm). Two fractions are collected and the solvent is evaporated. Yield: 0.3 g of fraction 1 and 0.4 g of fraction 2. Fraction 1 is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 0.1 g of intermediate 36 (2%) (mp. 248°C) (dia A). Fraction 2 is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 0.28 g of intermediate 37 (6%) (mp. 214° C.) (dia B).

Example A6.

Preparation of intermediate compound 32.

Methylbenzene (2 ml) was added to a mixture of benzo[b]thien-2-ylboronic acid (0.0016 mol), Pd(OAc) ₂ (0.002 g), K3PO4 (0.0021 mol) and dicyclohexyl(2',6'-dimethoxy[1,1'-biphenyl]-2-yl)phosphine (0.008 g) in a stream of N ₂ . The mixture is stirred for 5 minutes. A solution of compound 15 from WO 2004/011436 (dia B) (0.00108 mol) in methylbenzene (1 ml) was added. The mixture is stirred at 100° C.

- 36 040841 for 4 hours. The residue is purified by chromatography on a column of kromasil (eluent:

CH ₂ C1 ₂ /CH ₃ OH 99/1, then CH ₂ Cl ₂ /EtOAc/NH ₄ OH 95/5/0.5; 10 µm). Pure fractions are collected and the solvent is evaporated. Yield: 0.125 g of intermediate 32 (dia B) (19%).

Example A7.

a) Preparation of intermediate compound 33.

A mixture of intermediate 9 (prepared according to the procedure in step A3.a) (0.0076 mol), benzo[b]thien-2-ylboronic acid (0.009 mol), K2CO3 (0.02 mol) and Pd( PPh ₃ ) ₄ (0.0003 mol) in CH ₃ CH ₂ OH (2 ml) and toluene (25 ml) were stirred and heated at reflux for 16 hours, then cooled to room temperature and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried (MgSO4), filtered and the solvent was evaporated. The residue (4 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /cyclohexane 30/70; 15-40 μm). Pure fractions are collected and the solvent is evaporated. Yield: 1.45 g of intermediate 33.

b) Preparation of intermediates 34 and 35.

nBuLi 1.6 M in hexane (0.0045 mol) was added at -70°C to a mixture of N-(1methylethyl)-2-propanamine hydrochloride (1:1) (0.0044 mol) in THF (10 ml). The mixture is stirred at 20° C. for 20 minutes.

A solution of intermediate 33 (prepared according to the procedure in step A7.a) (0.0037 mol) in THF (10 ml) was added at -70°C. The mixture was stirred at -70°C for 2 hours. A solution of 3-(dimethylamino)-1-(3-fluorophenyl)-1-propanone (0.0037 mol) in THF (5 ml) was added at -70°C . The mixture is stirred at -70°C for 3 hours. Add 10% NH ₄ Cl. The mixture is extracted with EtOAc. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. Yield: 3 g. This fraction is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 99/1/0.1; 15-40 μm). Two fractions are collected and the solvent is evaporated. Yield: 0.35 g of fraction 1 and 0.38 g of fraction 2. Fraction 1 is crystallized from DIPE. The precipitate is filtered off and dried. Yield: 0.249 g of intermediate 34 (temp, melting point: 225° C.). Fraction 2 is crystallized from DIPE. The precipitate is filtered off and dried. Yield: 0.303 g of intermediate 35 (temp, melting point: 216°C).

Example A8.

a) Preparation of intermediate compound 68.

A suspension of PdCl2(PhCN)2 (0.25 g, 0.00065 mol), (X-phos) (0.002 mol) and Cs ₂ CO3 (0.13 mol) in

DMF (65 ml) was flushed with N2. 3-37 040841 bromquinoline (13.5 g, 0.065 mol) was added and the resulting mixture was stirred for 10 minutes at room temperature. Then 6-chloro-1-hexine (9.1 g, 0.078 mol) was added dropwise and the resulting mixture was stirred for 6 hours at 80°C. Additional 6-chloro-1-hexine (0.039 mol) was added and the reaction mixture was stirred for another hour at 80° C., then for 18 hours at room temperature. The mixture was cooled to room temperature and diluted with water (100 ml) then extracted with CH2Cl2 (3x200 ml). The organic layer is separated, washed with brine, then separated again. The combined organic layers are dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue was purified by reverse phase high performance liquid chromatography (Column: Xterra Prep MS C18, length: 10 cm, id: 19 mm, particle size: 5 µm; eluent: (0.2% NH4HCO3 in H ₂ O) /CH ₃ OH (optional)/CH ₃ CN gradient). The product fractions were combined and the solvent was evaporated to give Intermediate 68 (9 g, 57%).

b) Preparation of intermediates 69 and 70.

Intermediate 69 Intermediate 70

A mixture of intermediate 68 (prepared according to the procedure described in step A8.a) (0.00205 mol), (4-chlorophenyl)-boronic acid (0.0062 mol, 3 eq.), iodobenzene (0.0041 mol , 2 eq.), KHCO3 (0.0041 mol) in 1-methyl-2-pyrrolidinone (16 ml) and water (4 ml) were stirred for 10 minutes at 100°C. A suspension of PdCl ₂ (PhCN) 2 (0.000021 mol) in 1methyl-2-pyrrolidinone (0.16 ml) was added and the resulting mixture was stirred for 18 hours at 100°C. The solvent is then evaporated. The residue was partitioned between water (1.5 ml) and CH ₂ Cl ₂ (9 ml). The mixture is vigorously stirred and then filtered through an Isolute HM-N filter. The filter residue is washed twice with CH ₂ Cl ₂ (4.5 ml) and once with CH ₂ Cl ₂ (3 ml). The solvent is evaporated and the residue is purified by reverse phase HPLC. Yield: Intermediate 69 (53 mg) and Intermediate 70 (106 mg). The following intermediate compounds are presented in table. 1 (E/Z configuration not determined) was prepared according to the previous procedure.

Table 1

- 38 040841

60 O. sn ₃ 61 CN CO^~' C1 62 .sn ₃ С1 63 C1 64 Q ί T J t ^N y C1 65 Q ί T JY ^N 0 66 CN ό ί T J t ^N and 67 _O ^XI ₃ ^o

- 39 040841

Example A9.

a) Preparation of intermediate compound 71.

CH ₃ nBuLi 1.6M in hexane (0.0346 mol) is added dropwise at -20°C to a solution of N-(1methylethyl)-2-propanamine (0.0346 mol) in THF (70 ml) in a stream of N ₂ . The mixture is stirred at -20°C for 20 minutes, then cooled to -70°C. A solution of 6-bromo-2methoxy-3-(phenylmethyl)-quinoline (intermediate 3 (ex. A3) WO 2004/011436) (0.029 mol) in THF (90 ml) was added. The mixture is stirred at -70°C for one hour. A solution of 1-(5chloro-1-oxopentyl-1H-benzotriazole (0.0576 mol) in THF (100 ml) was added. The mixture was stirred at −70° C. for 3 h. H ₂ O was added. The mixture was extracted with EtOAc. Organic the layer was washed with H ₂ O, then with saturated aqueous NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated The residue (19 g) was purified by chromatography on a silica gel column (eluent: cyclohexane/AcOEt 93/7; 20-45 The fraction is collected and the solvent is evaporated off. Yield: 3.85 g crude residue (30%) After crystallization from DIPE, the precipitate is filtered off and dried. Yield: 2.65 g of intermediate 71 (21%).

b) Preparation of intermediate 72.

CH ₃

Mixture of intermediate 71 (0.00224 mol), (1S,4S)-2-benzyl-2,5diazabicyclo[2.2.1]heptane dihydrobromide (0.0045 mol) and potassium carbonate (0.009 mol) in acetonitrile (20 ml) stirred at reflux temperature for 24 hours and then cooled to room temperature. Add H2O. The mixture is extracted with EtOAc. The organic layer was washed with H ₂ O, then with saturated aqueous NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (1.55 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 95/5/0.1; 15-40 μm). The fraction is collected and the solvent is evaporated. Yield: 1.1 g of intermediate 72 (82%).

Example A10.

a) Preparation of intermediate compound 74.

A mixture of 7-chloro-1-phenyl-3-heptanone (prepared according to the procedure described in WO2007/000435) (3 g, 13.3 mmol), N-ethylmethylamine (2.8 ml, 26.6 mmol) and K ₂ CO ₃ (4.1 g, 29.3 mmol) in acetonitrile (30 ml) was stirred and heated at reflux overnight. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic layer is separated, washed with water and brine, dried over MgSO ₄ and evaporated to dryness. The residue is purified by column chromatography (SiO ₂ 15-40 μm, eluent: DCM/MeOH/NH ₄ OH aqueous solution: 97/3/0.1 to 95/5/0.5). The pure fractions are collected and the solvent is evaporated to dryness. Yield: 1.7 g of intermediate 74, 60%.

- 40 040841

b) Preparation of intermediate 73.

Intermediate 73 (mixture of diastereomers) n-BuLi (1.6 M in hexane, 7.4 ml, 11.8 mmol) was added dropwise to a solution of diisopropylamine (1.6 ml, 11.8 mmol) in THF (8 ml ) at a temperature of -20°C in a nitrogen atmosphere. The reaction mixture is stirred for 30 min and then cooled to -78°C. A solution of 6bromo-2-methoxy-3-(phenylmethyl)-quinoline (Intermediate 3 (Ex. A3) WO 2004/011436) (1.9 g, 5.9 mmol) in THF (10 ml) was added dropwise and then stirred for one hour at -78°C. A solution of intermediate 74 (1.9 g, 7.68 mmol) in THF (10 ml) was added dropwise, followed by stirring for one hour at -78°C. Add water and EtOAc, the organic layer is separated, washed with water and brine, dried over MgSO ₄ and evaporated to dryness. The residue is purified by column chromatography (SiO ₂ 15-40 µm, eluent: DCM/MeOH/NH4OH aqueous solution: 97/3/0.5). The pure fractions are collected and the solvent is evaporated to dryness. The second fraction from the column yielded intermediate 73 (0.22 g, 7%) as a mixture of diastereomers.

Example A11.

a) Preparation of intermediate 75.

Add dropwise a solution of 1-bromo-4-chlorobutane (22.25 ml, 0.19 mol) in diethyl ether (100 ml) (under N ₂ atmosphere) to a suspension of activated Mg turnings (4.67 g, 0.19 mol ) in diethyl ether (100 ml). Some iodine crystals are also added. The temperature in the flask is raised and the orange color of the reaction mixture changes to white. After a single addition of 1-bromo-4-chlorobutane was completed, the reaction mixture was cooled in an ice bath and 2-naphthalenecarboxaldehyde (20.00 g, 0.13 mol) was added dropwise as a solution in THF (200 ml, dry). The reaction mixture was stirred in an ice bath for 4 hours. The mixture is then quenched with NH ₄ Cl 1 N. Both phases are separated. The organic layer was washed with brine, dried (MgSO4), filtered and the solvent was evaporated. The residue is purified by flash chromatography (eluent: n-hexane/EtOAc 20:1). The desired fractions were collected and the solvent was evaporated to yield intermediate 75.

b) Preparation of intermediate 76.

Intermediate 75 (9.97 g, 0.04 mol) was dissolved in CH2Cl2 (120 ml) and the flask was cooled in an ice bath. MnO ₂ (34.85 g, 0.40 mol) was added and the reaction mixture was stirred in an ice bath for one hour and then overnight at room temperature. The next morning, additional MnO ₂ (10 equivalents) was added and, in the afternoon, additional MnO ₂ (10 equivalents) was added again. The mixture is stirred overnight at room temperature. The MnO ₂ is then removed by filtration through celite. The product is purified by flash chromatography (eluent: n-hexane/EtOAc 40:1). Yield: 6.91 g of intermediate 76 (70%).

c) Preparation of intermediate 77.

Mixture of intermediate 76 (1.00 g, 0.00405 mol), 1-methylhomopiperazine (1.01 ml, 0.0081 mol) and K ₂ CO ₃ (1.68 g, 0.0081 mol) in CH3CN (12 ,16 ml) heated at reflux temperature at 80°C over the weekend. Inorganic salts are removed by filtration and the crude products are purified by flash chromatography (eluent: n-hexane/EtOAc). The desired fractions are collected and the solvent is evaporated. Yield: 0.26 g of intermediate 77 (20%).

- 41 040841

d) Preparation of intermediate 78.

T OH I, ^{N CHz} ___J (/ \__ %\=/L Cri^ ' \ /

Intermediate 78 (mixture of diastereomers)

Lithium diisopropylamine (1.44 ml of a 2M solution in THF/heptane; 0.00288 mol) is dissolved in THF (9.61 ml; dry) and this solution is cooled to -70°C. Add 6-bromo-2methoxy-3-(phenylmethyl)-quinoline (Intermediate 3 (Ex. A3) WO2004/011436) (0.79 g, 0.0024 mol) as a solution in THF (7.21 ml) dropwise ; dry) and the resulting mixture was stirred for 2 hours at -70°C. Intermediate 77 (0.78 g, 0.0024 mol) was then added dropwise as a solution in THF (7.21 ml; dry) and the reaction mixture was stirred for 3 h at -70°C. H ₂ O (extinguishing solution) is then added (extinguishing at 70° C.) followed by EtOAc. The layers are separated and the organic layer is washed with brine, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue is purified by flash chromatography. The desired fractions are collected and the solvent is evaporated. Yield: 0.429 g of intermediate 78 as a mixture of diastereomers.

B. Obtaining final compounds.

Example B1.

Get connection 1.

A mixture of intermediate 4 (prepared according to the procedure in step A1.d) (0.0003 mol) and PPA (1.6 g) was stirred at 100° C. overnight. H ₂ O and K ₂ CO ₃ are added. The mixture is extracted with CH ₂ Cl ₂ . The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue is purified by chromatography on a column of kromasil (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH from 99/1/0.1 to 94/6/0.6; 3.5 μm). Pure fractions are collected and the solvent is evaporated. Yield: 0.13 g (84%). This fraction is purified by chromatography on a C18 column (eluent: CH3OH/NH4HCO3 0.5% 85/15; 5 µm). Pure fractions are collected and the solvent is evaporated. Yield: 0.13 g of compound 1.

Example B2.

Preparation of compounds 2, 3 and 4.

A mixture of intermediate 7 (prepared according to the procedure of step A2.c) (0.0002 mol) and PPA (1.3 g) was stirred at 100° C. for 18 h, then cooled to room temperature, poured in H ₂ O, basified with K ₂ CO ₃ and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue is purified by chromatography on a column of kromasil (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH from 99/1/0.1 to 94/6/0.6; 5 μm). Two fractions are collected and the solvent is evaporated. Yield: 0.021 g of fraction 1 and 0.046 g of fraction 2. Each fraction is purified by column chromatography over C18 (eluent: CH3OH/NH4HCO3 0.5% 85/15 to 80/20; 5 µm). Fraction 1 gives an increase to 0.003 g of compound 3 and 0.008 g of compound 4, and fraction 2 yields 0.027 g of compound 2.

- 42 040841

Example B3.

Preparation of compounds 5 and 6.

A mixture of intermediate 11 (prepared according to the procedure described in step A3.b1) (0.0002 mol) and PPA (1.5 g) was stirred at 100° C. overnight, then cooled to room temperature, poured into H ₂ O, alkalinized with K ₂ CO ₃ and extracted with EtOAc. The organic layer was washed with H ₂ O and saturated aqueous NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (0.17 g) is purified by kromasil column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 99/1/0.1 to 94/6/0.6; 5 µm) . Two fractions are collected and the solvent is evaporated. Yield: 0.011 g of compound 5 (8%) and 0.075 g of compound 6 (52%).

Example B4.

a) Preparation of compounds 7 and 8.

A mixture of intermediate 19 (0.00037 mol) and PPA (2 g) was stirred at 100° C. overnight, then brought to room temperature, poured into H ₂ O, basified with K ₂ CO ₃ 10% and extracted with EtOAc. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue (0.397 g) is purified by chromatography on a column of kromasil (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 97/3/0.1; 10 μm. Two fractions are collected and the solvent is evaporated. Yield: 0, 1 g of compound 7 and 0.006 g of compound 8.

b) Preparation of compounds 9 and 10.

connection 9 connection 10

A mixture of intermediate 48 (prepared according to the procedure described in step A3/b4) (0.009 mol) and PPA (50 g) was stirred at 100° C. for 2 h, poured onto ice, basified with K ₂ CO ₃ and extracted _{CH2Cl2 .} The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue (5 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 97/3/0.1; 15-40 μm). Two fractions are collected and the solvent is evaporated. Yield: 2 g of fraction A and 0.9 g of fraction B. Fraction B was placed in DIPE. The precipitate is filtered off, washed with activated carbon in 2-propanone and dried. Yield: 0.27 g of compound 9. Fraction A was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /iPrOH/NH ₄ OH 97/3/0.2; 15-35 μm). The desired fractions are collected, the solvent is evaporated off and the residue is dried. Yield: 0.3 g of compound 10.

Example B5.

a) Preparation of compound 11.

- 43 040841

SOC12 (0.0002 mol) was added dropwise at 5°C to a solution of intermediate 24 (prepared according to the procedure in step A5.d1) (0.0002 mol) in pyridine (1 ml). The mixture is stirred at 5°C for 2 hours, then stirred at room temperature overnight, diluted in H ₂ O and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue is purified by chromatography on a column of kromasil (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH from 99/1/0.1 to 94/6/0.6; 5 μm). Pure fractions are collected and the solvent is evaporated. Yield: 0.086 g of compound 11 (68%).

SOCl2 (0.0064 mol) was added at 0°C to a solution of intermediate 19 (prepared according to the procedure in step A3/b4) (0.0058 mol) in pyridine (4.4 ml). The mixture was stirred at 0°C for one hour, poured into H2O and extracted with EtOAc. The organic layer was washed with saturated NaCl solution, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (2 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 97/3/0.1; 15-40 μm). Yield: 1.7 g (57%). Crystallization from CH3CN gives an increase to 1.2 g of compound 8 (40%) (temp, melting point: 128°C).

Example B6.

Getting connection 12.

SOCl ₂ (0.0011 mol) was added dropwise at 0° C. to a solution of intermediate 46 (prepared according to the procedure in step 3.b3) (0.001 mol) in pyridine (6 ml). The mixture was stirred at 0° C. for 2 hours, then stirred at room temperature for 24 hours, poured into K ₂ CO ₃ 10% (aqueous solution) and extracted with EtOAc. The organic layer was washed with H2O, then with saturated aqueous NaCl, dried (MgSO4), filtered and the solvent was evaporated. The residue (1 g) is purified by silica gel column chromatography (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.5; 15-40 µm). Pure fractions are collected and the solvent is evaporated. The residue (0.15 g) is crystallized from diethyl ether. The precipitate is filtered off and dried. Yield: 0.052 g of compound 12 (10%) (melting point: 145°C).

- 44 040841

Example B7.

Getting connection 13.

SOC12 (0.0108 mol) was added dropwise to a solution of intermediate 27 (prepared according to the procedure in step A3.b5) (0.0098 mol) in pyridine (50 ml). The mixture was poured onto ice and extracted with EtOAc. The organic layer was separated, washed with a 10% K2CO3 solution, dried over MgSO ₄ , filtered and the solvent was evaporated. The residue (4.5 g) is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 99/1/0.1). Pure fractions are collected and the solvent is evaporated. Yield: 3.6 g (73.4%). Part of this fraction (2 g) is crystallized from DIPE. The precipitate is filtered off and dried. Yield: 1.6 g of compound 13.

Example B8.

Preparation of compounds 14 and 15.

SOCl ₂ (0.0004 mol) was added dropwise at 5°C to a solution of intermediate 28 (prepared according to the procedure in step 3.b6) (0.0003 mol) in pyridine (1.8 ml). The mixture is stirred at 5°C for 2 hours, then stirred at room temperature overnight, diluted in H ₂ O and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue is purified by chromatography on a column of kromasil (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH from 99/1/0.1 to 94/6/0.6; 5 μm). Pure fractions are collected and the solvent is evaporated. The residue is purified by column chromatography through C18 (eluent: CH3OH/NH4HCO3 0.5% 85/15; 5 µm). Pure fractions are collected and the solvent is evaporated. Yield: 0.021 g of compound 15 (11%) and 0.036 g of compound 14 (19%).

Example B9.

Preparation of compounds 16, 17 and 18.

SOCl2 (0.0003 mol) was added slowly at 5°C to a solution of intermediate 43 (prepared according to the procedure in step A3.b1) (0.0002 mol) in pyridine (1.3 ml). The mixture is stirred at 5° C. for 2 hours, then stirred at room temperature overnight. The residue is purified by kromasil column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 97/3/0.1; 10 μm). Three fractions are collected and the solvent is evaporated. Yield: 0.073 g of fraction A, 0.012 g of fraction B and 0.012 g of compound 16 (8%). Fraction A and fraction B were purified by column chromatography through C18 (eluent: CH3OH/NH4HCO3 0.5% 85/15; 5 µm). Two fractions are collected and the solvent is evaporated. Yield: 0.048 g of compound 17 (33%) and 0.01 g of compound 18 (7%).

- 45 040841

Example B10.

Piperidine (3 eq.) was added to a suspension of intermediate 69 (prepared according to the procedure in step A8.b) (0.0001 mol) and Na2CO ₃ (2 eq.) in CH3OH (3 ml). The reaction mixture is heated at reflux temperature for 18 hours. The mixture is then cooled. The solvent is evaporated. CH ₂ Cl ₂ (9 ml) and H ₂ O (1 ml) are added. The biphasic mixture is stirred vigorously for 10 minutes, then filtered through an Isolute HM-N filter. The filter residue is washed with CH ₂ Cl ₂ (3x3 ml) and the filtrate is evaporated. The residue was dissolved in CH ₂ Cl ₂ (2 ml), then purified using a Sep-Pak Vac 6cc Silica Cartridge (1 g; Waters cat. no. WAT036910; column pre-wetted with CH ₂ Cl ₂ (5 ml); sample solution loaded into 2 ml CH ₂ Cl ₂ eluent: CH ₂ C1 ₂ /CH ₃ OH 100/0 (7.5 ml), 99/1 (15 ml), 95/5 (10 ml), 0/100 (10 ml)) . The product fractions are collected and the solvent is evaporated. Yield: 0.033 g of compound 49.

Compound 19 was obtained in accordance with a similar procedure.

Example B11.

a) Preparation of compound 20.

A mixture of compound 4 (prepared according to the procedure described in example B2) (0.154 mol), phenylboronic acid (0.232 mol), Pd(OAc) ₂ (0.0003 g), K3PO4 (0.308 mol) and 2dicyclohexylphosphino-2', 6'-dimethoxy-1,1'-biphenyl (0.0013 g) in methylbenzene (1 ml) was stirred at 100° C. for 4 h under N2 flow, then diluted in H2O and extracted with CH2Cl2. The organic layer is separated, dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue is purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 94/6/0.6; 5 μm). Pure fractions are collected and the solvent is evaporated. Yield: 0.019 g (24%). This fraction is purified by C18 column chromatography (eluent: CH3OH/NH4HCO3 90/10; 5 µm). Pure fractions are collected and the solvent is evaporated. Yield: 0.009 g of compound 20.

b) Preparation of compounds 21 and 22.

A mixture of compound 10 (prepared according to the procedure described in Example B4/b) (0.0005 mol), 2-furanylboronic acid (0.0011 mol) and Pd(PPh ₃ ) ₄ (0.0022 mol) in Na ₂ CO ₃ 2M (16 ml) was stirred at 80°C overnight, then diluted in H ₂ O and extracted with EtOAc. The organic layer was washed with H2O, dried (MgSO4), filtered and the solvent was evaporated. The residue (0.38 g) is purified twice by chromatography on a column of kromasil (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 97/3/0.1; 10 μm, then CH3CN/NH4HCO3 0.5% 93/7; 5 µm). Two fractions are collected and the solvent is evaporated. Yield: 0.013 g of compound 22 (4%) and 0.109 g of fraction 1. Fraction 1 is purified by silica gel column chromatography (eluent: CH3OH/NH4HCO3 80/20; 5 μm). Three fractions are collected and the solvent is evaporated. Yield: 0.041 g of compound 21 (first fraction) (the other two fractions are a mixture of compounds 21 and 22).

- 46 040841

Example B12.

A mixture of compound 25 (prepared according to the procedure described in Example B5) (0.0002 mol) and CH3I (0.0003 mol) in CH3-C^OFCH3 (3 ml) was stirred at room temperature for 14 h, then evaporated . Yield: 0.107 g of compound 23 (83%).

Example B13.

Preparation of compounds 7 and 8.

SOCl ₂ (0.14 ml) was added at 0° C. to a solution of intermediate 19 (prepared according to the procedure in step A3.b4) (0.0016 mol) in pyridine (1.33 ml). The mixture was stirred at 0° C. for one hour, then stirred at room temperature for 30 minutes, poured into H ₂ O and extracted with EtOAc. The organic layer was washed with saturated NaCl solution, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue is purified by chromatography on a column of kromasil (eluent: CH ₂ Cl ₂ /CH3OH/NH ₄ OH 97/3/0.1; 10 μm). Three fractions are collected and the solvent is evaporated. Yield: 0.6 g of fraction A (69%), 0.015 g of fraction B and 0.12 g of compound 7 (14%). Fraction A is crystallized from DIPE/CH3CN. The precipitate is filtered off and dried. Yield: 0.31 g of compound 8 (36%) (temp, melting point: 128°C).

See also B4.a and B5.b.

Example B14.

Preparation of compound 60.

A solution of diethylcyanomethyl acetate (0.0005 mol) in THF (4 ml) was stirred and cooled at 0°C. Sodium hydride (60% in mineral oil) (0.0005 mol) is added in portions, then stirred for 30 minutes at 0°C. Intermediate 72 (prepared according to the procedure in step A9.b) in THF (2 ml) was added at 0° C., then the mixture was stirred for 18 hours at room temperature. H ₂ O is added. The mixture is extracted with EtOAc. The organic layer was washed with H ₂ O, then with saturated aqueous NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (0.22 g) is purified by chromatography on a column of kromasil (eluent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 98/2/0.2, then CH ₂ C1 ₂ /CH ₃ OH/NH ₄ OH 90/10/1, 35 µm). The fraction is collected and the solvent is evaporated. Yield: 0.06 g of compound 60 (30%).

- 47 040841

Example B15.

a) Preparation of compound 61.

Thionyl chloride (0.0004 mol) was added dropwise at 0° C. to a solution of intermediate 73 (0.0003 mol) in pyridine (0.4 ml). The mixture is stirred at 0°C for one hour. Add H2O. The mixture is extracted with EtOAc. The organic layer was washed with H2O, then with saturated aqueous NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue is purified by chromatography on a column of kromasil (eluent: CH2Cl2 then CH2Cl2/CH ₃ OH/NH ₄ OH 92/8/0.8; 3-5 μm). The fraction is collected and the solvent is evaporated. Yield: 0.02 g of compound 61 (Eisomer) (13%).

b) Preparation of compound 62.

Compound 62 (fumarate salt)

Compound 62 is prepared according to the procedure for the preparation of the compound presented in Example B15.a, but starting from intermediate compound 78. The residue is purified by chromatography on a column of kromasil (eluent: CH ₂ Cl ₂ then CH ₂ Cl ₂ /CH ₃ OH /NH ₄ OH 94/6/0.5, 10 µm). Two fractions are collected and the solvent is evaporated. Fractions F1 (0.07 g) and F2 (0.084 g). F1 is purified again by chromatography on a column of kromasil (eluent: CH ₂ Cl ₂ then CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH 94/6/0.6; 250x30 mm). Fraction F1.1 (0.037 g) was taken up in ethanol/acetone (5/95) and 1 eq. fumaric acid in acetone at room temperature. The precipitate is filtered off and dried. Yield: 0.019 g of compound 62 (3%; E-isomer; fumaric acid salt), temp., melting point: 204°C.

c) Preparation of compound 63.

- 48 040841

Diethylaminosulfotrifluoride (0.0015 mol) was added dropwise at 0° C. to a solution of intermediate 78 (0.0015 mol) in THF (90 ml). The mixture is stirred at room temperature for 2 days. The mixture was quenched with Na2CO3 then extracted with EtOAc. The organic layer is dried (MgSO ₄ ), filtered and the solvent is evaporated. The residue (0.96 g) was prepurified by column chromatography with kromasil (eluent: CH ₂ Cl ₂ then CH ₂ Cl ₂ /CH3OH/NH ₄ OH 95/5/0.5; 15-40 µm). A new fraction (0.63 g) was purified by Xbridge column chromatography (eluent: gradient CH3OH/NH4HCO3, 5%: 18-5 µm). Fraction 1 (0.08 g) is taken up in ethanol/acetone (5/95) and 1 equivalent of fumaric acid in acetone is added at room temperature. The precipitate is filtered off and dried. Yield: 0.07 g of compound 63 (Z-isomer; fumaric acid salt added) (6%), temp., melting point: 179°C.

Tab. 2-9 describe compounds of formula (Ia) which are prepared according to one of the samples above (Ex. No.)

For a number of compounds, melting point values are obtained using a Kofler apparatus, consisting of a heating plate with a linear temperature gradient, a sliding slider and a temperature scale in degrees Celsius.

table 2

Comm. no. Etc. no. ^R1 X ^{R6 R3} q ^{R4 R5} Properties 14 AT 8 -Vg ABOUT -n -SNz 1 -CH ₃ -SNz E or Z 16 AT 9 -W ABOUT -n S 1 -CH ₃ -SNz E 17 AT 9 -Vg ABOUT -n 1 -SNz -SNz Z 24 AT 5 -F ABOUT -n ^z o 1 -SNz -SNz Z 13 AT 7 -Vg ABOUT -n _/ ⁴ o 1 -SNz -SNz Z melt temp. 150°C 12 wb -Vg ABOUT -n kJ 3 -SNz -SNz E or Z melting point 145°C 25 AT 5 -Vg ABOUT -n 1 -SNz -SNz Z 8 B5.a -Vg ABOUT -H / 1 -SNz -SNz E melt temp. 128°C 61 B15.a -Vg ABOUT -H 3 -CH ₂ CH ₃ -SNz E 10 B5.b -Vg ABOUT -n Ί/ 1 -SNz -SNz 75/25 isomer ratio 28 AT 8 -Vg ABOUT -H % 1 -CH ₂ CH ₃ -CH ₂ CH ₃ Z 29 AT 5 -Vg ABOUT -F ^z o 1 -SNz -SNz Z 4 IN 1 -Vg S -n ^z o 1 -SNz -SNz Z

- 49 040841

thirty AT 5 -SNz 0 -H OU 1 -SNz -SNz Z 31 AT 5 -OSN ₃ 0 -n at 1 -SNz -SNz Z 21 VI.b OL o 0 -n X P 1 -SNz -SNz E/Z 60/40 AND AT 5 ABOUT O -H 1 -SNz -SNz Z 32 AT 5 OU 0 -n X......O |1.....J 1 -SNz -SNz 60/40' ratio isomers 20 VI.a o ^A S -n ^L o 1 -SNz -SNz Z 33 AT 5 nt O -n UJ 1 -SNz -SNz Z 34 AT 5 O 0 -H 1 -SNz -SNz 60/40 isomer ratio melt temp. 122°C

Table 3

^R6

I CH ₃

Comm. no. Etc. no. ^R1 X ^{R6 R3 R4 R5} Properties 15 AT 8 -W ABOUT -n -SNz -SNz -SNz E or Z 35 IN 1 -W ABOUT -n -SNz -CH ₃ -CH ₃ 75/25 isomer ratio 18 AT 9 -Vg ABOUT -n ^ζ Χζ S -CH ₃ -ch ₃ Z

- 50 040841

36 Bl -Br 0 -H -CH ₃ -SNz Ε/Ζηθ def. melting point 135°С 37 Bl -Br 0 -H -CH ₂ CH ₃ -CH ₂ CH ₃ Z 38 Bl -Br 0 -H -CH ₃ -SNz Z 9 B5.b -Br 0 -H z.....Q V -SNz -SNz Z 1 Bl -Br 0 -Cl -SNz -SNz Z 3 Bl -Br s -H -SNz -SNz E or Z 2 Bl -Br s -H ^Λθ -SNz -SNz E πππΖ 39 Bl -F 0 -H ^Λ ο -SNz -SNz E or 2 22 Bll.b OL 0 -H And -SNz -SNz mixture of isomers 40 Bll.a fV s -H -SNz -SNz E or Z 41 Bll.b O 0 -H And -SNz -SNz Ζ melt temp. 176°C

Table 4

Comm. no. Etc. no ^R1 O/K J FT Properties 6 VZ -Vg NN ¹ ΕπππΖ 5 vz -Vg N N V ΕμπηΖ 42 AT 8 -Vg N N V E or Z 43 IN 1 -Vg ''ΎΊ Ζ/Ε 90/10 44 AT 8 -Vg ^Ν CH ₃ Ζ/Ε 60/40 45 IN 1 -Vg ^N CH ₃ Ζ/Ε 90/10 46 VP.a And' NN ¹ Z

- 51 040841

Table 5

sn ₃

Comm. no. Etc. no ^{R1 R3} ( V / (Г—z At Properties 47 AT 8 -Vg ^ζϋ ^'N'^N E 48 AT 8 -Vg ^L o Z 23 AT 12 -Vg χ ₊ xn ₃ ^CH ₃ CH ₃ Z iodide salt 62 B15.b -Vg ^L co so t o 0 E fumarate melting point 204°С 63 B15.s -Vg ^L OE SO T About 0 χ Z fumarate melting point 179°С

Table 6

CH ₃

Comm. no. Etc. no. ^{R1 R3 R4 R5} Properties 7 B5.a -Vg -CH ₃ -CH ₃ E/Z 75/25

- 52 040841

Table 7

^R6

Comm. no. Etc. no. ^{R6 R3} Properties 49 bio -H E/Z not onp. 50 bio -H Cl E/Z not onp. 51 bio -H 0 sn ₃ E/Z not onp. 19 bio -Cl Ί E/Z not onp. 52 bio -Cl E/Z not onp. 53 bio -Cl Ό. _0CH3 E/Z not onp. 54 bio -CN E/Z not onp. 55 bio -CN Cl E/Z not onp. 56 bio -CN ^z 0 CH ₃ E/Z not onp. 57 bio -OCH ₃ E/Z not onp. 58 bio -OCH3 Cl E/Z not onp. 59 bio -OCH ₃ ^z / CH ₃ E/Z not onp.

- 53 040841

Table 8

I CH ₃

Comm. no. Etc. no. ^R1 X ^{R6 R3} q ^{R4 R5} Properties 26 AT 8 -W ABOUT -n 2 -CH ₃ -CH ₃ E 27 AT 8 -Vg ABOUT -n 2 -CH ₃ -SNz Z

When E or Z is represented in the above tables, this means that the compound is a pure isomer, but the absolute configuration is not determined.

When E/Z is not defined. are presented in the above tables, this means that the configuration is not determined.

LCMS conditions.

General technique a.

LC measurement is carried out using an Acquity UPLC (Waters) system comprising a binary pump, sample holder, heating column (set at 55°C), diode array detector (DAD), and column as defined in the respective methods below. The flow from the column is split in the MS spectrometer. The MS detector is formed with an electrospray ionization source. The mass spectrum is obtained by scanning from 100 to 1000 within 0.18 s using a delay time of 0.02 s. The capillary voltage of the needle crystal is 3.5 kV and the initial temperature is maintained at 140°C. Nitrogen is used as a spray gas. Data acquisition and accumulation was performed using the Waters-Micromass MassLynx-Openlynx data system.

General technique B.

HPLC measurement is carried out using an Alliance HT 2795 (Waters) system including a quaternary pump with degasser, an autosampler, a diode array detector (DAD) and a column as defined in the respective methods below, the column temperature is maintained at 30°C. The flow from the column is split in the MS spectrometer. The MS detector is formed with an electrospray ionization source. The capillary voltage of the needle crystal is 3 kV and the initial temperature is maintained at 100°C on the LCT (Time of Flight Zspray™ mass spectrometer from Waters - for method 1) and 3.15 kV at 110°C on the ZQ™ (simple quadrupole Zspray ™ mass spectrometer from Waters for methods 3 and 4). Nitrogen is used as a spray gas. Data acquisition and accumulation was performed using the Waters-Micromass MassLynx-Openlynx data system.

General technique C.

LC measurement is carried out using a UPLC (Ultra High Performance Liquid Chromatography) Acquity (Waters) system comprising a binary pump with a degasser, an autosampler, a diode array detector (DAD) and a column as defined in the respective methods below, the column temperature is maintained at 40°C . The stream from the column is injected into the MS detector. The MS detector is formed with an electrospray ionization source. The capillary voltage of the needle is 3 kV and the initial temperature is maintained at 130° C. on a Quattro (triple quadrupole mass spectrometer from Waters). Nitrogen is used as a spray gas. Data acquisition and accumulation was performed using the Waters-Micromass MassLynx-Openlynx data system.

Method 1.

In addition to general procedure B: Reverse phase HPLC was carried out on a Kromasil C18 column (5 μm, 4.6x150 mm) at a flow rate of 1.0 ml/minute. Three mobile phases are used (mobile phase A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile; mobile phase C: 0.2% formic acid + 99.8% ultrapure water) to drive the gradient from 30% A , 40% B and 30% C (hold for 1 min) to 100% B for 4 min, 100% B for 5 min and re-equilibrated with initial conditions for 3 min. An injection volume of 5 μl is used. The taper voltage is 20V for the positive ionization mode. The mass spectrum is acquired by scanning from 100 to 900 for 0.8 s using a scan delay of 0.08 s.

Method 2.

In addition to general procedure A: Reversed phase UPLC was performed on a bridged ethyl siloxane/silicone hybrid (BH) C18 column (1.7 μm, 2.1 x 50 mm; Waters Acquity) at a flow rate of 0.8 ml/minute . Two mobile phases are used (mobile phase A: 0.1% formic acid in H ₂ O/methanol 95/5; mobile phase B: methanol) to drive a gradient from 95% A and 5% B to 5% A and 95% B for 1.3 min and hold for 0.2 min. An injection volume of 0.5 μl is used. The taper voltage is 10 V for the positive ionization mode and 20 V for the negative ionization mode.

Method 3.

In addition to general procedure B: Reverse phase HPLC was performed on a Sunfire C18 column (3.5 μm, 4.6x100 mm) at an initial flow rate of 0.8 ml/minute. Two mobile phases are used (mobile phase A: 25% 7 mM ammonium acetate + 50% acetonitrile + 25% formic acid (2 ml/l); mobile phase B: 100% acetonitrile) to drive a gradient from 100% A (retention in for 1 min) to 100% B for 4 min, hold at 100% B at a flow rate of 1.2 ml/min for 4 min, and re-equilibrated with initial conditions for 3 min). An injection volume of 10 μl is used. The taper voltage is 20V for positive and negative ionization modes. The mass spectrum is acquired by scanning from 100 to 1000 for 0.4 s using a scan delay of 0.3 s.

Method 4.

In addition to general procedure B: Reverse phase HPLC was performed on an Xterra-MS C18 column (3.5 μm, 4.6x100 mm) at a flow rate of 0.8 ml/minute. Two mobile phases are used (mobile phase A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile; to drive a gradient from 80% A, 20% B (0.5 min hold) to 10% A, 90 % B for 4.5 min, hold at 10% A and 90% B for 4 min, and re-equilibrate with initial conditions for 3 min.

An injection volume of 10 μl is used. The taper voltage is 20V for positive and negative ionization modes. The mass spectrum is acquired by scanning from 100 to 1000 for 0.4 s using a scan delay of 0.3 s.

Method 5.

For compound (51), only the mass spectrum is recorded (no R(t)). The MS detector is formed with an electrospray ionization source. The mass spectrum is obtained by scanning from 100 to 1000 for 1 s using a delay time of 0.1 s. The capillary voltage of the needle crystal is 3 kV, and the initial temperature is maintained at 140°C. Nitrogen is used as a spray gas. Data acquisition and accumulation was performed using the Waters-Micromass MassLynx-Openlynx data system. The taper voltage is 10V for the positive ionization mode. Method 6 In addition to the general procedure C: reverse phase UPLC was carried out on a Waters Acquity BEN (bridged ethylsiloxane/silicone hybrid) C18 column (1.7 µm, 2.1 x 100 mm) at a flow rate of 0.35 ml/min. Two mobile phases are used (mobile phase A: 95% 7 mM ammonium acetate/5% acetonitrile; mobile phase B: 100% acetonitrile) to drive a gradient from 90% A and 10% B (hold for 0.5 min) to 8% A and 92% B for 3.5 min, hold for 2 min and return to initial state for 0.5 min, hold for 1.5 min. An injection volume of 2 μl is used. The taper voltage is 20V for positive and negative ionization modes. The mass spectrum is obtained by scanning from 100 to 1000 for 0.2 s using a delay between scans of 0.1 s.

Method 7.

In addition to the general procedure, C: reverse phase UPLC was run on a Waters Acquity BEN (bridged ethylsiloxane/silicone hybrid) C18 column (1.7 μm, 2.1 x 100 mm) at a flow rate of 0.35 ml/minute. Two mobile phases (mobile phase A: 95% 7 mM ammonium acetate/5% aceto

- 55 040841 nitrile; mobile phase B: 100% acetonitrile) is used to drive a gradient from 90% A and 10% B (0.5 min hold) to 8% A and 92% B over 3.5 min, 2 min hold and return to the initial state within 0.5 min, hold for 1.5 min. An injection volume of 2 μl is used. Taper voltages are 20, 30, 45, 60 V for the positive ionization mode. The mass spectrum is obtained by scanning from 100 to 1000 for 0.2 s using a delay between scans of 0.1 s.

Method 8.

In addition to general procedure B: Reverse phase HPLC was performed on a Sunfire C18 column (3.5 µm, 4.6x100 mm) with an initial flow rate of 0.8 ml/min. Use two mobile phases (mobile phase A: 35% 6.5 mM ammonium acetate + 30% acetonitrile + 35% formic acid (2 ml/l); mobile phase B: 100% acetonitrile) to drive the gradient from 100% A ( hold for 1 min) to 100% B for 4 min, hold at 100% B at a flow rate of 1.2 ml/min for 4 min, and re-equilibrated with initial conditions for 3 min. An injection volume of 10 μl is used. A positive ionization method is used with four different cone voltages of (20, 40, 50, 55 V). The mass spectrum is acquired by scanning from 100 to 1000 for 0.4 s using a scan delay of 0.1 s.

Method 9.

In addition to general procedure B: Reverse phase HPLC was performed on a Sunfire C18 column (3.5 µm, 4.6x100 mm) with an initial flow rate of 0.8 ml/min. Use two mobile phases (mobile phase A: 35% 6.5 mM ammonium acetate + 30% acetonitrile + 35% formic acid (2 ml/l); mobile phase B: 100% acetonitrile) to drive the gradient from 100% A ( hold for 1 min) to 100% B for 4 min, hold at 100% B at a flow rate of 1.2 ml/min for 4 min, and re-equilibrated with initial conditions for 3 min. An injection volume of 10 μl is used. The taper voltage is 20V for positive and negative ionization modes. The mass spectrum is acquired by scanning from 100 to 1000 for 0.4 s using a scan delay of 0.3 s.

When the compound is a mixture of isomers that give different peaks in the LCMS method, only the delay time of the main component is given in the LCMS table.

Table 10

Analytical data: (R(t) denotes dwell time in minutes; MH(+) denotes protonated molecular ion (free base); method refers to the method of use for LCMS.

LCMS Connection No. R(t) MH(+) Way 36 1.21 487 2 10 1.30 537 2 9 1.26 537 2 6 6.17 510 1 1 6.44 521 1 29 6.50 521 1 2 6.23 503 1 4 6.50 503 1 24 5.34 427 1 5 6.17 510 1 3 6.28 503 1 47 7.76 511 1 25 6.20 505 1 42 7.67 511 1 38 5.98 505 1 8 6.79 515 1 7 6.57 515 1 12 6.53 515 1 17 5.97 493 1 16 6.04 493 1 18 5.96 493 1

- 56 040841

44 6.17 542 1 48 6.19 542 1 45 6.14 542 1 43 6.63 529 1 39 5.13 427 1 35 5.41 425 1 15 5.57 425 1 14 5.47 425 1 AND 6.49 485 1 33 5.04 559 3 31 7.52 439 4 thirty 5.77 423 1 32 4.49 535 3 20 4.19 501 3 46 7.00 508 1 40 4.18 501 3 34 5.12 591 3 22 3.65 525 3 21 4.30 525 3 41 4.84 536 1 28 4.60 565 3 37 4.25 565 3 23 6.37 520 1 26 4.12 515 3 27 4.12 515 3 49 1.13 447 2 19 1.20 481 2 54 1.06 472 2 57 1.13 477 2 50 1.18 481 2 52 1.24 515 2 55 1.09 506 2 58 1.17 511 2 51 n.d. 477 5 53 1.20 511 2 56 1.06 502 2 59 1.08 507 2 62 6.26 634 6 63 5.68 634 7 61 5.67 557 8 60 5.18 621 9

D. Pharmacological examples.

D.1. In-vitro method for testing compounds against M. tuberculosis. Flat-bottomed sterile 96-well microtiter plates are filled with 100 µl of Middlebrook broth medium (1x). Then stock solutions (10x final test concentration) of the compounds are added in a volume of 25 µl to a set of paired wells in column 2 so as to allow evaluation of their effects on bacterial growth. Serial 5-fold dilutions are made directly in microtiter plates in columns 2-11 using a dedicated robotic system (Zymark Corp., Hopkinton, MA). Pipette tips are changed after every 3 dilutions to minimize dosing errors with highly hydrophobic compounds. Untreated controls with inoculum (column 1) or without inoculum (column 12) are included in each microtiter plate. Approximately 5000 CFU per well of Mycobacterium tuberculosis (H37RV strain), in a volume of 100 µl in Middlebrook broth medium (1x), is added to rows A to H, except column 12. The same volume of broth medium without inoculum is added to column 12 in rows from A to H. Cultures are incubated at 37°C for 7 days in a humidified atmosphere (incubator with open air valve and continuous ventilation). The day before the completion of the incubation, 6 days after the inoculation, resazurin (1:5) is added to all wells in a volume of 20 μl, and the plates are incubated for another 24 h at 37°C. On day 7, bacterial growth is quantified by fluorometry.

- 57 040841

Fluorescence is read in a computer-controlled fluorometer (Spectramax Gemini EM,

Molecular Devices) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The percentage of growth inhibition achieved by the compounds is calculated according to standard methods and expressed as IC ₉₀ values (μg/ml) (concentration that inhibits bacterial growth by 90%).

D.2. In-vitro method for testing compounds for antibacterial activity against M. Smegmatis strain ATCC607.

Flat-bottomed sterile 96-well microtiter plates are filled with 180 µl of sterile deionized water supplemented with 0.25% BSA. The stock solutions (7.8x final test concentration) of the compounds are then added in a volume of 45 µl to a set of paired wells in column 2 so as to allow evaluation of their effects on bacterial growth. Serial 5-fold dilutions (45 μl in 180 μl) are made directly in microtiter plates in columns 2-11 using a dedicated robotic system (Zymark Corp., Hopkinton, MA). Pipette tips are changed after every 3 dilutions to minimize dosing errors with highly hydrophobic compounds. Untreated controls with inoculum (column 1) or without inoculum (column 12) are included in each microtiter plate. Approximately 250 CFU per well of bacterial inoculum, in a volume of 100 µl in Mueller-Hinton broth medium, is added to rows A to H, except column 12. The same volume of broth medium without inoculum is added to column 12 in rows A to H. Cultures are incubated at 37°C for 48 hours in a humidified atmosphere of 5% CO ₂ (incubator with open air valve and continuous ventilation). At the end of the incubation, 2 days after inoculation, bacterial growth is quantified by fluorometry.

Fluorescence is read in a computer controlled fluorometer (Cytofluor, Biosearch) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm (gain 30). The percentage of growth inhibition achieved by the compounds is calculated according to standard methods and expressed as IC ₉₀ (μg/ml), which means the concentration that inhibits bacterial growth by 90%. The results are shown in table. eleven.

Table 11

Results of in vitro screening of compounds according to the invention for M. smegmatis (IC ₉₀ (μg/ml)).

Compound no. M. smegmatis 1C ₉₀ (µg/ml) 13 1.73 10 0.43

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D.3. In-vitro method for testing compounds for antibacterial activity against various non-mycobacterial strains.

Preparation of bacterial suspensions for susceptibility testing.

The bacteria used in this study are grown overnight in vials containing 100 ml of Mueller-Hinton Broth (Becton Dickinson - cat. No. 275730) in sterile deionized water, with shaking, at 37°C. Stock solutions (0.5 ml/tube) are stored at -70°C until use. Titration of bacteria is done in microtiter plates to determine TCID ₅₀ , TCID ₅₀ being the dilution that causes bacterial growth in 50% of the inoculated cultures. Typically, an inoculum level of approximately 100 TCID50 is used for susceptibility testing.

Antibacterial susceptibility test: determination of IC ₉₀ .

Microtiter plate study.

Flat-bottomed sterile 96-well microtiter plates are filled with 180 µl of sterile deionized water supplemented with 0.25% BSA. Then stock solutions (7.8x final test concentration) of the compounds are added in a volume of 45 µl to a set of paired wells in column 2. Serial five-fold dilutions (45 µl in 180 µl) are made directly in microtiter plates in columns 2 to 11. Untreated controls with inoculum (column 1) or without inoculum (column 12) are included in each microtiter plate. Depending on the type of bacterium, 10 to 60 CFU per well of bacterial inoculum (100 TCID ₅₀ ), in a volume of 100 µl in 2.8x Mueller-Hinton broth medium, is added to rows A to H, except column 12. Same volume broth medium without inoculum is added to column 12 in rows A to H. Cultures are incubated at 37° C. for 24 hours under normal atmosphere (incubator with open air valve and continuous ventilation). At the end of incubation, one day after inoculation, bacterial growth

- 60 040841 quantify using fluorometry. Resazurin (0.6 mg/ml) is then added in a µl volume to all wells 3 hours after inoculation and the plates are re-incubated overnight. A color change from blue to pink indicates bacterial growth.

Fluorescence is read in a computer controlled fluorometer (Cytofluor, Biosearch) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The percentage of growth inhibition achieved by the compounds is calculated according to standard methods. IC ₉₀ (expressed in μg/ml) means the concentration that inhibits bacterial growth by 90%. The results are shown in table. 12.

Agar dilution method.

MIC99 values (minimum concentration resulting in 99% inhibition of bacterial growth) can be determined by performing a standard NCCLS* agar dilution method in which the media used include Mueller-Hinton agar.

* Clinical laboratory standard institute. 2005. Methods for dilution Antimicrobial susceptibility tests for bacteria that grows Aerobically: approved standard -sixth edition.

Time of death studies.

The bactericidal or bacteriostatic activity of the compounds can be determined in a time-of-death study using the broth microdilution method*. In a time-to-kill study on Staphylococcus aureus and methicillin-resistant S. aureus (MRSA), the initial inoculum of S. aurues and MRSA is 106 cfu/ml in Muller Hinton broth. The antibacterial compounds are used at a concentration of 0.1 to 10 times the MIC (ie IC ₉₀ determined in a microtiter plate assay). The wells that were not injected with the antibacterial agent constituted the culture growth control. The plates containing the microorganism and test compounds are incubated at 37°C. After 0, 4, 24 and 48 hours of incubation, samples are removed for viable count by serial dilution (10 ^-1 to 10 ^-6 ) in sterile PBS and plated (200 µl) on Mueller Hinton agar. The plates are incubated at 37°C for 24 h and the number of colonies is determined. Death curves can be plotted by plotting log ₁₀ CFU per ml on the time scale. The bactericidal effect is usually defined as a 3-log ₁₀ reduction in CFU per ml compared to the untreated inoculum. The potential drug carryover effect is avoided by serial dilutions and colony counts at the highest dilution used for seeding.

*Zurenko, G.E. et al. In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob. Agents Chemother. 40, 839-845 (1996).

Determination of cellular levels of ATP.

To analyze changes in total cellular ATP concentration (using the ATP bio luminescence Kit, Roche), studies are performed by growing a stock culture of S. aureus (ATCC29213) in 100 ml Mueller Hinton vials and incubating in a shaker incubator for 24 hours at 37 °С (300 rpm). Measure OD ₄₀₅ nm and calculate CFU/ml. Dilute cultures to 1 x 10 ⁶ CFU/mL (final ATP concentration: 1 x 105 COE/100 µl per well) and add test compounds at 0.1 to 10 times the MIC (i.e. IC ₉₀ determined in the assay with microtiter plate). Incubate these tubes for 0, 30 and 60 minutes at 300 rpm and 37°C. Use 0.6 ml bacterial suspension from snap tubes and add to new 2 ml Eppendorf tubes. Add 0.6 ml cell lytic reagent (Roche kit), vortex at maximum speed and incubate for 5 minutes at room temperature. Cool on ice. Allow the luminometer to warm up to 30°C (Luminoskan Ascent Labsystems with injector). Fill one column (=6 wells) with 100 µl of the same sample. Add 100 µl of Luciferase reagent to each well using an injector system. Measure the luminescence for 1 s.

Table 12

IC ₉₀ values (µg/ml) determined from microtiter plate experiments.

1С ₉₀ (µg/ml) STA SPN EFA SPY RAE STA STA Compound no. 29213 6305 29212 8668 27853 RMETH 25923 1 8.27 1.65 2 7.98 1.59

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3 7.98 1.59 4 40 17.87 5 36, 14 36, 14 6 10, 18 10, 18 7 1, 63 2.05 8 8.17 2.05 9 2.69 9.56 10.72 10.72 9.56 3, 81 5, 38 10 4.79 12.03 5, 38 9.56 21.4 12.03 4.27 eleven 1.53 1.22 15, 33 7, 68 7, 68 12 8.17 10.29 13 8, 67 12.24 9, 73 12.24 10, 91 14 33.79 1.35 37.91 26, 84 37.91 15 33.79 6, 74 16 7.82 1.56 17 15, 6 7.82 39, 2 19, 65 43, 98 18 17.51 8.78 20 1.58 1.41 21 41, 68 23.44 22 20, 89 20, 89 23 1.65 1.85 1.65 6.55 24 33, 88 1.51 25 22.58 8.01 40, 15 17.93 40, 15 26 3.65 2.05 27 8.17 4.59 28 8.96 2.01 29 8.27 1.85 thirty 6, 7 1.34 11.91 6, 7 13.36 31 39, 09 7.8 32 1.69 1.9 9.51 3.79 3.79 33 8.86 7, 89 34 10.51 35 33.79 1.35 15, 09 1.35 15, 09 36 9, 73 5, 47 12.24 9, 73 12.24 12.24 10, 91 37 8.96 2.01 38 10, 08 8.01 8.01 3.58 8.99

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Claims (29)

39 33, 88 8.51 40 19, 93 3.98 15, 83 7.94 41 8.49 9.53 43 52.95 8.39 44 10, 82 10, 82 45 43, 09 10, 82 46 9, 03 8.05 48 10, 82 2.72 49 44, 66 8.91 50 9, 6 51 47, 67 21.29 52 10.29 10.29 53 9, 09 10.2 54 42.04 47, 17 55 8.02 10.1 56 12.6 57 9.51 58 10.2 12.84 59 11.34 60 1.97 2.48 61 1.76 1.76 62 22.52 63 2.25 STA 29213 means Staphylococcus aureus (ATCC29213); SPN 6305 means Streptococcus pneumoniae (ATCC6305); EFA 29212 means Enterococcus faecalis (ATCC29212); SPY 8668 means Streptococcus pyogens (ATCC8668); PAE 27853 means Pseudomonas aeruginosa (ATCC27853); STA RMETH means methicillin-resistant Staphylococcus aureus (MRSA) (clinically isolated at the University of Antwerp); STA 25923 stands for Staphylococcus aureus (ATCC25923). ATCC stands for American type tissue culture. CLAIM 1. Compound of formula (Ia) or any stereochemically isomeric form thereof, where Q is a radical of the formula (a-1) (a-2) ( ^a ' ³ ) p is an integer equal to 1; q is an integer equal to zero, 1, 2 or 3; R ¹ represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, C _1-6 -alkyloxy, phenyl or Het selected from furanyl, benzothienyl and pyridyl; R ² is hydrogen, C _1-6 alkyloxy, C _1-6 alkylthio; R ³ represents alkyl containing 1-6 carbon atoms, aryl-C _1-6 -alkyl, aryl, where aryl is selected from phenyl or naphthyl, optionally substituted with halogen or C _1-6 -alkyloxy; - 63 040841 R ^3a is hydrogen, cyano; R ⁴ and R ⁵ each independently represents alkyl containing 1-6 carbon atoms; or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a radical selected from the group consisting of piperidino, piperazino, morpholino, hexahydro-1H-1,4-diazepinyl, 2,5diazabicyclo[2.2.1]heptyl, imidazolyl, triazolyl, each radical is optionally substituted with 1, 2, 3 or 4 substituents, each substituent is independently selected from alkyl having 1-6 carbon atoms; R ⁶ is phenyl optionally substituted with halogen or C _1-6 alkyloxy; R ⁷ is hydrogen; or its pharmaceutically acceptable salts. 2. A compound according to claim 1, wherein R ² is methyloxy. 3. Connection according to any one of the preceding claims, where q is 1, 2 or 3. 4. A compound according to any one of claims 1 to 3, wherein R ⁴ and R ⁵ taken together with the nitrogen atom to which they are attached form a radical selected from the group consisting of hexahydro-1H-1,4 diazepinyl or 2, 5-diazabicyclo[2.2.1]heptyl, each of said rings being optionally substituted with C _1-6 alkyl. 5. A compound according to any one of the preceding claims, wherein Q is a radical of formula (a-1). 6. Connection according to any one of paragraphs. 1-4, where Q is a radical of formula (a-2). 7. The connection according to claim 1, where the connection is selected from and its pharmaceutically acceptable salt. 8. The use of a compound according to any one of claims 1 to 7 in medicine for the treatment of a bacterial infection. 9. Use according to claim 8, characterized in that the bacterial infection is an infection caused by Mycobacterium tuberculosis. 10. A pharmaceutical composition for the treatment of a bacterial infection, comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1-7. 11. The use of a compound according to any one of paragraphs. 1-7 for the manufacture of a medicament for the treatment of a bacterial infection. 12. Use according to claim 11, wherein the bacterial infection is an infection involving a gram-positive bacterium. 13. Use according to claim 12, characterized in that the Gram-positive bacterium is Streptococcus pneumoniae. 14. Use according to claim 12, characterized in that the Gram-positive bacterium is Staphylococcus aureus. 15. Use according to claim 14, characterized in that Staphylococcus aureus is methicillin resistant. 16. Compound formula (Sha) or a pharmaceutically acceptable salt thereof, where W1 is halogen and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , - 64 040841 p and q are as defined in claim 1. 17. A process for the preparation of a compound according to claim 1, characterized by reacting an intermediate compound of formula (II-a) or (II-c) with an acid, R ^e (R ¹ ) _f ,R ^Z •r ^£ zR zK c (CH ₂ )q Y where R ¹ , R ² , R ³ , R ^3a , R ⁴ , R ⁵ , R ⁶ , R ⁷ , p and q are as defined .1. 18. The method according to claim 17, wherein the compound of formula (Ia-1), (Ia-2), (Ia-3) is further converted into a therapeutically active non-toxic acid addition salt by treatment with an acid or into a therapeutically active non-toxic base addition salt. salt by treatment with base. 19. The method of claim 18, wherein additionally stereochemically isomeric forms or quaternary amines are obtained. 20. A method for preparing a compound according to claim 1, characterized by the reaction of an intermediate compound of formula (II-a) with SOCl ₂ in the presence of a solvent (1a-2) where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , p and q are as defined in paragraph 1. 21. The method of claim 20, wherein the compound of formula (Ia-1), (Ia-2) is further converted to a therapeutically active non-toxic acid addition salt by acid treatment, or to a therapeutically active non-toxic base addition salt by treatment with a base. 22. The method of claim 21, wherein additionally stereochemically isomeric forms or quaternary amines are obtained. 23. A process for preparing a compound according to claim 1, characterized by reacting an intermediate of formula (IIIa) with an intermediate of formula (IV) in the presence of a base and a solvent (Sha) ^(|a-1) where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , p and q are as defined in claim 1, and where W1 is an appropriate leaving group. 24. The method of claim 23 wherein the compound of formula (Ia-1) is further converted to a therapeutically active non-toxic acid addition salt by treatment with an acid, or to a therapeutically active non-toxic base addition salt by treatment with a base. 25. The method of claim 24, wherein additionally stereochemically isomeric forms or quaternary amines are obtained. 26. A method for preparing a compound according to claim 1, characterized by the reaction of an intermediate compound of formula (VII) with diethylcyanomethyl acetate in the presence of sodium hydride and a solvent - 65 040841 (la-4) (VII) where R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , p and q are as defined in claim 1. 27. The method of claim 26 wherein the compound of formula (1a-4) is further converted to a therapeutically active non-toxic acid addition salt by treatment with an acid, or to a therapeutically active non-toxic base addition salt by treatment with a base. 28. The method of claim 27, wherein additionally stereochemically isomeric forms or quaternary amines are obtained. 29. A pharmaceutical combination containing (a) a compound according to any one of claims 1 to 7 and (b) one or more antibacterial agents selected from antibiotics of the β-lactam group, tetracyclines, aminoglycosides, nucleosides, macrolides, ansamycins, peptides, peptide antibiotics to treat a bacterial infection. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2