HK1099297B

HK1099297B - Quinoline derivatives for use as mycobacterial inhibitors

Info

Publication number: HK1099297B
Application number: HK07106483.4A
Authority: HK
Inventors: Jérôme Emile Georges Guillemont; Elisabeth Thérèse Jeanne PASQUIER; David Françis Alain Lancois
Original assignee: Janssen Pharmaceutica N.V.
Priority date: 2004-01-29
Filing date: 2005-01-28
Publication date: 2012-06-29

Description

Quinoline derivatives as mycobacterial inhibitors

The present invention relates to novel substituted quinoline derivatives for the treatment of mycobacterial diseases, in particular diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium bovis (m.bovis), Mycobacterium avium (m.avium) and Mycobacterium marinum (m.marinum).

Background

Mycobacterium tuberculosis is the causative agent of Tuberculosis (TB), a serious and potentially fatal infection that is spread throughout the world. Estimates made by the world health organization show that over 8 million people become infected with TB each year, while 2 million people die of tuberculosis each year. In the last decade, TB cases have increased by 20% worldwide, with the most impoverished areas being the most heavily burdened. If this trend continues, the incidence of TB will increase by 41% in the next 20 years. Fifty years since the introduction of effective chemotherapy, TB remains the leading infectious cause of adult death following AIDS worldwide. Complicating the TB epidemic is the increasing number of multi-drug resistant strains and the lethal symbiosis with HIV. People who are HIV positive and infected with TB have a 30-fold higher probability of developing active TB than people who are HIV negative, TB being responsible for 1/3HIV/AIDS patient deaths worldwide.

The existing methods for treating tuberculosis all involve the combination of a plurality of medicines. For example, the U.S. Public Health Service (Public Health Service) recommended a regimen of two months combined use of isoniazid, rifampin, and pyrazinamide, followed by four months of use of isoniazid and rifampin alone. Patients infected with HIV continued to use these drugs for seven months. For patients infected with Mycobacterium tuberculosis multi-drug resistant strain, drugs such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin and ofloxacin are added in the combination therapy. There is neither a single drug that is effective in the clinical treatment of tuberculosis, nor any combination of drugs that makes a treatment period of less than six months possible.

There is a great medical need for new drugs that can provide a regimen that facilitates patient and drug provider compliance to improve existing treatments. Treatment regimens that are shorter in duration and require less monitoring are the best way to achieve this. During the booster or bactericidal phase (bacterial phase) of the simultaneous administration of the four drugs, the therapeutic effect appears mostly in the first 2 months; the bacterial load is greatly reduced and the patient turns to be infection free. A 4-6 month maintenance or sterilization phase is required to remove stubborn bacilli and minimize the risk of relapse. Effective sterilizing agents that shorten the treatment period to 2 months or less would be highly beneficial. Drugs that require less intensive monitoring to facilitate compliance are also needed. Clearly, a compound that reduces both the overall treatment period and the frequency of administration would provide the greatest benefit.

Complicating the TB epidemic is the emergence of an increasing number of multi-drug resistant strains or MDR-TB. Up to 4% of all cases worldwide are considered MDR-TB, which is resistant to the most potent drugs isoniazid and rifampicin among the standard four drugs. MDR-TB can be fatal without treatment and cannot be adequately treated by standard therapy, thus requiring "second line" medication for up to 2 years. These drugs are generally toxic, expensive and less potent. In the absence of effective therapies, infectious MDR-TB patients continue to transmit disease, producing new infections by MDR-TB strains. There is an urgent medical need for new drugs with a new mechanism of action, which are likely to show activity against MDR strains.

It is an object of the present invention to provide novel compounds, in particular substituted quinoline derivatives, which have the property of inhibiting the growth of mycobacteria and are therefore useful in the treatment of mycobacterial diseases, in particular diseases caused by pathogenic mycobacteria such as mycobacterium tuberculosis, mycobacterium bovis, mycobacterium avium, mycobacterium smegmatis (m.

Substituted quinolines have been disclosed in US 5,965, 572 (U.S.) for the treatment of antibiotic resistant infections and in WO 2004/34265 for inhibiting the growth of bacterial microorganisms. WO 2004/011436 describes quinoline derivatives as antimycobacterial agents.

Summary of The Invention

The present invention relates to novel substituted quinoline derivatives of formula (I)

A pharmaceutically acceptable acid or base addition salt thereof, a quaternary amine thereof, a stereochemically isomeric form thereof, a tautomeric form thereof and a N-oxide form thereof, wherein:

R¹is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkoxy, alkylthio, alkoxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl;

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

s is an integer equal to 0, 1, 2, 3 or 4;

R²is hydrogen; halogen; an alkyl group; a hydroxyl group; a mercapto group; optionally substituted by amino or mono-or di (alkyl) amino or of formulaWherein Z is CH₂、CH-R⁸、O、S、N-R⁸T is an integer equal to 1 or 2, the dotted line represents an optional bond; an alkoxy group; an alkylthio group; mono-or di (alkyl) amino, wherein alkyl may be optionally substituted with one or two substituents independently selected from alkoxy, Ar, Het, morpholinyl or 2-oxopyrrolidinyl; ar; het or formulaWherein Z is CH₂、CH-R⁸、O、S、N-R⁸(ii) a t is an integer equal to 1 or 2; the dotted line represents an optional bond;

R³is alkyl, Ar-alkyl, Het or Het-alkyl;

q is an integer equal to 0, 1, 2, 3 or 4;

R⁴and R⁵Each independently is hydrogen, alkyl or benzyl; or

R⁴And R⁵And the N to which they are attached may form a group selected from pyrrolidinyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of said rings being optionally substituted with alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, mono-or dialkylamino, alkylthio, alkoxyalkyl, alkylthioalkyl, and pyrimidinyl;

R⁶is hydrogen, halogen, haloalkyl, hydroxy, Ar, alkyl, alkoxy, alkylthio, alkoxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; or two ortho-positions R⁶The groups may form together with the phenyl ring to which they are attached a naphthyl group;

r is an integer equal to 1, 2, 3, 4 or 5;

R⁷is hydrogen, alkyl, Ar or Het;

R⁸is hydrogen, alkyl, hydroxy, aminocarbonyl, mono-or di (alkyl) aminocarbonyl, Ar, Het, alkyl substituted by one or two Ar, Het-C (═ O) -, or Ar-C (═ O) -;

alkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms linked to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted by halogen, hydroxy, alkoxy or oxo;

ar is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl, 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, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, morpholinyl, and mono-or dialkylaminocarbonyl; het is a monocyclic heterocycle selected from the group consisting of N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from the group consisting of quinolinyl, isoquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1, 4] dioxinyl or benzo [1, 3] dioxolyl; each monocyclic and bicyclic heterocycle may optionally be substituted on carbon with 1, 2 or 3 substituents selected from halo, hydroxy, alkyl or alkoxy;

halogen is a substituent selected from fluorine, chlorine, bromine and iodine;

haloalkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halogen atoms;

provided that when the groupAt the 3-position of the quinoline moiety; r⁷At the 4-position of the quinoline moiety, R²At position 2 of the quinoline moiety and represents hydrogen, hydroxy, mercapto, alkoxy, alkoxyalkoxy, alkylthio, mono-or di (alkyl) amino or formulaGroup of (1), which

In which Y is CH₂O, S, NH or N-alkyl;

s is 1, 2, 3 or 4.

Detailed Description

In the context of the present application, alkyl is a straight-chain or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms linked to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted by halogen, hydroxy, alkoxy or oxo. Preferably, the alkyl group is methyl, ethyl or cyclohexylmethyl. More preferably, the alkyl group is C_1-6Alkyl groups, which as a group or part of a group include straight and branched chain saturated hydrocarbon groups having 1 to 6 carbon atoms, such as methyl, ethyl, butyl, pentyl, hexyl, 2-methylbutyl, and the like.

In the context of this application, Ar is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl, 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, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, morpholinyl, and mono-or dialkylaminocarbonyl. Preferably Ar is naphthyl or phenyl, each optionally substituted with 1 or 2 halo substituents.

Het is, within the scope of the present application, a monocyclic heterocycle selected from the group consisting of N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from the group consisting of quinolinyl, isoquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1, 4] dioxinyl or benzo [1, 3] dioxolyl; each of the monocyclic and bicyclic heterocycles may optionally be substituted on carbon by 1, 2 or 3 substituents selected from halo, hydroxy, alkyl or alkoxy. Preferably Het is thienyl.

In the context of the present application, halogen is a substituent selected from the group consisting of fluorine, chlorine, bromine and iodine, haloalkyl is a straight-chain or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted by one or more halogen atoms. Preferably halogen is bromine, fluorine or chlorine, preferably haloalkyl is trifluoromethyl.

Within the scope of the present application, the quinoline moieties are numbered as follows:

radical (I)R²、R⁷And R¹Can be located at any available position on the quinoline moiety.

Whenever used hereinafter, the term "compounds of formula (I)" or any subgroup thereof is intended to also include their N-oxide forms, their salts, their quaternary amines, their tautomeric forms and their stereochemically isomeric forms. Of particular interest are stereochemically pure compounds of formula (I).

An object embodiment of the present invention relates to compounds of the following formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof, wherein

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

s is an integer equal to 0, 1, 2, 3 or 4;

R²is hydrogen; halogen; an alkyl group; a hydroxyl group; a mercapto group; optionally substituted by amino or mono-or di (alkyl) amino or of formulaWherein Z is CH₂、CH-R⁸、O、S、N-R⁸T is an integer equal to 1 or 2, the dotted line represents an optional bond; an alkoxy group; an alkylthio group; mono-or di (alkyl) amino, wherein alkyl may be optionally substituted with one or two substituents independently selected from alkoxy, Ar, Het, morpholinyl or 2-oxopyrrolidinyl; het or formulaWherein Z is CH₂、CH-R⁸、O、S、N-R⁸(ii) a t is an integer equal to 1 or 2; the dotted line represents an optional bond;

R³is alkyl, Ar-alkyl, Het or Het-alkyl;

q is an integer equal to 0, 1, 2, 3 or 4;

R⁴and R⁵Each independently is hydrogen, alkyl or benzyl; or R⁴And R⁵And the N to which they are attached may form a group selected from pyrrolidinyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl, and thiomorpholinyl, optionally substituted with alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, mono-or dialkylamino, alkylthio, alkoxyalkyl, alkylthioalkyl, and pyrimidinyl;

R⁶is hydrogen, halogen, haloalkyl, hydroxy, Ar, alkyl, alkoxyA group, alkylthio, alkoxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; or

Two ortho-positions R⁶The groups may form together with the phenyl ring to which they are attached a naphthyl group;

r is an integer equal to 1, 2, 3, 4 or 5;

R⁷is hydrogen, alkyl, Ar or Het;

R⁸is hydrogen, alkyl, aminocarbonyl, mono-or di (alkyl) aminocarbonyl, Ar, Het, alkyl substituted by one or two Ar, Het-C (═ O) -;

ar is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl, 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, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, morpholinyl, and mono-or dialkylaminocarbonyl; het is a monocyclic heterocycle selected from the group consisting of N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1, 4] dioxinyl, or benzo [1, 3] dioxolyl; each monocyclic and bicyclic heterocycle may optionally be substituted on carbon with 1, 2 or 3 substituents selected from halo, hydroxy, alkyl or alkoxy;

halogen is a substituent selected from fluorine, chlorine, bromine and iodine;

haloalkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted by one or more halogen atoms;

provided that when the groupAt the 3-position of the quinoline moiety; r⁷At the 4-position of the quinoline moiety, R²At position 2 of the quinoline moiety and represents hydrogen, hydroxy, mercapto, alkoxy, alkoxyalkoxy, alkylthio, mono-or di (alkyl) amino or formulaWherein Y is CH₂O, S, NH or N-alkyl;

s is 1, 2, 3 or 4.

Preferably the present invention relates to a compound of formula (I) as described above or any subgroup thereof, provided that the group isAt the 3-position of the quinoline moiety; r⁷At the 4-position of the quinoline moiety, R²When located at the 2-position of the quinoline moiety, s is 1, 2, 3 or 4.

Preferably the present invention relates to a compound of formula (I) as described above or any subgroup thereof, provided that the group isAt the 3-position of the quinoline moiety; s is 1, 2, 3 or 4.

Preferably the present invention relates to a compound of formula (I) as described above or any subgroup thereof, provided that the group isNot in the 3-position of the quinoline moiety.

Preferably the present invention relates to a compound of formula (I) as described above or any subgroup thereof, a pharmaceutically acceptable acid or base addition salt thereof, a quaternary amine thereof, a stereochemically isomeric form thereof, a tautomeric form thereof and a N-oxide form thereof, wherein the compound has the formula

Preferably the present invention relates to a compound of formula (I-a-1) as described above or any subgroup thereof.

Preferably the present invention relates to a compound of formula (I-a-1-1) or any subgroup thereof

A pharmaceutically acceptable acid or base addition salt thereof, a quaternary amine thereof, a stereochemically isomeric form thereof, a tautomeric form thereof and an N-oxide form thereof.

Preferably the present invention relates to a compound of formula (I) as described above or any subgroup thereof wherein: r¹Is hydrogen, halo, cyano, Ar, Het, alkyl and alkoxy; p is an integer equal to 1, 2, 3 or 4; specifically 1 or 2; more specifically 1; s is an integer of 0 or 1;

R²is hydrogen; an alkyl group; a hydroxyl group; optionally substituted by amino or mono-or di (alkyl) amino or of formulaWherein Z is CH₂、CH-R¹⁰、O、S、N-R¹⁰T is an integer equal to 1 or 2, the dotted line represents an optional bond; an alkoxy group; an alkylthio group; mono-or di (alkyl) amino; ar; het or formulaWherein Z is CH₂、CH-R¹⁰、O、S、N-R¹⁰(ii) a t is an integer equal to 1 or 2; the dotted line represents an optional bond; in particular R²Is hydrogen, hydroxy, alkoxy, alkoxyalkoxy, alkylthio or of the formulaWherein Y is O; more specifically R²Is hydrogen, halogen or alkyl, more particularly R²Is hydrogen or alkyl;

R³is alkyl, Ar-alkyl or Het; specifically Ar;

q is an integer equal to 0, 1, 2 or 3; specifically 1;

R⁴and R⁵Each independently is hydrogen, alkyl or benzyl; or

R⁴And R⁵And the N to which they are attached may form a group selected from pyrrolidinyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyrazinyl, morpholinyl, and thiomorpholinyl, optionally substituted with alkyl and pyrimidinyl; in particular R⁴And R⁵Is an alkyl group; more specifically R⁴And R⁵Is C_1-6Alkyl, preferably methyl;

R⁶is hydrogen, halogen or alkyl; or

r is an integer equal to 1;

R⁷is hydrogen or Ar; in particular hydrogen or phenyl;

alkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms linked to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted by halogen or hydroxy;

ar is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halo, haloalkyl, cyano, alkoxy, and morpholinyl;

het is a monocyclic heterocycle selected from N-phenoxypiperidinyl, furanyl, thienyl, pyridinyl, pyrimidinyl; or a bicyclic heterocycle selected from benzothienyl, 2, 3-dihydrobenzo [1, 4] dioxinyl or benzo [1, 3] dioxolyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom with 1, 2 or 3 alkyl substituents;

halogen is a substituent selected from fluorine, chlorine and bromine.

For the compounds of formula (I) above or any subgroup thereof, R is preferred¹Is hydrogen, halogen, Ar, Het, alkyl or alkoxy. More preferably R¹Is hydrogen, halogen, Ar, alkyl or alkoxy; even more preferably R¹Is halogen. Most preferred is R¹Is bromine or chlorine.

For the compounds of formula (I) above or any subgroup thereof, it is preferred that p is equal to 1 or 2. More preferably p is equal to 1.

For the compounds of formula (I) above or any subgroup thereof, R is preferred²Is hydrogen; halogen; an alkyl group; a hydroxyl group; a mercapto group; optionally substituted by amino or mono-or di (alkyl) amino or of formulaWherein Z is CH₂、CH-R⁸、O、S、N-R⁸T is an integer equal to 1 or 2, the dotted line represents an optional bond; an alkoxy group; an alkylthio group; mono-or di (alkyl) amino, wherein alkyl may be optionally substituted with one or two substituents independently selected from alkoxy, Ar, Het, morpholinyl or 2-oxopyrrolidinyl; het or formulaWherein Z is CH₂、CH-R⁸、O、S、N-R⁸(ii) a t is an integer equal to 1 or 2; the dotted line represents an optional bond.

Likewise, a target group of compounds of formula (I) above or any subgroup thereof are those compounds wherein R is²Is hydrogen; an alkyl group; optionally substituted by amino or mono-or di (alkyl) amino or of formulaWherein Z is CH₂、CH-R¹⁰、O、S、N-R¹⁰T is an integer equal to 1 or 2, the dotted line represents an optional bond; mono-or di (alkyl) amino; ar; het or formulaWherein Z is CH₂、CH-R¹⁰、O、S、N-R¹⁰(ii) a t is an integer equal to 1 or 2; the dotted line represents an optional bond. More preferably R²Is hydrogen, halogen, alkyl, alkoxy or alkylthio. Even more preferably R²Is hydrogen, halogen or C_1-6Alkyl (e.g., ethyl). Most preferred is R²Is hydrogen or C_1-6Alkyl (e.g., ethyl).

For the compounds of formula (I) above or any subgroup thereof, R is preferred³Is naphthyl, phenyl or Het, each optionally substituted with 1 or 2 substituents, preferably halogen or haloalkyl, most preferably halogen. More preferably R³Is optionally substituted naphthyl or optionally substituted phenyl. Most preferred is R³Is naphthyl or optionally substituted phenyl (e.g. 3-halophenyl or 3, 5-dihalophenyl).

For the compounds of formula (I) above, or any subgroup thereof, q is equal to 0, 1 or 2. More preferably q is equal to 1.

For the compounds of formula (I) above or any subgroup thereof, R⁴And R⁵Each independently hydrogen or alkyl, more preferably hydrogen or C_1-6Alkyl groups, such as methyl or ethyl, most preferably methyl.

For the compounds of formula (I) above or any subgroup thereof, R⁴And R⁵And the N to which they are attached form a group selected from imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl, optionally substituted by alkyl, halogen, haloalkyl, hydroxy, alkoxy, alkylthio, alkoxyalkyl or alkylthioalkyl, preferably by alkyl, most preferably by methyl or ethyl.

For the compounds of formula (I) above or any subgroup thereof, R⁶Is hydrogen, halogen, haloalkyl, hydroxy, Ar, alkyl, alkoxy, alkylthio, alkoxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl. More preferably R⁶Is hydrogen, alkylOr a halogen. Most preferred is R⁶Is hydrogen. Preferably r is 1 or 2. More preferably r is 1.

For the compounds of formula (I) above or any subgroup thereof, R is preferred⁷Is hydrogen, methyl or Ar, more preferably hydrogen or Ar, for example phenyl.

For the compounds of formula (I) above or any subgroup thereof, R is preferred⁸Is hydrogen, alkyl, aminocarbonyl, mono-or di (alkyl) aminocarbonyl, Ar, Het, alkyl substituted by one or two Ar, Het-C (═ O) -.

For the compounds of formula (I) above or any subgroup thereof, preferably s is an integer equal to 0 or 1.

A target group of compounds of formula (I) above or any subgroup thereof are the compounds wherein

R¹Is halogen, in particular bromine;

p is equal to 1;

s is equal to 0 or 1;

R²is hydrogen, halogen or alkyl; in particular hydrogen or alkyl;

R³is optionally substituted phenyl or optionally substituted naphthyl, in particular 3-halophenyl, 3, 5-dihalophenyl or naphthyl;

R⁴and R⁵Is C_1-6Alkyl, in particular methyl;

R⁶is hydrogen, r is 1;

R⁷is hydrogen or Ar, in particular hydrogen or phenyl.

The intermediate of interest of the present invention is an intermediate of formula (II)

Wherein R is¹、R²、R⁶、R⁷P and s are as defined above, in particular the target intermediates are intermediates of formula (II-a)

Wherein R is¹、R²、R⁶、R⁷P and s are as defined above.

Pharmaceutically acceptable acid addition salts are defined as compounds of formula (I) above or any subgroup thereof including the therapeutically active non-toxic acid addition salt forms which can be formed. The acid addition salts can be prepared by reaction of the starting materials with suitable acids, for example, inorganic acids such as hydrohalic acids (particularly hydrochloric acid, hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid; organic acids such as acetic acid, glycolic acid, propionic 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, p-aminosalicylic acid and pamoic acid, obtained by treating the base form of the compound of formula (I) above or any subgroup thereof.

The compounds of formula (I) above, or any subgroup thereof, containing an acidic proton, may also be converted into their therapeutically active non-toxic base addition salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, the ammonium salts, the alkali metal and alkaline earth metal salts, in particular the lithium, sodium, potassium, magnesium and calcium salts, the salts of organic bases, such as the benzathine (benzathine) salt, the N-methyl-D-glucamine salt, the hydroxylamine (hybramine) salt, and the salts of amino acids, such as the arginine and lysine salts.

Conversely, said acid or base addition salt forms can be converted into the free form by treatment with a suitable base or acid.

The term "addition salt" as used within the scope of the present application also includes the solvates which the compounds of formula (I) above, or any subgroup thereof and salts thereof, are able to form. Such solvates include, for example, hydrates and alcoholates.

The term "quaternary amine" as used above defines a quaternary ammonium salt which can be formed by reaction of a compound of formula (I) above, or any subgroup thereof, with a suitable quaternizing agent, such as an optionally substituted alkyl, aryl or aralkyl halide (e.g. methyl or benzyl iodide). Other reactants having good leaving groups may also be used, such as alkyl triflates, alkyl mesylates and alkyl p-toluenesulfonates. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counter ions include chloride, bromide, iodide, trifluoroacetate and acetate. The selected counter ions may be introduced using an ion exchange resin.

The term "stereochemically isomeric forms" as used herein defines all possible isomeric forms which the compounds of formula (I) above, or any subgroup thereof, may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More specifically, chiral (stereogenic) centers can have either the R-or S-configuration. The substituents on the divalent cyclic (partially) saturated groups may have either the cis or trans configuration. The stereochemically isomeric forms of the above compounds of formula (I) or any subgroup thereof are expressly included within the scope of the present invention.

According to CAS nomenclature conventions, when two chiral centers of known absolute configuration are present in a molecule, the least numbered chiral center, i.e., the reference center, is given an R or S label (based on Cahn-Ingold-Prelog sequencing rule). Configuration of the second chiral center with a relative tag [ R ]^*，R^*]Or [ R ]^*，S^*]Is represented by the formula (I) in which R^*Always defined as the center of reference, [ R ]^*，R^*]Denotes centers having the same chirality, [ R ]^*，S^*]Representing centers of different chirality. For example, if the least numbered chiral center in the molecule has the S configuration and the second center is R, then a stereogenic center is presentThe symbol is designated as S- [ R ]^*，S^*]. If "α" and "β" are used: the position of the most preferred substituent on the asymmetric carbon atom with the lowest ring number in the ring system is always forced to be in the "alpha" position of the middle plane (mean plane) defined by the ring system. The position of the most preferred substituent on another asymmetric carbon atom in the ring system relative to the position of the most preferred substituent on the reference atom is designated as "α" if it is on the same side of the mid-plane defined by the ring system and as "β" if it is on the other side of the mid-plane defined by the ring system.

The compounds of formula (I) above, or any subgroup thereof, and certain intermediate compounds, always have at least one chiral center in their structure, which may result in the appearance of at least two stereochemically different structures.

The compounds of formula (I) above, or any subgroup thereof, prepared by the methods described below, may be synthesized as racemic mixtures of enantiomers which can be separated from each other by resolution methods well known in the art. The compounds of formula (I) above, or any subgroup thereof, racemic compounds, may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are then liberated therefrom with a base. Another way of separating the enantiomeric forms of the above compounds of formula (I) or any subgroup thereof involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if it is desired to obtain a particular stereoisomer, said compound will be synthesized by stereospecific methods of preparation. These processes will advantageously use enantiomerically pure starting materials.

The tautomeric forms of the above compounds of formula (I) or any subgroup thereof are intended to include the above compounds of formula (I) or any subgroup thereof wherein, for example, an enol group is converted into a keto group (keto-enol tautomerism).

The N-oxide forms of the compounds of the invention are intended to include compounds of formula (I) as described above or any subgroup thereof wherein one or several quaternary nitrogen atoms are oxidized to the so-called N-oxide, in particular N-oxides wherein the nitrogen of the amine group is oxidized.

The present invention also includes derivative compounds (often referred to as "prodrugs") of the pharmacologically active compounds of the present invention that degrade in vivo to yield the compounds of the present invention. Prodrugs are generally, but not always, less potent at the target receptor than the compounds into which they degrade. Prodrugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or ineffective. For example, the desired compound may simply be poorly soluble, may be difficult to transport across the mucosal epithelium, or may have an undesirably short plasma half-life. Further discussion of Prodrugs can be found in Stella, V.J., et al, "Prodrugs", Drug Delivery Systems, 1985, pp.112-176 and Drugs, 1985, 29, pp.455-473.

Prodrug forms of the pharmacologically active compounds of the invention are generally the compounds of the above formula (I) having an esterified or amidated acid group or any subgroup thereof, the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof. Such esterified acid groups include those of the formula-COOR^xWherein R is^xIs C_1-6Alkyl, phenyl, benzyl or one of the following groups:

amidated groups include the formula-CONR^yR^zWherein R is^yIs H, C_1-6Alkyl, phenyl or benzyl, R^zis-OH, H, C_1-6Alkyl, phenyl or benzyl.

Compounds of the invention having an amino group can be derivatized with a ketone or aldehyde, such as formaldehyde, to form Mannich bases. This base hydrolyzes in aqueous solution with first order kinetics.

The compounds of the present invention have surprisingly been shown to be suitable for the treatment of mycobacterial diseases, particularly diseases caused by pathogenic mycobacteria, including drug-resistant and multi-drug resistant mycobacteria such as mycobacterium tuberculosis, mycobacterium bovis, mycobacterium avium, mycobacterium smegmatis and mycobacterium marinum. The invention therefore also relates to the above-defined compounds of formula (I) or any subgroup thereof, the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof, as hereinbefore defined, for use as a medicament.

The invention also relates to compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of the invention. For administration purposes, the compounds of the present invention may be formulated in a variety of pharmaceutical forms. Illustrative of suitable compositions are all compositions commonly employed for systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate association with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in single dosage form, especially suitable for oral administration or parenteral injection. For example, in preparing the compositions in oral dosage form, in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols and the like; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, although other ingredients may be included, for example to aid solubility. For example, injectable solutions may be prepared in which the carrier comprises saline solution, dextrose solution, or a mixed solution of saline and dextrose. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are designed to be converted to liquid form preparations shortly before use.

Depending on the mode of administration, the pharmaceutical composition preferably comprises 0.05 to 99% by weight, more preferably 0.1 to 70% by weight of the active ingredient of formula (I) or any subgroup thereof, and preferably 1 to 99.95% by weight, more preferably 30 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total composition.

The pharmaceutical compositions may additionally comprise various other ingredients well known in the art, such as lubricants, stabilizers, buffers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavoring agents, or coloring agents.

It is particularly advantageous to formulate the above pharmaceutical compositions in a single dosage form for ease of administration and uniformity of dosage. As used herein, "unit dosage form" refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof (segregatedmultiple). The daily dosage of the compounds of the invention will, of course, vary with the compound employed, the mode of administration, the desired treatment and the mycobacterial disease to be assessed. In general, however, satisfactory results will be obtained when the compounds of the invention are administered in a daily dosage of not more than 1 gram, for example in the range of 10-50mg/kg body weight.

Furthermore, the present invention also relates to the use of a compound of formula (I) as described above or any subgroup thereof, a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a tautomeric form thereof and a N-oxide form thereof, as well as any of the above pharmaceutical compositions thereof, for the manufacture of a medicament for the prevention or treatment of mycobacterial diseases.

Thus, in another aspect, the invention provides a method of treating a patient suffering from, or at risk of, a mycobacterial disease, said method comprising administering to the patient a therapeutically effective amount of a compound or composition of the invention.

The compounds of the present invention may also be combined with one or more other anti-mycobacterial drugs.

Accordingly, the present invention also relates to a combination of (a) a compound of formula (I) as described above or any subgroup thereof and (b) one or more other antimycobacterial agents.

The invention also relates to a combination of (a) a compound of formula (I) as defined above or any subgroup thereof and (b) one or more other antimycobacterial agents for use as a medicament.

Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of (a) a compound of formula (I) as described above or any subgroup thereof and (b) one or more other antimycobacterial agents are also encompassed by the present invention.

Other mycobacterial drugs that may be combined with a compound of formula (I) above or any subgroup thereof are e.g. rifampicin; isoniazid; pyrazinamide; amikacin; ethionamide; moxifloxacin; ethambutol; streptomycin; p-aminosalicylic acid; a cyclic serine; capreomycin; kanamycin; thiosemicarbazide; PA-824; quinolones/fluoroquinolones such as ofloxacin, ciprofloxacin, sparfloxacin; macrolides such as clarithromycin, clofazimine, amoxicillin-clavulanate complex, rifamycin, rifabutin, rifapentine.

Preferably the compounds of formula (I) as described above or any subgroup thereof according to the invention are combined with rifapentine and moxifloxacin.

General preparation

The compounds of the invention can generally be prepared by a series of steps, each of which is known to the skilled worker.

The compounds of formula (I) may be prepared by reacting an intermediate of formula (II) with a compound of formula (III) in the presence of a suitable coupling agent and a suitable solvent, optionally in the presence of a suitable baseIntermediates, coupling agents such as n-butyllithium, secBuLi, solvents such as tetrahydrofuran, bases such as 2, 2, 6, 6-tetramethylpiperidine, NH (CH)₂CH₂CH₃)₂Or N, N-diisopropylamine or trimethylethylenediamine.

In the above reaction, the obtained compound of formula (I) may be isolated and, if necessary, purified according to methodologies generally known in the art, such as extraction, crystallization, distillation, trituration and chromatography. In the case of crystallization of the compound of formula (I), it may be isolated by filtration. Otherwise, crystallization may result from the addition of a suitable solvent, such as water; acetonitrile; alcohols such as methanol, ethanol; and combinations of said solvents. Alternatively, the reaction mixture can be evaporated to dryness and the residue purified by chromatography (e.g., reverse phase HPLC, flash chromatography, etc.). The reaction mixture can also be purified by chromatography without prior evaporation of the solvent. The compound of formula (I) may also be isolated by recrystallization from a suitable solvent, such as water; acetonitrile; alcohols, such as methanol; and combinations of the solvents.

One skilled in the art will recognize what method should be used, what solvent is most suitable for use, or finding the most suitable separation method is within routine experimentation.

The compounds of formula (I) may be further prepared by converting the compounds of formula (I) into each other according to group conversion reactions known in the art.

The compounds of formula (I) may be converted to the corresponding N-oxide form according to methods well known in the art for converting a trivalent nitrogen to its N-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids such as perbenzoic acid or haloperoxybenzoic acids such as 3-chloroperbenzoic acid, peroxy alkanoic acids such as peracetic acid, alkyl hydroperoxides such as t-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 these solvents.

By reacting with a suitable catalyst, a suitable solvent and a suitable base in the presence of a suitable catalystReaction of a compound of formula (I) wherein R is¹Conversion of a compound of formula (I) representing halogen into R¹Compounds of formula (I) representing Het, e.g. pyridyl, catalysts, e.g. Pd (PPh)₃)₄A solvent such as dimethyl ether or an alcohol such as methanol, etc., and a base such as sodium carbonate or potassium carbonate.

By reacting with Sn (CH) in the presence of a suitable catalyst, a suitable solvent₃)₄Reaction of a compound of formula (I) wherein R is¹Conversion of a compound of formula (I) representing halogen into R¹Compounds of formula (I) representing methyl, catalysts such as Pd (PPh)₃)₄Solvents such as toluene.

Certain compounds of formula (I) and certain intermediates in the present invention may consist of mixtures of stereochemically isomeric forms. Pure stereochemically isomeric forms of said compounds and of said intermediates may be obtained by applying methods well known in the art. For example, diastereomers may be separated by physical methods such as selective crystallization or chromatographic techniques such as counter-current distribution, liquid chromatography, and the like. Enantiomers can be obtained from racemic mixtures as follows: first converting the racemic mixture into a mixture of diastereomeric salts or compounds with a suitable resolving agent, such as a chiral acid; the mixture of diastereomeric salts or compounds is then physically separated by methods such as selective crystallization or chromatographic techniques such as liquid chromatography; finally converting said isolated diastereomeric salt or compound into the corresponding enantiomer. Pure stereochemically isomeric forms may also be obtained from pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening (interacting) reaction occurs stereospecifically.

Another way of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, particularly using a chiral stationary phase.

It will be appreciated that in the above or following preparations, the reaction product may be isolated from the reaction medium by methods well known in the art, such as extraction, crystallization, distillation, trituration and chromatography, and may be further purified if necessary.

Some of the intermediates and starting materials are well known compounds and are commercially available or can be prepared according to methods well known in the art.

WhereinThe intermediate of formula (II) in which the group is located at the 2-position of the quinoline ring, s is an integer equal to 1, and the 4-position of the quinoline ring is unsubstituted, is represented by formula (II-a), which can be prepared by reacting the intermediate of formula (IV) with phenoxybenzene in the presence of ethyl acetate.

Wherein R is²And R⁷Intermediates of formula (IV) representing hydrogen, which can be prepared by reacting an intermediate of formula (V) with an intermediate of formula (VI) in the presence of a suitable base such as sodium hydroxide, are represented by formula (IV-a).

Wherein

Intermediates of formula (II) wherein the group is at the 2-position of the quinoline ring and s is 0, which can be prepared by reacting Zn, chlorotrimethylsilane, 1, 2-dibromoethane, Pd (PPh)₃)₄And a suitable solvent such as tetrahydrofuran, by reacting an intermediate of formula (VII) wherein W is₁Represents a suitable leaving group, e.g. halogen such as chlorine, etc., W in the intermediate of formula (VIII)₂Represents a suitable leaving group, for example halogen such as chlorine, bromine and the like.

Wherein W₁An intermediate of formula (VII) representing chlorine is represented by formula (VII-a) which can be prepared by reacting an intermediate of formula (IX) with POCl₃And reacting to prepare the compound.

Intermediates of formula (IX) may be prepared by reacting an intermediate of formula (X) with 4-methylbenzenesulfonyl chloride in the presence of a suitable solvent, such as dichloromethane, and a suitable base, such as potassium carbonate.

Intermediates of formula (X) can be prepared by reacting an intermediate of formula (XI) with a suitable oxidizing agent, such as 3-chloroperbenzoic acid, in the presence of a suitable solvent, such as dichloromethane.

Intermediates of formula (II) wherein s is 0 are represented by formula (II-c) which can be prepared by reacting an intermediate of formula (XII) with Et in the presence of a suitable acid such as trifluoroacetic acid and a suitable solvent such as dichloromethane₃SiH reaction.

Intermediates of formula (XII) can be prepared by reacting an intermediate of formula (XIII), wherein W is W, with an intermediate of formula (XIV), in the presence of a suitable coupling agent and a suitable solvent, optionally in the presence of a suitable base₃Represents a suitable leaving group, for example halogen such as chlorine or bromine, etc., coupling agents such as n-butyllithium, secBuLi, solvents such as tetrahydrofuran, bases such as 2, 2, 6, 6-tetramethylpiperidine, NH (CH)₂CH₂CH₃)₂N, N-diisopropylamine or trimethylethylenediamine.

Wherein the radical is located at the 8-position of the quinoline ring, R²At the 2 position, R⁷At position 4, R¹Intermediates of formula (XII) located at the 6-position of the quinoline ring are represented by formula (XII-a) and can be prepared by reacting an intermediate of formula (XV) with an intermediate of formula (XIV) in the presence of a suitable coupling agent, such as n-butyllithium, secBuLi, and a suitable solvent, such as tetrahydrofuran, optionally in the presence of a suitable base, such as 2, 2, 6, 6-tetramethylpiperidine, NH (CH)₂CH₂CH₃)₂N, N-diisopropylamine or trimethylethylenediamine.

The intermediates of formula (III) are commercially available compounds or can be prepared by conventional reaction methods generally known in the art. For example, an intermediate compound of formula (III) wherein q is equal to 1, represented by formula (III-a), can be prepared according to the following reaction scheme (1):

scheme 1

Reaction scheme (1) comprises a step (a) wherein R is suitably in the presence of a suitable Lewis acid and a suitable reaction inert solvent³By Friedel-Craft reaction with an appropriate acid chloride, e.g., 3-chloropropionyl chloride or 4-chlorobutyryl chloride, a Lewis acid such as A1Cl₃、FeCl₃、SnCl₄、TiCl₄Or ZnCl₂A reaction-inert solvent such as dichloromethane or dichloroethane. The reaction is conveniently carried out between room temperature and reflux temperature. In the next step (b), an amino group (e.g., -NR) is introduced by reacting the intermediate compound obtained in step (a) with a suitable amine⁴R⁵)。

Intermediates of formula (III) can be prepared by reacting an intermediate of formula (XVI) and an intermediate of formula (XVII) with formaldehyde in the presence of a suitable solvent, e.g., an alcohol such as ethanol, and a suitable acid such as HCl.

Obviously, in the above and in the following reactions, the reaction product may be isolated from the reaction medium by methods well known in the art, such as extraction, crystallization and chromatography, and may be further purified if necessary. It is also clear that the reaction products present in more than one enantiomeric form can be separated from their mixtures by well-known techniques, in particular preparative chromatography such as preparative HPLC. In general, the compounds of formula (I) may be isolated in their isomeric forms.

The following examples illustrate the invention without limiting it.

Experimental part

The absolute stereochemical configuration of the chiral carbon atom in certain compounds has not been determined experimentally. In these cases, the stereochemically isomeric form which is isolated first is designated "a" and the stereochemically isomeric form which is isolated second is designated "B", without any further indication of the actual stereochemical configuration. However, one skilled in the art can unambiguously distinguish the "A" and "B" isomeric forms using methods well known in the art, such as X-ray diffraction. The separation method is described in detail below.

For certain final compounds, the stereochemical configuration is indicated in the structure. These configurations are relative configurations, indicating that the groups of interest are located in the same or opposite planes of the molecule

Hereinafter, "DIPE" is defined as diisopropyl ether, "THF" is defined as tetrahydrofuran, "HOAc" is defined as acetic acid, and "EtOAc" is defined as ethyl acetate.

A. Preparation of intermediate compounds

Example A1

Preparation of intermediate 1 and intermediate 2

A mixture of 5-bromo-1H-indole-2, 3-dione (0.221mol) in NaOH 3N (500ml) was stirred at 80 ℃ for 30 minutes and then cooled to room temperature. 4-phenyl-2-butanone (0.221mol) was added. The mixture was stirred, refluxed for 90 minutes, cooled to room temperature and acidified with HOAc to pH 5. Filtering off the precipitate with H₂And O washing and drying. Yield: 75g (95%) of a mixture of intermediate 1 and intermediate 2.

Example A2

Preparation of intermediate 3

Intermediate 1 and intermediate 2 in 1, 1' -oxybis [ benzene ]]The mixture (0.21mol) in (600ml) was stirred at 300 ℃ for 12 hours. EtOAc was added. The mixture was extracted three times with HCl 6N and K₂CO₃Basification of the solid with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (36g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 99/1; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 11g (16%) of intermediate 3.

Example A3

Preparation of intermediate 4

1- (3-fluorophenyl)) Ethanone (0.195mol), formaldehyde (0.235mol) and NH (CH)₃)₂A mixture of HC1(0.235mol) in ethanol (300ml) and concentrated HCl (1ml) was stirred and refluxed overnight before returning to room temperature. The precipitate was filtered, washed with ethanol and dried. The mother liquor was evaporated (motherlayer). The residue was taken up in diethyl ether. The precipitate was filtered, washed with diethyl ether and dried. The fraction is absorbed in K₂CO₃10% of the total. CH for precipitation₂Cl₂And (5) washing and drying. Yield: 18.84g (49%) of intermediate 4.

Example A4

a. Preparation of intermediate 5

6-bromo-2 (1H) -quinolinone (0.089mol) in POCl₃The mixture in (55ml) was stirred at 60 ℃ overnight and then at 100 ℃ for 3 hours, the solvent was evaporated. The residue is taken up in CH₂Cl₂In, pouring ice water and using NH₄Basification of OH, concentration, filtration through celite, and addition of CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. Yield: 14.5g intermediate 5 (67%).

b. Preparation of intermediate 6

A mixture of Zn (0.029mol) and 1, 2-dibromoethane (0.001mol) in THF (6ml) was stirred and refluxed for 10 minutes, then cooled to room temperature. Chlorotrimethylsilane (0.001mol) was added. The mixture was stirred at room temperature for 30 minutes. A THF solution (25ml) of bromomethylbenzene (0.025mol) was added dropwise at 5 ℃ for 90 minutes. The mixture was stirred at 0 ℃ for 2 hours. Intermediate 5 (prepared according to A4. a) (0.021mol) is addedTHF solution (75 ml). Adding Pd (PPh)₃)₄(0.0008 mol). The mixture was stirred, refluxed for 2 hours, then cooled to room temperature and poured into NH₄Cl 0%, extracted with EtOAc. H for organic layer₂O washing, then washing with saturated NaCl, drying (MgSO)₄) Filtered and the solvent evaporated. The residue (12g) was purified by column chromatography on silica gel (eluent: cyclohexane/CH)₂Cl₂50/50, respectively; 20-45 μm). The two fractions were collected and the solvent was evaporated. Yield of the second fraction: 2.5g of intermediate 6.

Example A5

a. Preparation of intermediate 7

nBuLi (1.6M) (0.066mol) was added dropwise to a mixture of 6-bromo-2-chloro-3-ethylquinoline (0.055mol) in THF (150ml) at-50 ℃. The mixture was stirred at-50 ℃ for 1 hour. A THF solution (70ml) of benzaldehyde (0.066mol) was added at-70 ℃. The mixture was stirred at-70 ℃ for 1 hour, H was poured in at 0 ℃₂O, extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (15g) was crystallized from DIPE/iPrOH. The precipitate was filtered off and dried. Yield: 7.6g intermediate 7 (46%).

b. Preparation of intermediate 8

Intermediate 7 (prepared according to A5. a) (0.021mol), Et₃SiH (0.21mol) and CF₃COOH (0.21mol) in CH₂Cl₂The mixture in (100ml) was stirred at room temperature for 3 days. Addition of H₂And O. CH for the mixture₂Cl₂And (4) extracting. Separating the organic layer with K₂CO₃10% wash, dry over magnesium sulfate, filter, evaporate solvent. The residue (8g) was purified by column chromatography over silica gel (eluent: cyclohexane/AcOEt 95/5; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 3.8g (64%, m.p.: 66 ℃).

Example A6

a. Preparation of intermediate 9

At-70 ℃ and N₂N-butyllithium (0.055mol) was slowly added under a stream to a mixture of 7-bromo-2-chloro-3-ethylquinoline (0.037mol) in THF (100 ml). The mixture was stirred for 2 hours then benzaldehyde (0.055mol) in THF (55ml) was added. The mixture was stirred for 3 hours, water was added at-20 ℃ and the mixture was extracted with EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue (12.2g) was purified by column chromatography on silica gel (eluent: cyclohexane/AcOEt 80/20; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 6.1g of intermediate 9 (56%).

b. Preparation of intermediate 10

Intermediate 9 (prepared according to A6. a) (0.0205mol), Et₃SiH (0.205mol) and CF₃COOH (0.205mol) in CH₂Cl₂The mixture in (300ml) was stirred at room temperature for 7 days. Addition of H₂And O. CH for the mixture₂Cl₂And (4) extracting. Separating the organic layer with K₂CO₃10% wash, dry over magnesium sulfate, filter, evaporate solvent. The residue (7.1g) was purified by column chromatography on silica gel (eluent: cyclohexane/AcOEt 95/5; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 4.8g of intermediate10(83％)。

Example A7

a. Preparation of intermediate 11

At-20 ℃ and N₂N-butyllithium (0.0090mol) was slowly added under a stream to a mixture of 2, 2, 6, 6-tetramethylpiperidine (0.0090mol) in THF (15 mL). The mixture was stirred for 20 minutes and then cooled to-70 ℃. A solution of 6-bromo-2-chloro-4-phenylquinoline (0.0060mol) in THF (40mL) was added. The mixture was stirred for 1 hour. A THF solution (15ml) of benzaldehyde (0.0090mol) was added. The mixture was stirred at-70 ℃ for 1 hour and then at room temperature for 3 hours. Addition of H₂And O. The mixture was extracted with EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue (3.0g) was purified by column chromatography on silica gel (eluent: cyclohexane/AcOEt: 95/5; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 1.8g of intermediate 11 (71%).

b. Preparation of intermediate 12

Intermediate 11 (prepared according to A7. a) (0.0042mol), Et₃SiH (0.0424mol) and CF₃COOH (0.0424mol) in CH₂Cl₂The mixture in (100ml) was stirred at room temperature for 24 hours. Addition of H₂And O. CH for the mixture₂Cl₂And (4) extracting. Separating the organic layer with K₂CO₃10% wash, dry over magnesium sulfate, filter, evaporate solvent. The residue (1.3g) was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 0.66g (38%, m.p.: 121 ℃ C.).

B. Of the final compoundsPreparation of

Example B1

Preparation of Compound 1 and Compound 4

Compound 1(dia A) Compound 4(dia B)

nBuLi 1.6M (0.0072mol) was added to a mixture of N- (1-methylethyl) -2-propylamine-hydrochloric acid (1: 1) (0.0071mol) in THF (25ml) at-20 ℃ in a stream of nitrogen. The mixture was stirred for 20 minutes and then cooled to-70 ℃. A solution of intermediate 3(0.0061mol) in THF (5ml) was added. The mixture was stirred for 2 hours. A solution of intermediate 4(0.0061mol) in THF (5ml) was added at-70 ℃. The mixture was stirred at-70 ℃ for 3 hours. Addition of NH₄Cl 10%. The mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (3.4g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 97/3/0.1; 15-40 μm). The two fractions were collected and the solvent was evaporated. The first residue (0.9g) was crystallized from isopropyl ether. The precipitate was filtered off and dried. Yield: 0.49g of Compound 1 (diastereomer A) (m.p.: 136 ℃ C.). The second residue (0.79g) was crystallized from isopropyl ether. The precipitate was filtered off and dried. Yield: 0.105g of Compound 4 (diastereomer B) (m.p.: 179 ℃ C.).

Example B2

Preparation of Compound 2 and Compound 3

Compound 2(dia A) Compound 3(dia B)

nBuLi 1.6M (0.0072mol) was added dropwise to a solution of N- (1-methylethyl) -propylamine hydrochloride (1: 1) (0.0071mol) in THF (25ml) at-20 ℃ in a stream of nitrogen. The mixture was stirred for 20 minutes. Then cooled to-70 ℃. A solution of intermediate 3(0.0061mol) in THF (5ml) was added. The mixture was stirred for 2 hours. A solution of 3- (dimethylamino) -1- (1-naphthyl) -1-propanone (0.0062mol) in THF (5ml) was added at-70 ℃. The mixture was stirred at-70 ℃ for 3 hours. Addition of NH₄Cl 10%. The mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (4g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 97/3/0.1; 15-40 μm). The two fractions were collected and the solvent was evaporated. The first residue (0.61g) was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 0.303g of Compound 2 (diastereomer A) (m.p.143 ℃ C.). The second residue (0.56g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 98/2). The pure fractions were collected and the solvent was evaporated. Yield: 0.104g of Compound 3 (diastereomer B) (m.p.: 69 ℃ C.).

Example B3

Preparation of Compounds 5 and 6

Compound 5(dia A) Compound 6(dia B)

N-BuLi 1.6M (0.0048mol) was added to a mixture of N- (1-methylethyl) -2-propylamine (0.0049mol) in THF (15ml) at-70 ℃. The mixture was stirred at-20 ℃ for 20 minutes. A solution of intermediate 6 (prepared according to A4. b) (0.004mol) in THF (5ml) was added at-70 ℃. The mixture was stirred at-70 ℃ for 2 hours. A solution of intermediate 4 (prepared according to A3) (0.004mol) in THF (5ml) was added at-70 ℃. The mixture was stirred at-70 ℃ for 3 hours. Addition of NH₄And Cl10 percent. The mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. Yield: 2.1 g. This fraction was purified by silica gel column chromatography (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 96.5/3.5/0.1; 15-40 μm). The two fractions were collected and the solvent was evaporated. Yield: 0.123g fraction A and 0.122g fraction B. Fraction A was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 98/2; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.119 g. The fraction is absorbed at ipr₂In O/pentane. The mixture was evaporated. Yield: 0.077g of Compound 5 (mp.: 58 ℃ C.). Fraction B was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 0.039g of Compound 6 (mp.: 134 ℃ C.).

Example B4

Preparation of Compounds 13 and 14

Compound 13(dia A) Compound 14(dia B)

N-BuLi 1.6M (0.013mol) was added to a mixture of N- (1-methylethyl) -2-propylamine (0.013mol) in TF (25ml) at-20 ℃ in a stream of nitrogen. The mixture was stirred at-20 ℃ for 20 minutes and then cooled to-70 ℃. A solution of intermediate 8 (prepared according to A5. b) (0.0106mol) in THF (25ml) was added. The mixture was stirred at-70 ℃ for 45 minutes. A solution of 3- (dimethylamino) -1- (1-naphthyl) -1-propanone (0.013mol) in THF (20ml) was added. The mixture was stirred at-70 ℃ for 2 hours and poured at-30 ℃ with H₂O, extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (5.5g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 99/I/0.1; 15-40 μm). The two fractions were collected and the solvent was evaporated. Yield: 0.33g of compound 13 (diastereomer A) (3%) and 0.11g of compound 14 (diastereomer B) (1%).

The following compounds were prepared according to the methods described above. Because, unlike the above purification, purification of the residue is indicated (^*)。

Example B5

Preparation of Compounds 7 and 8

Compound 7 (diastereomer A) Compound 8 (diastereomer B)

N-butyllithium (0.0043mol) was slowly added to a mixture of diisopropylamine (0.0043mol) in THF (10ml) at-20 ℃ under a stream of nitrogen. The mixture was stirred for 20 minutes and then cooled to-70 ℃. Intermediate 10 (prepared according to A6. b) was added) (0.0036mol) in THF (10 ml). The mixture was stirred for 2 hours. A solution of 3- (dimethylamino) -1- (1-naphthyl) -1-propanone (0.0043mol) in THF (10ml) was added. The mixture was stirred for 2 hours. Addition of H₂And O. The mixture was extracted with EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. Residue of (^*) (18g) purification by silica gel column chromatography (eluent: CH (CH)₂Cl₂/MeOH/NH₄OH 98/2/0.2; 15-40 μm). The two fractions were collected and the solvent was evaporated. Yield: 0.17g fraction 1 and 0.15g fraction 2. Fraction 1 was crystallized from MeOH. The precipitate was filtered off and dried. Yield: 0.082g Compound 7 (5% diastereomer A). Fraction 2 was purified by column chromatography on silica gel (eluent: CH)₂Cl₂MeOH: 98/2, respectively; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.13g of Compound 8 (7%, diastereomer B).

Example B6

Preparation of Compounds 11 and 12

Compound 11 (diastereomer A) Compound 12 (diastereomer B)

N-butyllithium (0.002mol) was slowly added to a mixture of diisopropylamine (0.002mol) in THF (5ml) at-20 deg.C under a stream of nitrogen. The mixture was stirred for 20 minutes and then cooled to-70 ℃. A solution of intermediate 12 (prepared according to A7. b) (0.0017mol) in THF (7ml) was added. Stirring the mixtureFor 2 hours. A solution of 1- (3, 5-difluorophenyl) -3-dimethylamino-1-propanone (0.002mol) in THF (4ml) was added. The mixture was stirred for 2 hours. Addition of H₂And O. The mixture was extracted with EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue (11g) was purified by column chromatography on silica gel (eluent: CH)₂CI₂MeOH: 99/1, respectively; 15-40 μm). The two fractions were collected and the solvent was evaporated. Yield: 0.061g fraction 1 and 0.070g fraction 2. Fraction 1 was crystallized from MeOH. The precipitate was filtered off and dried. Yield: 0.046g of Compound 11 (5%, m.p.: 220 ℃, diastereomer A). Fraction 2 was crystallized from MeOH. The precipitate was filtered off and dried. Yield: 0.053g (5%, m.p.: 216 ℃, diastereomer B).

C. Analytical method

The mass of the compound was recorded by LCMS (liquid chromatography-mass spectrometry). Three methods were used as described below. The data are summarized in table 1 below.

LCMS-method 1

LCMS analysis (anodic electrospray ionization, scanning from 100-900 atomic mass units (amu)) was performed on a Kromasil C18 column (Interchim, Montlucon, France; 5 μm, 4.6X 150mm) at a flow rate of 1 ml/min. The following gradient conditions were run using two mobile phases (mobile phase A: 30% 6.5mM ammonium acetate + 40% acetonitrile + 30% formic acid (2ml /); mobile phase B: 100% acetonitrile): 100% A1 min, 100% B in 4 min, 100% B5 min, 100% A in 3 min, rebalancing with 100% A for 2 min.

LCMS-method 2

LCMS analysis (anodic and cathodic (pulsed) electrospray ionization, scanning from 100-. The following gradient conditions were run using two mobile phases (mobile phase A: 35% 6.5mM ammonium acetate + 30% acetonitrile + 35% formic acid (2ml /); mobile phase B: 100% acetonitrile): 100% A1 min, 100% B in 4 min, 100% B4 min (flow 1.2 ml/min), 100% A in 3 min (flow 0.8 ml/min), re-equilibration with 100% A for 1.5 min.

Table 1: LCMS parent peak

No.	MH+	LCMS-method
			Compound 7	509	1
Compound 9	495	2
			Compound 15	495	1
Compound 13	509	1
			Compound 14	509	1

D. Pharmacology ofExamples of the invention

D.1.In vitro method for testing resistance of a compound to mycobacterium tuberculosis

Sterile plastic flat-bottomed 96-well microtiter plates were filled with 100. mu.l Middlebrook (1X) broth. Subsequently, compound stock solutions (10 × final assay concentration) were added to a series of replicate test wells of a 2-column microtiter plate in a volume of 25 μ l to evaluate the effect of compounds on bacterial growth. Serial five-fold dilutions were made directly in 2 to 11 columns of microtiter plates using a custom-made robotic system (Zymark corp. hopkinton, ma). The pipette tip was changed after each 3 dilutions to minimize pipetting errors for highly hydrophobic compounds. Untreated control samples with (1 column) and without (12 columns) inoculum were included in each microtiter plate. In addition to 12 columns, 100. mu.l of Mycobacterium tuberculosis (strain H37 RV) (Middlebrook (1X) broth) was added to the A to H rows of each column, with FU at about 5000C per well. The same volume of broth without inoculum was added to row 12, rows a to H. The cultures were incubated for 7 days at 37 ℃ in a humidified atmosphere (incubator air valve open, continuous aeration). One day before the end of incubation, i.e.6 days after inoculation, resazurin (1: 5) was added to all wells in a volume of 20. mu.l and the microtiter plates were incubated for a further 24 hours at 37 ℃. On day 7, bacterial growth was quantified by fluorimetry.

Fluorescence values were read in a computer controlled fluorometer (Spectramax Gemini EM, molecular devices) at 530nm excitation wavelength and 590nm emission wavelength. Percent growth inhibition achieved by the compounds was calculated according to standard methods and MIC data (expressed as IC90 in micrograms/ml) was calculated.

D.2.In vitro method for testing the antibacterial Activity of Compounds against Mycobacterium smegmatis ATCC607 Strain Method of

Sterile plastic flat-bottomed 96-well microtiter plates were filled with 180. mu.l of sterile deionized water supplemented with 0.25% BSA. Subsequently, compound stock solution (7.8 × assay final concentration) was added to microtiter plate 2 in a volume of 45 μ lA series of replicate wells in the column to evaluate the effect of the compound on bacterial growth. Serial five-fold dilutions (45 μ Ι in 180 μ Ι) were made directly in 2 to 11 columns of microtiter plates with a custom made robotic system (Zymark corp. hopkinton, ma). The pipette tip was changed after each 3 dilutions to minimize pipetting errors for highly hydrophobic compounds. Untreated control samples with (1 column) and without (12 columns) inoculum were included in each microtiter plate. In addition to 12 columns, 100. mu.l of bacterial inoculum (in 2.8X Mueller-Hinton broth) was added to row A to row H of each column, with approximately 250C FU per well. The same volume of broth without inoculum was added to row 12, rows a to H. At humidified 5% CO₂Cultures were incubated at 37 ℃ for 48 hours under atmosphere (incubator air valve open, continuous ventilation). At the end of the incubation, two days after inoculation, the bacterial growth was quantified by fluorimetry. Alamar Blue (10X) was therefore added to all wells in a volume of 20. mu.l and the microtiter plates were incubated for a further 2 hours at 50 ℃.

Fluorescence values were read in a computer controlled fluorometer (Cytofluor, Biosearch) at an excitation wavelength of 530nm and an emission wavelength of 590nm (gain 30). The percent growth inhibition achieved by the compounds was calculated according to standard methods. pIC₅₀Defined as the concentration at which the inhibition of bacterial growth reached 50%. The results are shown in table 2.

TABLE 2: results of in vitro screening of Mycobacterium smegmatis and Mycobacterium tuberculosis with the Compounds of the invention (pIC)₅₀)

Compound numbering	Mycobacterium smegmatis pIC₅₀	KnotMycobacterium tuberculosis pIC₅₀
			1	6.2
2	6.5
			3	5.7
6	4.9
			15	64	5
10	5.9	5.1

14	5.9
		13	5.8
9	5.8
		8	5.8
11	5.7

Claims

1. A compound of the general formula (I)

A pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or a tautomeric form thereof, wherein:

R¹is hydrogen, halogen, cyano, hydroxy, or alkyl;

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

s is an integer equal to 0, 1 or 2;

R²is hydrogen or halogen; (ii) a

R³Is Ar;

q is an integer equal to 1;

R⁴and R⁵Each independently is an alkyl group;

R⁶is hydrogen;

r is an integer equal to 1;

R⁷is hydrogen, alkyl or Ar;

ar is a carbocyclic ring selected from phenyl or naphthyl, each optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from hydroxy, halo, cyano, nitro or amino;

halogen is a substituent selected from fluorine, chlorine, bromine and iodine;

provided that when the groupAt the 3-position of the quinoline moiety; r⁷At the 4-position of the quinoline moiety, R²At position 2 of the quinoline moiety and represents hydrogen; s is 1.

2. The compound of claim 1, provided that the groupAt the 3-position of the quinoline moiety; r⁷At the 4-position of the quinoline moiety, R²When located at the 2-position of the quinoline moiety, s is 1 or 2.

3. The compound of claim 1, wherein the compound is of formula (I-a)

Wherein R is¹-R⁷P, s, r and q are as defined in claim 1.

4. The compound of claim 1, wherein the compound is of formula (I-b)

Wherein R is¹-R⁷P, s, r and q are as defined in claim 1.

5. The compound of claim 1, wherein the compound is of formula (I-c)

Wherein R is¹-R⁷P, s, r and q are as defined in claim 1.

6. The compound of claim 1 or 2, wherein R¹Is halogen.

7.A compound according to claim 1 or 2, wherein p is equal to 1.

8. The compound of claim 1 or 2, wherein R²Is hydrogen, halogen or C_1-6An alkyl group.

9. The compound of claim 1 or 2, wherein R³Is naphthyl or phenyl, each optionally substituted with 1 or 2 substituents, preferably halogen.

10. The compound of claim 1 or 2, wherein R⁴And R⁵Each independently is C_1-6An alkyl group.

11. The compound of claim 1 or 2, wherein R⁷Is hydrogen or Ar.

12. A compound according to claim 1 or 2, wherein s is an integer equal to 0 or 1.

13. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1 to 12.

14. Use of a compound according to claim 1 or 2 or a composition according to claim 13 for the manufacture of a medicament for the treatment of mycobacterial diseases.

15. A process for the preparation of a compound according to claim 1, characterized in that

Reacting an intermediate of formula (II) with an intermediate of formula (III) in the presence of a suitable coupling agent and a suitable solvent, optionally in the presence of a suitable base,

wherein R is¹-R⁷P, s, r and q are as defined in claim 1;

or, optionally, the compounds of formula (Ia) or (Ib) are converted into each other according to art-known conversion methods, and further optionally, the compounds of formula (Ia) or (Ib) are converted into therapeutically active non-toxic acid addition salts by treatment with an acid, or into therapeutically active non-toxic base addition salts by treatment with a base, or vice versa, the acid addition salt form is converted into the free base by treatment with a base, or the base addition salt is converted into the free acid by treatment with an acid; and optionally, preparing stereochemically isomeric forms or tautomeric forms thereof.

16. The compound of claim 1 or 2, wherein R¹Is bromine.

17. The compound of claim 10, wherein R⁴And R⁵Each is methyl.

18. The compound of claim 1 or 2, wherein R¹Is halogen; p is equal to 1; s is equal to 0 or 1; r²Is hydrogen or halogen; r³Is optionally substituted phenyl or optionally substituted naphthyl; r⁴And R⁵Is C_1-6An alkyl group; r⁶Is hydrogen, r is 1; r⁷Is hydrogen or Ar.

19. The compound of claim 18, wherein R¹Is bromine; r²Is hydrogen; r³Is 3-halophenyl, 3, 5-dihalophenyl or naphthyl; r⁴And R⁵Is methyl; r⁷Is hydrogen or phenyl.

20. The compound of claim 1 or 2, wherein alkyl is C_1-6An alkyl group.

21. The use of claim 14, wherein the mycobacterial disease is a disease caused by mycobacterium tuberculosis.