WO2004032856A2

WO2004032856A2 - Compounds

Info

Publication number: WO2004032856A2
Application number: PCT/US2003/031795
Authority: WO
Inventors: Jian Jin; Jeffrey K. Kerns; Feng Wang; Yonghui Wang
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 2002-10-07
Filing date: 2003-10-07
Publication date: 2004-04-22
Anticipated expiration: 2005-04-07
Also published as: AU2003275480A8; AU2003275480A1; WO2004032856A3

Abstract

Oxazolidin-2-one of the formula as further defined herein are useful for inhibiting the chemokine receptor nominated CCR8, resulting in treatment of diseases such as asthma and the like.

Description

Compounds

Scope of the Invention

This invention relates to certain substituted oxazolidin-2-one and their use for inhibiting the chemokine receptor nominated CCR8, [also known as ChemRl (1), TER1(2) and CMKBR8 (systematic Human Genome nomenclature)], resulting in treatment of diseases such as asthmatic conditions and the like.

Background of the Invention

Recruitment of activated T lymphocytes to sites of inflammation is a tightly controlled process regulated by a multiplicity of molecules, in particular, chemokines. Chemokines are small molecular weight secreted proteins that direct leukocyte trafficking through interaction with G-protein coupled seven-transmembrane receptors.

In asthma, T lymphocytes of the Th2 subtype are involved with the initiation and the maintenance of airway inflammation and obstruction following antigen challenge.

Activated Th2 CD4+ lymphocytes are recruited to the airways where they produce the cytokines IL-4, IL-5 and IL-13. These cytokines recruit eosinophils as well as additional

Th2 cells to the lungs and ensure their survival upon their arrival. Large numbers of Th2 lymphocytes and their concomitant cytokine secretions have been recovered in bronchoalveolar lavage fluid as well as in bronchial biopsies from asthmatic patients and in animal models of asthma. Recently, bronchial biopsies and bronchoalveolar lavage fluid was analysed for the presence of chemokines and their cognate receptors before and following antigen challenge of atopic asthmatic patients (Panina-Bordignon, et al. 2001. J. Gin. Invest 107(11): 1357).

These data demonstrated that Th2 cells expressing CCR8 were increased in the lung of challenged asthmatics, but were undetectable in healthy controls. It was found that the number of CCR8+ Th2 lymphocytes in the airway after challenge correlated with the degree of bronchoconstriction during the late airway response (LAR). Furthermore TARC

(thymus- and activation-regulated chemokine) which may activate CCR8 was highly upregulated in the airway epithelia after challenge. These data suggest that expression of

CCR8 by activated Th2 lymphocytes in asthmatic airways is important for the specific recruitment of these cells to the site of inflammation during the LAR. Thus, inhibition of

CCR8 could decrease the ability of activated CCR8+ Th2 lymphocytes to home to the lungs during the asthmatic inflammatory response.

Further support for the hypothesis that CCR8 blockade would inhibit asthmatic inflammation and hyperreactivity is provided by data reported by Chensue, et al. (2001. J. Exp. Med. 193:573). They demonstrated that in mice, deletion of CCR8 significantly attenuated Th2 cytokine production and associated eosinophil accumulation following antigen challenge of these animals. Furthermore, the development of antigen-induced airways hyperreactivity was inhibited in these animals. Thus, these data support the idea that blockade of CCR8 might provide significant therapeutic value for the treatment of asthma.

Accordingly, there is provided herein compounds and methods for treating an asthmatic condition and other conditions mediated by CCR8 where inhibition of this chemokine receptor would effect a positive outcome in a patient suffering from or predisposed to suffer from such a malady. Summary of the Invention

In a first aspect, this invention relates to compounds of Formula I

wherein n is O or l; m is 0 or 1 ; p is 1, 2 or 3;

Ar is unsubstituted quinolinyl, [l,5]naphthyridinyl or pyridinyl; or quinolinyl, [l,5]naphthyridinyl or pyridinyl substituted with one or more radicals selected from the group consisting of C_j-Cg alkoxy, C_j-Cg alkyl, halo, cyano and trihalomethyl; R is C_j-Cg branched or unbranched alkyl, Cβ-Cg cycloalkyl lower alkyl, unsubstituted or substituted phenyl lower alkyl, unsubstituted or substituted pyridyl lower alkyl, unsubstituted or substituted indolyl lower alkyl, unsubstituted or substituted N-(lower alkyl)indolyl lower alkyl, unsubstituted or substituted quinolinyl lower alkyl, unsubstituted or substituted naphthyl lower alkyl, unsubstituted or substituted benzofuranyl lower alkyl, unsubstituted or substituted benzothiophenyl lower alkyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of Cj-Cg alkoxy, Cj-Cg alkyl, halo, cyano and trihalomethyl; or a pharmaceutically acceptable salt thereof. Another aspect of this invention is that of a pharmaceutical formulation comprising a compound of Formula I alone in admixture with a pharmaceutically acceptable excipient and administering this preparation to a mammal in need thereof in an amount effective for inhibiting CCR8 to a degree which effects prevention of a condition or treatment of a condition associated with the inhibition of CCR8.

A further object of this invention is the use of a compound of Formula I in the manufacture of a medicament for treating or preventing a condition associated with the inhibition of CCR8.

In a particular aspect, the methods of this invention are especially useful for treatment of an asthmatic condition. Detailed Description Definitions and Preferred Embodiments

The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently bonded compounds that release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

The meaning of any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.

Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).

The term "C Cg alkyl" and ""C Cg alkyl" is used herein includes both straight or branched chain radicals of 1 to 6 or 8 carbon atoms. By example this term includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like. "Lower alkyl" has the same meaning as C_j.Cg alkyl. Herein "C_j.Cg alkoxy" includes straight and branched chain radicals of the likes of - O-CH3, -O-CH2CH3, and the n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert- butoxy, pentoxy, and hexoxy, and the like.

'^-Cg-cycloalkyl" as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.

"Halogen" or "halo" means F, Cl, Br, and I.

Preferred Embodiments

The preferred compounds of Formula I include those compounds wherein n is O; m is l; p is 1;

Ar is unsubstituted or substituted quinolinyl, or unsubstituted or substituted [l,5]naphthyridinyl; and

R is unsubstituted or substituted phenyl lower alkyl, unsubstituted or substituted indolyl lower alkyl, unsubstituted or substituted benzothiophenyl lower alkyl,unsubstituted or substituted naphthalenyl lower alkyl, or C^-Cg branched or unbranched alkyl.

More preferred are the compound of Formula I wherein:

Ar is Cj-Cg alkoxy-substituted quinolinyl, or C1 -Cg alkoxy-substituted [l,5]naphthyridinyl; and R is indolyl lower alkyl, Ci -Cg alkyl-substituted indolyl lower alkyl, halo- substituted phenyl lower alkyl, C_j-Cg alkyl-substituted phenyl lower alkyl, benzothiophenyl lower alkyl, naphthalenyl lower alkyl, or C3-C8 branched or unbranched alkyl.

Even more prefered are those compounds where n is 0; m is 1; p is 1; Ar is 6-methoxyquinolin-4-yl, or 6-methoxy[l,5]naphthyridin- 4-yl; and R is lH-indol-2-ylmethyl, l-methyl-lH-indol-2-ylmethyl, 3,4-dimethylbenzyl, 3- phenylpropyl, 4-bromobenzyl, 3,4-dichlorobenzyl, l-benzo[b]thiophen-2-ylmethyl, hexyl, or l-naphthalen-2-ylmethyl.

The most preferred compounds are:

3-[l-(lH-indol-2-ylmethyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin- 2-one;

3-[l-(3,4-dichlorobenzyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin-2- one;

5-(6-methoxyquinolin-4-yl)-3-[l-(l-methyl-lH-indol-2-ylmethyl)-piperidin-4-yl]- oxazolidin-2-one; 3-(l-benzo[b]thiophen-2-ylmethylpiperidin-4-yl)-5-(6-methoxyquinolin-4-yl)- oxazolidin-2-one;

5-(6-methoxyquinolin-4-yl)-3-(l-naphthalen-2-ylmethylρiperidin-4-yl)-oxazolidin- 2-one; 5-(6-methoxyquinolin-4-yl)-3-[l-(3-phenylpropyl)-ρiρeridin-4-yl]-oxazolidin-2-one

3-[l-(4-chlorobenzyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin-2-one

3-[l-(3,4-dimethylbenzyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin- 2-one;

3-[l-(4-bromobenzyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin-2- one,

3-(l-hexyl-piperidin-4-yl)-5-(6-methoxy-quinolin-4-yl)-oxazolidin-2-one;

3-[l-(lH-indol-2-ylmethyl)-piperidin-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one;

5-(6-methoxy-[l,5]naphthyridin-4-yl)-3-[l-(l-methyl-lH-indol-2-ylmethyl)- piperidin-4-yl]-oxazolidin-2-one;

3-[l-(3,4-dichloro-benzyl)-piperidin-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one;

3-[ 1 -(3,4-dimethyl-benzyl)-piperidin-4-yl]-5-(6-methoxy-[ 1 ,5]naphthyridin-4-yl)- oxazolidin-2-one; 3-[l-(4-bromo-benzyl)-piperidm-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one;

5-(6-methoxy-[l,5]naphthyridin-4-yl)-3-[l-(3-phenyl-propyl)-piperidin-4-yl]- oxazolidin-2-one;

3-( 1 -{ [3-methyl-4-(methyloxy)phenyl]methyl } -4-piperidinyl)-5-[6-(methyloxy)-4- quinolinyl]-l,3-oxazolidin-2-one;

3-(l-{[3-chloro-4-(methyloxy)phenyl]methyl}-4-piperidinyl)-5-[6-(methyloxy)-4- quinolinyl]- 1 ,3-oxazolidin-2-one;

3-(l-{[3-(methyloxy)-4-nitrophenyl]methyl}-4-piperidinyl)-5-[6-(methyloxy)-4- quinolinyl]-l,3-oxazolidin-2-one; 3-(l-{[3-fluoro-4-(methyloxy)phenyl]methyl}-4-piperidinyl)-5-[6-(methyloxy)-4- quinolinyl]-l,3-oxazolidin-2-one;

5-[6-(methyloxy)-4-quinolinyl]-3-(l-{[4-(methylthio)phenyl]methyl}-4- piperidinyl)-l,3-oxazolidin-2-one;

5-[6-(methyloxy)-4-quinolinyl]-3-{l-[(4-methylphenyl)methyl]-4-piperidinyl}-l,3- oxazolidin-2-one; 3-{l-[(3-fluoro-4-methylphenyl)methyl]-4-piperidinyl}-5-[6-(methyloxy)-4- quinolinyl]-l,3-oxazolidin-2-one;

5-[6-(methyloxy)-4-quinolinyl]-3-(l-{[4-(trifluoromethyl)ρhenyl]methyl}-4- ρiperidinyl)-l,3-oxazolidin-2-one; 3-{ l-[(4-methyl-3-nitrophenyl)methyl]-4-piperidinyl }-5-[6-(methyloxy)-4- quinolinyl]-l,3-oxazolidin-2-one;

3-{ l-[(3,5-dimethylphenyl)methyl]-4-piperidinyl}-5-[6-(methyloxy)-4-quinolinyl]- 1 ,3-oxazolidin-2-one;

3-(l-{[4-chloro-3-(trifluoromethyl)phenyl]methyl}-4-piperidinyl)-5-[6- (methyloxy)-4-quinolinyl]-l,3-oxazolidin-2-one; and

3-{l-[(4-chloro-3-nitrophenyl)methyl]-4-piperidinyl}-5-[6-(methyloxy)-4- quinolinyl]-l,3-oxazolidin-2-one.

Formulations

This invention also provides a pharmaceutical composition that comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament. Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation may be a buffered, isotonic, or aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation and intranasal preparations. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternately, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.

For rectal administration, the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository. Utility of the Invention

The compounds of Formula I are useful as inhibitors of the chemokine receptor known as CCR8. The present invention provides methods of treatment of diseases caused by pathological levels of CCR8, or the CCR8 chemokine ligand, 1-309, which methods comprise administering to an animal in need thereof a therapeutically effective amount of a compound of the present invention. This course of treatment is particularly useful in treating mammals, most particularly humans.

Examples of disease states in which the compound of the invention has potentially beneficial anti-inflammatory effects include diseases of the respiratory tract such as bronchitis (including chronic bronchitis), bronchiectasis, asthma (including allergen- induced asthmatic reactions), chronic obstructive pulmonary disease (COPD), cystic fibrosis, sinusitis and rhinitis. Other relevant disease states include diseases of the gastrointestinal tract such as intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure. Furthermore, the compound of the invention may be used to treat nephritis, skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions and diseases of the central nervous system which have an inflammatory component (e.g. Alzheimer's disease, meningitis, multiple sclerosis) HIV and AIDS dementia.

Compounds of the present invention may also be of use in the treatment of nasal polyposis, conjunctivitis or pruritis.

Further examples of disease states in which the compound of the invention have potentially beneficial effects include cardiovascular conditions such as atherosclerosis, peripheral vascular disease and idiopathic hypereosinophilic syndrome. Other diseases for which the compound of the present invention may be beneficial are other hypereosinophilic diseases such as Churg-strauss syndrome. Additionally, eosinophilia is commonly found in parasitic diseases, especially helminth infections, and thus the compound of the present invention may be useful in treating inflammation arising from hyper-eosinophilic states of diseases such as hydatid cyst (Echinococcus sp.), tapeworm infections (Taenia sp.), blood flukes (schistosomiasis), and nematode (round worms) infections such as:- Hookworm (Ancylostoma sp.), Ascaris, Strongyloides, Trichinella, and particularly lymphatic filariasis including Onchocerca, Brugia, Wucheria (Elephantiasis).

The compound of the invention may be useful as an immunosuppressive agent and so have use in the treatment of auto-immune diseases such as allograft tissue rejection after transplantation, rheumatoid arthritis and diabetes. Compounds of the invention may also be useful in inhibiting metastasis.

Diseases of principal interest include asthma, COPD and inflammatory diseases of the upper respiratory tract involving seasonal and perennial rhinitis.

Preferred diseases of principal interest include asthma and inflammatory diseases of the upper respiratory tract involving seasonal and perennial rhinitis. Further diseases also of principle interest include inflammatory diseases of the gastrointestinal tract such as inflammatory bowel disease.

It will be appreciated by those skilled in the art that references herein to treatment or therapy extend to prophylaxis as well as the treatment of established conditions.

No unacceptable toxicological effects are expected when compounds of Formula I are administered in accordance with the present methods.

Biological Assay for the Determination of the Inhibition of I-309-mediated Intracellular Calcium Mobilization (FLIPR Assay)

RBL-2H3 cells expressing the human CCR-8 receptor were grown in cell medium (EMEM medium with Earl's salts) containing 2mM L-Glutamine, 0.4 mg/ml G418 Sulfate from GIBCO BRL and 10% heat inactivated fetal calf serum from Hyclone Laboratories. The cells were seeded 60,000 cells,/well into 96-well black clear bottom sterile plates from Costar. The seeded plate was incubated overnight at 37° C in 5% CO2 On the day of the assay the cell medium was aspirated before addition of calcium dye loading solution consisting of: 1 mg/mL bovine serum albumin (BSA), 1.5 mJVI sulfinpyrazone from SIGMA and 4 uM Fluo-3 AM dye from Molecular Probes in cell medium, thereafter the 96-well plate was incubated for 1 hour at 37° C.

After aspirating the solution, 100 *Ls of fresh assay buffer (Kreb's Ringer Henseleit pH 7.4 containing 1 mM CaCl2, 1-1 ^ MgCl2, 1.5 mM sulfinpyrazone and 1.0 mg/mL Gelatin) was added to all the wells and the plate was incubated for 10 minutes at 37 °C. before transferring to the Fluorescent Imaging Plate Reader (FLIPR) instrument. The assay and data acquisition were initiated by first addition of 50 »ls of compound diluted to a relevant concentration in assay buffer. After 5 mins read 2nd addition of 50 »ls human 1-309 challenge, diluted to an appropriate concentration in assay buffer with 1 mg/mL BSA (no gelatin) was added to the plate and data was acquired from an additional 1.5 mins. Concentration response data for compounds showing inhibition of calcium mobilization were performed in the presence of 35 nM human 1-309 to obtain the IC50 values. IC50 is the concentration of compound needed to inhibit 50% of the human 1-309 response. Synthetic Methods

Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions.

Such protective groups are described generally in Green, T.W, Protective Groups in Organic Synthesis, John Wiley & Sons, New York (1981).

Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li⁺, Na⁺, K⁺, CsX, Mg⁺ and NH ⁺ are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfates, phosphates, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.

Compounds of Formula I were prepared by two methods detailed in Schemes I and II and the Examples below. These methods are illustrative, as it is believed other preparatory methods can be used to make one or more of the compounds of Formula I.

Scheme I provides a first graphical representation of one of the general synthetic methods used to make the present compounds. The definition of n, m, p, and P in this scheme is the same as given above for Formula I, unless noted otherwise. Scheme I

X = C or N ¹ X = C or N

In this scheme, the epoxide ring opening of 1 was carried out with mono-Boc protected diamines under reflux conditions to give alcohol 2. Oxazolidinone ring formation led to 3, which upon removal of the Boc protecting group yielded secondary amines 4. Reductive alkylation of 4 with various aldehydes afforded targeted compound 5.

More specifically, in Scheme I, the conditions were as follows: a) mono-Boc protected diamines, LiClO , CH₃CN, reflux; b) 1,1-carbonyldiimidazole, 4-dimethylamino pyridine, dichloromethane, room temperature; c) 30% trifluoroacetic acid in dichloromethane, room temperature; d) RCHO, Na(OAc)₃BH, dichloromethane, room temperature.

Other compounds of Formula I are prepared by the steps and chemistries outlined in Scheme II. "Ar" and "R" in this scheme are equivalent to or the same as the definitions given for same for Formula I above. Scheme II

In Scheme II, the conditions were as follows: a) Me₂S, Me₂SO₄, NaOMe, CH₃CN, rt; b) 4-amino-piperidine-l-carboxylic acid tert-butyl ester, LiClO₄, CH₃CN, reflux; c) 1,1- carbonyldiimidazole, 4-dimethylamino pyridine, dichloromethane, room temperature; d) 30% trifluoroacetic acid in dichloromethane, room temperature; e) RCHO, Na(OAc)₃BH, dichloromethane, room temperature.

More specifically, epoxides 7 were synthesized from the corresponding aldehydes 6 via one-pot process under mild conditions. Epoxide ring opening of 7 with 4-amino- piperidine-1-carboxylic acid tert-butyl ester, followed by oxazolidinone ring formation, gave 8, which upon hydrolysis and reductive alkylation afforded the targeted compounds 9.

Synthetic Examples Example 1

Preparation of 5-(6-methoxy-qumolin-4-yl)-3-(l-naphthalen-2-yl-methyl-piperidin-4-yl)- oxazolidin-2-one 1 (a) Preparation of 4-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethylamino]- piperidine-1-carboxylic acid tert-butyl ester To a solution of 6-methoxy-4-oxiranylquinoline (1.4g, 6.97mmol), which was made acoording to Davies, et al (PCT application WO 00/78748 published 28 December 2000) in 23mL of acetonitrile, was added 4-amino-piperidine-l-carboxylic acid tert-butyl ester (1.39g, 6.95mmol), followed by lithium perchlorate (0J4g, 6.98mmol). The mixture was heated under reflux overnight. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine. The organic extracts were dried over anhydrous sodium sulfate and concentrated. Silica gel chromatography with 3- 5% of methanol in dichloromethane as eluting solvents afforded the desired product as a solid (l.Og, 36%). MS (ESI): 402 (MH*).

1(b) Preparation of 4-[5-(6-methoxy-quinolin-4-yl)-2-oxo-oxazolidin-3-yl]- piperidine-1-carboxylic acid tert-butyl ester To a solution of 4-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethylamino]-piperidine-

1-carboxylic acid tert-butyl ester (0.90g, 2.24mmol) in 22mL of dichloromethane, was added 1,1-carbonyldiimidazole (0.44g, 2.92mmol) and 4-N,N-dimethylaminopyridine (0.34g, 2.82mmol). The mixture was stirred at rt for 4 h and then concentrated to dryness. The residue was subject to silica gel chromatography (0.5-2% of methanol in dichloromethane), which led to the oxazolidinone product as a solid (0.9g, 94%). MS (ESI): 428 (MH^1").

1(c) Preparation of 5-(6-methoxy-quinolin-4-yl)-3-piperidin-4-yl-oxazolidin-2- one

. To 4-[5-(6-methoxy-quinolm-4-yl)-2-oxo-oxazolidin-3-yl]-piperidine-l-carboxylic acid tert-butyl ester (0.89g, 2.08mmol) was added 26ml of 30% trifluroacetic acid in dichloromethane. The solution was stirred at rt for 4 h and then concentrated to dryness. The residue was dissolved in dichloromethane and washed with 2N aqueous sodium hydroxide solution. The organic extracts were dried over anhydrous sodium sulfate. Removal of solvents in vacuo afforded the desired secondary amine as a solid (0.64g, 94%). MS (ESI): 328 (MH⁺).

1 (d) Preparation of 5-(6-methoxy-quinolin-4-yl)-3-( l-naphthalen-2-yl-methyl- piperidin-4-yl)-oxazolidin-2-one

To a solution of 5-(6-methoxy-quinolin-4-yl)-3-piperidin-4-yl-oxazolidin-2-one (30mg, 0.092mmol) in lmL of dichloromethane, was added 2-naphthaldehyde (14.6mg, 0.092mmol). The mixture was stirred at rt for 4 h, then sodium triacetoxyborohydride (47mg, 0.23mmol) was added. After stirring at rt for 2 h, the resulting mixture was evaporated in vacuo to dryness. The residue was dissolved in lmL of MeOH, and purified using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 3.2 min, hold for 1 min where A = H2O (0.1% trifluoroacetic acid) and B = CH₃CN (0.1% trifluoroacetic acid) pumped at 25 mL/min, to yield 5-(6-methoxy-quinolin-4-yl)-3-(l-naphthalen-2-yl-methyl-piperidin-4-yl)- oxazolidin-2-one as a mono-trifluoroacetic acid salt (white solid, 32mg, 75%) . MS (ESI): 468 (MH÷).

Proceeding in a similar manner, but replacing 2-naphthaldehyde with the appropriate aldehyde, the compounds listed in Table 1 were prepared. Table 1

Proceeding in a similar manner, but starting with 2-methoxy-8-oxiranyl- [l,5]naphthyridine which was prepared according to Davies, et al (PCT application WO 02/56882 published on 25 July 2002), and replacing 2-naphthaldehyde with the appropriate aldehyde, the compounds listed in Table 2 were prepared.

Table 2

Example 67 Preparation of 3-f 1 -( lH-indol-2-ylmethyl)-piperidin-4-yll-5-quinolin-4-yl-oxazolidin-2-one 67(a) Preparation of 4-oxiranyl-quinoline

Following procedure of Kutsuma et al S. Heterocycles 1977, 8, 397-401, to a solution of methyl sulfate (0.82g, 6.51mmol) in 5mL of acetonitrile was added dropwise dimethyl sulfide (0.45g, 7.23mmol). After the mixture was stirred at rt overnight under argon, sodium methoxide (0.39g, 7.23mmol) was added . After stirring at rt for 30min, a solution of quinoline-4-carbaldehyde (OJOg, 4.46mmol) in 0.5mL of acetonitrile was added. The resulting mixture was stirred at rt for an additional 1 hour, then poured into water and extracted with diethyl ether. The ether extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was filtered through silica gel eluting with 0.5-2% of methanol in dichloromethane to afford the desired epoxide (0.60g, 79%). MS (ESI): 172(MΗ⁺).

67(b) Preparation of 4-(2-oxo-5-quinolin-4-yl-oxazolidin-3-yl)-piperidine-l- carboxylic acid tert-butyl ester To a solution of 4-oxiranyl-quinoline (0.6g, 3.5mmol) in 12mL of acetonitrile, was added 4-amino-piperidine-l-carboxylic acid tert-butyl ester (O.llg, 3.85mmol), followed by lithium perchlorate (0.41g, 3.85mmol). The mixture was heated under reflux for 2 days. The solvent was removed under reduced pressure. The residue was worked up with ethyl acetate and brine and the organic extracts were dried over anhydrous sodium sulfate and concentrated. Silica gel chromatography with 2-3% of methanol in dichloromethane as eluting solvents afforded the desired product as a solid (0.85g, 65%).

To a solution of above 4-(2-hydroxy-2-quinolin-4-yl-ethylamino)-piperidine-l- carboxylic acid tert-butyl ester (0.8g, 2.16mmol) in 22mL of dichloromethane, was added 1,1-carbonyldiimidazole (0.46g, 2.81mmol) and 4-N,N-dimethylaminopyridine (0.33g, 2J2mmol). The mixture was stirred at rt for 4 h and the solvent was evaporated. The residue was subject to silica gel chromatography (0.5-2% of methanol in dichloromethane), which led to the oxazolidinone product as a solid (0.8g, 94%). MS (ESI): 398 (MH⁺)

67(c) Preparation of 3-[l-(l H-indol-2-yl-methyl)-piperidin-4-yl]-5-quinolin-4-yl- oxazolidin-2-one

To 4-(2-oxo-5-quinolin-4-yl-oxazolidin-3-yl)-piperidine-l-carboxylic acid tert- butyl ester (OJg, 0J9mmol) was added 26ml of 30% trifluroacetic acid in dichloromethane. The solution was stirred at rt for 4 hours and then concentrated to dryness. The residue was taken into dichloromethane and washed up with 2N aqueous sodium hydroxide solution. The organic extracts were dried over anhydrous sodium sulfate. Removal of solvents afforded the desired secondary amine as a solid (0.52g, 99%).

To a solution of above 3-piperidin-4-yl-5-quinolin-4-yl-oxazolidin-2-one (lOOmg, 0.34mmol) in 3.4mL of dichloromethane, was added 1 H-indole-2-carbaldehyde (49mg, 0.34mmol). The mixture was stirred at rt for 4 h, then sodium triacetoxyborohydride (178mg, 0.84mmol) was added. After stirring at rt for 2 hours, the mixture was worked up with dichloromethane and washed with saturated sodium bicarbonate solution. The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography with 1- 3% of methanol in dichloromethane afforded 3-[l-(l H-indol-2-yl-methyl)-piperidin-4-yl]- 5-quinolin-4-yl-oxazolidin-2-one as a white solid (124mg, 86%). MS (ESI): 427(MΗ⁺). Proceeding in a similar manner, but starting with the appropriate aldehyde for epoxide formation, and using the appropriate aldehyde for the reductive animation step, the compounds listed in Table 3 were prepared. Table 3

Claims

What is claimed is:

1. A compound of Formula I

wherein n is O or 1; m is 0 or 1; p is 1, 2 or 3;

Ar is unsubstituted quinolinyl, [l,5]naphthyridinyl or pyridinyl; or quinolinyl, [l,5]naphthyridinyl or pyridinyl substituted with one or more radicals selected from the group consisting of C_j-Cg alkoxy, C -Cg alkyl, halo, cyano and trihalomethyl;

R is C -Cg branched or unbranched alkyl, C3-C6 cycloalkyl lower alkyl, unsubstituted or substituted phenyl lower alkyl, unsubstituted or substituted pyridyl lower alkyl, unsubstituted or substituted indolyl lower alkyl, unsubstituted or substituted N-(lower alkyl)indolyl lower alkyl, unsubstituted or substituted quinolinyl lower alkyl, unsubstituted or substituted naphthyl lower alkyl, unsubstituted or substituted benzofuranyl lower alkyl, unsubstituted or substituted benzothiophenyl lower alkyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C -Cg alkoxy, Cj-Cg alkyl, halo, cyano and trihalomethyl; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein n is 0; m is 1; p is 1; Ar is unsubstituted or substituted quinolinyl, or unsubstituted or substituted

[l,5]naphthyridinyl; and

R is unsubstituted or substituted phenyl lower alkyl, unsubstituted or substituted indolyl lower alkyl, unsubstituted or substituted benzothiophenyl lower alkyl,unsubstituted or substituted naphthalenyl lower alkyl, or C1-C8 branched or unbranched alkyl; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 wherein Ar is C -Cg alkoxy-substituted quinolinyl, or C -Cg alkoxy-substituted [l,5]naphthyridinyl; and

R is indolyl lower alkyl, Cχ-Cg alkyl-substituted indolyl lower alkyl, halo- substituted phenyl lower alkyl, Cχ-Cg alkyl-substituted phenyl lower alkyl, benzothiophenyl lower alkyl, naphthalenyl lower alkyl, or C3-C8 branched or unbranched alkyl; or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 - 3 wherein n is 0; m is 1; is l;

Ar is 6-methoxyquinolin-4-yl, or 6-methoxy[l,5]naphthyridin-4-yl; and R is lH-indol-2-ylmethyl, l-methyl-lH-indol-2-ylmethyl, 3,4-dimethylbenzyl, 3- phenylpropyl, 4-bromobenzyl, 3,4-dichlorobenzyl, l-benzo[b]thiophen-2-ylmethyl, hexyl, or l-naphthalen-2-ylmethyl; or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1-4 which is 3-[l-(lH-indol-2-ylmethyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin-

2-one; 3-[l-(3,4-dichlorobenzyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin-2- one;

5-(6-methoxyquinolin-4-yl)-3-[l-(l-methyl-lH-indol-2-ylmethyl)-piperidin-4-yl]- oxazolidin-2-one ;

3-(l-benzo[b]thiophen-2-ylmethylpiperidin-4-yl)-5-(6-methoxyquinolin-4-yl)- oxazolidin-2-one;

5-(6-methoxyquinolin-4-yl)-3-(l-naphthalen-2-ylmethylpiperidin-4-yl)-oxazolidin- 2-one;

5-(6-methoxyquinolin-4-yl)-3-[l-(3-phenylpropyl)-piperidin-4-yl]-oxazolidin-2-one

3-[l-(4-chlorobenzyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin-2-one 3-[l-(3,4-dimethylbenzyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin-

2-one; or

3-[l-(4-bromobenzyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin-2- one;

3-(l-hexyl-piperidin-4-yl)-5-(6-methoxy-quinolin-4-yl)-oxazolidin-2-one; 3-[l-(l H -indol-2-ylmethyl)-piperidin-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one;

5-(6-methoxy-[ l,5]naphthyridin-4-yl)-3-[ 1 -( 1-methyl- 1 H -indol-2-ylmethyl)- piperidin-4-yl]-oxazolidin-2-one; 3-[l-(3,4-dichloro-benzyl)-piperidin-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one;

3-[l-(3,4-dimethyl-benzyl)-piperidin-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one ;

, 3-[l-(4-bromo-benzyl)-piperidin-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one;

5-(6-methoxy-[ 1 ,5]naphthyridin-4-yl)-3-[ 1 -(3-phenyl-propyl)-piperidin-4-yl]- oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 which is 3-[l-(lH-indol-2-ylmethyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin-

2-one;

5-(6-methoxyquinolin-4-yl)-3- [ 1 -( 1 -methyl- 1 H-indol-2-ylmethyl)-piperidin-4-yl] - oxazolidin-2-one;

5-(6-methoxyquinolin-4-yl)-3-(l-naphthalen-2-ylmethylpiperidin-4-yl)-oxazolidin- 2-one; 5-(6-methoxyquinolin-4-yl)-3-[l-(3-phenylpropyl)-piperidin-4-yl]-oxazolidin-2-one

3-[l-(4-chlorobenzyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin-2-one 3-[l-(3,4-dimethylbenzyl)-piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-oxazolidin- 2-one;

3-(l-hexyl-piperidin-4-yl)-5-(6-methoxy-quinolin-4-yl)-oxazolidin-2-one; 3-[l-(lH-indol-2-ylmethyl)-piperidin-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one ;

5-(6-methoxy-[l,5]naphthyridin-4-yl)-3-[l-(l-methyl-lH-indol-2-ylmethyl)- piperidin-4-yl]-oxazolidin-2-one; 3-[l-(3,4-dichloro-benzyl)-piperidin-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one;

3-[l-(3,4-dimethyl-benzyl)-piperidin-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one; 3-[l-(4-bromo-benzyl)-ρiperidin-4-yl]-5-(6-methoxy-[l,5]naphthyridin-4-yl)- oxazolidin-2-one;

5-(6-methoxy-[ 1 ,5]naphthyridin-4-yl)-3-[ 1 -(3-phenyl-propyl)-piperidin-4-yl]- oxazolidin-2-one ;

3-(l-{[3-methyl-4-(methyloxy)phenyl]methyl}-4-piperidinyl)-5-[6-(methyloxy)-4- quinolinyl]- 1 ,3-oxazolidin-2-one;

3-(l-{[3-chloro-4-(methyloxy)phenyl]methyl}-4-piperidinyl)-5-[6-(methyloxy)-4- quinolinyl]-l,3-oxazolidin-2-one;

5-[6-(methyloxy)-4-quinolinyl]-3-{ l-[(4-methylphenyl)methyl]-4-piperidinyl}-l,3- oxazolidin-2-one;

3-{ l-[(3-fluoro-4-methylphenyl)methyl]-4-piperidinyl}-5-[6-(methyloxy)-4- quinolinyl]-l,3-oxazolidin-2-one;

5-[6-(methyloxy)-4-quinolinyl]-3-(l-{[4-(trifluoromethyl)phenyl]methyl}-4- piperidinyl)-l,3-oxazolidin-2-one; 3-{ l-[(4-methyl-3-nitrophenyl)methyl]-4-piperidinyl}-5-[6-(methyloxy)-4- quinolinyl]- 1 ,3-oxazolidin-2-one;

3-(l-{[4-chloro-3-(trifluoromethyl)phenyl]methyl}-4-piperidinyl)-5-[6- (methyloxy)-4-quinolinyl]-l,3-oxazolidin-2-one; or

3-{ l-[(4-chloro-3-nitrophenyl)methyl]-4-piperidinyl}-5-[6-(methyloxy)-4- quinolinyl]-l,3-oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

7. A pharamceutical formulation comprising a compound of Formula I according to any one of claims 1-6 alone in admixture with a pharmaceutically acceptable excipient.

8. A method for treating asthma, which method comprises administering to a mammal in need thereof an effective amount of a compound of Formula I according to any one of claims 1-6 alone or admixed with a pharmaceutically acceptable carrier.