US20040063753A1

US20040063753A1 - Pyridinone derivatives for treatment of atherosclerosis

Info

Publication number: US20040063753A1
Application number: US10/399,022
Authority: US
Inventors: Deirdre Hickey; Robert Ife; Colin Leach; John Liddle; Ivan Pinto; Stephen Smith; Steven Stanway
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 2000-10-10
Filing date: 2001-10-05
Publication date: 2004-04-01
Also published as: NO325107B1; ZA200302785B; MXPA03003176A; WO2002030904A1; PL207560B1; CN1479724A; US7235566B2; CA2425268C; AU1052402A; CN1280275C; KR100824134B1; ES2378059T3; PT2258688E; GC0000307A; BR0114576A; CZ304558B6; IL155278A; GB0024808D0; DK2258688T3; PL366334A1

Abstract

Compounds of formula (I): are inhibitors of the enzyme L_p-PLA₂and are of use in therapy, in particular for treating atherosclerosis.

Description

The present invention relates to certain novel pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of atherosclerosis.

WO 95/00649 (SmithKline Beecham plc) describes the phospholipase A ₂enzyme Lipoprotein Associated Phospholipase A₂(Lp-PLA₂), the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996:16;591-9) wherein it is referred to as LDL-PLA₂. A later patent application (WO 95/09921, Icos Corporation) and a related publication in Nature (Tjoelker et al, vol 374, Apr. 6, 1995, 549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA₂and suggest that it may have potential as a therapeutic protein for regulating pathological inflammatory events.

It has been shown that Lp-PLA ₂is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form. The enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid. Both products of Lp-PLA₂action are biologically active with lysophosphatidylcholine, in particular having several pro-atherogenic activities ascribed to it including monocyte chemotaxis and induction of endothelial dysfunction, both of which facilitate monocyte-derived macrophage accumulation within the artery wall. Inhibition of the Lp-PLA₂enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.

A recently published study (WOSCOPS—Packard et al, N. Engl. J. Med. 343 (2000) 1148-1155) has shown that the level of the enzyme Lp-PLA₂is an independent risk factor in coronary artery disease.

The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA ₂could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA₂inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.

In addition, Lp-PLA ₂inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA₂. Examples of such disorders include psoriasis.

Furthermore, Lp-PLA ₂inhibitors may also have a general application in any disorder that involves lipid oxidation in conjunction with Lp-PLA₂activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arhritis, stroke, myocardial infarction, ischaemia, reperfusion injury and acute and chronic inflammation.

Patent applications WO 96/12963, WO 96/13484, WO 96/19451, WO 97/02242, WO 97/217675, WO 97/217676, WO 96/41098, and WO 97/41099 (SmithKline Beecham plc) disclose inter alia various series of 4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitors of the enzyme Lp-PLA ₂. These are irreversible, acylating inhibitors (Tew et al, Biochemistry, 37, 10087, 1998).

A further class of compounds has now been identified which are non-acylating inhibitors of the enzyme Lp-PLA ₂. Thus, WO 99/24420, WO 00/10980, WO 00/66566, WO 00/66567 and WO 00/68208 (SmithKline Beecham plc) disclose a class of pyrimidone compounds. We have now found that the pyrimidone ring may be replaced by a pyridone ring, to give compounds having good activity as inhibitors of the enzyme Lp-PLA₂.

Accordingly, the present invention provides a compound of formula (I):

in which:

R ¹is an aryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C_(1-6)alkyl, C_(1-6)alkoxy, C_(1-6)alkylthio, hydroxy, halogen, CN, mono to perfluoro-C_(1-4)alkyl, mono to perfluoro-C_(1-4)alkoxyaryl, and arylC_(1-4)alkyl;

R ²is halogen, C_(1-3)alkyl, C_(1-3)alkoxy, hydroxyC_(1-3)alkyl, C_(1-3)alkylthio, C_(1-3)alkylsulphinyl, aminoC_(1-3)alkyl, mono- or di-C_(1-3)alkylaminoC_(1-3)alkyl, C_(1-3)alkylcarbonylaminoC_(1-3)alkyl, C_(1-3)alkoxyC_(1-3)alkylcarbonylaminoC_(1-3)alkyl, C_(1-3)alkylsulphonylaminoC_(1-3)alkyl, C_(1-3)alkylcarboxy, C_(1-3)alkylcarboxyC_(1-3)alkyl, and

R ³is hydrogen, halogen, C_(1-3)alkyl, or hydroxyC_(1-3)alkyl; or

R ²and R³together with the pyridone ring carbon atoms to which they are attached form a fused 5-or 6-membered carbocyclic ring; or

R ²and R³together with the pyridone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from halogen, C_(1-4)alkyl, cyano, C_(1-3)alkoxyC_(1-3)alkyl, C_(1-4)alkoxy or C_(1-4)alkylthio, or mono to perfluoro-C_(1-4)alkyl;

R ⁴is hydrogen, C_(1-6)alkyl which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁹R¹⁰, NR⁷COR⁸, mono- or di-(hydroxyC_(1-6)alkyl)amino and N-hydroxyC_(1-6)alkyl-N—C_(1-6)alkylamino; or

R ⁴is Het-C_(0-4)alkyl in which Het is a 5- to 7-membered heterocyclyl ring comprising N and optionally O or S, and in which N may be substituted by COR⁷, COOR⁷, CONR⁹R¹⁰, or C_(1-6)alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰or NR⁹R¹⁰, for instance, piperidin-4-yl, pyrrolidin-3-yl;

R ⁵is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C_(1-6)alkyl, C_(1-6)alkoxy, C_(1-6)alkylthio, arylC_(1-6)alkoxy, thydroxy, halogen, CN, COR⁷, carboxy, COOR⁷, NR⁷COR⁸, CONR⁹R¹⁰, SO₂NR⁹R¹⁰, NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C_(1-4)alkyl and mono to perfluoro-C_(1-4)alkoxy;

R ⁶is an aryl or a heteroaryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C_(1-6)alkyl, C_(1-6)alkoxy, C_(1-6)alkylthio, C_(1-6)alkylsulfonyl, arylC_(1-6)alkoxy, hydroxy, halogen, CN, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁷COR⁸, SO₂NR⁹R¹⁰, NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C_(1-4)alkyl and mono to perfluoro-C_(1-4)alkoxy, or C_(5-10)alkyl;

R ⁷and R⁸are independently hydrogen or C_(1-12)alkyl, for instance C_(1-4)alkyl (e.g. methyl or ethyl);

R ⁹and R¹⁰which may be the same or different is each selected from hydrogen, or C_(1-12)alkyl, or R⁹and R¹⁰together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C_(1-4)alkyl, C_(1-4)alkylcarboxy, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine; and

X is a C _(2-4)alkylene group (optionally substituted by 1, 2 or 3 substituents selected from methyl and ethyl), CH═CH, (CH₂)_nS or (CH₂)_nO where n is 1, 2 or 3.

In a further aspect the present invention provides a compound of formula (I) as defined above in which:

R ²and R³together with the pyridone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from halogen, C_(1-4)alkyl, cyano, C_(1-4)alkoxy or C_(1-4)alkylthio, or mono to perfluoro-C_(1-4)alkyl.

Representative examples of R ¹when an aryl group include phenyl and naphthyl. Preferably, R¹is phenyl optionally substituted by halogen, C_(1-6)alkyl, trifluoromethyl, C_(1-6)alkoxy, preferably, from 1 to 3 fluoro, more preferably, 2,3-difluoro.

Representative examples of R ²include methyl, ethyl, and trifluoroethyl when R³is hydrogen. Representative examples of R³include methyl when R²is methyl.

Further representative examples of R ²and R³include when R²and R³together with the pyridone ring carbon atoms to which they are attached form a fused 5-membered carbocyclic (cyclopentenyl) ring, or a fused benzo, pyrido, pyrazolo or thieno ring.

Further representative examples of R ²and R³include when R²and R³, together with the pyridone ring carbon atoms to which they are attached, form a pyrazolo ring substituted on the N atom by C_(1-3)alkyl or methoxyethyl; and when R²and R³, together with the pyridone ring carbon atoms to which they are attached, form either a thiazolyl, thieno or pyrido ring substituted by methyl.

Preferably, R ²and R³together with the pyridone ring carbon atoms to which they are attached form a fused 5-membered carbocyclic (cyclopentenyl) ring or a fused benzo, pyrido, thieno or pyrazolo ring.

Preferably, R ²and R³, together with the pyridone ring carbon atoms to which they are attached, form a fused thiazolyl ring substituted by methyl.

Representative examples of R ⁴include hydrogen, methyl, 2-(diethylamino)ethyl, 2-(piperidin-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl, 3-(morpholin-4-yl)propyl, 1-ethyl-piperidin-4-yl and 1-ethyl-pyrrolidin-2-ylmethyl. Preferably R⁴is 2-diethylamino)ethyl or 1-ethyl-piperidin-4-yl.

Further representative examples of R ⁴include piperidin-4-yl substituted at the 1-position by methyl, isopropyl, 1-(2-methoxyethyl), 1-(2-hydroxyethyl), t-butoxycarbonyl or ethoxycarbonylmethyl; ethyl substituted at the 2-position by aminoethyl; 1-ethylpiperidinylmethyl; piperidin-4-yl; 3-diethylaminopropyl; 4-pyrrolidin-1-ylbutyl and 1-ethylpyrrolidin-3-yl.

Preferably R ⁴is 1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or 1-ethylpyrrolidin-3-yl.

Representative examples of R ⁵include phenyl and pyridyl. Preferably, R⁵is phenyl.

Representative examples of R ⁶include phenyl optionally substituted by halogen, or trifluoromethyl, preferably at the 4-position and hexyl. Preferably, R⁶is phenyl substituted by trifluoromethyl at the 4-position.

Further representative examples of R ⁶include phenyl substituted by 1 or more C_(1-3)alkyl. Preferably, R⁶is phenyl substituted by ethyl in the 4-position.

Preferably, R ⁵and R⁶together form a 4-(phenyl)phenyl or a 2-(phenyl)pyridinyl substituent in which the remote phenyl ring may be optionally substituted by halogen or trifluoromethyl, preferably at the 4-position.

Preferably X is C _(2-4)alkylene, more preferably C_(2-3)alkylene, most preferably, (CH₂)₂, or CH₂S.

It will be appreciated that within the compounds of formula (I) there is a sub-group of compounds (group A) in which:

R ¹is phenyl substituted by 2,3-difluoro;

R ²and R³, together with the pyridone ring carbon atoms to which they are attached, form a fused 5-membered carbocyclic (cyclopentenyl) ring, or a fused benzo or pyrido ring;

R ⁴is 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl, 1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or 1-ethylpyrrolidin-3-yl;

R ⁵is phenyl;

R ⁶is phenyl substituted by ethyl or trifluoromethyl in the 4-position; and

X is CH ₂S.

It will be appreciated that within the compounds of formula (I) there is a further sub-group of compounds (group B) in which:

R ¹is phenyl substituted by 2,3-difluoro;

R ²and R³, together with the pyridone ring carbon atoms to which they are attached, form a fused thiazolyl ring substituted by methyl, or a benzo or pyrido ring;

R ⁵is phenyl;

R ⁶is phenyl substituted by trifluoromethyl in the 4-position; and

X is (CH ₂)₂.

It will be appreciated that within the compounds of formula (I) there is a further sub-group of compounds (group C) in which:

R ¹is phenyl substituted by 2,3-difluoro;

R ²and R³, together with the pyridone ring carbon atoms to which they are attached, form a fused benzo or pyrido ring;

R ⁴is 1-(2-methoxyethyl)piperidin-4-yl;

R ⁵and R⁶together form a 4-(phenyl)phenyl substituent in which the remote phenyl ring is substituted by trifluoromethyl, preferably at the 4-position; and

X is CH ₂S or (CH₂)₂.

It will be appreciated that compounds of the present invention may comprise one or more chiral centres so that stereoisomers may be formed. The present invention covers all such stereoisomers, including individual diastereoisomers and enantiomers, and mixtures thereof.

It will be appreciated that in some instances, compounds of the present invention may include a basic function such as an amino group as a substituent. Such basic functions may be used to form acid addition salts, in particular pharmaceutically acceptable salts. Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts may be formed from inorganic and organic acids. Representative examples thereof include maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, taurocholic acid, benzenesulfonic, p-toluenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

It will be appreciated that in some instances, compounds of the present invention may include a carboxy group as a substituent. Such carboxy groups may be used to form salts, in particular pharmaceutically acceptable salts. Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Preferred salts include alkali metal salts such as the sodium and potassium salts.

When used herein, the term “alkyl” and similar terms such as “alkoxy” includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.

When used herein, the term “aryl” refers to, unless otherwise defined, a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, for instance phenyl or naphthyl.

When used herein, the term “heteroaryl” refers to a mono- or bicyclic heteroaromatic ring system comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms. A bicyclic heteroaromatic ring system may include a carbocyclic ring.

When used herein, the terms “halogen” and “halo” include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively.

Most preferred compounds of formula (1) are:

N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide;

N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide;

or a pharmaceutically acceptable salt thereof, in particular the bitartrate, hydrochloride, dihydrochloride or paratoluenesulfonate salt.

Since the compounds of the present invention, in particular compounds of formula (I), are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.

When some of the compounds of this invention are allowed to crystallise or are re-crystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or re-crystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all polymorphic forms of the compounds of formula (I).

Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A ₂(Lp-PLA₂) and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis. In a further aspect therefore the present invention provides a compound of formula (I) for use in therapy.

The compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA ₂and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, compounds of formula (I) may have a general application in any disorder that involves lipid oxidation in conjunction with enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, ischaemia, reperfusion injury, sepsis, and acute and chronic inflammation.

Further applications include any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA ₂. Examples of such disorders include psoriasis.

Accordingly, in a further aspect, the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA ₂which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme. The disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidised free fatty acids; with lipid oxidation in conjunction with Lp-PLA₂activity; or with endothelial dysfunction.

Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with an anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal, anti-inflammatory, or anti-hypertension agent or an agent for lowering Lp(a). Examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs. Examples of agents for lowering Lp(a) include the aminophosphonates described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar SA and SmithKline Beecham).

A preferred combination therapy will be the use of a compound of the present invention and a statin. The statins are a well known class of cholesterol lowering agents and include atorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin, lovastatin and rosuvastatin (also referred to as S-4522 or ZD 4522, Astra Zeneca). The two agents may be administered at substantially the same time or at different times, according to the discretion of the physician.

A further preferred combination therapy will be the use of a compound of the present invention and an anti-diabetic agent or an insulin sensitiser, as coronary heart disease is a major cause of death for diabetics. Within this class, preferred compounds for use with a compound of the present invention include the PPARgamma activators, for instance GI262570 (GlaxoSmithlhine) and the glitazone class of compounds such as rosiglitazone (Avandia, GlaxoSmithKline), troglitazone and pioglitazone.

In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository.

Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository. Compounds of formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I). The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

A compound of formula (I) may be prepared by reacting an acid compound of formula (II):

in which X, R ¹, R²and R³are as hereinbefore defined,

with an amine compound of formula (III):

R⁶—R⁵—CH₂NHR⁴ (III)

in which R ⁴, R⁵and R⁶are as hereinbefore defined; under amide forming conditions.

Suitable amide forming conditions are well known in the art and include treating the acid of formula (II) with the amine of formula (III) in the presence of a coupling agent such as 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (DEC) and 1-hydroxybenzotriazole (HOBt), or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and di-isopropylethylamine, in an aprotic solvent such as dichloromethane or dimethylfomiamide.

A compound of formula (II) may be readily prepared from a corresponding ester of formula (IV):

in which X, R ¹, R²and R³are as hereinbefore defined, and R¹¹is C_(1-6)alkyl, for example ethyl or t-butyl,

by treating with a de-esterifying agent, for instance, when R ¹¹is t-butyl trifluoroacetic acid or when R¹¹is ethyl, sodium hydroxide in dioxan.

The overall synthesis of compounds of formula (I) is illustrated in the following scheme wherein R ¹to R¹¹are as hereinbefore defined:

Referring to the scheme, the ester (IV) is usually prepared by N-1 alkylation of (V) using (VI), in which R ¹¹is as hereinbefore defined e.g. (VI) is t-butyl bromoacetate or ethyl bromoacetate, in the presence of a bas e.g. BuLi THF or sodium hydride in N-methyl pyrrolicinone (NMP) (step c).

When X is CH ₂S, the key intermediate (IV) may be synthesised by reacting (XX) with dimethyloxosulfonium methylide, generated via the treatment of trimethylsulfoxonium iodide with sodium hydride at low temperature, to yield a sulfur ylid (XXII) (step q). Subsequent treatment of (XXII) with carbon disulfide in the presence of diisopropylamine, followed by R¹CH₂—L⁴, where L⁴is a leaving group, yields intermediate (IV) (step r).

Alternatively, when X is CH ₂S, the R¹X substituent may be introduced by displacement of a leaving group L²(e.g. Cl) (step e) either on a pyridine (VIII) or pyridine N-oxide (XIV), to give 2-substituted pyridines (VII) and (XV). Transformation of (VII) or (XV) to the 4-pyridone (V) is accomplished by deprotection of the 4-oxygen (e.g. using (Ph₃P)₃RhCl when in aq. ethanol when R¹²=allyl) (step d), followed, for (XVI), by removal of the N-oxide substituent, using hydrogen in the presence of Pd/C in acetic acid (step k). The pyridine (VIII) or pyridine N-oxide (XIV) may be prepared by steps (i), (h), (g), (f), and (j), in which:

(j) treatment of (VIII) with m-chloroperbenzoic acid in dichloromethane;

(f) treatment of (IX) with R ¹²OH (X), in which R¹²is allyl, and sodium hydride in DMF;

(g) treatment of (XI) with phosphorus oxychloride;

(h) treatment of (XII) with aq HCl with heating;

(i) treatment of (XIII) with di-lower alkyl malonate and sodium alkoxide in alcohol (in which R ¹³is C_(1-6)alkyl, typically R¹³=Et); and

R ¹—CH₂SH (XIX) is typically prepared from the thioacetate, which is formed from the corresponding alkyl bromide R¹—CH₂Br.

Alternatively, when X is CH ₂S and R²and R³, together with the pyridone ring carbon atoms to which they are attached, form a fused benzo ring, intermediate (IV) may be synthesised from known starting materials by steps (s), (c) and (v) in which:

(s) treatment of Meldrum's acid (XXIII) with sodium hydride at low temperature, followed by reaction with phenylisothiocyanate and subsequent treatment with R ¹CH₂—L⁴;

(c) as hereinbefore discussed;

(v) treatment of (XXV) with trifluoroacetic acid.

When X is alkylene, it is preferable to use steps (m) and (h) (intermediates (XVII), (XVIII)) or steps (n) and (p) (intermediates (XIX), (XX), (XXI)) in which:

(h) transformation of a 4-substituted pyridine into a 4-pyridone e.g. by treatment of (XVII) R ¹⁴═Cl with aq HCl and dioxan, or deprotection of R¹⁴═OR¹², e.g. using conditions of step (d).

(m) chain extension of a 2-alkyl pyridine, e.g. where X═YCH ₂CH₂by treatment of a 2-methylpyridine (XVIII) with R¹—Y—CH₂—L⁴(XVI) in which L⁴is a leaving group and a strong base, such as BuLi, in THF.

In the alternative route, the 3-ester group is removed from intermediate (XIX) R ¹⁵═C_(1-6)alkyl by heating in diphenyl ether where R¹⁵=tBu (step n); Intermediate (XIX) is formed from the 2,6-dioxo-1,3-oxazine (XX) and ester (XXI) by treatment with a base such as NaH in DMF or 1,8-diazabicyclo[5.4.0]undec-7-ene in dichloromethane.

Synthesis of (XX) from known starting materials may be achieved via steps (w) and (c) or steps (y) and (c) in which:

(w) treatment of (XXVII) with azidotrimethylsilane in THF;

(y) treatment of (XXVI) with phosgene;

(c) as hereinbefore described.

It will be appreciated by those skilled in the art that all other starting materials and intermediates are either known compounds or may be prepared by literature methods, such as those described in “Comprehensive Organic Transformations: a guide to functional group preparations” by Richard Larock (VCH, 1989), incorporated herein by reference.

As will be appreciated by those skilled in the art it may be necessary or desirable at any stage in the synthesis of compounds of formula (I) to protect one or more sensitive groups in the molecule so as to prevent undesirable side reactions. The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See for example, those described in ‘Protective Groups in Organic Synthesis’ by Theodora W Green and Peter G M Wuts, second edition, (John Wiley and Sons, 1991), incorporated herein by reference, which also describes methods for the removal of such groups.

The present invention will now be illustrated by the following examples.

EXAMPLES

The structure and purity of the intermediates and examples was confirmed by 1H-NMR and (in nearly all cases) mass spectroscopy, even where not explicitly indicated below [0117]
Intermediate A1 4-(4-Trifluoromethylphenyl)benzaldehyde [0118]
A 3 L 3-neck flask fitted with top stirrer, condenser and argon inlet/outlet was charged with 4-trifluoro-methybenzene boronic acid (90.0 g, 0.474 mol), 4-bromobenzaldehyde (83.29 g, 0.450 mol) and 1,2-dimethoxyethane (1.3 L), followed by 2M aqueous sodium carbonate (474 ml) and palladium acetate (5.32 g, 0.0237 mol). The stirring mixture was heated to reflux for 4 h under argon, then allowed to cool to room temperature over 16 h. The reaction mixture was filtered through hyflo. The filtrate was diluted with saturated brine and extracted 3× with ethyl acetate. The combined extracts were dried over magnesium sulfate and filtered through hyflo, giving a clear orange filtrate which was evaporated to a solid (ca. 120 g, crude). Flash chromatography (silica, 10-50% dichloromethane in pet. ether, 10% steps) gave a white solid which dissolved in hexane (500 ml) on boiling. Crystallisation, finally in ice, gave the title compound as a solid which was filtered off, washed with ice cold hexane and dried, (86.33 g, 77%). [0119] ¹H-NMR (CDCl₃) δ7.77-8.03 (8H, m), 10.09 (1H, s).
Intermediate A2 N,N-diethyl-N′-4′-trifluoromethylbiphenyl-4-ylmethyl)ethane-1,2-diamine [0120]
4-(4-Trifluoromethylphenyl)benzaldehyde (85.43 g, 0.3414 mol) (Int. A1) and 4A molecular sieve (400 g, predried at 120° C.) were suspended in dichloromethane (1.4 L), then N,N-diethyl-ethylenediamine (47.97 ml, 0.3414 mol) was added. The mixture was left at room temperature for 16 h with occasional shaking, then the sieves were filtered off and washed with dichloromethane. The combined filtrates were evaporated to a yellow solid and dried under high vacuum. This material (1 14.3 g, 0.328 mol) in ethanol (1 L) was cooled in an ice bath, and sodium borohydride (12.41 g, 0.328 mol) was added under argon with stirring. Hydrogen evolution was observed. After 30 min the ice bath was removed, and the cloudy yellow solution was left to stand at room temperature for 16 h. The solvent was removed in vacuo, water and brine were added, and the mixture was extracted 3× with dichloromethane. The combined extracts were dried over potassium carbonate and evaporated to give the title compound as a yellow solid, (112.1 g, 98%). [0121] ¹H-NMR (CDCl₃) δ7.66 (4H, s), 7.53-7.56 (2H, m), 7.40-7.44 (2H, m), 3.86 (2H, s), 2.47-2.75 (9H, m), 0.96-1.10 (6H, m); MS(APCI+) found (M+1)=-351, C₂₀H₂₅F₃N₂requires 350.
Intermediate A3—4-(4-Trifluoromethylphenyl)benzonitrile [0122]
Prepared by the method of intermediate A1 using 4-trifluoromethylbenzeneboronic acid and 4-bromobenzonitrile. [0123] ¹H-NMR (d6 DMSO) δ7.99-7.94 (6H, m), 7.86 (2H, d); MS(APCI+) found (M+1)=248, C₁₄H₈NF₃requires 247.
Intermediate A4—(4-Trinfluoromethylphenyl)benzylamine, Free Base and hydrochloride salt [0124]
(a) A solution of intermediate A3 (75.5 g, 0.306 mol) in anhydrous THF (500 ml) was added dropwise to a solution of lithium aluminum hydride (460 ml, 1.0M solution in TRF) at 0° C. under argon. The mixture was stirred at room temperature for 16 h, then water (17 ml), 10% aqueous sodium hydroxide solution (10 ml) and water (50 ml) were carefully added dropwise over 8 h under argon. The mixture was stirred for 16 h, then filtered through celite and the filtrate evaporated. The residue was dissolved in dichloromethane (500 ml) and washed with brine, dried and evaporated to give the title compound as a cream solid (66.3 g, 86%). [0125] ¹H-NMR (CDCl₃) δ7.68 (4H, s), 7.57 (2H, d), 7.42 (2H, d), 3.94 (2H, s), 1.50 (2H, s); MS(APCI+) found (M-NH₂)=235, C₁₄H₁₂F₃N requires 251.
(b) To a solution of intermediate A3 (96.7 g, 0.39 mol) in absolute ethanol (5L) and concentrated hydrochloric acid (200 ml) was added 10% palladium on charcoal (30.0 g, 54% H[0126] ₂O paste). The mixture was stirred under 50 psi hydrogen for 16 h. Additional 10% palladium on charcoal (25.0 g, 54% H₂O paste) was added and the mixture was stirred under 50 psi hydrogen for further 16 h. The mixture was filtered through celite and the solvent evaporated to give the hydrochloride salt of the title compound as a cream solid (102.5 g, 91%). ¹H-NMR (d6 DMSO) δ8.61 (3H, s), 7.93 (2H, d), 7.83 (2H, d), 7.80 (2H, d), 7.65 (2H, d), 4.08 (2H, s); MS(APCI+) found (M-NH₂)=235, C₁₄H₁₂F₃N requires 251.
Intermediate A5—N-(1-Methyl-piperidin-4-yl)-4-(4-trifluoromethylphenyl)benzylamine [0127]
A mixture of intermediate A4 hydrochloride salt (6.0 g, 20.87 mmol), 1-methyl-piperidin-4-one (2.56 ml, 20.84 mmol), sodium triacetoxyborohydride (6.20 g, 29.25 mmol) and acetic acid (1.3 ml) in dichloroethane (50 ml) was stirred at room temperature under argon for 16 h then poured into 2M sodium hydroxide solution (150 ml). The organic phase was separated and the aqueous layer extracted with dichloromethane. The combined organic phases were washed with brine, dried and evaporated. Chromatography (silica, dichloromethane to 97:3 dichloromethane/methanolic ammonia) gave the product as a cream solid (6.3 g, 87%). [0128] ¹H-NMR (CDCl₃) δ7.68 (4H, s), 7.57 (2H, d), 7.42 (2H, d), 3.87 (2H, s), 2.82 (2H, m), 2.52 (1H, m), 2.27 (3H, s), 1.90-2.02 (4H, m), 1.45-1.51 (2H, m); MS(APCI+) found (M+1)=349, C₂₀H₂₃N₂F₃requires 348.
The following intermediate was made as described in WO 00/66567 [0129]

No. Structure Name

A6
4-(4-Chloro- phenyl)- benzylamine

The following intermediates were made by the method of Intermediate A1:



No.	Precursors	Name

A7	4-bromobenzaldehyde,	4-
	4-methylbenzeneboronic acid	(4-methylphenyl)benzaldehyde
A8	4-bromobenzaldehyde,	4-
	4-ethylbenzeneboronic acid	(4-ethylphenyl)benzaldehyde
A9	4-isopropyliodobenzene	4-
	4-formylbenzeneboronic acid	(4-isopropylphenyl)benzaidehyde
A10	4-bromo-o-xylene	4-
	4-formylbenzeneboronic acid	(3,4-dimethylphenyl)benzaldehyde
A11	3,4-difluoroiodobenzene	4-
	4-formylbenzeneboronic acid	(3,4-difluorophenyl)benzaldehyde

The following intermediates were made by the method of Intermediate A2: Amine precursors were either commercially available, or readily prepared from commercially available materials by literature methods or minor modifications thereof.



No.	Precursor	Structure	Name


A20	Int. A1		N-(2-(piperidin-1-yl)ethyl)-4-(4- trifluoromethylphenyl)benzylamine

A22	Int. A1		N-(2-(pyrrolidin-1-yl)ethyl)-4-(4- trifluoromethylphenyl)benzylamine

A23	Int. A1		(±)-N-(1-ethylpyrrolidin-2-ylmethyl)- 4-(4-trifluoromethylphenyl)benzylamine

A24	Int. A1		N-(3-diethylaminopropyl)-4-(4- trifluoromethylphenyl)benzylamine

A25	Int. A1		N-(1-ethylpiperidin-4-ylmethyl)-4-(4- trifluoromethylphenyl)benzylamine

A26	Int. A7		N-(2-diethylaminoethyl)-4-(4-methyl- phenyl)benzylamine

A27	Int. A8		N-(2-diethylaminoethyl)-4-(4-ethyl- phenyl)benzylamine

A28	Int. A9		N-(2-diethylaminoethyl)-4-(4- isopropylphenyl)benzylamine

A29	Int. A8		N-(1-ethylpiperidin-4-yl)-4-(4-ethyl- phenyl)benzylamine

A30	Int. A10		N-(2-diethylaminoethyl)-4-(3,4- dimethylphenyl)benzylamine

A31	Int. A11		N-(2-diethylaminoethyl)-4-(3,4- difluorophenyl)benzylamine

A32	Int. A1		N-(4-(pyrrolidin-1-yl)butyl)-4-(4- trifluoromethylphenyl)benzylamine

A33	Int. A1		N-(2-(N′-t-butoxycarbonyl-N′- ethylamino)ethyl)-4-(4-trifluoro- methylphenyl)benzylamine

The following intermediates were made by the method of Intermediate A5: Piperidone precursors were either commercially available, or readily prepared from commercially available materials by literature methods or minor modifications thereof.



No.	Precursor	Structure	Name


A40	Int. A4		N-(1-ethylpiperidin-4-yl)-4-(4- trifluoromethylphenyl)benzylamine

A41	Int. A4		N-(1-isopropylpiperidin-4-yl)-4- (4-trifluoromethylphenyl)benzylamine

A42	Int. A4		N-(1-(2-methoxyethyl)piperidin-4- yl)-4-(4-trifluoromethylphenyl)- benzylamine

A43	Int. A4		N-(1- ethoxycarbonylmethylpiperidin-4- yl)-4-(4-trifluoromethylphenyl)- benzylamine

A44	Int. A6		N-(1-ethylpiperidin-4-yl)-4- (chlorophenyl)benzylamine

A45	Int. A6		N-(1-methylpiperidin-4-yl)-4-(4- chlorophenyl)benzylamine

A46	Int. A6		N-(1-isopropylpiperidin-4-yl)-4- (4-chlorophenyl)benzylamine

A47	Int. A6		N-(1-(2-methoxyethyl)piperidin-4- yl)-4-(4-chlorophenyl)benzylamine

A48	Int. A4		N-(1-(t-butoxycarbonyl)piperidin- 4-yl)-4-(4-trifluoromethyl- phenyl)benzylamine

Intermediate B1—Thioacetic Acid S-(2,3-difluorobenzyl)ester [0133]
Potassium thioacetate (13.45 g, 1.2 equiv) was added portionwise to a solution of 2,3-difluorobenzyl bromide (20 g, 1 equiv) in dimethylformamide (200 ml) and the reaction stirred for 4 h at room temperature. The resultant solid was filtered off and the filtrate partitioned between diethyl ether and water, the organic phase was dried and evaporated. Chromatography (silica, 20:1 petrol/ethyl acetate) gave the title compound as a yellow oil (18.35 g). [0134] ¹H-NMR (CDCl₃) δ2.35 (3H, s), 4.15 (2H, d), 6.98-7.13 (5H, m).
Intermediate B2—2,3-Difluorobenzyl mercaptan. [0135]
A mixture of thioacetic acid S-(2,3-difluorobenzyl)ester (Intermediate B1) (18.35 g, 1 equiv) and potassium carbonate (25.11 g, 2 equiv) in methanol (200 ml) and water (400 ml) was stirred overnight before being poured into dichloromethane (500 ml). The organic phase was dried and evaporated and distilled (125° C. @ 5.6 mBar) to give the title compound as a colourless oil (12.15 g). [0136] ¹H-NMR (CDCl₃) δ 1.89 (1H, t), 3.78 (2H, d), 7.05 (3H, m).
Intermediate B3—Ethyl 2,4-dihydroxy-6,7-dihydro-5 H-[1]pyrindine-3-carboxylate. [0137]
A mixture of ethyl 2-amino-1-cyclopentene-1-carboxylate (10.1 g, 1 equiv), diethyl malonate (9.9 ml, 1 equiv), sodium ethoxide (26.7 ml, 1.1 equiv, 21 wt. % solution in ethanol) in ethanol was heated in a sealed vessel to 110° C. for 96 h. After cooling the solvent was removed and the residue suspended in water. The suspension was acidified with aqueous hydrochloric acid (pH ˜3) and the precipitate was collected and dried to give the title compound as a light brown solid (11.52 g). [0138] ¹H-NMR (d6-DMSO) δ1.27 (3H, t), 2.00 (2H, qn), 2.60 (2H, t), 2.73 (2H, t), 4.30 (2H, q), 11.62 (1H, br s), 13.18 (1H, br s).
Intermediate B4—2,4-Dihydroxy-6,7-dihydro-5H-[1]pyrindine. [0139]
A mixture of ethyl 2,4-dihydroxy-6,7-dihydro-5H-[1]pyrindine-3-carboxylate (Int. B3) (11.52 g) and aqueous hydrochloric acid (2M, 100 ml) was heated together overnight. After cooling the solvent was removed by freeze drying and the title compound obtained as a brown solid (8.02 g). [0140] ¹H-NMR (d₆-DMSO) 2.09 (2H, qn), 2.72 (2H, t), 2.93 (2H, t), 6.56 (1H, s); MS (APCI+) found (M+1)=152; C₈H₉NO₂requires 151.
Intermediate B5—2,4-Dichloro-6,7-dihydro-5 H-[1]pyrindine. [0141]
A mixture of 2,4-dihydroxy-6,7-dihydro-5H-[1]pyrindine (Int B4) (8.02 g) and phosphorous oxychloride (40 ml) was heated to reflux overnight. The excess phosphorous oxychloride was evaporated off and the residue poured over ice. The resulting brown solid was filtered off and dried (7.36 g). [0142] ¹H-NMR (CDCl₃) δ2.17 (2H, m), 2.96 (2H, t), 3.07 (2H, t), 7.12 (1H, s); MS (APCI+) found (M+1)=188; C₈H₇ ³⁵Cl₂N requires 187.
Intermediate B6—4-Allyloxy-2-chloro-6,7-dihydro-5H-[1]pyrindine. [0143]
Allyl alcohol (4.1 ml, 1.2 equiv) was added dropwise to a suspension of sodium hydride (2.2 g, 1.1 equiv, 60% dispersion in mineral oil) in dimethylformamide (80 ml) under argon at 0° C. The reaction mixture was stirred for 20 min prior to adding dropwise to a solution of 2,4-dichloro-6,7-dihydro-5H-[1]pyrindine (Int. B5) (9.42 g, 1 equiv) in dimethylformamide (70 ml) at 0° C., stirring was continued at ambient temperature overnight. The solvent was evaporated and the residue partitioned between water and ethyl acetate, the organic phase was dried and evaporated. Chromatography (silica, 10:1 toluene/ethyl acetate) gave the title compound as an off white solid (8.99 g). [0144] ¹H-NMR (CDCl₃) δ2.11 (2H, m), 2.84 (2H, t), 2.97 (2H, t), 4.58 (2H, m), 5.30-5.46 (2H, m), 5.94-6.07 (1H, m), 6.59 (1H, s); MS (APCI+) found (M+1)=210; C₁₁H₁₂ ³⁵ClNO requires 209.
Intermediate B7—4Allyloxy-2-chloro-6,7-dihydro-5H-[1]pyrindine-1-oxide [0145]
A mixture of 3-chloroperbenzoic acid (19.5 g, 1.5 equiv) and 4-allyloxy-2-chloro-6,7-dihydro-5H[1]-[1]pyrindine (Int B6) (8.99 g, 1 equiv) in dichloromethane (100 ml) was stirred at ambient temperature under argon for 4 h, washed with aqueous sodium bicarbonate, dried and evaporated. Chromatography (silica, 5% methanol in dichloromethane) gave the title compound as a white solid (6.98 g). [0146] ¹H-NMR (CDCl₃) δ2.19 (2H, qn), 2.97 (2H, t), 3.22 (2H, t), 4.57 (2H, m), 5.30-5.45 (2H, m), 5.93-6.08 (1H, m), 6.80 (1H, s); MS (APCI+) found (M+1)=226; C₁₁H₁₂ ³⁵ClNO₂requires 225.
Intermediate B8—4-Allyloxy-2-(4-fluorobenzylthio)-6,7-dihydro-5H-[1]pyrindine 1-oxide [0147]
4-Fluorobenzyl mercaptan (1.59 g, 1.2 equiv) was added dropwise to a suspension of sodium hydride (0.372 g, 1.0 equiv, 60% dispersion in mineral oil) in dimethylformamide (30 ml) under argon at 0° C. The reaction was stirred for 20 min, before adding dropwise to a solution of 4-allyloxy-2-chloro-6,7-dihydro-5 H-[1]pyrindine-1-oxide (Int. B7) (2.1 g, 1 equiv) in dimethylformamide (20 ml) at 0° C., stirring was continued at ambient temperature overnight. The solvent was evaporated and the residue partitioned between water and ethyl acetate, the organic phase was dried and evaporated. Chromatography (silica, 3% methanol in dichloromethane) gave the title compound as an off white solid (2.65 g). [0148] ¹H-NMR (CDCl₃) δ2.16 (2H, qn), 2.91 (2H, m), 3.18 (2H, t), 4.14 (2H, s), 4.43 (2H, m), 5.28 (2H, m), 5.84-5.97 (1H, m), 6.37 (1H, s), 7.00 (2H, m), 7.39 (2H, m); MS (APCI+) found (M+1)=332; C₁₈H₁₈FNO₂S requires 331.
Intermediate B9—2-(4-Fluorobenzylthio)-1-oxy-6,7-dihydro-5H-[1pyrindin-4-ol [0149]
A mixture of 4-allyloxy-2-(4-fluorobenzylthio)-6,7-dihydro-5H-[1]pyrindine 1-oxide (Int. B8) (2.65 ), triphenylphosphine rhodium (I) chloride (0.740 g, 10 mol %) and 1,4-diazobicyclo[2,2,2]octane (0.27 g, 30 mol %) in ethanol (90 ml) and water (10 ml) was heated to reflux overnight. The solvent was removed and the residue chromatographed (silica, 4% methanol in dichloromethane) to yield the title compound as a brown solid (1.75 g). [0150] ¹H-NMR (d₆-DMSO) δ2.07 (2H, m), 2.80 (2H, t), 2.91 (2H, t), 4.14 (2H, s), 6.58 (1H, s), 7.15 (2H, m), 7.47 (2H, m); MS (APCI+) found (M+1)=292; C₁₅H₁₄FNO₂S requires 291.
Intermediate B10—4Chloro-2-(2-2,3difluorophenyl)ethyl)quinoline [0151]
Butyllithium (4.76 ml, 2.5M in hexanes, 1 equiv) was added dropwise to a solution of 4-chloroquinaldine (2.4 ml, 1 equiv) in tetrahydrofuran (30 ml) at −78° C. and the reaction mixture stirred for 15 min. 2,3-Difluorobenzyl bromide (1.82 ml, 1.2 equiv) was added dropwise and stirring was continued for 1 h. After warming to room temperature the solution was diluted with water and ethyl acetate and the organic phase dried and evaporated. Chromatography (silica, 10:1 petrol/ethyl acetate) gave the title compound as a white solid (3.16 g). [0152] ¹H-NMR (CDCl₃) δ3.23 (4H, m), 6.89-6.99 (3H, m), 7.33 (1H, s), 7.59 (1H, m), 7.74 (1H, m), 8.04 (1H, d), 8.15 (1H, d); MS (APCI+) found (M+1)=304; C₁₇H₁₂ ³⁵ClF₂N requires 303.

The following intermediates were prepared by the method of intermediate B10



No.	Precursor	Structure	Name


B11	4-Fluorobenzyl bromide		4-Chloro-2-(2-(4-fluorophenyl)ethyl)- quinoline

B12	3,4-Difluorobenzyl bromide		4-Chloro-2-(2-(3,4-difluorophenyl)- ethyl)quinoline

B13	2,4-Difluorobenzyl bromide		4-Chloro-2-(2-(2,4-difluorophenyl)- ethyl)quinoline

B14	2-Fluorobenzyl bromide		4-Chloro-2-(2-(2-fluorophenyl)- ethyl)quinoline

B15	3-Chlorobenzyl bromide		4-Chloro-2-(2-(3-chlorophenyl)- ethyl)quinoline

B16	2,3,4-Trifluoro- benzyl bromide		4-Chloro-2-(2-(2,3,4-trifluoro- phenyl)ethyl)quinoline

B17	3-Fluorobenzyl bromide		4-Chloro-2-(2-(3-fluorophenyl)- ethyl)quinoline

Intermediate B20—2,4-Dichloroquinoline [0154]
A mixture of 2,4-dihydroxyquinoline (14 g) and phosphorus oxychioride (40 ml) was heated to reflux overnight. The excess phosphorous oxychloride was evaporated off and the residue poured over ice. The resulting solid was filtered off and dried to give the title compound as a brown solid (13.86 g). [0155] ¹H-NMR (CDCl₃) δ7.82 (1H, m), 7.96 (2H, m), 8.03 (1H, d), 8.21 (1H, dd); MS (APCI+) found (M+1)=198; C₉H₅ ³⁵Cl₂N requires 197.
Intermediate B21 —4-Allyloxy-2-chloroquinoline [0156]
Allyl alcohol (7.1 ml, 1.2 equiv) was added dropwise to a suspension of sodium hydride (3.83 g, 1.1 equiv, 60% dispersion in mineral oil) in dimethylformamide (120 ml) under argon at 0° C. The reaction mixture was stirred for 20 min prior to adding dropwise to a solution of 2,4-dichloroquinoline (Int. B20) (17.26 g, 1 equiv) in dimethylformamide (80 ml) at 0° C., stirring was continued at ambient temperature overnight The solvent was evaporated and the residue partitioned between water and ethyl acetate, the organic phase was dried and evaporated. Chromatography (silica, toluene) gave the title compound as an off white solid (13.56 g). [0157] ¹H-NMR (CDCl₃) δ4.77 (2H, m), 5.30-5.57 (2H, m), 6.08-6.20 (1H, m), 6.73 (1H, s), 7.52 (1H, m), 7.71 (1H, m), 7.92 (1H, d), 8.17 (1H, dd); MS (APCI+) found (M+1)=220; C₁₂H₁₀ ³⁵ClNO requires 219.
Intermediate B22—4-Allyloxy-2-(2,3-difluorobenzylthio)quinoline [0158]
2,3-Difluorobenzyl mercaptan (Int B2) (2 g, 1.1 equiv) was added dropwise to a suspension of sodium hydride (0.477 g, 1.05 equiv, 60% dispersion in mineral oil) in dimethylformamide (50 ml) under argon at 0° C. The reaction mixture was stirred for 20 min, before adding dropwise to a solution of 4-allyloxy-2-chloroquinoline (Int. B21) (2.49 g, 1 equiv) in dimethylformamide (30 ml) at 0° C. and stirring was continued at ambient temperature overnight. The solvent was evaporated and the residue partitioned between water and ethyl acetate, the organic phase was dried and evaporated. Chromatography (silica, 2:1 petrol/toluene) gave the title compound as an off white solid (2.26 g). [0159] ¹H-NMR (CDCl₃) δ4.68 (4H, m), 5.34-5.53 (2H, m), 6.06-6.17 (1H, m), 6.54 (1H, s), 6.96 (2H, m), 7.41 (2H, m), 7.41 (2H, m), 7.65 (1H, dt), 7.90 (1H, dd), 8.11 (1H, dd); MS (APCI+) found (M+1)=344; C₁₉H15F₂NOS requires 343.
The following intermediate was prepared by the method of intermediate B22: [0160]

No. Precursors Structure Name

B23 Int. B21, 4-Fluorobenzyl mercaptan
4-Allyloxy-2-(4-fluorobenzylthio)quinoline
Intermediate B24—4-Allyloxy-2-(2,3-difluorobenzylthio)-6,7-dihydro-5H-[1]pyrindine-1-oxide [0161]
The title compound was prepared from Intermediate B7 and 2,3-difluorobenzylthiol by the method of Intermediate B8. [0162]
Intermediate B25—2-(2,3-Difluorobenzylthio)-1-oxy-6,7-dihydro-5H-[1]pyrindin-4-ol [0163]
The title compound was prepared from Intermediate B24 by the method of Intermediate B9. [0164]
Intermediate B26-3-azaisatoic anhydride [0165]
To a stirring solution of 2,3-pyridinedicarboxylic anhydride (100 g, 1 equiv) in anhydrous tetrahydrofuran (1L) was added dropwise under argon at 38-46° C. over 1.25 h azidotrimethylsilane (97.9 ml, 1.1 equiv). The temperature was maintained at 45-50° C. for a further 2 h then the mixture refluxed for 30 min, cooled to ambient temperature and ethanol (43 ml, 1.1 equiv) added dropwise. On stirring for 16 h an off-white solid was obtained which was filtered, washed and dried, to give the title compound (90.7 g). [0166] ¹H-NMR (d₆-DMSO) δ7.25-7.35 (1H, m), 8.30-8.35 (1H, dd), 8.65-8.7 (1H, dd), 11.3 (1H, br s)
Intermediate B30—6-Methyl-1H-thieno[3,2-d](1,3]oxazine-2,4-dione [0167]
Methyl 3-amino-5-methylthiophene-2-carboxylate (2.0 g, 11.7 mmol) and sodium hydroxide (0.89 g, 22.2 mmol) in 1:1 dioxan/water (40 ml) was heated at reflux for 18 h, then the solvent was removed in vacuo. The crude solid was dissolved in water (30 ml) and phosgene (15 ml, 20% solution in toluene, 30 mmol) was added over 10 min with stirring. After a further 30 min the precipitate was filtered off, washed with water and dried to yield the title compound (0.44 g). [0168] ¹H-NMR (CDCl₃) δ2.5 (3H, s), 6.7 (1H, s), 12.5 (1H, s); MS (APCI+) found (M+H—CO₂)=140.

The following intermediates were prepared by the method of Intermediate B30:



No.	Structure	Name


B31		1H-thieno[3,2-d][1,3]oxazine-2,4-dione

B32		1H-thieno[2,3-d][1,3]oxazine-2,4-dione

B33		1H-thieno[3,4-d][1,3]oxazine-2,4-dione

B34		2-methylthiazolo[4,5-d][1,3]oxazine-5,7-dione

B35		2-methyl-2,7-dihydropyrazolo[3,4-d][1,3]oxazine-4,6-dione

B36		2-(4-methoxybenzyl)-2,7-dihydropyrazolo[3,4-d][,3]oxazine- 4,6-dione

B37		4-fluoroisatoic anhydride

The following intermediates were prepared by the method of Washburne and Park, Tet Lett. 243 (1976): [0170]

No. Structure Name

B40
5-ethyl-3H-[1,3]oxazine-2,6-dione

B41
4,5-dimethyl-3H-[1,3]oxazine-2,6-dione
Intermediate B45—1,5,6,7-tetrahydrocyclopenta[d][1,3]oxazine-[0171] 2-4-dione
Tetrarnethylsilylazide (1.28 ml, 1 equiv) was added dropwise to a solution of 1-cyclopentene-1,2-dicarboxylic anhydride (1.33 g, 1 equiv) in dichloromethane (20 ml) and the mixture was warmed to 35° C. After ca. 4 h gas evolution had ceased. Ethanol (1 equiv) was added and stirring continued for 10 min, then the solvent was removed in vacuo and the residue triturated with ether to obtain the title compound (0.74 g). [0172] ¹H-NMR (d₆-DMSO) δ2.00 (2H, m), 2.47 (2H, m), 2.68 (2H, m), 11.8 (1H, br s); MS (APCI−) found (M−1)=152; C₇H₇NO₃requires 153.
The following intermediate was prepared by the method of Int. B45 [0173]

No. Structure Name

B46
5,6,7,8-tetrahydro-1H- benzo[d][1,3]oxazine-2-4-dione
Intermediate B50—Ethyl (2,4-dioxo4H-pyrido[2,3-d][1,3]oxazin-1-yl)acetate [0174]
A 2:1 mixture of 3- and 6-azaisatoic anhydride (3.55 g, 21.6 mmol) ([0175] Synthesis 1982, 11, 972) was added portionwise to a suspension of sodium hydride (0.95 g, 60% in oil, 23.8 mmol) in DMF (40 ml). After stirring for 1 h, ethyl bromoacetate (2.64 ml, 23.8 mmol) was added. The reaction mixture was stirred overnight. The solvent was removed under reduced pressure. Ice/water was added to the residue and stirred for 1h. The resulting pink solid was collected by filtration, washed with water and dried under vacuum at 40° C. The product was a 4:1 mixture of the [2,3-d] and the [3,2-d]isomers. ¹H-NMR data of the title compound. ¹H-NMR (d₆-DMSO) δ1.21 (3H, t), 4.18 (2H, q), 4.92 (2H, s), 7.45 (1H, dd), 8.47 (1H, dd), 8.77 (1H, dd); MS (APCI+) found (M+1)=251; C₁₁H₁₀N₂O₅requires 250.
The title compound could also be prepared by the following method: [0176]
To a stirring mixture of 3-azaisatoic anhydride (Int. B26) (84.36 g, 1 equiv) and N,N-diisopropylethylamine (94 ml, 1.05 equiv) in N-methylpyrrolidone (420 ml) was added dropwise under argon at 45-50° C., ethyl bromoacetate (57 ml, 1 equiv). After 16 h at 50° C. the mixture was cooled (ice bath) and water (560 ml) added with vigorous stirring. The solid which precipitated was filtered, washed with water and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. An insoluble solid was filtered off and discarded and the ethyl acetate layer washed again with saturated sodium bicarbonate, dried (Na[0177] ₂SO₄) and evaporated. The residue was triturated with a 1:1 mixture of ether/light petrol, filtered, washed and dried to give the title compound as an off-white solid, yield (56.0 g).

The following intermediates were prepared by the method of Intermediate B50:



No.	Precursor	Structure	Name


B51	Int. B40		ethyl(5-ethyl-2,6-dioxo-6H-[1,3]oxazin-3-yl)acetate

B52	Int. B41		ethyl(4,5-dimethyl-2,6-dioxo-6H- [1,3]oxazin-3-yl)acetate

B53	Int. B37		ethyl 7-fluoro-2,4-dioxo-4H-benzo[d][1,3]- oxazin-1-yl)acetate

B54	Int. B30		ethyl(6-methyl-2,4-dioxo-4H- thieno[3,2-d][1,3]oxazin-1-yl)acetate

B55	Int. B33		ethyl(2,4-dioxo-4H- thieno[3,4-d][1,3]oxazin-1-yl)acetate

B56	Int. B31		ethyl(2,4-dioxo-4H-thieno[3,2-d]- [1,3]oxazin-1-yl)acetate

B57	Int. B32		ethyl(2,4-dioxo-4H-thieno[2,3-d]- [1,3]oxazin-1-yl)acetate

B58	Int. B34		ethyl(6-methyl-2,4-dioxo-4H- thiazolo[4,5-d][1,3]oxazin-1-yl)acetate

B59	Int. B35		ethyl(2-methyl-4,6-dioxo-2,4-dihydro- pyrazolo[3,4-d][1,3]oxazin-7-yl)acetate

B60	Int. B36		ethyl(2-(4-methoxybenzyl)-4,6-dioxo-2,4- dihydropyrazolo[3,4-d][1,3]oxazin-7-yl)acetate

B61	Int. B45		ethyl(2,4-dioxo-1,5,6,7-tetrahydro- cyclopenta[d][1,3]oxazin-3-yl)acetate

B62	Int. B46		ethyl(2,4-dioxo-5,6,7,8-tetrahydro-1H- benzo[d][1,3]oxazin-3-yl)acetate

Intermediate B70—5-(2,3-difluorophenyl)-3-oxopentanoic acid tert-butyl ester [0179]
To an ice cooled stirring suspension of sodium hydride (1.96 g, 49.1 mmol, 60% dispersion in oil) in dry tetrahydrofuran (100 ml) was added dropwise under an argon atmosphere tert-butylacetoacetate (7.4 ml, 44.6 mmol). After a further 15 min, n-butyllithium (18.7 ml, 46.8 mmol, 2.5M in hexanes) was added dropwise maintaining the reaction temperature below 10° C. 2,3-Difluorobenzyl bromide (11.08 g, 53.5 mmol) was added dropwise 20 min later, then the mixture allowed to warm to ambient temperature. After a further 15 min the reaction mixture was poured onto a mixture of water (150 ml) and glacial acetic acid (10 ml), extracted 3 times with ethyl acetate and the combined extracts washed with saturated sodium hydrogen carbonate then brine, dried (MgSO[0180] ₄) and evaporated to a yellow oil. Chromatography (fine silica, ethyl acetate-light petrol) gave the title compound as a yellow oil, yield 9.05 g (71%). ¹H NMR (CDCl₃) δ1.45 (9H, s), 2.84-2.91 (2H, m), 2.95-3.00 (2H, m), 3.35 (2H, s), 6.92-7.04 (3H, m).
Intermediate B71—(3-tert-butoxycarbonylmethyl-2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-4H-[1,8]naphthyridin-1-yl)acetic acid ethyl ester [0181]
To a stirring suspension of sodium hydride (0.562 g, 14.06 mmol, 60% dispersion in oil) in dry DMF (50 ml) was added dropwise 5-(2,3-difluorophenyl)-3-oxopentanoic acid tert-butyl ester (Int. B70) (3.63 g, 12.78 mmol). After 10 min, (2,4-dioxo-4H-pyrido[2,3-d][1,3]oxazin-1-yl)acetic acid ethyl ester (Int. B50 (3.21 g, 12.78 mmol) was added and the mixture stirred for 16 h. The solvent was evaporated and the residue treated with saturated aq. ammonium chloride and extracted 3 times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO[0182] ₄) and concentrated. Chromatography (fine silica, ethyl acetate-light petrol) gave the title compound as a light brown solid, yield 1.88 g (31%). ¹H NMR (d6-DMSO) δ1.31 (3H, t), 1.63 (9H, s), 2.95-3.03 (2H, m), 3.08-3.13 (2H, m), 4,27 (2H, q), 5.31 (2H, s), 7.01-7.11(3H, m), 7.35-7.38 (1H, m), 8.67-8.71 (2H, m).
The title compound was also made by the following method: [0183]
To an ice-cooled solution of intermediate B50 (55.9 g, 1 equiv) and intermediate B70 (63.5 g, 1 equiv) in dichloromethane (700 ml) was added dropwise under argon over 45 min 1,8-diazabicyclo[5.4.0]undec-7-ene (40 ml, 1.2 equiv). After 1 h the ice bath was removed and after a further 2.5 h the mixture was washed with saturated aqueous ammonium chloride, dried (Na[0184] ₂SO₄) and evaporated. The crude product was chromatographed (fine silica, ethyl acetate-dichloromethane) then triturated with light petrol to give the title compound (80.27 g).

The following intermediates were prepared by the method of Intermediate B71:



No.	Precursor	Structure	Name


B72	Int. B51		2-[2-(2,3-difluorophenyl)ethyl)-3-tert- butoxycarbonyl-5-ethyl-4-oxo-4H- pyridin-1-yl]acetic acid, ethyl ester

B73	Int. B52		2-[2-(2,3-difluorophenyl)ethyl)-3-tert- butoxycarbonyl-5,6-dimethyl-4-oxo- 4H-pyridin-1-yl]acetic acid, ethyl ester

B74	Int. B54		5-[2-(2,3-difluorophenyl)ethyl)-6-tert- butoxycarbonyl-2-methyl-7-oxo-7H- tieno[3,2-b]pyridin-4-yl]acetic acid, ethyl ester

B75	Int. B55		2-[2-(2,3-difluorophenyl)ethyl)-3-tert- butoxycarbonyl-4-oxo-4H- thieno[3,4-b]pyridin-1-yl]acetic acid, ethyl ester

B76	Int. B58		2-[5-(2,3-difluorophenyl)ethyl)-6-tert- butoxycarbonyl-2-methyl-7-oxo-7H- thiazolo[4,5-b]pyridin-4-yl]acetic acid, ethyl ester

B77	Int. B59		2-[6-(2,3-difluorophenyl)ethyl)-5-tert- butoxycarbonyl-2-methyl-4-oxo-4H- pyrazolo[3,4-b]pyridin-7-yl]acetic acid, ethyl ester

B78	Int. B61		2-[2-(2,3-difluorophenyl)ethyl)-3-tert- butoxycarbonyl-4-oxo-5,6- trimethylenepyridin-1-yl]acetic acid, ethyl ester

B79	Int. B62		2-[2-(2,3-difluorophenyl)ethyl)-3-tert- butoxycarbonyl-4-oxo-5,6- tetramethylenepyridin-1-yl]acetic acid, ethyl ester

Intermediate B80—5-(2,3-difluorophenyl)-3-oxopentanoic acid ethyl ester [0186]
Prepared from ethyl acetoacetate by the method of Int. B70. [0187] ¹H NMR (CDCl₃) δ1.27 (3H, t), 2.86-3.02 (4H, m), 3.43 (2H, s), 4.18 (2H, q), 6.92-7.07 (3H, m).
Intermediate B91—Ethyl 2-[6-(2-(2,3-difluorophenyl)ethyl)-2-(4-methoxybenzyl)-4-oxo-2,4-dihydropyrazolo[3,4-b]pyridin-7-yl]acetate [0188]
To sodium hydride (0.315 g) in dry DMF (8 ml) at 0° C. under argon was added a solution of intermediate B70 (2.23 g) in dry DMF (8 ml) dropwise. After stirring at 0° C. for 30 min, a solution of intermediate B60 (2.82 g) in dry DMF was added and the mixture allowed to warm to room temperature. After 4 h at room temperature, the mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The combined extracts were dried over MgSO[0189] ₄and evaporated under reduced pressure to give an oil that was chromatographed on silica gel. This gave a yellow oil (2.3 g). A portion of this material (0.50 g) in TFA (5 ml) was stirred at room temperature for 4 h, then evaporated to dryness. A portion of the residue was added to diphenyl ether (5 ml), heated to reflux for 40 min, then cooled and poured into hexane. The precipitate was filtered off and washed with hexane to obtain the title compound. ¹H-NMR (CDCl₃) δ1.27 (3H, t), 2.81 (2H, m), 3.01 (2H, m), 3.81 (3H, s), 4.25 (2H, s), 5.27 (2H, s), 5.96 (1H, s), 6.88-7.10 (5H, m), 7.23 (2H, d), 7.88 (1H, s).
Intermediate B92—Ethyl 2-[6-(2-(2,3-difluorophenyl)ethyI)4-oxo-2,4-dihydropyrazolo[3,4-b]-pyridin-7-yl]acetate [0190]
A mixture of Int. B91 (0.48 g) and TFA (50 ml) was heated at reflux for 17 h, then the TFA was removed in vacuo. The residue was extracted with dichloromethane, and the combined extracts were chromatographed (silica, 10% methanol in dichloromethane) to obtain the title compound as a dark solid (0.23 g, 64%). [0191] ¹H-NMR (CDCl₃) δ1.27 (3H, t), 2.85 (2H, m), 3.02 (2H, m), 4.97 (2H, s), 6.01 (1H, s), 6.95-7.09 (3H, m), 8.24 (1H, s).
Intermediate B93—5-(2-(2,3-Difluorophenyl)ethyl)-3-(pyrazol-4-ylamino)pent-2-enoic acid ethyl ester [0192]
4-Nitropyrazole (3.55 g, 1 equiv) in ethanol (150 ml) was hydrogenated over 10% palladium on charcoal, then the catalyst was filtered off, Int. B80 (8.0 g, 1 equiv) was added and the solvent was removed in vacuo. Concentrated hydrochloric acid (0.5 ml) was added, and the mixture was heated to 100° C. under argon for 2 h. Ethyl acetate was added and the solution was washed with aq. sodium bicarbonate, dried and evaporated. Chromatography (silica, dichloromethane/ethyl acetate) yielded the title compound as a pale solid (5.7 g, 56%). [0193] ¹H-NMR (CDCl₃) δ1.29 (3H, t), 2.48 (2H, t), 2.80 (2H, t), 4.15 (2H, q), 4.74 (1H, s), 6.78 (1H, m), 6.95 (2H, m), 7.46 (2H, s), 9.75 (1H, s), 11.1 (1H, br s).
Intermediate B94—5-(2-(2,3-Difluorophenyl)ethyl)-2,4-dihydropyrazolo[4,3-b]pyridin-7-one [0194]
Intermediate B93 (6.7 g) was added portionwise to refluxing Dowtherm (100 ml) and heating was continued for 1 h. After cooling, the mixture was poured into hexane and the precipitate was filtered off, washed with hexane and dried; yield 4.5 g (78%). [0195] ¹H-NMR (d₆-DMSO) δ2.89 (2H, m), 3.06 (2H, m), 5.81 (1H, s), 7.07-7.36 (3H, m), 7.76 (1H, s), 11.7 (1H, br s), 13.6 (1H, br s).
Intermediate B95—7Chloro-5-(2-(2,3-difluorophenyl)ethyl)-2,4-dihydropyrazolo[4,3-b]pyridin [0196]
A mixture of Intermediate B94 (4.5 g) and phosphorus oxychloride (90 ml) was heated at reflux for 2 h, then excess phosphorus oxychloride was removed in vacuo and the residue was poured into water and basified with sodium bicarbonate. The product was extracted into ethyl acetate and the extracts dried and evaporated to obtain the title compound (4.6 g, 96%). [0197] ¹H-NMR (CDCl₃) δ3.22 (4H, m), 6.89-7.06 (3H, m), 7.21 (1H, s), 8.34 (1H, s), 11.0 (1H, br s).
Intermediates B96 and B97—5-(2-(2,3-difluorophenyl)ethyl)-l-methyl-2,4-dihydropyrazolo[4,3-b]-pyridin-7-one and 5(2-(2,3-difluorophenyl)ethyl)-2-methyl-2,4-dihydropyrazolo[4,3-b]pyridin-7-one [0198]
A mixture of Intermediate B95 (4.3 g, 1 equiv), sodium hydroxide (l.5 g, 2.5 equiv) and 90% aq. ethanol (15 ml) was heated to reflux and a solution of iodomethane (1.82 ml, 2 equiv) in diethyl ether (15 ml) was added dropwise (CARE). After 3 h at reflux a flirter 2 equivalents of iodomethane was added, and heating was continued for 2 h. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate, and the solution washed with water, dried and evaporated to obtain a crude mixture of products in a ratio of ca. 3:2. These were separated by chromatography (silica, dichloromethane-ethyl acetate). Early fractions gave the 1-methyl isomer (Int. B96, 2.1 g); [0199] ¹H-NMR (CDCl₃) δ3.17 (4H, m), 4.36 (3H, s), 6.90-7.04 (3H, m), 7.12 (1H, s), 8.15 (1H, s). Later fractions gave the 2-methyl isomer (Int. B97, 1.2 g); ¹H-NMR (CDCl₃) δ3.16 (4H, m), 4.29 (3H, s), 6.90-7.04 (3H, m), 7.15 (1H, s), 8.14 (1H, s). The identity of the two isomers was confirmed by NOE experiments.
Intermediate B98-5-(2-(2,3-Difluorophenyl)ethyl)-1-methyl-2,4-dihydropyrazolo[4,3-b]pyridin-7-one [0200]
A mixture of Int. B96 (2.1 g), 2M hydrochloric acid (10 ml) and dioxan (3 ml) was heated at reflux for 4 days, then extracted with dichloromethane/methanol. Drying and evaporation of the extracts gave the title compound (1.7 g). [0201] ¹H-NMR (d₆-DMSO) δ2.98-3.14 (4H, m), 4.22 (3H, s), 6.22 (1H, s), 7.12-7.33 (3H, m), 7.89 (1H, s), 13 (1H, v br s); MS (APCI+) found (M+1)=290; C₁₅H₁₃F₃N₂O requires 289.
Intermediate B99—5-(2-(2,3-Difluorophenyl)ethyl)-2-methyl-2,4-dihydropyrazolo[4,3-b]pyridin-7-one [0202]
Hydrolysis of Int. B97 was carried out by the method of Int. B98. [0203] ¹H-NMR (d₆-DMSO) δ2.82 (2H, m), 3.03 (2H, m), 4.02 (3H, s), 5.66 (1H, s), 7.10 (2H, m), 7.25 (1H, m), 8.00 (1H, s), 11.5 (1H, b br s); MS (APCI+) found (M+1)=290; C₁₅H₁₃F₃N₂O requires 289.
Intermediate B100—Dimethyloxosulphonium-2-(ethoxycarbonylmethylamino)benzoylmethylide [0204]
To a solution of trimethylsulphoxonium iodide (99 g, 0.45 mol) in DMSO (1L) at 5° C. was added sodium hydride (19.4 g, 0.485 mol, 60% in oil) over 0.5 h and the solution stirred for a flither 0.5 h until the reaction subsided. Ethyl 2-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-yl)acetate (100 g, 0.44 mol) was then added to the solution over 0.33 h and stirred for a further 3 h after which time the reaction mixture was heated at 50° C. for 1.5 h. After cooling to ambient the solution was poured onto ice and the precipitate filtered off and washed with water then pentane. The solids were dried in vacuo at 40° C. to provide the product (124.4 g, 94%). [0205] ¹H-NMR (d₆-DMSO) δ1.2 (3H, t), 3.5 (6H, s), 3.98 (2H, q), 5.46 (1H, s), 6.44 (1H, d), 6.52 (1H, t), 7.17 (1H, t), 7.47 (1H, d), 8.93 (1H, br t).

The following intermediates were prepared by the method of intermediate B100



No.	Precursor	Structure	Name


B101	Int. B53		Dimethyloxosulphonium-2-(ethoxycarbonyl- methylamino)-4-fluorobenzoylmethylide

B102	Int. B56		Dimethyloxosulphonium-3-(ethoxycarbonyl- methylamino)thien-2-ylcarbonylmethylide

B103	Int. B57		Dimethyloxosulphonium-2-(ethoxycarbonyl- methylamino)thien-3-ylcarbonylmethylide

B104	Int. B59		Dimethyloxosulphonium-3-(ethoxycarbonyl- methylamino)-1-methylpyrazin-4- ylcarbonylmethylide

B105	Int. B50		Dimethyloxosulphonium-2-(ethoxycarbonyl- methylamino)pyridin-3-ylcarbonylmethylide

Intermediate B110—5-(1-(2,3-Difluorobenzylthio)-1-phenylaminomethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione [0207]
To hexane washed sodium hydride (7.45 g, 60% in oil) under argon, was added N-methylpyrrolidone (NMP) (270 ml) and the mixture cooled in an ice-salt bath. 2,2-Dimethyl-1,3-dioxane-4,6-dione (26.8 g) was added portionwise over 20 min keeping the temperature between 5-10° C. Effervescence was noted during the addition. The mixture was stirred at room temperature for 1 h and phenylisothiocyanate (25.2 g) added over 15 min. The mixture was stirred at room temperature for 2.5 h and cooled to 15° C. in a cold water bath. 2,3-Difluorobenzyl bromide (38.6 g) was added over 10 min and stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (1.2L) and water. The organic layer was washed with further water and then brine and dried over MgSO[0208] ₄. The solvent was removed under reduced pressure and the residue triturated with 40-60° C. petrol and the solid collected by filtration. Crystallisation from methyl t.butyl ether gave the title compound as a pale yellow solid (51.4 g). ¹H-NMR (d₆-DMSO) δ1.64 (6H, s), 4.16 (2H, d), 7.1-7.25 (2H, m), 7.25-7.5 (6H, m), 12.12 (1H, br s); MS (APCI−) found (M−1)=404; C₂₀H₁₇F₂NO₄S requires 405.
Intermediate B111—Ethyl 2-(1-(2,3-difluorobenzylthio)-1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidene)-methyl)phenylamino)acetate [0209]
To hexane washed sodium hydride (1.0 g, 60% in oil) under argon, was added NMP (30 ml). A solution of 5-(1-(2,3-Difluorobenzylthio)-1-phenylaminomethylene)-2,2dimethyl-[1,3]dioxane-4,6-dione (10.0 g) (intermediate B110) in NMP (20 ml) was added by syringe over 15 min at room temperature and stirred for 30 min. Ethyl bromoacetate (4.5 g) was added and the mixture heated at 60° C. for 6 h. The mixture was partitioned between ethyl acetate and water and the aqueous layer extracted with further ethyl acetate. The combined organic layers were washed with further water and brine, dried over MgSO[0210] ₄, and the solvent removed under reduced pressure. The orange oil so obtained was triturated with diethyl ether/40-60° C. petrol to give a solid that was collected by filtration. This solid was recrystallised from methyl t-butyl ether to give the title compound (7.37 g). ¹H-NMR (d₆-DMSO) δ1.24 (3H, t), 1.55 (6H, br s), 4.19 (2H, q), 4.37 (2H, d), 4.81 (2H, br s), 6.85-7.5 (8H, 2×m).
Intermediate B112—2-(2-(2,3-Difluorophenyl)ethyl)-6-methylpyrido[1,2-a]pyrimid-4-one [0211]
A mixture of 2-amino-6-methylpyridine (0.55 g, 1 equiv), Int. B80 (1.5 g, 1.15 equiv) and polyphosphoric acid (3 ml) was heated to 110° C. for 6 h, then ice/water was added and the solution adjusted to pH 7 with aq. sodium hydroxide. The precipitate was filtered off, washed with water and dried to obtain the title compound (1.3 g). [0212] ¹H-NMR (d₆-DMSO) δ2.89 (2H, m), 3.04 (3H, s), 3.12 (2H, m), 6.11 (1H, s), 6.62 (1H, d), 6.95-7.04 (3H, m), 7.35-7.44 (2H, m); MS (APCI+) found (M+1)=301; C₁₇H₁₄F₂N₂O requires 300.
Intermediate B113—2-(2-(2,3-Difluorophenyl)ethyl)-7-methyl-1H-[1,8]naphthyridin-4-one [0213]
A mixture of Int. B112 (1.0 g) and diphenyl ether (10 ml) was heated to reflux for 4 h, then cooled to 0° C. The resulting solid was filtered off, washed thoroughly with hexane and dried to obtain the title compound (0.67 g). [0214] ¹H-NMR (d₆-DMSO) δ2.58 (3H, s), 2.91 (2H, m), 3.09 (2H, m), 5.90 (1H, s), 6.62 (1H, d), 7.10-7.30 (4H, m), 8.26 (1H, d); MS (APCI+) found (M+1)=301; C₁₇H₁₄F₂N₂O requires 300.
Intermediate C1—2-(2,3-Difluorobenzylthio)-1H-quinolin-4-one [0215]
A mixture of 4-allyloxy-2-(2,3-difluorobenzylthio)quinoline (Int. B22) (2.24 g), triphenylphosphine rhodium (I) chloride (0.302 g, 5 mol %) and 1,4-diazobicyclo[2,2,2]octane (0.147 g, 20 mol %) in ethanol (30 ml) and water (1.5 ml) was heated to reflux for 4 h. The solvent was removed and the residue partitioned between water and dichloromethane, the organic phase dried and evaporated. Chromatography (silica, 4% methanol in dichloromethane) yielded the title compound as an off white solid (1.25 g). [0216] ¹H-NMR (d₆-DMSO) δ4.55 (2H, s), 6.37 (1H, br s), 7.15 (1H, m), 7.31 (3H, m), 7.65 (2H, m), 8.02 (1H, d), 11.75 (1H, br s); MS (APCI+) found (M+1)=304; C₁₆H₁₁F₂NOS requires 303.
The following intermediate was prepared by the method of intermediate C1: [0217]

No. Precursor Structure Name

C2 Int. B23
2-(4-Fluorobenzylthio)-1H-quinolin-4-one
Intermediate C3—2-(2-(2,3-Difluorophenyl)ethyl)-1H-quinolin-4-one [0218]
4-Chloro-2-(2,3-difluorophenylethyl)quinoline (Int B10) (2.83 g) was heated to reflux in aqueous hydrochloric acid (2M, 15 ml) and dioxane (6 ml) for 72 h. The reaction mixture was extracted with dichloromethane (90 ml) and methanol (10 ml), and the organic phase dried and evaporated to give the title compound as a white solid (2.61 g). [0219] ¹H-NMR (d₆-DMSO) δ3.15 (4H, s), 6.46 (1H, s), 7.15 (2H, m), 7.27 (1H, m), 7.51 (1H, m), 7.82 (2H, m), 8.15 (1H, d); MS (APCI+) found (M+1)=286; C₁₇H₁₃F₂NO requires 285.

The following intermediates were prepared by the method of intermediate C3:




No.	Precursor	Structure	Name


C4	Int. B11		2-(2-(4-Fluorophenyl)ethyl)-1H-quinolin-4-one

C5	Int. B12		2-(2-(3,4-Difluorophenyl)ethyl)-1H-quinolin-4- one

C6	Int. B13		2-(2-(2,4-Difluorophenyl)ethyl)-1H-quinolin-4- one

C7	Int. B14		2-(2-(2-Fluorophenyl)ethyl)-1H-quinolin-4-one

C8	Int. B15		2-(2-(3-Chlorophenyl)ethyl)-1H-quinolin-4-one

C9	Int. B16		2-(2-(2,3,4-Trifluorophenyl)ethyl)-1H-quinolin-4- one

C10	Int. B17		2-(2-(3-Fluorophenyl)ethyl)-1H-quinolin-4-one

Intermediate C11—2-(4-Fluorobenzylthio)-1,5,6,7-tetrahydro-[1]pyrindin-4-one [0221]
A mixture of 2-(4-fluorobenzylthio)-1-oxy-6,7-dihydro-5H-[1]pyrindin-4-ol (Int. B9) (1.54 g) and palladium/carbon (0.3 g, 20 wt %) in acetic acid (80 ml) was heated to 50° C. in an atmosphere of H[0222] ₂at 50 psi overnight. The catalyst was filtered off and solvent evaporated to give the title compound as a brown foam (1.21 g). ¹H-NMR (CDCl₃) δ2.03 (2H, m), 2.81 (4H, m), 4.14 (2H, s), 6.46 (1H, s), 6.89 (2H, m), 7.21 (2H, m); MS (APCI+) found (M+1)=276; C₁₅H₁₄FNOS requires 275.
The following intermediate was prepared by the method of Int. C11 [0223]

No. Precursor Structure Name

C12 Int. B25
2-(2,3-Difluorobenzylthio)-1,5,6,7-tetrahydro- [1]pyrindin-4-one
Intermediate D1—[2-(2,3-Difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]acetic acid tert butyl ester. [0224]
Butyllithium (2.5 M in hexanes, 1.52 ml, 1.05 equiv) was added dropwise to a solution of 2-(2,3-difluorobenzylthio)-1H-quinolin-4-one (Int. C1) (1.1 g, 1 equiv) in tetrahydrofuran (20 ml) at 0° C. under argon. The reaction mixture was stirred for 10 min prior to the addition of t-butyl bromoacetate (1.76 ml), 3 equiv) and stirring continued for 60 h at 45° C. The solution was diluted with dichloromethane (40 ml) and washed with aqueous ammonium chloride and aqueous sodium bicarbonate, dried and evaporated. Chromatography (silica, 5% [2M ammonia in methanol] in dichloromethane) yielded the title compound as a yellow foam (0.193 g). [0225] ¹H-NMR (CDCl₃) δ1.44 (9H, s), 4.29 (2H, s), 5.30 (2H, br s), 6.45 (1H, s), 7.06-7.24 (4H, m), 7.39 (1H, t), 7.63 (1H, dt), 8.41 (1H, dd); MS (APCI+) found (M+1)=418; C₂₂H₂₁F₂NO₃S requires 417.

The following intermediates were prepared by the method of Intermediate D1:



No.	Precursor	Structure	Name


D2	Int. C3		[2-(2-(2,3-Difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tert butyl ester.

D3	Int. C2		[2-(4-Fluorobenzylthio)-4-oxo-4H- quinolin-1-yl]acetic acid tert butyl ester.

D4	Int. C4		[2-(2-(4-Fluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tert butyl ester.

D5	Int. C5		[2-(2-(3,4-Difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tert butyl ester.

D6	Int. C6		[2-(2-(2,4-Difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tert butyl ester.

D7	Int. C7		[2-(2-(2-Fluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tert butyl ester.

D8	Int. C8		[2-(2-(3-Chlorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tert butyl ester.

D9	Int. C9		[2-(2-(2,3,4-Trifluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]acetic acid tert butyl ester.

D10	Int. C10		[2-(2-(3-Fluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tert butyl ester.

D11	Int. B99		t-Butyl [5-(2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-2,7-dihydropyrazolo[4,3-b]- pyridin-4-yl]acetate

D12	Int. B98		t-Butyl [5-(2-(2,3-difluorophenyl)ethyl)1- methyl-7-oxo-1,7-dihydropyrazolo[4,3-b]- pyridin-4-yl]acetate

D13	Int. C12		t-Butyl [2-(2,3-difluorobenzylthio)-4-oxo- 5,6-trimethylenepyridin-1-yl]acetate

D14	Int. C3		Methyl 2-(2-(2-(2,3-difluorophenyl)ethyl)- 4-oxo-4H-quinolin-1-yl)acetate

D15	Int. B113		Ethyl [2-(2-(2,3-difluorophenyl)ethyl)-7- methyl-4-oxo-4H-[1,8]naphthyridin-1-yl]- acetate

Intermediate D20—[2-(4Fluorobenzylthio)-4-oxo-4,5,6,7-tetrahydro-[1]pyrindin-1-yl]acetic acid tert butyl ester. [0227]
A mixture of 2-(4-fluorobenzylthio)-1,5,6,7-tetrahydro-[1]pyrindin-4-one (Int. C11) (1.21 g, 1 equiv), t-butyl iodoacetate (3.18 g, 3 equiv) and diisopropylethylamine (3.05 ml, 4 equiv) in dichloromethane (40 ml) was stirred at ambient temperature under argon for 48 h, then the solution was washed with aqueous ammonium chloride and aqueous sodium bicarbonate, dried and evaporated. Chromatography (silica, 5% methanol in dichloromethane) yielded the title compound as a off white foam (0.982 g). [0228] ¹H-NMR (CDCl₃) δ1.47 (9H, s), 2.09 (2H, m), 2.84 (4H, m), 4.07 (2H, s), 4.56 (2H, s), 6.45 (1H, s), 6.99 (2H, m), 7.25 (2H, m); MS (APCI+) found (M+1)=390; C₂₁H₂₄FNO₃S requires 389.
Intermediate D25—Ethyl (2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl)acetate [0229]
(a) A mixture of dimethyloxosulphonium-2-(ethoxycarbonylmethylamino)benzoylmethylide (0.30 g, 1.01 mmol) (intermediate B100), carbon disulphide (0.13 ml, 2.05 mmol) and diisopropylethylamine (0.35 ml, 2.02 mmol) in DMF (4 ml) was shaken under argon for 18 h then 2,3-difluorobenzyl bromide (0.42 g, 2.02 mmol) added and the reaction shaken for a further 7 h. The solution was concentrated and the residues separated between ethyl acetate and water. The organics were isolated, dried (MgSO[0230] ₄) and concentrated. Purification by chromatography over silica eluting using a gradient from dichloromethane to dichloromethane/ether 3:1 yielded the title compound (0.14 g, 36%). ¹H-NMR (d₆-DMSO) δ1.2 (3H, t, J=7Hz), 4.18 (2H, q, J=7Hz), 4.5 (2H, s), 5.3 (2H, s), 6.3 (1H, s), 7.18 (1H, m), 7.3 (1H, m), 7.4 (2H, m), 7.6 (1H, d, J=8.5Hz), 7.7 (1H, t, J=7Hz), 8.1 (1H, d, J=8 Hz). MS (APCI+) found (M+1)=390; C₂₀H₁₇F₂NO₃S requires 389.
(b) Ethyl (1-(2,3-difluorobenzylthio)-1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidene)-methyl)-phenylamino)acetate (intermediate B111) (0.85 g) under argon was stirred with trifluoroacetic acid (10 ml) at room temperature overnight. The mixture was evaporated under reduced pressure, dissolved in dichloromethane, washed with sodium bicarbonate solution and dried over Na[0231] ₂SO₄. The solvent was removed under reduced pressure and the residue triturated with diethyl ether to give the title compound (0.43 g). ¹H-NMR (CDCl₃) δ1.27 (3H, t), 4.26 (2H, q), 4.29 (2H, s), 5.1 (2H, br s), 6.45 (1H, s), 6.95-7.25 (4H, m), 7.39 (1H, t), 7.64 (1H, dt), 8.42 (1H, dd). Mass spectrum as above.
Intermediate D26—(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl)acetic acid ethyl ester [0232]
(3-tert-Butoxycarbonylmethyl-2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-4H-[1,8]naphthyridin-1-yl)acetic acid ethyl ester (Int. B71) (1.35 g, 2.86 mmol) was added portionwise to boiling diphenyl ether (10 ml) with stirring. After 20 min, the dark solution was allowed to cool to ambient temperature. Petroleum ether (b.p. 60-80° C.) was added to the point of cloudiness to give the product as a crystalline solid (0.724 g). [0233] ¹H NMR (d₆-DMSO) δ1.19 (3H, t), 3.02-3.09 (4H, m), 4.16 (2H, q), 5.31 (2, s), 6.10 (1H, s), 7.13-7.21 (2H, m), 7.26-7.33 (1H, m), 7.46-7.49 (1H, m), 8.49 (1H, m), 8.76 (1H, m). MS (APCI+), found (M+1)=373, C₂₀H₁₈F₂N₂O₃requires 372.

The following intermediates were prepared by the method of Intermediate D26:




No.	Precursor	Structure	Name


D27	Int. B72		Ethyl [2-(2-(2,3-difluorophenyl)ethyl)- 5-ethyl-4-oxo-4H-pyridin-1-yl]acetate

D28	Int. B73		Ethyl [2-(2-(2,3-difluorophenyl)ethyl)- 5,6-dimethyl-4-oxo-4H-pyridin-1-yl]- acetate

D29	Int. B74		Ethyl 5-[2-(2-(2,3- difluorophenyl)ethyl)-2-methyl-7-oxo- 7H-thieno[3,2-b]pyridin-4-yl]acetate

D30	Int. B75		Ethyl [2-(2-(2,3-difluorophenyl)ethyl)- 4-oxo-4H-thieno[3,4-b]pyridin-1-yl]- acetate

D31	Int. B76		Ethyl [5-(2-(2,3-difluorophenyl)ethyl)- 2-methyl-7-oxo-7H-thiazolo[4,5-b]- pyridin-4-yl]acetate

D32	Int. B77		Ethyl [6-(2-(2,3-difluorophenyl)ethyl)- 2-methyl-4-oxo-4H-pyrazolo[3,4-b]- pyridin-7-yl]acetate

D33	Int. B78		Ethyl [2-(2-(2,3-difluorophenyl)ethyl)- 4-oxo-5,6-trimethylenepyridin-1-yl]- acetate

D34	Int. B79		Ethyl [2-(2-(2,3-difluorophenyl)ethyl)- 4-oxo-5,6-tetramethylenepyridin-1-yl]- acetate

The following intermediates were prepared by the method of Intermediate D25, method A:




No.	Precursor	Structure	Name


D40	Int. B101		Ethyl [2-(2,3-difluorobenzylthio)-7- fluoro-4-oxo-4H-quinolin-1-yl]acetate

D41	Int. B102		Ethyl [5-(2,3-difluorobenzylthio)-7- oxo-7H-thieno[3,2-b]pyridin-4-yl]- acetate

D42	Int. B103		Ethyl [5-(2,3-difluorobenzylthio)-7- oxo-7H-thieno[2,3-b]pyridin-4-yl]- acetate

D43	Int. B104		Ethyl [6-(2,3-difluorobenzylthio)-2- methyl-4-oxo-2,4-dihydro- pyrazolo[3,4-b]pyridin-7-yl]acetate

D44	Int. B105		Ethyl [2-(2,3-difluorobenzylthio)-4- oxo-4H-[1,8]naphthyridin-1-yl]acetate

Intermediate D50—Ethyl [6-(2-(2,3-difluorophenyl)ethyl)-2-ethyl-4-oxo-2,4-dihydropyrazolo[3,4-b]pyridin-7-yl]acetate [0236]
A mixture of Intermediate B92 (0.120 g, 1 equiv), potassium carbonate (0.070 g, 1.5 equiv) and iodoethane (1 equiv) in dry DMF (1.5 ml) was stirred at room temperature for 4 days. Ethyl acetate was added, the solution was washed with aq. sodium bicarbonate, then dried and evaporated Chromatography (silica, 0-10% methanol in dichloromethane) gave the title compound as abrown solid (0.1 g, 77%). [0237] ¹H-NMR (CDCl₃) δ1.28 (3H, t), 1.54 (3H, t), 2.82 (2H, m), 3.02 (2H, m), 4.21-4.28 (4H, 2×q), 4.93 (2H, s), 5.96 (1H, s), 6.93-7.08 (3H, m), 8.01 (1H, s); MS (APCI+) found (M+1)=390; C₂₀H₂₁F₂O₃requires 389.

The following intermediate was prepared by the method of Intermediate 50:



No.	Precursor	Structure	Name


D51	Int. B92, 2-iodo- propane		Ethyl [6-(2-(2,3-difluorophenyl)ethyl)- 2-isopropyl-4-oxo-2,4-dihydropyrazolo- [3,4-b]pyridin-7-yl]acetate

D52	Int. B92, 1-bromo-2- methoxy- ethane		Ethyl [6-(2-(2,3-difluorophenyl)ethyl)- 2-(2-methoxyethyl)-4-oxo-2,4-dihydro- pyrazolo[3,4-b]pyridin-7-yl]acetate

Intermediate E1—[2-(2,3-Difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]acetic acid [0239]
(a) Trifluoroacetic acid (0.5 ml) was added to a solution of Int. D1 (0.193 g) in dichloromethane (5 ml) under argon, and stirred overnight at room temperature. Evaporation of the solvent and trituration with ether gave the title compound as a white solid (0.153 g). [0240]
(b) To a solution of Int. D25 (21.56 g, 0.055 mol) in dioxan (200 ml) was added sodium hydroxide (6.0 g, 0.15 mol) in water (200 ml) and the solution stirred for 2.5 h then concentrated. The residues were dissolved in water and acidified to pH 2 with 2M hydrochloric acid and the precipitate collected and washed sequentially with water, ether and then hexane. The solids were dried in vacuo at 40° C. to provide the title compound (20.0 g, 100%). [0241] ¹H-NMR (d₆-DMSO) δ4.5 (2H, s), 5.2 (2H, br s), 6.3 (1H, s), 7.18 (1H, m), 7.3 (1H, m), 7.4 (2H, m), 7.6 (1H, d, J=8.5 Hz), 7.7 (1H, t, J=8 Hz), 8.1 (1H, d, J=8 Hz). MS (APCI+) found (M+1)=362; C₁₈H₁₃F₂NO₃S requires 361.

The following intermediates were prepared by the method of Intermediate E1(a):




No.	Precursor	Structure	Name


E2	Int. D2		[2-(2-(2,3-Difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-acetic acid

E3	Int. D3		[2-(4-Fluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-acetic acid

E4	Int. D20		[2-(4-Fluorobenzylthio)-4-oxo-4,5,6,7- tetrahydro-[1]pyridin-1-yl]-acetic acid

E5	Int. D4		[2-(2-(4-Fluorophenyl)ethyl-4-oxo- 4H-quinolin-1-yl]-acetic acid

E6	Int. D5		[2-(2-(3,4-Difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-acetic acid

E7	Int. D6		[2-(2-(2,4-Difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-acetic acid

E8	Int. D7		[2-(2-(2-Fluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-acetic acid

E9	Int. D8		[2-(2-(3-Chlorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-acetic acid

E10	Int. D9		[2-(2-(2,3,4-Trifluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-acetic acid

E11	Int. D10		[2-(2-(3-Fluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-acetic acid

E12	Int. D13		[2-(2,3-difluorobenzylthio)-4-oxo-5,6- trimethylenepyridin-1-yl]acetic acid

E13	Int. D11		[5-(2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-2,7- dihydropyrazolo[4,3-b]pyridin-4-yl]- acetic acid

E14	Int. D12		[5-(2-(2,3-difluorophenyl)ethyl)-1- methyl-7-oxo-1,7- dihydropyrazolo[4,3-b]pyridin-4-yl]- acetic acid

The following intermediates were prepared by the method of Intermediate E1(b):



No.	Precursor	Structure	Name


E2	Int. D14	(2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl)acetic acid

E21	Int. D26	(2-[2-(2,3-difluorophenyl)ethyl]-4- oxo-4H-[1,8]naphthyridin-1-yl)acetic acid

E22	Int. D40	[2-(2,3-difluorobenzylthio)-7-fluoro-4- oxo-4H-quinolin-1-yl]acetic acid

E23	Int. D27	[2-(2-(2,3-difluorophenyl)ethyl)-5- ethyl-4-oxo-4H-pyridin-1-yl]acetic acid

E24	Int. D28	[2-(2-(2,3-difluorophenyl)ethyl)-5,6- dimethyl-4-oxo-4H-pyridin-1-yl]acetic acid

E25	Int. D41	[5-(2,3-difluorobenzylthio)-7-oxo-7H- thieno[3,2-b]pyridin-4-yl]acetic acid

E26	Int. D29	5-[2-(2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-7H-thieno[3,2- b]pyridin-4-yl]acetic acid

E27	Int. D30	[2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-thieno[3,4-b]pyridin-1-yl]-acetic acid

E28	Int. D31	[5-(2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-7H-thiazolo[4,5-b]- pyridin-4-yl]acetic acid

E29	Int. D43	[6-(2,3-difluorobenzylthio)-2-methyl- 4-oxo-2,4-dihydropyrazolo[3,4-b]- pyridin-7-yl]acetic acid

E30	Int. D32	[6-(2-(2,3-difluorophenyl)ethyl)-2- methyl-4-oxo-4H-pyrazolo[3,4-b]- pyridin-7-yl]acetic acid

E31	Int. D50	[6-(2-(2,3-difluorophenyl)ethyl)-2- ethyl-4-oxo-2,4- dihdropyrazolo[3,4-b]pyridin-7-yl]- acetic acid

E32	Int. D51	[6-(2-(2,3-difluorophenyl)ethyl)-2- isopropyl-4-oxo-2,4-dihydropyrazolo- [3,4-b]pyridin-7-yl]acetic acid

E33	Int. D15	[2-(2-(2,3-difluorophenyl)ethyl)-7- methyl-4-oxo-4H-[1,8]naphthyridin-1- yl]acetic acid

E34	Int. D44	[2-(2,3-difluorobenzylthio)-4-oxo-4H- [1,8]naphthyridin-1-yl]acetic acid

E35	Int. D42	[5-(2,3-difluorobenzylthio)-7-oxo-7H- thieno[2,3-b]pyridin-4-yl]acetic acid

E36	Int. D33	[2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-5,6-trimethylenepyridin-1-yl]- acetic acid

E37	Int. D34	[2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-5,6-tetramethylenepyridin-1-yl]- acetic acid

E38	Int. D52	[6-(2-(2,3-difluorophenyl)ethyl)- 2-(2-methoxyethyl)-4-oxo-2,4- dihydropyrazolo[3,4-b]pyridin-7-yl]acetic acid

Example 1

N-(2-Diethylaminoethyl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4ylmethyl)acetamide bitartrate [0244]
A mixture of 2-(2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl)acetic acid (Int. E1) (0.15 g, 1 equiv), N,N-diethyl-N′-(4′-trifluoromethylbiphenyl-4-ylmethyl)ethane-1,2-diamine (Int. A2) (0.145 g, 1 equiv), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.154 g, 1.2 equiv) and diisopropylamine (0.174 ml, 2.4 equiv) in dichloromethane (10 ml) was stirred at room temperature overnight, then washed with aqueous ammonium chloride and aqueous sodium bicarbonate. The organic layer was dried and evaporated, and the product purified by column chromatography (silica, 4% [2M ammonia in methanol] in dichloromethane). Product fractions were evaporated to an off-white foam (0.201 g). This free base (0.201 g) was dissolved in methanol (10 ml), tartaric acid (0.044 g) was added, the mixture stirred for 5 min then evaporated. Trituration with ether gave the bitartrate salt as an off-white solid (0.209 g). [0245] ¹H-NMR (d₆-DMSO, ca 2:1 rotamer mixture) δ1.03 (6H, m), 2.59 (6H, m), 3.41-3.62 (2H, m), 4.26 (2H, 2× s), 4.65-4.83 (2H, m), 5.12-5.56 (2H, m), 6.44 (1H, 2× s), 6.93-7.12 (3H, m), 7.30-7.75 (11H, m), 8.41 (1H, 2× d); MS (APCI+) found (M+1)=694; C₃₈H₃₆F₅N₃O₂S requires 693.

Example 2

N-(2-Diethylaminoethyl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide [0246]
A mixture of 2-[2-(2-(2,3-difluorophenyl)ethyl)4oxo-4H-quinolin-1-yl]-acetic acid (Int. E2) (0.26 g, 1 equiv), N,N-diethyl-N′-(4′-trifluoromethylbiphenyl-4-ylmethyl)ethane-1,2-diamine (Int A2) (0.265 g, 1 equiv), HATU (0.28 g, 1.2 equiv) and diisopropylamine (0.32 ml, 2.4 equiv) in dichloromethane (15 ml) was stirred at room temperature overnight, then washed with aqueous ammonium chloride and aqueous sodium bicarbonate. The organic layer was dried and evaporated, and the product purified by column chromatography (silica, 2% [2M ammonia in methanol] in dichloromethane). Product fractions were evaporated to an off-white foam (0.201 g). Trituration with ether gave the title compound as a white solid (0.476 g). [0247] ¹H-NMR (d₆-DMSO, ca 2:1 rotamer mixture) δ0.93 (6H, 2× t), 2.38-2.80 (4H, m), 2.90-3.05 (4H, m), 3.45 (2H, m), 4.30-4.95 (4H, m), 5.23-5.58 (2H, m), 6.06 (1H, 2× s), 7.14-7.38 (7H, m), 7.50-7.95 (7H, m), 8.16 (1H, m); MS (APCI+) found (M+1)=676; C₃₉H₃₈F₅N₃O₂requires 675.

Example 3

N-(2-Diethylaminoethyl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0248]
Treatment of N-(2-Diethylaminoethyl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide (Ex 2) with d-tartaric acid as for Example 1 gave the title compound as the bitartrate salt. [0249]

Example 4

N-(2-Diethylaminoethyl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-5,6-trimethylenepyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0250]
The free base was prepared from Int. E12 and Int. A2 by the method of Example 1. The bitartrate was formed as in example 1. [0251] ¹H NMR (d₆-DMSO) δ0.93, 0.99 (6H, 2× t), 1.95 (2H, m), 2.57-2.88 (8H, m), 3.21-3.60 (4H, m), 4.21 (2H, s), 4.23, 4.29 (2H, 2× s), 4.64, 4.75 (2H, 2× s) 6.15 6.17 (1H, 2× s), 7.12-7.21 (2H, m), 7.34-7.45 (3H, m), 7.67 (1H, d), 7.71 (1H, d), 7.85 (4H, m); MS (APCI) found (M+1)=684; C₃₇H₃₈F₅N₃O₂S requires 683.

Example 5

N-1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide [0252]
The free base was prepared from Int. E1 and Int. A42 by the method of Example 1, except using DMF as solvent in place of dichloromethane. 1.97 g of this material was crystallised from n.butyl acetate (10 ml) to give the title compound (1.35 g). [0253] ¹H-NMR (CD₃OD) δ1.7-2.05 (4H, m), 2.05-2.3 (2H, 2× t), 2.5-2.65 (2H, m), 2.95-3.1 (2H, m), 3.3 (3H, s), 3.45-3.55 (2H, m), 3.9-4.05+4.4-4.5 (1H, 2× m), 4.37+4.48 (2H, 2×s), 4.71+4.87 (2H, 2× br s), 5.31+5.68 (2H, 2× s), 6.44+6.52 (1H, 2×s), 6.95-7.3 (3H, m), 7.35-7.85 (11H, m), 8.2-8.35 (1H, m); MS (APCI+) found (M+1) 736; C₄₀H₃₈F₅N₃O₃S requires 735.

Example 6

N-(1-Methylpiperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0254]
The free base was prepared from Int. E1 and Int. A5 by the method of Example 1, except using DMF as solvent in place of dichloromethane. Chromatography (acetone to acetone/MeOH 4:1) yielded the free base (˜7:3 rotomer mixture); [0255] ¹H-NMR (CDCl₃) δ1.7-1.8 (3.7H, m), 1.9-2.15 (2.3H, m), 2.26 (2.1H, s), 2.3 (0.9H, s), 2.9 (1.4H, d, J=11.5 Hz), 2.98 (0.6H, d, J=10 Hz), 3.7 (0.3H, m), 4.2 (1.4H,s), 4.27 (0.6H, s), 4.62 (0.7H, m), 4.69 (0.6H, s), 4.73 (1.4H, s), 5.01 (1.4H, br s), 5.35 (0.6H, (0.6H, br s), 6.41 (0.7H, s), 6.49 (0.3H, s), 6.9-7.2 (4H, m), 7.29-7.75 (1OH, m), 8.38 (0.7H, d, J=8 Hz), 8.4 (0.3H, d, J=8 Hz); MS (APCI+) found (M+1)=692; C₃₈H₃₄F₅N₃O₂S requires 691
Conversion to bitartrate salt was carried out as in Example 1. [0256]

Example 7

N-(1-Methylpiperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0257]
To a stirring mixture of intermediate A5 (12.53 g, 1 equiv) and diisopropylethylamine (18.82 ml, 3 equiv) in dry THF (125 ml) under an argon atmosphere was added in one portion O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (16.65 g, 1.5 equiv). A solution of Int. E21 (12.4 g, 1 equiv), in dry N-methylpyrrolidone (25 ml) and dry THF (100 ml) was then added dropwise over 1.5 h. After 72 h the solvents were evaporated under reduced pressure and the residue treated with aqueous sodium bicarbonate and extracted 3 times with ethyl acetate. The combined extracts were washed with aqueous sodium bicarbonate, aqueous ammonium chloride then aqueous sodium bicarbonate, dried (Na[0258] ₂SO₄) and evaporated. The residue was chromatographed (fine silica, 2M ammonia in methanol/dichloromethane) and the product obtained dissolved in dichloromethane and washed twice with 0.5M aqueous sodium hydroxide then brine, dried (Na₂SO₄) and the solvent evaporated. Crystallisation then recrystallisation from acetonitrile gave the free base, 10.75 g. This material (10.69 g, 1 equiv) together with L-tartaric acid (2.39 g, 1 equiv) was dissolved in methanol (50 ml) and evaporated to a thick syrup which was triturated with ether to give the bitartrate salt as an off-white solid (12.4 g). ¹H NMR (d₆-DMSO), 81.58-1.66 and 1.80-2.05 (4H, m), 2.40-2.65 (5H, m), 2.93-3.19 (6H, m), 4.15 (2H, s), 4.16-4.38 (1H, m), 4.62, 4.88, 5.42, 5.68 (4H, 4× s), 6.00, 6.03 (1H, 2× s), 7.10-7.97 (13H, m), 8.48 (1H, m), 8.82-8.90 (1H, m); MS (APCI+) found (M+1)=675; C₃₈H₃₅F₅N₄O₂requires 674.

Example 8

N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide [0259]
To a stirring mixture of Int. A42 (14.12 g, 1 equiv) and diisopropylethylamine (18.82 ml, 3 equiv) in dry THF (125 ml) under an argon atmosphere was added in one portion O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (16.65 g, 1.5 equiv). A solution of Int. E21 (12.4 g, 1 equiv), in dry N-methylpyrrolidone (25 ml) and dry THF (100 ml) was then added dropwise over 1.5 h. After 16 h the solvents were evaporated under reduced pressure and the residue treated with 1M hydrochloric acid (200 ml) and extracted 3 times with ethyl acetate. The combined extracts were washed with 1M hydrochloric acid (200 ml), brine, 2M sodium hydroxide ×2, dried (Na[0260] ₂SO₄) and evaporated. The residue was chromatographed (fine silica, 2M ammonia in methanol/dichloromethane) and the oil obtained dissolved in ether and allowed to crystallise then recrystallised from dichloromethane/ether, yield 11.98 g (free base). 13.64 g of title compound formed in the same manner as above was recrystallised from hot n.butyl acetate (70 ml) to give crystalline title compound (11.5 g). ¹H NMR (CD₃OD), δ1.6-2.35 (6H, m), 2.45-2.65 (2H, 2× m), 2.9-3.12 (4H, m), 3.12-3.55 (2H, 2×t), 4.17+4.40 (1H, 2× m), 4.71+4.93 (2H, s), 5.3-6.0 (2H, br), 6.26+6.31 (1H, 2×s), 7.0-7/35 (3H, m), 7.3-7.4 (1H, d), 7.45-7.6 (2H, m), 7.6-7.9 (6H, m), 8.61 (1H, br t), 8.87 (1H, m); MS (APCI+) found (M+1)=719, C₄₀H₃₉F₅N₄O₃requires 718.

Example 9

N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3difluorobenzylthio)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0261]
The free base was prepared from Int. E34 and Int. A42 by the method of Example 7. Chromatography (EtOAc/acetone/MeOH 9:1) yielded the free base. [0262] ¹H-NMR (d₆-DMSO) (˜1:1 rotomer mixture): a δ1.55 (1H, br d, 11 Hz), 1.75-1.9 (4H, m), 2.15 (0.5H, t, J=8 Hz), 2.3 (1H, br t, J=11 Hz), 2.66 (2H, m), 3.06 (2H, br t, 12 Hz), 3.2 (1.5H, s), 3.25 (1.5H, s), 3.3 (0.5H, t, J=7 Hz), 3.45 (2H, m), 4.1 (0.5H, m), 4.2 (2H, s), 4.25 (0.5H, m), 4.5 (1H, s), 4.59 (2H, br s), 4.8 (1H, br), 5.75 (1H, br), 6.35 (0.5H, s), 6.38 (0.5H, s), 7.16 (1H, m), 7.2-7.4 (4H, m), 7.6 (2H, d, J=8 Hz), 7.7 (5H, m), 8.5 (1H, m), 8.7 (2H, br), 8.82 (1H, m); MS (APCI+) found (M+1)=737; C₃₉H₃₇F₅N₄O₃S requires 736.

Example 10

N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-ethylbiphenyl-4-ylmethyl)acetamide bitartrate [0263]
The free base was prepared from Int. E1 and Int A29 by the method of Example 1, except using DMF as solvent in place of dichloromethane. The bitartrate salt was formed as in example 1. [0264] ¹H NMR (d₆-DMSO) δ1.07 (3H, t), 1.22 (3H, t), 1.70-1.91 (4H, m), 2.37 (2H, m), 2.66 (4H, m), 3.20 (2H,m), 4.12 (2H, s), 4.44 (3H, m), 4.70 (2H, m), 5.34 (2H, m), 6.27, 6.33 (1H, 2× s), 7.11-7.76 (14H,m), 8.14 (1H, m); MS (APCI) found (M+1)=666; C₄₀H₄₁F₂N₃O₂S requires 665.

Example 11

N-(1-Ethylpiperidin-4-yl)-2-[5-(2-(2,3-difluorophenyl)ethyl)-2-methyl-7-oxo-7H-thiazolo[4,5-b]pyridin-4-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0265]
Prepared from intermediate E28 (0.15 g) and intermediate A40 (0.149 g) using HATU (0.188 g) and diisopropylamine (0.172 ml) followed by bitartrate salt formation as in example 1. [0266] ¹H-NMR (d₆-DMSO) δ0.95-1.15 (3H, m), 1.6-2.1 (4H, m), 2.84 (3H, 2×s), 2.3-3.25 (10H, m) 4.14 (2H, s), 4.05-4.4 (1H, 2×m), 4.62+4.83 (2H, 2× br s), 5.37+5.62 (2H, 2×br s), 6.02+6.05 (1H 2× s), 7.05-7.4 (4H, m), 7.5-7.7 (2H, m), 7.7-8.0 (5H, m); MS (APCI+) found (M+1)=709; C₃₈H₃₇F₅N₄O₂S requires 708.

Example 12

(±)N-(1-Ethylpyrrolidin-3-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0267]
Prepared from intermediate E2 (0.295 g) and A23 (0.30 g) using HATU (0.395 g) and diisopropylamine (0.3 ml) followed by bitartrate salt formation as in example 1. Spectral details of the free base are quoted below. [0268] ¹H-NMR (CDCl₃) δ1.0-1.2 (3H, m), 1.8-2.15 (1H, m), 2.15-3.15 (11H, m), 4.6-5.2 (5H, m), 6.14+6.24 (1H, 2× s), 6.8-7.8 (14H, m), 8.25-8.45 (1H, m); MS (APCI+) found (M+1)=674; C₃₉H₃₆F₅N₃O₂requires 673.

Example 13

(±)N-(1-Ethylpyrrolidin-3-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0269]
Prepared from intermediate E1 (0.312 g) and A23 (0.30 g) using HATU (0.395 g) and diisopropylamine (0.3 ml) followed by bitartrate salt formation as in example 1. Spectral details of the free base are quoted below. [0270] ¹H-NMR (CDCl₃) δ0.95-1.35 (3H, m), 1.8-2.8 (6H, m), 2.8-3.1 (2H, m), 4.19+4.25 (2H, 2×s), 4.5-5.5 (5H, m), 6.36+6.43 (1H, 2× s), 6.85-7.2 (4H, m), 7.2-7.85 (10H, m), 8.25-8.5 (1H, m).

Example 14

N-(4-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0271]
Example 5 was converted to the bitartrate by the method of example 1. [0272]

Example 15

N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide dihydrochloride [0273]
Example 5 (1.0 g) was dissolved in isopropanol (10 ml) and 1 M HCl in diethyl ether (4 ml) added. A thick precipitate formed. The mixture was evaporated under reduced pressure and the residue dissolved in isopropanol (10 ml) with heating. On cooling a thick precipitate formed that was filtered and dried. 0.2 g of this material was recrystallised from further isopropanol (10 ml) to give the title compound (0.132 g). [0274] ¹H-NMR (CD₃OD) δ1.9-2.6 (4H, m), 3.0-3.5 (4H, m), 3.36+3.41 (3H, 2×s), 3.5-3.8 (4H, m), 7.0-7.5 (4H, m), 7.5-7.65 (3H, m), 7.65-7.85 (5H, m), 7.9-8.2 (2H, m), 8.4-8.55 (1H, m).

Example 16

N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide mono paratoluenesulphonate [0275]
To a solution of example 5 (1.0 g) in tetrahydrofuran (THF) (10 ml) was added a solution of paratoluenesulphonic acid monohydrate (1 equiv) in THF (5 ml) and the mixture stirred at 0° C. After 18 h, further THF was added and the mixture filtered and dried to give a solid (0.87 g). 0.7 g of this material was dissolved in THF (9 ml) and left at 0° C. for 18 h. The solid formed was filtered and washed with further THF (2 ml) and dried to give the title compound as a crystalline salt (0.67 g). [0276] ¹H-NMR (CD₃OD) δ1.9-2.4 (4H, m), 2.31 (3H, s), 3.0-3.45 (7H, m′s), 3.5-3.75 (4H, m), 4.3-4.55 (3H, m), 4.6-5.0 (2H, m), 5.40+5.73 (2H, 2× s), 6.47 (1H, s), 6.95-7.3 (5H, m), 7.3-7.85 (13H, m),

Example 17

N-(1-(2-Methoxyethyl)piperidin-4yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0277]
Example 8 (8 g, 1 equiv) together with L-tartaric acid (1.67 g, 1 equiv) was dissolved in methanol (50 ml) and evaporated to a thick syrup which was triturated with ether to give the bitartrate salt as an off-white solid (9.54 g). [0278] ¹H NMR (CD₃OD), δ1.53-1.64 and 1.70-1.87 (4H, m), 2.15-2.43 and 2.55-2.69 (4H, m), 2.93-3.50 (11 H, m), 4.05-4.32 (1H, m), 4.19 (2H, s), 4.61, 4.87, 5.42, 5.67 (4H, 4× s), 6.08, 6.11 (1H, 2× s), 7.09-7.94 (12H, m), 8.49 (1H, m), 8.82-8.90 (1H, m); MS (APCI+) found (M+1)=719, C₄₀H₃₉F₅N₄O₃requires 718.

Example 18

N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide monohydrochloride [0279]
Example 8 (0.5 g) in methylethylketone (4 ml) was mixed with 4M HCl in dioxane (0.174 ml). After 18 h at 0° C., a small amount of solid was filtered off. The mother liquors were evaporated under reduced pressure and the residue crystallised from acetone (4 ml). The solid so formed was recrystallised from acetone to give the title compound (0.336 g). [0280] ¹H NMR (CD₃OD), δ1.85-2.5 (4H, m), 2.95-3.15 (4H, br), 3.15-3.5 (7H, ss+m), 3.8 (4H, m), 4.38+4.61 (1H, br m), 4.74+4.97 (2H, 2×s), 5.4-6.0 (2H, br), 6.29 (1H, s), 7.0-7.25 (3H, m), 7.3-7.65 (2H, m), 7.65-7.9 (7H, m), 8.6-8.7 (1H, m), 8.8-8.9 (1H, m).

Example 19

N-(9-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H -[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide dihydrochloride [0281]
Example 8 (0.321 g) in ethanol (3 ml) was stirred overnight with 4M HCl in dioxan (0.25 ml). The solid was collected by filtration, washed with ethanol and dried to give the title compound (0.31 g). [0282] ¹H NMR (CD₃OD), δ1.8-2.55 (4H, m), 3.0-3.8 (15H, m), 4.15-5.1 (3H, m), 5.6-6.6 (2H, br), 6.94+6.97 (1H, 2×s), 7.0-7.25 (3H, m), 7.3-7.95 (9H, m), 8.8-8.95 (1H, m), 9.15-9.25 (1H, m).

The following Examples were made by the general method of Example 1, using an appropriate solvent such as dimethylformamide or dichloromethane:



Ex.
No.	Precursors	Structure	Name


20	Int. E3 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(4- fluorobenzylthio)-4-oxo-4H-quinolin-1- yl]-N-(4′-trifluoromethylbiphenyl-4- ylmethyl)-acetamide bitartrate

21	Int. E4 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(4- fluorobenzylthio)-4-oxo-5,6-trimethylene- pyridin-1-yl]-N-(4′- trifluoromethyl-biphenyl-4- ylmethyl)acetamide bitartrate

22	Int. E12 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-5,6- trimethylenepyridin-1-yl]-N-(4′- trifluoromethyl-biphenyl-4- ylmethyl)acetamide bitartrate

23	Int. E5 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(4- fluorophenyl)ethyl)4-oxo-4H- methylbiphenyl-4-ylmethyl)-acetamide

24	Int. E6 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2- (3,4-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

25	Int. E8 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2- (2-fluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

26	Int. E9 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2- (3-chlorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

27	Int. E21 Int A2	N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-[1,8]naphthyridin-1-yl)]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

28	Int. E21 Int A40	N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-[1,8]naphthyridin-1-yl)]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide

29	Int. E2 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

30	Int. E2 Int. A22	N-(2-Pyrrolidin-1-ylethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)-acetamide bitartrate

31	Int. E2 Int. A41	N-(1-Isopropylpiperidin-4-yl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

32	Int. E2 Int. A20	N-(2-piperidin-1-ylethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

33	Int. E22 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)7-fluoro-4-oxo- 4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

34	Int. E26 Int. A2	N-(2-Diethylaminoethyl)-5-[2-(2- (2,3-difluorophenyl)ethyl)-2-methyl-7- oxo-7H-thieno[3,2-b]pyridin-4-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)- acetamide bitartrate

35	Int. E24 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-5,6- dimethyl-4-oxo-4H-pyridin-1-yl]- N-(4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

36	Int. E23 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-5-ethyl- 4-oxo-4H-pyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

37	Int. E2 Int. A42	N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

38	Int. E2 Int. A5	N-(1-methylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

39	Int. E27 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-thieno[3,4-b]pyridin-1-yl]-N- (4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

40	Int. E1 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

41	Int. E1 Int. A22	N-(2-pyrrolidin-1-ylethyl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

42	Int. E30 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[6-(2- (2,3-difluorophenyl)ethyl)-2- methyl-4-oxo-4H-pyrazolo[3,4- b]pyridin-7-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

43	Int. E1 Int. A41	N-(1-isopropylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

44	Int. E2 Int. A25	N-(1-ethylpiperidin-4-ylmethyl)-2- [2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

45	Int. E1 Int. A24	N-(3-Diethylaminopropyl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

46	Int. E2 Int. A32	N-(4-pyrrolidin-1-ylbutyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)4-oxo- 4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

47	Int. E2 Int. A24	N-(3-Diethylaminopropyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitaxtrate

48	Int. E1 Int. A32	N-(4-pyrrolidin-1-ylbutyl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

49	Int. E25 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[5-(2,3- difluorobenzylthio)-7-oxo-7H- thieno[3,2-b]pyridin-4-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

50	Int. E28 Int. A2	N-(2-Diethylaminoethyl)-2-[5-(2- (2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-7H-thiazolo[4,5- b]pyridin-4-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

51	Int. E1 Int. A27	N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4′-ethylbiphenyl- 4-ylmethyl)acetamide bitartrate

52	Int. E2 Int. A27	N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′- ethylbiphenyl-4-ylmethyl)- acetamide bitartrate

53	Int. E1 Int. A28	N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzyltbio)-4-oxo-4H- quinolin-1-yl]-N-(4′- isopropylbiphenyl4-ylmethyl)- acetamide bitartrate

54	Int. E2 Int. A28	N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′- isopropylbiphenyl-4-ylmethyl)- acetamide bitartrate

55	Int. E34 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

56	Int. E34 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

57	Int. E2 Int. A26	N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

58	Int. E1 Int. A26	N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4′- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

59	Int. E2 Int. A43	N-(1-Ethoxycarbonylmethylpiperidin-4-yl)-2- [2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

60	Int. E21 Int. A41	N-(1-isopropylpiperidin-4-yl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-[1,8]naphthyridin-1-yl]-N- (4′-trifluoromethyibiphenyl-4- ylmethyl)acetamide bitartrate

61	Int. E1 Int. A30	N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(3′,4′- dimethylbiphenyl-4-ylmethyl)- acetamide bitartrate

62	Int. E21 Int. A48	N-(1-(t-butoxycarbonyl)piperidin-4- yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

63	Int. E1 Int. A31	N-(2-Diethylaminoethyl)-2-[2-(2,3- difluoroberizylthio)-4-oxo-4H- quinolin-1-yl]-N-(3′,4′- difluorobiphenyl-4-ylmethyl)- acetamide bitartrate

64	Int. E35 Int. A2	N-(2-Diethylaminoethyl)-2-[6-(2,3- difluorobenzylthio)-4-oxo-4H- thieno[2,3-b]pyridin-7-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

65	Int. E34 Int. A5	N-(1-methylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

66	Int. E2 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3,4-trifluorophenylethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

67	Int. E29 Int. A2	N-(2-diethylaminoethyl)-2-[6-(2,3- difluorobenzylthio)-2-methyl-4- oxo-2,4-dihydro- pyrazolo[3,4-b]pyridin-7-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

68	Int. E31 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[6-(2- (2,3-difluorophenyl)ethyl)-2-ethyl- 4-oxo-2,4- dihydropyrazolo[3,4-b]pyridin-7- yl]-N-(4′-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate

69	Int. E32 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[6-(2- (2,3-difluorophenyl)ethyl)-2-isopropyl-4- oxo-2,4-dihydropyrazolo[3,4-b]pyridin-7- yl]-N-(4′-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate

70	Int. E2 Int. A29	N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′-ethyl- biphenyl-4-ylmethyl)acetamide bitartrate

71	Int. E28 Int. A41	N-(1-isopropylpiperidin-4-yl)-2-[5- (2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-7H-thiazolo[4,5- b]pyridin-4-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

72	Int. E28 Int. A42	N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[5-(2-(2,3- difluorophenyl)ethyl)-2-methyl-7- oxo-7H-thiazolo[4,5-b]pyridin-4- yl]-N-(4′-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate

73	Int. E36 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 5,6-trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

74	Int. E36 Int. A5	N-(1-methylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 5,6-trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

75	Int. E36 Int. A42	N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[2-(2,3- difluorophenyl)ethyl)-4-oxo-5,6- trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

76	Int. E36 Int. A41	N-(1-isopropylpiperidin-4-yl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-4- oxo-5,6-trimethylenepyridin-1-yl]- N-(4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

77	Int. E13 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[5-(2- (2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-2,7- dihydropyrazolo[4,3-b]pyridin-4- yl]-N-(4′-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate

78	Int. E14 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[5-(2- (2,3-difluorophenyl)ethyl)-1- methyl-7-oxo-1,7- dihydropyrazolo[4,3-b]pyridin-4- yl]-N-(4′-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate

79	Int. E36 Int. A2	N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 5,6-trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

80	Int. E33 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-7- methyl-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

81	Int. E33 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-7- methyl-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

82	Int. E33 Int. A5	N-(1-methylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-7- methyl-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

83	Int. E33 Int. A41	N-(1-isopropylpiperidin-4-yl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-7- methyl-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

84	Int. E33 Int. A42	N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-7-methyl-4- oxo-4H-[1,8]naphthyridin-1-yl]-N- (4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

85	Int. E12 Int. A5	N-(1-methylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-5,6- trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

86	Int. E12 Int. A40	N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-5,6- trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

87	Int. E12 Int. A41	N-(1-isopropylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-5,6- trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

88	Int. E12 Int. A42	N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[2-(2,3-difluorobenzylthio)-4- oxo-5,6-trimethylenepyridin-1-yl]- N-(4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

89	Int. E37 Int. A2	N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 5,6-tetramethylenepyridin-1-yl]-N- (4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

90	Int. E1 Int. A45	N-(1-methylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4′- chlorobiphenyl-4-ylmethyl)- acetamide bitartrate

91	Int. E2 Int. A45	N-(1-methylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′- chlorobiphenyl-4-ylmethyl)- acetamide bitartrate

92	Int. E2 Int. A44	N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′- chlorobiphenyl-4-ylmethyl)- acetamide bitartrate

93	Int. E2 Int. A47	N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4′- chlorobiphenyl-4-ylmethyl)- acetamide bitartrate

94	Int. E2 Int. A46	N-(1-isopropylpiperidin-4-yl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-N-(4′- chlorobiphenyl-4-ylmethyl)- acetamide bitartrate

95	Int. E30 Int. A2	N-(2-diethylaminoethyl)-2-[6-(2- (2,3-difluorophenyl)ethyl)-2- methyl-4-oxo-4H-pyrazolo[3,4- b]pyridin-7-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

96	Int. E34 Int. A48	N-(1-(t-butoxycarbonyl)piperidin-4- yl)-2-[2-(2,3-difluorobenzylthio)-4- oxo-4H-[1,8]naphthyridin-1-yl]-N- (4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide

97	Int. E38 Int. A40	N-(1-ethylpiperidin-4-yl)-2-[6-(2- (2,3-difluorophenyl)ethyl)-2-(2- methoxyethyl)-4-oxo-4H-pyrazolo- [3,4-b]pyridin-7-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

The following intermediates were prepared by the method of Example 1, but were not included in biological testing:



No.	Precursors	Structure	Name


F1	Int. E1 Int. A48		N-(1-(t-butoxycarbonyl)piperidin-4- yl)-2-[2-(2,3-difluorobenzylthio)-4- oxo-4H-quinolin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide

F2	Int. E2 Int. A48		N-(1-(t-butoxycarbonyl)piperidin-4- yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide

F3	Int. E36 Int. A48		N-(1-(t-butoxycarbonyl)piperidin-4- yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-5,6- trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide

F4	Int. E1 Int. A33		N-(2-(N′-ethyl-N′-(t- butoxycarbonyl)aminoethyl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide

F5	Int. E2 Int. A33		N-(2-(N′-ethyl-N′-(t- butoxycarbonyl)aminoethyl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide

Example 99

N-(2-Diethylaminoethyl)-2-[4-oxo-2-(2-(2,3,4-trifluorophenyl)ethyl)-4H-quinolin-1-yl]-N-(4′-trifluoromethyl-biphenyl-4-ylmethyl)acetamide bitartrate [0285]
A solution of N,N-diethyl-N′-(4′-trifluoromethyl-biphenyl-4-ylmethyl)ethane-1,2-diamine (0.242 g, 0.69 mmol) (Int. A2), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide (0.265 g, 1.39 mmol), 1-hydroxybenzotriazole hydrate (0.02 g), 2-(4-oxo-2-[2-(2,3,4-trifluorophenyl)ethyl]-4H-quinolin-1-yl)-acetic acid (Int E10) (0.25, 0.69 mmol) and N,N-diisopropylethylamine (0.15 ml, 0.86 mmmol) in dichloromethane (5 ml) was stirred at ambient temperature overnight then washed with aqueous sodium bicarbonate and evaporated. The residue was purified by chromatography (10 g silica cartridge, dichloromethane-50% acetone/dichloromethane) and triturated with hexane to give the title compound as a white solid (0.23 g, 47%). [0286] ¹H-NMR (d6 DMSO, rotamer mixture) δ0.89-0.98 (6H, m), 2.33-2.67 (6H, m), 2.84-3.00 (4H, m), 3.45-3.61 (2H, m), 4.67/4.92 (2H, 2× s), 5.24/5.50 (2H, 2× s), 6.02/6.05 (1H, 2× s), 7.19-7.20 (4H, m), 7.51-7.88 (9H, m), 8.16 (1H, t); MS (APCI+) found (M+1)=694; C₃₉H₃₇F₆N₃O₂requires 693.
d-Tartaric acid (0.028 g, 0.19mmol) was added to a solution of the free base (0.13 g, 0.19 mmol) in methanol (5 ml) with stirring. The resulting solution was evaporated to yield the salt (0.158 g). [0287] ¹H-NMR (d6 DMSO, rotamer mixture) δ1.00 (6H, br s), 2.51-2.97 (10H, m), 3.64 (2H, br s), 4.23 (2H, br s), 4.67/4.93 (2H, 2× s), 5.28/5.50 (2H, 2× s), 6.05 (1H, br s) 7.23-7.83 (13H, m), 8.17 (1H, s); MS (APCI+) found (M+1)=694; C₃₉H₃₇F₆N₃O₂requires 693.

The following compounds were prepared by the method of Example 99



Ex.
No.	Precursors	Structure	Name


100	Int. E7 Int. A2		N-(2-Diethylaminoethyl)-2-[2-(2- (2,4-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

101	Int. E11 Int. A2		N-(2-Diethylaminoethyl)-2-[2-(2- (3-fluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

Example 105

N-(piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0289]
To intermediate F1 (0.55 g) in dichloromethane (6 ml) was added trifluoroacetic acid (2.5 ml) at room temperature. The mixture was stirred for 2 h, the solvent removed under reduced pressure and diethyl ether added. The solid so formed was filtered and washed with diethyl ether to give a solid that was partitioned between dilute sodium bicarbonate and dichloromethane. The aqueous layer was extracted with further dichloromethane and the combined organic layers dried over K[0290] ₂CO₃, filtered and evaporated under reduced pressure to a solid (0.42 g). This free base (0.42 g) was dissolved in methanol (10 ml), tartaric acid (0.044 g) was added, the mixture stirred for 5 min then evaporated under reduced pressure. Trituration with ether gave the bitartrate salt as an off-white solid (0.46 g). ¹H-NMR (d6 DMSO, rotamer mixture) δ1.6-2.05 (4H, m), 2.7-3.05 (2H, m), 3.1-3.4 (2H, m), 3.88 (2H, s), 4.1-5.8 (7H, br ms) 6.27+6.32 (1H, 2×s), 7.05+7.55 (6H, m), 7.55-7.95 (8H, m), 8.14 (1H, dt); MS (APCI+) found (M+1)=678; C₃₇H₃₂F₅N₃O₂S requires 677.

The following examples were prepared by the method of Example 105:



Ex.
No.	Precursors	Structure	Name


106	Int. F2		N-(piperidin-4-yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide bitartrate

107	Int. F3		N-(piperidin-4-yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-5,6- trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate

108	Example 62		N-(piperidin-4-yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-yl- methyl)acetamide bitartrate

109	Example 96		N-(piperidin-4-yl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-yl- methyl)acetamide trifluoroacetate

110	Int. F4		N-(2-ethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide

111	Int. F5		N-(2-ethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide

Example 115

N-(1-(2-hydroxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate [0292]
A mixture of Example 59 (0.18 g, 1 equiv), lithium borohydride (0.12 ml, 2M in THF, 1 equiv) and dry THF (2 ml) was heated at reflux under argon overnight, then a further 0.06 ml portion of lithium borohydride solution was added and heating continued for 4 h. Evaporation, aqueous workup and chromatography (silica, 0-10% methanol in dichloromethane) gave the title compound (0.06 g). The bitartrate was prepared as in example 1. [0293] ¹H-NMR (DMSO, rotamer mixture) δ1.5-2.1 (4H, m), 2.5-3.65 (12H, m), 4.15 (2H, s), 3.85-5.8 (SH, br m), 6.01+6.06 (1H, 2× s), 7.0-7.95 (14H, m), 8.05-8.2 (1H, m); MS (APCI+) found (M+1)=704; C₄₀H₃₈F₅N₃O₃requires 703.
Biological Data [0294]
1. Screen for Lp-PLA[0295] ₂inhibition.
Enzyme activity was determined by measuring the rate of turnover of the artificial substrate (A) at 37 C in 50 mM HEPES (N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid) buffer containing 150 mM NaCl, pH 7.4. [0296]
Assays were performed in 96 well titre plates. [0297]
Recombinant LpPLA2 was purified to homogeneity from baculovirus infected Sf9 cells, using a zinc chelating column, blue sepharose affinity chromatography and an anion exchange column. Following purification and ultrafiltration, the enzyme was stored at 6 mg/ml at 4° C. Assay plates of compound or vehicle plus buffer were set up using automated robotics to a volume of 170 μl. The reaction was initiated by the addition of 20 μl of 10× substrate (A) to give a final substrate concentration of 20μM and 10 μl of diluted enzyme to a final 0.2 nM LpPLA2. [0298]
The reaction was followed at 405 nm and 37° C. for 20 minutes using a plate reader with automatic mixing. The rate of reaction was measured as the rate of change of absorbance. [0299]
Results [0300]
The compounds described in the Examples were tested as described above and had IC[0301] ₅₀values in the range <0.1 to 100 nM.

Claims

1. A compound of formula (I):

in which:

R¹is an aryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C_(1-6)alkyl, C_(1-6)alkoxy, C_(1-6)alkylthio, hydroxy, halogen, CN, mono to perfluoro-C_(1-4)alkyl, mono to perfluoro-C_(1-4)alkoxyaryl, and arylC_(1-4)alkyl;

R²is halogen, C_(1-3)alkyl, C_(1-3)alkoxy, hydroxyC_(1-3)alkyl, C_(1-3)alkylthio, C_(1-3)alkylsulphinyl, aminoC_(1-3)alkyl, mono- or di-C_(1-3)alkylaminoC_(1-3)allyl, C_(1-3)alkylcarbonylaminoC_(1-3)alkyl, C_(1-3)alkoxyC_(1-3)alkylcarbonylaminoC_(1-3)alkyl, C_(1-3)alkylsulphonylaminoC_(1-3)alkyl, C_(1-3)alkylcarboxy, C_(1-3)alkylcarboxyC_(1-3)alkyl, and

R³is hydrogen, halogen, C_(1-3)alkyl, or hydroxyC_(1-3)alkyl; or

R²and R³together with the pyridone ring carbon atoms to which they are attached form a fused 5-or 6-membered carbocyclic ring; or

R²and R³together with the pyridone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from halogen, C_(1-4)alkyl, cyano, C_(1-3)alkoxyC_(1-3)alkyl, C_(1-4)alkoxy or C_(1-4)alkylthio, or mono to perfluoro-C_(1-4)alkyl;

R⁴is hydrogen, C_(1-6)alkyl which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁹R¹⁰, NR⁷COR⁸, mono- or di-(hydroxyC_(1-6)allyl)amino and N-hydroxyC_(1-6)alkyl-N—C_(1-6)alkylamino; or

R⁴is Het-C_(0-4)alkyl in which Het is a 5- to 7-membered heterocyclyl ring comprising N and optionally O or S, and in which N may be substituted by COR⁷, COOR⁷, CONR⁹R¹⁰, or C_(1-6)alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰or NR⁹R¹⁰, for instance, piperidin4-yl, pyrrolidin-3-yl;

R⁵is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C_(1-6)alkyl, C_(1-6)alkoxy, C_(1-6)alkylthio, arylC_(1-6)alkoxy, hydroxy, halogen, CN, COR⁷, carboxy, COOR⁷, NR⁷COR⁸, CONR⁹R¹⁰, SO₂NR⁹R¹⁰, NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C_(1-4)alkyl and mono to perfluoro-C_(1-4)alkoxy;

R⁶is an aryl or a heteroaryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C_(1-6)alkyl, C_(1-6)alkoxy, C_(1-6)alkylthio, C_(1-6)alkylsulfonyl, arylC_(1-6)alkoxy, hydroxy, halogen, CN, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁷COR⁸, SO₂NR⁹R¹⁰, NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C_1-4)alkyl and mono to perfluoro-C_(1-4)alkoxy, or C_(5-10)alkyl;

R⁷and R⁸are independently hydrogen or C_(1-12)alkyl, for instance C_(1-4)alkyl (e.g. methyl or ethyl);

R⁹and R¹⁰which may be the same or different is each selected from hydrogen, or C_(1-12)alkyl, or R⁹and R¹⁰together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C_(1-4)alkyl, C_(1-4)alkylcarboxy, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine; and

X is a C_(2-4)alkylene group (optionally substituted by 1, 2 or 3 substituents selected from methyl and ethyl), CH═CH, (CH₂)_nS or (CH₂)_nO where n is 1, 2 or 3.

2. A compound of formula (I) as claimed in claim 1 in which R¹is phenyl optionally substituted by halogen, C_(1-6)alkyl, trifluoromethyl, C_(1-6)alkoxy.

3. A compound of formula (I) as claimed in claim 1 or 2 in which R²and R³together with the pyridone ring carbon atoms to which they are attached form a fused thiazolyl ring substituted by methyl, or a fused 5-membered carbocyclic (cyclopentenyl) ring, or a fused benzo, pyrido, thieno or pyrazolo ring.

4. A compound of formula (I) as claimed in any of claims 1 to 3 in which R⁴is selected from the group consisting of 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl, 1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperdin-4-yl or 1-ethylpyrrolidin-3-yl.

5. A compound of formula (I) as claimed in any of claims 1 to 4 in which R⁵is phenyl.

6. A compound of formula (I) as claimed in any of claims 1 to 5 in which R⁶is phenyl substituted by trifluoromethyl or ethyl in the 4-position.

7. A compound of formula (I) as claimed in any of claims 1 to 6 in which R⁵and R⁶together form a 4-(phenyl)phenyl or a 2-(phenyl)pyridinyl substituent in which the remote phenyl ring may be optionally substituted by halogen or trifluoromethyl, preferably at the 4-position.

8. A compound of formula (I) as claimed in any of claims 1 to 7 in which X is C_(2-4)alkylene or CH₂S.

9. A compound of formula (I) as claimed in any of claims 1 to 8 in which R¹is phenyl substituted by 2,3-difluoro; R²and R³, together with the pyridone ring carbon atoms to which they are attached, form a fused 5-membered carbocyclic (cyclopentenyl) ring, or a fused benzo or pyrido ring; R⁴is 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl, 1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or 1-ethylpyrrolidin-3-yl; R⁵is phenyl; R⁶is phenyl substituted by ethyl or trifluoromethyl in the 4-position; and X is CH₂S.

10. A compound of formula (I) as claimed in any of claims 1 to 9 in which R¹is phenyl substituted by 2,3-difluoro; R²and R³, together with the pyridone ring carbon atoms to which they are attached, form a fused thiazolyl ring substituted by methyl, or a benzo or pyrido ring; R⁴is 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl, 1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or 1-ethylpyrrolidin-3-yl; R⁵is phenyl; R⁶is phenyl substituted by trifluoromethyl in the 4-position; and X is (CH₂)₂.

11. A compound of formula (I) as claimed in any of claims 1 to 10 in which R¹is phenyl substituted by 2,3-difluoro; R²and R³, together with the pyridone ring carbon atoms to which they are attached, form a fused benzo or pyrido ring; R⁴is 1-(2-methoxyethyl)piperidin-4-yl; R⁵and R⁶together form a 4-(phenyl)phenyl substituent in which the remote phenyl ring is substituted by trifluoromethyl, preferably at the 4-position; and X is CH₂S or (CH2)₂.

12. A compound of formula (I) as claimed in claim 1 and as named in any one of Examples 1 to 115.

13. A compound of formula (I) as defined in claim 1 selected from the group consisting of

N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide;

N-(1-(2-methoxyethyl)piperidin-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide;

14. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 and a pharmaceutically acceptable carrier.

15. A compound of formula (I) as claimed in claim 1 for use in therapy.

16. The use of a compound of formula (I) as claimed in claim 1 for the manufacture of a medicament for treating atherosclerosis.

17. A method of treating a disease state associated with activity of the enzyme Lp-PLA₂which method involves treating a patient in need thereof with a therapeutically effective amount of a compound of formula (1) as claimed in claim 1.

18. A process for preparing a compound of formula (I) as defined in claim 1 which process comprises reacting an acid compound of formula (II):

in which X, R¹, R²and R³are as hereinbefore defined, with an amine compound of formula (III):

R⁶—R⁵—CH₂NHR⁴ (III)

in which R⁴, R⁵and R⁶are as hereinbefore defined; under amide forming conditions.