WO2002030911A1 - Pyrimidinone derivatives and their use in the treatment of atherosclerosis - Google Patents

Abstract

Compounds of formula (I) are inhibitors of the enzyme Lp-PLA2 and are of use in therapy, in particular for treating athereosclerosis.

Description

PYRIMIDINONE DERIVATIVES AND THEIR USE IN THE TREATMENT OF ATHEROSCLEROSIS

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 pic) describes the phospholipase A2 enzyme 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 ofthe 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, 6 April 1995,

549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA2 and suggest that it may have potential as a therapeutic protein for regulating pathological inflammatory events.

It has been shown that Lp-PLA2 is 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 ofthe oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid. Both products of Lp-PLA2 action 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 ofthe Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition ofthe 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 ofthe enzyme Lp-PLA2 is 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- PLA2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA2 inhibitor 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-PLA2 inhibitors 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-PLA2 inhibitors may also have a general application in any disorder that involves lipid oxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, ischaemia, reperfusion injury and acute and chronic inflammation.

Patent applications WO 96/12963, WO 96/13484, WO96/19451, WO 97/02242, W097/217675, WO 97/217676, WO 96/41098, and WO 97/41099 (SmithKline Beecham pic) disclose inter alia various series of 4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitors of he enzyme p-PLA2- 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 ofthe enzyme Lp-PLA₂. Thus, WO 99/24420, WO 00/10980, WO 00/66566, WO 00/66567 and WO 00/68208 (SmithKline Beecham pic) disclose a class of pyrimidone compounds which are exemplified by an optionally substituted 2-benzylthio or 2-benzyloxy substituent. We have now found that this may be replaced by a carbon linker, to give compounds having good activity as inhibitors ofthe enzyme Lp- PLA₂.

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

in which:

R¹ is an aryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or to

fused 5 -or 6-membered carbocyclic ring; or

R² and R^ together with the pyrimidone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from halogen, Cπ _4)alkyl, cyano, Cπ-6)^alkoxy,

or mono to perfluoro-C( \ _4)alkyl; R4 is hydrogen, Cπ .g-_jalkyl which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁹RlO, NR⁷COR⁸, mono- or di-(hydroxyCπ-6)^alky ^amino and N-hydroxyCn _6)alkyI-N-Cπ-6)^alkyl^amino; or R4 is Het-C(Q-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(i _6)alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰ or NR⁹R¹⁰, for instance, piperidin-4-yl, pyrrolidin-3-yl; R5 is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cπ _6)alkyl, Cπ .g-_jalkoxy, Cπ .g-_jalkylthio, arylCπ_6)alkoxy, hydroxy, halogen, CN, COR⁷, carboxy, COOR⁷, NR'COR⁸, CONR⁹R¹⁰, S0₂NR⁹R¹⁰, NR⁷S0₂R⁸, NR⁹R*0, mono to perfluoro-Cπ _4)alkyl and mono to perfluoro-Cπ _4)alkoxy;

R^ is 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 Cπ .18)^alkyl, Cπ .\ §\alkoxy,

to perfluoro-Cπ--4)alkoxy, or C(5_ι Q)alkyl;

R⁷ is hydrogen or Cπ _i2)alkyl, for instance Cπ -4)alkyl (e.g. methyl or ethyl); R⁸ is hydrogen, OCπ .g^alkyl, or Cπ _i2)alkyl, for instance Cπ _4)alkyl (e.g. methyl or ethyl);

R⁹ and R^ which may be the same or different is each selected from hydrogen, or Cπ _ι 2)alkyl, or R⁹ and R!" together 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, Cπ -4)^alkyl, Cπ . 4)alkylcarboxy, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine; and

X is C(2-4)^alkylene, optionally substituted by 1,2 or 3 substituents selected from methyl and ethyl, or CH=CH.

Representative examples of R* when an aryl group include phenyl and naphthyl. Preferably, R! is phenyl optionally substituted by halogen, Cπ .^alkyl, trifluoromethyl, Cπ .g^alkoxy, preferably, from 1 to 3 fluoro, more preferably, 2,3-difluoro.

Further representative examples of R* include phenyl substituted by trifluoromethoxy or cyano.

Representative examples of B?- include methyl, ethyl, and trifluoroethyl when R^ is hydrogen. Representative examples of B? include methyl when R² is methyl.

Preferably R² is ethyl when R^ is hydrogen.

Further representative examples of R^ and R^ include when R^ and R^ together with the pyrimidine 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 R² and R^ include when R^ and R^, together with the pyrimidine ring carbon atoms to which they are attached, form a fused benzo ring substituted by Cπ _4)alkyl, trifluoromethyl, or 1 or 2 halogen atoms; and when R² and R^, together with the pyrimidine ring carbon atoms to which they are attached, form a fused thieno ring substituted by methyl.

Preferably, R^ and R^ together with the pyrimidine 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. Representative examples of R^ include hydrogen, methyl, 2-(diethylamino)ethyl, 2-(piperidin-l-yl)ethyl, 2-(pyrrolidin-l-yl)ethyl, 3-(morpholin-4-yl)propyl, l-ethyl-piperidin-4-yl and l-ethyl-pyrrolidin-2- ylmethyl. Preferably * is 2-(diethylamino)ethyl or l-ethyl-piperidin-4-yl.

Further representative examples of R^ include piperidin-4-yl substituted at the 1 -position by methyl, 2- methoxyethyl, isopropyl, l-ethoxycarbonylmethyl or t-butoxycarbonyl; ethyl substituted at the 2-position by ethylamino, t-butylamino or morpholin-4-yl; 2-methylpropyl substituted in the 2-position by dimethylamino, ethylamino, (morpholin-4-yl), (piperidin-1-yl), isopropylamino, diethylamino, dimethylamino, pyrrolidin- 1 -ylmethyl or pyrrolidin- 1 -yl; propyl substituted at the 3-position by piperidin-1-yl, pyrrolidin- 1-yl, diethylamino; butyl substituted at the 4-position by pyrrolidin- 1-yl; 1- ethylpiperidin-4-ylmethyl; 2-methoxyethyl; t-butoxycarbonylmethyl; 2-hydroxyethyl; hydroxycarbonylmethyl; and piperidin-4-yl. Preferably R4 is l-methylpiperidin-4-yl or l-(2- methoxyethyl)piperidin-4-yl.

Representative examples of R^ include phenyl and pyridyl. Preferably, R^ is phenyl.

Further representative examples of R^ include thienyl, pyrimidyl and furyl. Preferably, R^ is thienyl.

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

Further representative examples of R^ include phenyl substituted by methylthio, Cπ .g^alkyl, cyano, methylsulfonyl, piperidin-1-ylsulfonyl or pentafluoroethyl; and thienyl optionally substituted by halogen or trifluoromethyl. Preferably, R> is thien-2-yl substituted by trifluoromethyl in the 5-position.

Preferably, R^ and R^ together 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.

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

R⁷ and R⁸ are independently hydrogen or Cπ .12)alkyl, for instance Cπ _4)alkyl (e.g. methyl or ethyl).

Representative examples of X include (CH2)3, vinyl, (CH2)2 and (CH2)2 substituted by one or more methyl.

Preferably X is C(2-4)alkylene, more preferably C -3)alkylene, most preferably, (CH2)2-

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

A) in which:

R* is phenyl substituted by 1 to 3 fluoro;

R2 is ethyl when R^ is hydrogen;

R4 is 2-(diethylamino)ethyl, l-ethyl-piperidin-4-yl, l-methylpiperidin-4-yl or l-(2- methoxyethyl)piperidin-4-yl; R5 is phenyl, thienyl or pyridyl;

R^ is phenyl substituted by trifluoromethyl at the 4-position, or thien-2-yl substituted by trifluoromethyl in the 5-position; and

X is (CH₂)₂.

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

(group B) in which:

R¹ is phenyl substituted by 2,3 difluoro;

R2 and R-*, together with the pyrimidine 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;

R⁴ is 2-(diethylamino)ethyl, l-ethyl-piperidin-4-yl, l-methylpiperidin-4-yl or l-(2- methoxyethyl)piperidin-4-yl;

R^ is phenyl, thienyl or pyridyl;

R6 is phenyl substituted by trifluoromethyl at the 4-position, or thien-2-yl substituted by trifluoromethyl in the 5-position; and

X is (CH₂)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! is phenyl substituted by 2,3 difluoro;

R2 and R^, together with the pyrimidine ring carbon atoms to which they are attached, form a fused pyrido ring;

R4 is l-methylpiperidin-4-yl or l-(2-methoxyethyl)piperidin-4-yl;

R5 and R6 together form a 4-(phenyl)phenyl in which the remote phenyl ring is substituted by trifluoromethyl, preferably at the 4-position; and

X is (CH₂)₂.

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

It will be appreciated that in some instances, compounds ofthe 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 saits 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 ofthe 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, «-propyl, iso-propyl, «-butyl, -sec-butyl, z^'sø-butyl, t-butyl, «-pentyl and ra-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 (I) are: N-(l-Methylpiperidin-4-yl)-(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-pyrido[2,3-φyrimidin-l-yl)-N- (4-(4-trifluoromethylphenyl)phenyl)methylacetamide;

N-(l-(2-Methoxyethyl)piperidin-4-yl)-(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-pyrido[2,3- ύf]pyrimidin-l-yl)-N-(4-(4-trifluoromethylphenyl)phenyl)methylacetamide; or a pharmaceutically acceptable salt thereof, in particular the bitartrate salt.

Since the compounds ofthe 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 ofthe compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds ofthe 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 ofthe 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 ofthe 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 ofthe compounds of formula (I). Compounds ofthe present invention are inhibitors ofthe enzyme lipoprotein associated phospholipase A2 (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-PLA2 and 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 ofthe brain such as Alzheimer's Disease, myocardial infarction, 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-PLA2- 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 ofthe enzyme L -PLA2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor ofthe 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 PLA2 activity; with ischemia and reperfusion; or with endothelial dysfunction.

Compounds ofthe 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 ofthe 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 ofthe 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 ofthe physician.

A further preferred combination therapy will be the use of a compound ofthe 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 ofthe present invention include the PPARgamma activators, for instance GI262570 (GlaxoSmithKline) and the glitazone class of compounds such as rosiglitazone (Avandia, GlaxoSmithKline), troglitazone and pioglitazone. In therapeutic use, the compounds ofthe 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. Compound's 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 ofthe 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 ofthe 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 ofthe 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, ofthe compound ofthe 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):

(II) in which X, R , R2 and R^ are as hereinbefore defined, with an amine compound of formula (III):

R⁶-R⁵-CH₂NHR⁴

(III) in which R⁴, R^ and R" are 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 l-(3-dimethyl-aminopropyl)-3- ethylcarbodiimide (DEC), or 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), preferably in the presence of di-isopropylethylamine.

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

(IV) in which X, Rl, R^ and R^ are as hereinbefore defined, by reaction with a compound of formula (V):

LCH₂C0₂R^u

(V) in which L is a leaving group such as halo, for example, iodo, and R^ 1 is Cπ .g^alkyl, for example t- butyl, in the presence of a base such as a tertiary amine, for example di-isopropylethylamine; to form an intermediate ester (VI),

(VI) in which X, R*, R², R^ and R^ are as hereinbefore defined, and thereafter, removing R^, by treating with a de-esterifying agent, for instance, for t-butyl, trifluoroacetic acid.

It will be appreciated that removal of Rl * may be carried out as a separate step, so that an acid of formula (II) is isolated or, alternatively, that the acid of formula (II) is formed from the intermediate ester (VI) as a preliminary first step, prior to reaction with an amine of formula (III).

The pyrimidone of formula (IV) may be readily prepared by adapting a standard pyrimidone synthesis involving an amidine and a 1,3-dicarbonyl compound, by reacting an amidine of formula (VII):

(VII) in which R* and X are as hereinbefore defined, preferably as a salt thereof, for instance the hydrochloride salt, with a compound of formula (VIII):

(VIII) in which R² and R^ are as hereinbefore defined.

It will be appreciated that in the compound of formula (IV), when R^ is hydrogen, the compound of formula (VIII) is a 1,3-aldehyde ester and further, that in the compound of formula (IV), when R^ is other than hydrogen, the compound of formula (VIII) is a 1,3-keto ester.

For compounds of formula (II) in which R² and R^ together with the pyrimidone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring optionally substituted by halogen, Cπ . g)alkyl, cyano, mono to perfluoro-C(i _4)alkyl, it is found more convenient to adopt a slightly different strategy whereby the amidine of formula (VII) is reacted with a compound ofthe formula (IX):

(IX) in which R² and R^ together with the pyrimidone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring optionally substituted by halogen, Cπ -.g^alkyl, cyano, mono to perfluoro- Cπ _4)alkyl , and R¹ * is as hereinbefore defined, for example ethyl, under standard pyrimidone ring forming conditions, in the presence of a base such as pyridine, to give an intermediate ester (VI) which can then be converted into a compound of formula (II), for instance by treatment with aqueous sodium hydroxide.

Alternatively, for compounds of formula (II) in which R² and R^ together with the pyrimidone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring optionally substituted by halogen, Cπ.g^alkyl, cyano, mono to perfluoro-Cπ _4)alkyl, the pyrimidone ring may be formed by reacting a compound of formula (X):

(X) in which R² and R^ together with the pyrimidone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring optionally substituted by halogen, Cπ _g)alkyl, cyano, mono to perfluoro- Cπ _4)alkyl, and R^ is as hereinbefore defined, for example ethyl, with an acyl chloride compound ofthe formula (XI):

(XI) in which R^ and X are as hereinbefore defined; under standard pyrimidone ring forming conditions, in a solvent such as benzene, or via a two step procedure by treatment with pyridine, followed by a suitable base e.g. NaH in DMF, followed by treatment ofthe intermediate so formed with an acid e.g. p-toluene sulfonic acid in refluxing toluene; to give an intermediate ester (VI) which can then be converted into a compound of formula (II), for instance by treatment with aqueous sodium hydroxide.

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), incoφorated herein by reference.

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

Examples

The structure and purity ofthe intermediates and examples was confirmed by 1H-NMR and (in nearly all cases) mass spectroscopy, even where not explicitly indicated below.

Intermediate Al — 3-(2,3-DifIuorophenyl)propionic acid

A solution of 2,3-difluorocinnamic acid (9.14g) in ethanol (250ml) with 10% palladium/carbon catalyst was hydrogenated for 5h at room temperature and atmospheric pressure. The reaction mixture was filtered through celite and concentrated in vacuo to give the title compound as a colourless solid (9.05g, quant.) iH-NMR (CDC1₃) δ 2.70 (2H, t), 3.02 (2H, t) and 7.01 (3H, m).

Intermediate A2 — 3-(2,3-Difluorophenyl)propanenitrile

To a solution of 3-(2,3-difluorophenyl)-propionic acid (Al) (6.83g, 36mmol) in anhydrous dichloromethane (50ml) containing a few drops of DMF was added oxalyl chloride (6.4ml, 73 mmol) at 0°C under argon. The solution was stirred at ambient temperature for 2h and the solvent removed in vacuo. The residue was dissolved in sulfolane (30ml) and added to sulfamide (4.23g, 44mmoI) and the mixture heated at 120°C for 3h. The brown solution was cooled, poured into 2M sodium hydroxide solution (300ml) and extracted with ether. The combined extracts were washed with water, dried (MgSθ4) and evaporated to give the title compound as a brown oil (6.04g, 98%). Η -NMR (CDCI3) δ 2.68 (2H, t), 3.04 (2H, t), 7.01-7.15 (3H, m).

Intermediate A3 — 3-(2,3-Difluorophenyl)propionamidine hydrochloride

A solution of 3-(2,3-difluorophenyl)-propionitrile (Int A2) (6.04g) in saturated ethanolic hydrogen chloride (30ml) was stirred at ambient temperature overnight then concentrated to a brown solid. The residue was triturated with ether, dissolved in ethanol (50ml) and the solution saturated with ammonia gas. The mixture was stirred at room temperature overnight, concentrated and the residue triturated with ether to give the title compound as a white solid (7.02g, 88%). Η-NMR (DMSO) δ 2.72 (2H, t), 3.06 (2H, t), 7.16-7.36 (3H, m), 8.77 (2H, s), 9.16 (2H, s). Intermediate A4 — 4-(4-Fluorophenyl)-butyramide

To a solution of 4-(4-fluorophenyl)-butyric acid (6.7g) in chloroform (15ml) at 0°C was added 0.1ml DMF followed by the addition of oxalyl chloride (3.35ml) over 20min. The solution was stirred for 2h then concentrated. The crude acid chloride was dissolved in chloroform (150ml) and cooled to 0°C, whereupon concentrated ammonia solution (6ml) was added over 15min and the resulting solution stirred for 2h. The reaction mixture was washed with water and the organic phase dried (MgS0₄) and concentrated in vacuo. The crude product was chromatographed over silica using a gradient elution from ether to 2:1 acetone/ether to yield the title compound (2.86g, 43%). -NMR (CDC1₃) δ 1.96 (2H, app q), 2.21 (2H, t), 2.65 (2H, t), 5.41 (2H, br s), 6.96 (2H, m), 7.14 (2H, m). MS (APCI+) M+l=182, Ci₀Hi₂FNO requires 181.

Intermediate A5 — 4-(4-FluorophenyI)-butyronitrile

4-(4-Fluorophenyl)-butyramide (Int. A4) (2.63g) was dissolved in trifluoroacetic anhydride (10ml) and stirred for 2h. The solution was concentrated and then dissolved in dichloromethane and washed with 2N sodium hydroxide solution. The organics extracts were isolated, dried (MgS0 ) and concentrated to yield the product (2.3g, 100%) which contained ~5% starting amide as an impurity. *H-NMR (CDC1 ) δ 1.96 (2H, app q), 2.31 (2H, t), 2.75 (2H, t), 6.98 (2H, m), 7.14 (2H, m). MS (APCI+) M+l=164, C_I0H₁₀FN requires 163.

Intermediate A6 — Benzyl (£)-3-(3-cyano-4-fluorophenyl)-acrylate

To a solution of 3-cyano-4-fluorobenzaldehyde (2.00g, 13.4mmol) in dichloromethane (50ml) was added benzyl triphenylphosphoanylidene acetate (5.5 lg, 13.4mmol) portionwise over 15min. The reaction mixture was stirred for 2h, concentrated and the residues chromatographed over silica with a gradient elution using 1 : 1 hexane/dichloromethane to dichloromethane to yield product as a white solid (3.27g, 87%). ^-NMR (CDC1₃) δ 5.26 (2H, s), 6.08 (1H, d), 7.2-7.5 (6H, m), 7.6 (1H, d), 7.75 (2H, d).

Intermediate A7 — 3-(3-Cyano-4-fluorophenyl)-propionic acid

Benzyl (-δ)-3-(3-cyano-4-fluorophenyl)-acrylate (Int. A6) (1.72g, 6.1 mmol) was dissolved in 1:1 dichloromethane/ethanol (50ml) and 10% palladium on charcoal (0.5g) added. The mixture was hydrogenated for 2h at ambient pressure, filtered and concentrated to provide the title compound as a white solid (1.2g, 100%).¹H-NMR (CDC1₃) δ 2.69 (2H, t), 2.97 (2H, t), 7.11 (1H, m), 7.43 (3H, m). Intermediate A8 — 3-(3-Cyano-4-fluorophenyl)-propionyl chloride

3-(3^'-Cyano-4-fluorophenyl)-propionic acid (Int. A7) was dissolved in dichloromethane (30ml) containing 0.1ml DMF and oxalyl chloride (0.79g, 6.2mmol) added dropwise over 5min. The reaction mixture was stirred for 2h then concentrated in vacuo to yield the title compound as an oil (1.3g, 100%). H-NMR (CDC1₃) δ 3.02 (2H, t), 3.21 (2H, t), 7.13 (1H, t), 7.45 (2H, m).

Intermediate A9 — E-3-(4-Fluorophenyl)acrylonitrile

A suspension of 3-(4-fluorophenyl)acrylic acid (2.5g, 15mmol) in dry dichloromethane (50ml) was treated with DMF (2 drops), oxalyl chloride (2.6ml, 30mmol) and the reaction was stirred at room temperature under argon for 3h. The reaction mixture was evaporated to dryness and azeotroped with dichloromethane (25ml x 2) and evaporated to dryness giving a yellow oil. The acid chloride was mixed with sulfolane (15ml) and treated with sulfamide (1.73g, 0.018 moles) (A. Hulkenberg and J.J. Troost, Tetrahedron Letters Vol.23, No.14, 1505-1508, 1982) and the reaction mixture was heated to 120°C for 3h. The reaction mixture was cooled, poured into IN NaOH (100ml) and extracted with 1 : 1 diethyl etheπhexane (3 x 75ml). The organic extracts were combined, washed with water (3 x 50ml), dried (MgS04) and evaporated to dryness. Purification by flash column chromatography eluted with 2: 1 hexane:ethyl acetate gave E-3-(4-fluorophenyl)acrylonitrile as a cream solid (2.12g, 96%) ; ^H-NMR (CDCI3) 5.77, 5.83 (1H, d), 7.16 (2H, m), 7.26, 7.40 (1H, d), 7.45 (2H, m). MS (APCI+) M+l=148, CoH₆FN requires 147.

Intermediate A10 — E-3-(4-Fluorophenyl)acrylamidine hydrochloride

E-3-(4-fluorophenyl)acrylonitrile (Int. A9) (1.0g,6.8mmol) in dry ethanol (35ml) was cooled in an ice- bath and HCl (gas) was bubbled into the solution for 10 minutes. The mixture was allowed to stand at room temperature for 133h. The reaction mixture was evaporated to dryness and the residue was suspended in diethyl ether (20ml) and the yellow solid was collected by filtration and dried to give E-3- (4-fluorophenyl)acrylimidic acid ethyl ester hydrochloride (0.86g, 55%); *H-NMR (dg-DMSO) 1.45 ( 3H, t,), 4.52 (2H, q), 6.94, 7.00 (1H, d), 7.36 (2H, m), 7.81 (2H, m), 7.92, 7.99 (1H, d), 11.5 (1H, bs); MS (APCI+) M+l=194, !H₁₂FNO requires 193. A solution of E-3-(4-fluorophenyl)acrylimidic acid ethyl ester hyrochloride (0.86g, 0.00374 moles) in dry methanol (20ml) was treated with a solution of ammonia (0.064g, 3.8mmol) in dry methanol (0.51ml) and the resulting solution was allowed to stand at room temperature for 48h. The reaction mixture was evaporated to dryness, mixed with diethyl ether and evaporated to give E-3-(4-fluorophenyl)acrylamidine hydrochloride as a solid (0.75g, 100%); H-NMR (d₆-DMSO) 6.72, 6.79 (1H, d) 7.35 (2H, m), 7.67 (2H, m), 7.87, 7.94 (1H, d), 8.8, 9.15 (2xbs). MS (APCI+) M+l=165, C₉H₉FN₂ requires 164. Intermediate A14 - f-E' ζ)-3-(2-(trifluoromethyI)-4-fluorophenyl)-acrylonitrile

Diethyl cyanomethylphosphonate (9ml) was added to a suspension of NaH (2.1g) in THF (50ml) and DMF (50ml) at 0°C, warmed to room temperature for 20 min and then cooled to 0°C. A solution of 2- (trifluoromethyl)-4-fluoro-benzaldehyde (lOg) in THF (50ml) was added and the reaction mixture allowed to warm to room temperature and stirred for 3h. The mixture was diluted with saturated aq. NH₄C1 solution and extracted with diethyl ether. The organic extracts were washed with water, dried, and evaporated to give an oil. This oil was chromatographed (silica, dichloromethane/hexane) to give the title compound (1:1 E/Z mixture) as a semi-solid (8.5g). ^ΪH-NMR (CDC1 ) 5.67 (0.5H, dd), 5.86 (0.5H, d), 7.3-7.4 (2.5H, m), 7.4, 7.5 (IH, d), 8.0-8.1 (0.5H, m).

Intermediate A1S 3-(2-(trifluoromethyl)-4-fluorophenyl)-propionitriIe

(-£/Z -3-(2-(trifluoromethyl)-4-fluorophenyl)-acrylonitrile (Int. A14) (7.5g) in methanol (300ml) was treated with Pd/C (100 mg) and hydrogenated for 6h. The mixture was filtered and the filtrate evaporated to give the title compound as a oil (6g). Η-NMR (CDCI3) δ 2.64 (2H, t), 3.12 (2H, t), 7.22-7.30 (IH, m), 7.36-7.46 (2H, m).

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

No. Precursor Name

A20 3-(2,4-Difluorophenyl)acrylic acid 3-(2,4-Difluorophenyl)propionic acid

A21 : 3-(2,5-Difluorophenyl)acrylic acid 3-(2,5-Difluorophenyl)propionic acid

A22 ^' 3-(2,6-Difluorophenyl)acrylic acid 3-(2,6-Difluorophenyl)propionic acid A23 3-(3,5-Difluorophenyl)acryIic acid 3-(3 ,5-DifluorophenyI)propionic acid A24 3-(2-Fluorophenyl)acrylic acid 3-(2-Fluorophenyl)propionic acid A25 3-(3-Fluorophenyl)acrylic acid 3-(3-Fluorophenyl)propionic acid A26 3-(2,3,4-Trifluorophenyl)acrylic acid 3-(2,3,4-Trifluorophenyl)propionic acid

A27 . 3-(2,3,5-Trifluorophenyl)acrylic acid 3-(2,3,5-Trifluorophenyl)propionic acid A28 3-(2,4,5-Trifluorophenyl)acrylic acid 3-(2,4,5-Trifluorophenyl)propionic acid A29 3-(3,4,5-Trifluorophenyl)acrylic acid 3-(3 ,4,5-Trifluorophenyl)propionic acid A30 3-(3-Cyanophenyl)acrylic acid 3-(3-Cyanophenyl)propionic acid

The following intermediates were made by the method of Intermediate A6:

No. Precursor Name

A31 2,3,6-trifluoro-benzaldehyde Benzyl (E)-3-(2,3,6-trifluorophenyl)-acrylate

A32 2,4,6-trifluoro-benzaldehyde Benzyl (E)-3-(2,4,6-trifluorophenyl)-acrylate The following intermediates were made by the method of Intermediate A7:

No. Precursor Name

A33 ; Benzyl (-E)-3-(2,3,6-trifluorophenyl)- 3-(2,3,6-Trifluorophenyl)propionic acid acrylate (A31)

A34 Benzyl (E)-3-(2,4,6-trifluorophenyl)- 3-(2,4,6-Trifluorophenyl)propionic acid acrylate (A32)

The following intermediates were made by the method of Intermediate A14:

No. Precursor Name

A36 3-(trifluoromethyl)-4-fluoro- (ϊ/Z -3-(3-(trifluoromethyl)-4-fluorophenyl)- benzaldehyde acrylonitrile

A37 3-chloro-4-fluoro-benzaldehyde C£7ζ -3-(3-chloro-4-fluorophenyl)-acrylonitrile

The following intermediates were made by the method of Intermediate A15:

No. Precursor Name

A38 f£/Z -3-(3-(trifluoromethyl)-4-fluoro 3-(3-(trifluoromethyl)-4-fluorophenyl)- phenyl)-acrylonitrile (A36) propanenitrile

A39 f£/Z 3-(3-chloro-4-fluorophenyl)- 3 -(3 -chloro-4-fluorophenyl)-propanenitrile acrylonitrile (A37)

The following acid chloride intermediates were made from the corresponding acids by the method of Intermediate A8:

^••^" No. Precursor Name

¹ A51 A20 3-(2,4-Difluorophenyl)propionyl chloride

A52 A22 3-(2,6-Difluorophenyl)propionyl chloride

A53 A23 3-(3,5-Difluorophenyl)propionyl chloride

: A54 _: Al 3-(2,3-Difluorophenyl)propionyl chloride

' A55 3-(3 ,4-Difluorophenyl)propionic acid 3-(3 ,4-Difluorophenyl)propionyl chloride

A56 A24 3 -(2-Fluorophenyl)propionyl chloride

_, A57 A25 3 -(3 -Fluorophenyl)propionyl chloride - A59 A26 3-(2,3,4-Trifluorophenyl)propionyl chloride

A60 A27 3-(2,3,5-Trifluorophenyl)propionyl chloride

A61 A28 3-(2,4,5-Trifluorophenyl)propionyl chloride

A62 A29 3-(3,4,5-Trifluorophenyl)propionyl chloride

A63 A30 3-(3-Cyanophenyl)propionyl chloride

A64 A33 3-(2,3 ,6-Trifluorophenyl)propionyl chloride A65 A34 3-(2,4,6-Trifluorophenyl)propionyl chloride

A66 ■ 3-methyl-3-phenylbutyric acid 3-methyl-3-phenylbutyryl chloride

A67 2-methyl-3-phenylprioponic acid 2-methyl-3 -phenylpropionyl chloride The following nitrile intermediates were made from the corresponding acids by the method of Intermediate A2:

No. Precursor Name i A71 ^■ 3-phenyl-butyric acid 3-phenyl-butyronitrile

A72 A20 3-(2,4-Difluorophenyl)propanenitrile

A73 A21 3-(2,5-Difluorophenyl)propanenitrile

A74 3-(3,4-Difluorophenyl)propionic acid 3 -(3 ,4-Difluorophenyl)propanenitrile A75 A24 3-(2-fluorophenyl)propanenitrile A76 A25 3-(3-fluorophenyl)propanenitrile

A77 3-(3-chlorophenyl)propionic acid 3-(3-chlorophenyl)propanenitrile A78 3-(4-chlorophenyl)propionic acid 3-(4-chIorophenyI)propanenitriIe

A79 3-(4-methylphenyl)propionic acid 3 -(4-methylphenyl)propanenitrile

A80 3-(4-(trifluoromethyl)phenyl)propionic 3-(4-(trifluoromethyl)phenyl)propanenitrile acid

A81 3-(4-methoxyphenyl)propionic acid 3 -(4-methoxyphenyl)propanenitrile

A82 3-(4-(trifluoromethoxy)phenyl)propionic 3-(4-(trifluoromethoxy)phenyl)propanenitrile acid

A85 A26 3-(2,3,4-Difluorophenyl)propanenitrile

The following intermediate was made by the method of Intermediate A4:

No. Precursor Name

A83 3-(4-fluorophenyl)propionic acid 3 -(4-fluorophenyl)propionamide

The following intermediate was made by the method of Intermediate A5:

■ No. Precursor Name

^; A84 3-(4-fluorophenyl)propionamide (A83) 3-(4-fluorophenyl)propanenirrile

The following amidine intermediates were made from the corresponding nitriles by the method of Intermediate A3:

No. ! Precursor ' Name

A91 : A15 3-(2-(trifluoromethyI)-4-fluorophenyl)-propionamidine hydrochloride

A93 ^' A38 3 -(3 -(trifluoromethyl)-4-fluorophenyl)-propionamidine hydrochloride

A94 A39 3-(3-chloro-4-fluorophenyl)-propionamidine hydrochloride

A95 A71 3-phenyl-butyramidine hydrochloride

A97 A72 3 -(2,4-Difluorophenyl)-propionamidine hydrochloride A98 ^■ A73 . 3-(2,5-Difluorophenyl)-propionamidine hydrochloride A99 A74 3-(3 ,4-Difluorophenyl)-propionamidine hydrochloride

A106 A81 3 -(4-methoxyphenyl)-propionamidine hydrochloride A107 A82 3-(4-(trifluoromethoxy)phenyl)-propionamidine hydrochloride

A108 A84 3-(4-fluorophenyl)-propionamidine hydrochloride

A110 3 -phenyl-propanenitrile 3 -pheny 1-propionamidine hydrochloride

Alll 3 -(2-chlorophenyl)- 3-(2-chlorophenyl)-propionamidine hydrochloride propanenitrile

A112 A5 4-(4-fluorophenyl)-butyramidine hydrochloride

A113 A85 3-(2,3,4-trifluorophenyl)-propionamidine hydrochloride

Intermediate Bl — 2-[2-(2,3-Difluorophenyl)ethyl]-l,5,6,7-tetrahydrocyclopentapyrimidin-4-one

To a solution of 3-(2,3-difluorophenyl)-propionamidine hydrochloride (Int. A3) (3.90g, 17.7mmol) in ethanol (80ml) was added sodium ethoxide (1.44g, 21.2mmol) in portions and resulting slurry stirred at ambient temperature for lh. 2-Oxo-cyclopentanecarboxylic acid ethyl ester (3.09ml, 21.2mmol) was then added and the mixture refluxed for 2 days. Evaporation of the reaction mixture followed by chromatography (silica, dichloromethane-acetone) gave the title compound (2.76g, 56%) as a cream solid. Η-NMR (DMSO) δ 1.94 (2H, m), 2.59 (2H, t), 2.72 (2H, t), 2.82 (2H, t), 3.05 (2H, t), 7.07-7.29 (3H, m), 12.20 (IH, s); MS (APCI+) found (M+l) = 277; Cι₅H₁ F₂N₂0 requires 276.

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

No. P Prreeccursors Name

B2 ^' A91 2-[2-(2-trifluoromethyl-4-fluorophenyl)-ethyl]- 1 ,5,6,7-tetrahydro- cyclopentapyrimidin-4-one

B3 A93 2-[2-(3-trifluoromethyl-4-fluorophenyl)-ethyl]- 1 ,5,6,7-tetrahydro- cyclopentapyrimidin-4-one

B4 A94 2-[2-(3-chloro-4-fluorophenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin- 4-one

B5 ■ A95 . 2-[2-phenyl-prop- 1 -yl]- 1 ,5,6,7-tetrahydro-cycIopentapyrimidin-4-one

B6 _. A97 , 2-[2-(2,4-Difluorophenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin-4- one

B7 A98 i 2-[2-(2,5-Difluorophenyl)-ethyl]- 1,5,6, 7-tetrahydro-cyclopentapyrimidin-4- one

B8 . A99 j 2-[2-(3,4-Difluorophenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin-4- one

B9 A100 2-[2-(2-Fluorophenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin-4-one

BIO ^: A101 : 2-[2-(3-Fluorophenyl)-ethyl]- 1 ,5,6,7-tetrahydro-cyclopentapyrimidin-4-one

Bll A102 2-[2-(3-Chlorophenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin-4-one

B12 A103 2-[2-(4-Chlorophenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin-4-one

B13 A104 2-[2-(4-Methylphenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin-4-one

B14 A105 2-[2-(4-(trifluoromethyl)phenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopenta- pyrimidin-4-one

B15 A106 , 2-[2-(4-Methoxyphenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin-4-one

B16 A107 2-[2-(4-(trifluoromethoxy)phenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopenta- pyrimidin-4-one

B17 A108 2-[2-(4-fluorophenyl)-ethyl]- 1 ,5,6,7-tetrahydro-cyclopentapyrimidin-4-one

B18 A110 : 2-[2-phenyl-ethyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin-4-one

B19 ; Al l l : 2-[2-(2-chlorophenyl)-ethyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin-4-one

B20 ^: A112 2-[3-(4-fluorophenyl)-propyl]-l,5,6,7-tetrahydro-cyclopentapyrirnidin-4-one

B21 ; A10 ' (E)-2-[2-(4-fluorophenyl)-vinyl]-l,5,6,7-tetrahydro-cyclopentapyrimidin-4- j _ i one . . . . ..

Intermediate B40 — 5-Ethyl-2-[2-(4-fluorophenyl)ethyl]-lH-pyrimidin-4-one.

Sodium (0.23g) in dry ethanol (10ml) was treated with 3-(4-fluorophenyl)propionamidine hydrochloride (Int. A108) (1.02g). Ethyl 2-formylbutyrate (0.72g) was added and the mixture refluxed for 6h then maintained at room temperature for a further 24h. The reaction mixture was concentrated in vacuo, and the residue treated with water and acidified with cone, hydrochloric acid. The white precipitate was filtered off, washed with water and dried in vacuo at 40°C overnight, to give the title compound, (982mgs, 80%) -NMR (CDC1₃) δ 1.22 (3H, t), 2.52 (2H, q), 2.94 (2H, m), 3.09 (2H, m), 6.96 (2H, m), 7.24 (2H, m), 7.84 (IH, s) and 13.06 (IH, br. s). (APCI+) Found (M+1) = 247, C,₄Hι₅FN₂0 requires 246.

The following intermediates were made by the method of Intermediate B40:

No. Precursors Name

B41 A110 2-(2-phenylethyl)-5-methyl-lH-pyrimidin-4-one Methyl 2-formylpropionate

B42 A112 j 5-ethyl-2-[3-(4-fluorophenyl)propyl]-lH- Ethyl 2-formylbutyrate _ j pyrimidin-4-one

B43 A108 ] 2-[2-(4-fluorophenyl)ethyl]-5-(2,2,2-

Ethyl 4,4,4-Trifluoro-2-formylbutyrate j trifluoroethyl)-lH-pyrimidin-4-one

B44 A108 ^■ 5,6-dimethyl-2-[2-(4-fluorophenyl)ethyl]-lH-

Ethyl 2-acetylpropionate ' _pyιiπύdin-4-one

Intermediate B50 — 2-(2-[2-(2,3-Difluorophenyl)-ethyl]-4-oxo-4,5,6,7-tetrahydro-cycIopenta- pyrimidin-l-yl)-acetic acid ethyl ester

A mixture of Intermediate Bl (2.76g, lO.Ommol), ethyl iodoacetate (3.55ml, 30.0mmol) and N,N- diisopropylethylamine (5.22ml, 30.0mmol) in dichloromethane (40ml) was stirred at 30°C for 3 days. Further ethyl iodoacetate (3.55ml, 30.0mmol) and N,N-diisopropylethylamine (5.22ml, 30.0mmol), was added, the mixture stirred for 10 days and then washed with water, dried (MgS04) and evaporated. The residue was purified by chromatography (silica, ethyl acetate/acetone) to give the title compound as a brown solid (0.67g, 19%). Η-ΝMR (DMSO) δ 1.21 (3H, t), 1.96 (2H, m), 2.59 (2H, t), 2.83-3.01 (4H, m), 3.04 (2H, t), 4.20 (2H, q), 4.92 (2H, s), 7.10-7.30 (3H, m); MS (APCI+) found (M+1) = 363; Ci9H₂øF₂Ν θ3 requires 362.

Intermediate B51 — t-Butyl 2-(5-ethyI-2-(2-(4-fluorophenyl)ethyl)-4-oxo-4H-pyrimidin-l-yl)- acetate

5-Ethyl-2-[2-(4-fluorophenyl)ethyl]-lH-pyrimidin-4-one (B40) (955mgs) in dichloromethane (20mls) was tieated with t-butyl iodoacetate, (2.82g) and diisopropylethylamine (2.03mls) at room temperature for 3 days. The solution was washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulphate. The solution was concentrated to give a semi-solid which was triturated with etheπdichloromethane, 5:1, giving the title compound as a white solid, (l.lOlg, 79%), *H-NMR (CDCI3) 5 1.16 (3H, t), 1.47 (9H, s), 2.47 (2H, q), 2.74 (2H, t), 3.14 (2H, t), 4.27 (2H, s), 6.90 (IH, s), 6.98 (2H, m) and 7.17 (2H, m). (APCI+) Found (M+1) = 361, C₂₀H₂₅FN₂O₃ requires 360. Intermediate B52 — Ethyl (2,4-dioxo-4H-pyrido[2,3-rf][l,3]oxazin-l-yl)acetate

A 2:1 mixture of 3- and 6-azaisatoic anhydride (3.55g, 21.6mmol) (Synthesis 1982, 11, 972) was added portionwise to a suspension of sodium hydride (0.95g, 60% in oil, 23.8mmol) in DMF (40ml). After stirring for lh, ethyl bromoacetate (2.64ml, 23.8mmol) 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 lh. 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 ofthe [2,3-c?] and the [3,2-d] isomers. ^ Η-NMR (dg- DMSO) δ 1.21 (3Η, t), 4.18 (2H, q), 4.92 (2H, s), 7.45 (IH, dd), 8.47 (IH, dd), 8.77 (IH, dd); MS (APCI+) found (M+1) = 251; CπH₁₀N₂θ5 requires 250.

Intermediate B53 — Ethyl 2-(2-(2,3-difluorophenyl)ethyl-4-oxo-4H-pyrido[2,3-rf]pyrimidin-l- yl)acetate

Intermediate B52 (as a 4:1 mixture ofthe [2,3-d\ and the [3,2-cf| isomers) (l.Og, 3.99mmol) and 3-(2,3- difluorophenyl)propionamidine hydrochloride (Int. A3) (1.0g, 4.53mmol) were added to pyridine (25ml) and heated under reflux for 16h. The solvent was evaporated under reduced pressure. The residue was partitioned between dichloromethane and water and then filtered through a celite pad. The organic layer was separated, washed with water, dried (MgS04), filtered and concentrated. Purification by chromatography (silica gel, EtOAc) gave the title compound (0.885g, 59%) as an orange gum. Η-NMR (CDC1₃) δ 1.29 (3H, t), 3.05 (2H, t), 3.31 (2H, t), 4.26 (2H, q), 5.22 (2H, s), 7.01-7.09 (3H, m), 7.45 (IH, dd), 8.64 (IH, dd), 8.70 (IH, dd); MS (APCI+) found (M+1) = 374; C₁₉H₁₇F₂N θ3 requires 373.

Intermediate B55 — Ethyl 2-(2,4-dioxo-4H-thieno[3,2-d][l,3]oxazin-l-yl)acetate.

Sodium hydride (851mg, 60% dispersion in oil) in dry N,N-dimethylformamide (DMF) (15ml) was cooled under argon in an ice bath. A solution of lH-thieno[3,2-d][l,3]oxazine-2,4-dione (3g) in DMF (10ml) was added over ca 20min. The reaction mixture was stirred for 30 min at room temperature, then recooled in an ice bath. Ethyl iodoacetate (4.55g) was added and the mixture stirred at room temperature for ca 2h. The solution was concentrated to about half volume and cooled in an ice bath. Water was added (ca 200ml). After 10 min the precipitate was filtered off and washed with water and hexane and dried at 40°C in vacuo overnight. The title compound was obtained as a white solid (3.62g, 80%). 1H- NMR (CDCI3) δ 1.30 (3H, t), 4.28 (2H, q), 4.71 (2H, s), 6.77 (1H, d), 7.87 (IH, d). (APCI+) Found (M+1) = 256, CιoH₉NO_sS requires 255.

Intermediate B56 — Ethyl 2-((2-Carbamoylthiophen-3-yl)-(3-(2,3-difluorophenyl)propanoyl)- amino)acetate.

Ethyl 2-(2,4-dioxo-4H-thieno[3,2-d][l,3]oxazin-l-yl)acetate (B55) (lg) in (THF) (20ml) was cooled in an ice bath and treated with 0.880 aqueous ammonia (20ml) for 30min then stirred at room temperature for a further 30min. The THF was removed in vacuo and the aqueous solution treated with ethyl acetate and acidified with 5M hydrochloric acid. The aqueous solution was extracted with ethyl acetate. The combined organic phases were washed with brine, dried and concentrated to a solid. The crude amide as a suspension in dichloromethane (10ml) was treated with diisopropylethylamine (0.82ml) followed by a solution of 3-(2,3-difluorophenyl)propionoyl chloride (Int. A54) in dichloromethane (20ml). After lh at room temperature, the dichloromethane was removed and replaced with ethyl acetate. The solution was washed with saturated sodium bicarbonate, brine and then dried and concentiated. After purification on a silica chromatography column eluting with 50% ethyl acetate/hexane, the title compound was obtained as a colourless solid (518mgs, 33%); -NMR (CDCI3) δ 1.31 (3H, t), 2.46 (IH, m), 2.64 (IH, m), 2.95 (2H, t), 3.90 (IH, d), 4.24 (2H, m), 4.77 (IH, d), 5.69 (IH, br. s), 6.74 (IH, d), 6.86 (IH, m), 6.96 (2H, m), 7.52 (IH, d) and 8.60 (IH, br. s). (APCI+) Found (M+1) = 397, Cι₈Hι₈F₂N₂0₄S requires 396.

Intermediate B57 — Ethyl 2-(2-(2-(2,3-Difluorophenyl)ethyl)-4-oxo-4H-thieno[3,2-d]pyrimidin-l- yl)acetate.

Ethyl 2-((2-carbamoylthiophen-3-yl)-(3-(2,3-difluorophenyl)propanoyl)amino)acetate (Int. B56) (500mg) in dry DMF (3ml) was cooled in an ice bath and treated portion wise with sodium hydride (50mg, 60% dispersion in oil). The reaction mixture was stirred at room temperature for 30min to give an orange homogeneous solution. Excess 1M hydrogen chloride in ether was added giving a pale yellow solution and a precipitate. The mixture was heated in an oil bath at I20°C for 30min. The solution was concentiated and re-dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate, brine, dried and concentrated in vacuo to give a solid. Trituration with ether afforded the title compound as a white solid (375mgs, 78%); 1H-NMR (CDCI3) δ 1.29 (3H, t), 3.01 (2H, t), 3.30 (2H, t), 4.29 (2H, q), 4.84 (2H, s), 6.96 (IH, d), 7.03, (3H, m) and 7.77 (IH, d). (APCI+) Found (M+1) = 379, Cι₈Hι₆F₂N₂θ₃S requires 378. Intermediate B58 — 3-(3-(2,3-DifluorophenyI)-propanoylamino)-l-methyl-lH-pyrazole-4- carboxylic acid amide

To a solution of 3-(2,3-difluorophenyl)-propionic acid (Int. Al) (6.83g, 36.69mmol) in anhydrous dichloromethane (50ml) containing a few drops of DMF was added oxalyl chloride (6.4ml, 73.38mmol) at 0°C under argon. The solution was then stirred at ambient temperature for 2h and the solvent removed in vacuo. The residue was dissolved in dichloromethane (20ml) and added to a slurry of 3 -amino- 1- methyl-lH-4-carboxylic acid amide (4.4g, 23.66mmol) (Patent to Ciba Ltd., GB 884851) in dichloromethane (30ml) and pyridine (30ml) at 0°C under argon. The mixture was stirred at room temperature for 3h, the solvent evaporated in vacuo and the solid residue washed aqueous sodium bicarbonate, water and dried in vacuo to yield the title compound (4.0g, 55%) as a cream solid. Η-NMR (DMSO) δ 2.56-3.00 (4Η, m), 3.76 (3H, s), 7.08-7.28 (5H, m), 8.06 (IH, s), 9.92 (IH, s); MS (APCI+) found (M+1) = 309; Ci4H₁ F₂N4θ requires 308.

Intermediate B59 — 2-((4-Carbamoyl-l-methyl-lH-pyrazol-3-yl)-(3-(2,3-difluorophenyI)- propanoyl)-amino)-acetic acid ethyl ester

To a suspension of sodium hydride (60% dispersion in mineral oil, 260mg, 6.5mmol) in anhydrous DMF (5ml) under argon at 0°C was added a solution of 3-[3-(2,3-difluorophenyl)-propanoylamino]-l-methyl- lH-pyrazole-4-carboxylic acid amide (Int. B58) (2.0g, 6.49mmol) in anhydrous DMF (5ml). The reaction mixture was allowed to warm to room temperature over 30min and then ethyl iodoacetate (0.15ml, 1.27mmol) was added at 0°C. The mixture was stirred at ambient temperature overnight, washed with brine, dried (MgSθ4) and evaporated. The residue was purified by flash chromatography (fine silica, dichloromethane-methanol) to give the title compound as a cream solid (1.4g, 55%). Η- NMR (DMSO) δ 1.18 (3Η, t), 2.41 (2H, t), 2.87 (2H, t), 3.82 (3H, s), 4.10 (2H, q), 4.26 (2H, s), 6.99-7.24 (4H, m), 7.55 (IH, s), 8.16 (IH, s); MS (APCI+) found (M+1) = 395; C₁₈H₂oF₂N₄0₄ requires 394.

Intermediate B60 — 2-(4-(3-(2,3-DifluorophenyI)-propanoyIcarbamoyl)-l-methyl-lH-pyrazol-3- ylamiπo)-acetic acid ethyl ester

To a solution of 2-((4-carbamoyl-l-methyl-lH-pyrazol-3-yl)-[3-(2,3-difluorophenyl)-propanoyl]-amino)- acetic acid ethyl ester (Int. B59) (1.3g, 3.3mmol) in anhydrous DMF (12ml) under argon was added sodium hydride (60% dispersion in mineral oil, 132mg, 3.3mmol) in one portion. The reaction mixture was stirred for lh at ambient temperature and then poured into saturated ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSθ4 and evaporated to give the title compound as a cream solid (1.2g, 92%). 'H-NMR (DMSO) δ 1.18 (3H, t), 2.95 (2H, t), 3.08 (2H, t), 3.63 (3H, s), 3.95 (2H, d), 4.10 (2H, q), 6.33 (IH, t), 7.03-7.27 (3H, m), 8.23 (IH, s), 10.45 (IH, s); MS (APCI+) found (M+1) = 395; C₁₈H₂₀F₂N θ4 requires 394.

Intermediate B61 — 2-(6-(2-(2,3-Difluorophenyl)-ethyl)-2-methyl-4-oxo-2,4-dihydro-pyrazoIo[3,4- rf]pyrimidin-7-yI)-acetic acid ethyl ester

A suspension of p-toluenesulfonic acid monohydrate (200mg) and 2-(4-(3-(2,3-difluorophenyl)- propanoylcarbamoyl)-l-methyl-lH-pyrazol-3-ylamino)-acetic acid ethyl ester (Int B60) (1.2g, 3.04mmol) in toluene (100ml) was refluxed for 3h. The mixture was cooled and dichloromethane (200ml) was added. The resulting solution was washed with aqueous sodium bicarbonate solution, brine, dried (MgS04) and evaporated. The residue was purified by flash chromatography (silica, 5% methanol/dichloromethane) to give the title compound as a cream solid (650mg, 57%). Η-NMR (DMSO) δ 1.20 (3Η, t), 2.94-3.09 (4H, m), 3.95 (3H, s), 4.18 (2H, q), 5.05 (2H, s), 7.11-7.29 (3H, m), 8.39 (IH, s); MS (APCI+) found (M+1) = 377; C₁₈H₁₈F₂N₄0₃ requires 376.

Intermediate B65 — Ethyl 2-(2-[2-(2,3-difluorophenyl)-ethyl]-4-oxo-4H-quinazolin-l-yl)-acetate

To a solution of 3-(2,3-difluorophenyl)-propionic acid (Int. Al) (5g, 26.9mmol) in anhydrous dichloromethane (50ml) containing a few drops of DMF was added oxalyl chloride (4.7ml, 53.8mmol) at 0°C under argon. The solution was then stirred at ambient temperature for 2h and the solvent removed in vacuo. The residue which contained the acid chloride (Int. A54) was dissoved in toluene (50ml) and added to a slurry of (2-carbamoylphenylamino)-acetic acid ethyl ester (5.0g, 22.5mmol) in toluene (50ml) containing pyridine (1ml) and 4-dimethylaminopyridine (DMAP) (lOOmg). After 16h at 90°C the solvent was evaporated and the solid residue washed with water, aqueous ammonia and ether to give the title compound (6.9g, 82%) as a cream solid. Η-NMR (DMSO) δ 1.24 (3H, t), 3.13 (2H, t), 3.34 (2H, m),

4.24 (2H, q), 5.48 (2H, s), 7.19 (IH, m), 7.29-7.35 (2H, m), 7.60-7.72 (2H, m), 7.94 (IH, t), 8.19 (IH, d); MS (APCI+) found (M+1) = 373; C2θHι₈F₂N₂θ3 requires 372. ^'

Intermediate B66 — 5-Methyl-l-H-thieno[2,3-d][l,3]oxazine-2,4-dione

A mixture of ethyl 2-amino-4-methylthiophene-3-carboxylate (5g, 0.03 mol) in methanol (25ml) and aq. 2M sodium hydroxide (20.24ml, 0.04 mol) was heated under reflux for 4h. After cooling the solvents were evaporated, the residue dissolved in water (30ml) and a 20% solution of phosgene in toluene (24ml, 0.05 mol) added dropwise with ice cooling. After a further 30 min the solid which had precipitated was filtered, washed with water then ether, and dried to give the title compound 2.93 g (59%). Η NMR (d6- DMSO) δ 2.31 (3H, s), 6.78 (IH, s), 12.50 (IH, br. s).

Intermediate B67 — 2-(5-Methyl-2,4-dioxo-4 H-thieno[2,3-«7][l,3]oxazin-l-yl)-acetic acid ethyl ester

To a stirring suspension of sodium hydride (0.7g, 17.6mmol, 60% dispersion in oil) in dry DMF (30ml) 5-methyl-l H-thieno[2,3-<f][l,3]oxazine-2,4-dione (Int. B66) (2.93g, 16mmol) was added portionwise under argon. After lh, ethyl bromoacetate (1.95ml, 17.6mmol) was added dropwise with ice cooling. When addition was complete the reaction was allowed to warm to ambient temperature. After 16h the solvent was evaporated and the residue treated with water. The precipitated solid was filtered, washed with water and dried, to give the title compound (4.18g, 97%). Η NMR (d6-DMSO) δ 1.22 (3Η, t), 2.34 (3H, s), 4.15 (2H, q), 4.75 (2H, s), 6,95 (IH, s).

Intermediate B68 — Ethyl 2-(2-[2-(4-fluorophenyl)-ethyl]-4-oxo-4H-quinazolin-l-yl)-acetate

A solution of 3-(4-fluorophenyl)-propionamidine hydrochloride (Int. A 108) (0.42g, 2.05mmol) and ethyl 2-(2,4-dioxo-4H-benzo[J][l,3]oxazin-l-yl)-acetate (0.51g, 2.05mmol) in pyridine (20ml) was heated at reflux for 16h, allowed to cool then concentrated in vacuo. The residues were chromatographed over silica eluting with ethyl acetate to yield the product as a white solid (0.26g, 36%). Η-NMR (CDC1₃) δ 1.24 (3Η, t,), 3.0 (2H, m), 3.17 (2H, m), 4.24 (2H, q), 5.29 (2H, s), 6.95 (2H, m), 7.2-7.3 (3H, m), 7.40 (IH, m), 7.67 (IH, m), 8.29 (IH, dd); MS (APCI+) found (M+1) = 355; C20H19FN2O3 requires 354.

Intermediate CI — 2-(2-(2-(2,3-Difluorophenyl)-ethyl)-4-oxo-4,5,6,7-tetrahydro-cyclopenta- pyrimidin-l-yl)-acetic acid

A solution of 2-(2-[2-(2,3-difluorophenyl)-ethyl]-4-oxo-4,5,6,7-tetrahydro-cyclopentapyrimidin- 1 -yl)- acetic acid ethyl ester (B50) (0.66g, 1.83mmol), sodium hydroxide (0.15g, 3.67mmol) in methanol (6ml) and water (2ml) was stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue dissolved in water (2ml). Acidification to pH 1 with 2M hydrochloric acid gave a solid that was filtered, washed with water and dried in vacuo to give the desired product (0.50g, 82%) as a cream solid. Η-NMR (DMSO) δ 1.96 (2H, m), 2.63 (2H, t), 2.85-3.03 (6H, m), 4.91 (2H, s), 7.10-7.34 (3H, m); MS (APCI+) found (M+1) = 335; C₁₇H₁₆F₂N₂θ3 requires 334.

Intermediate C2 — 2-(5-ethyl-2-(2-(4-fluorophenyl)ethyl)-4-oxo-4H-pyrimidin-l-yl)acetic acid

t-Butyl 2-(5-ethyl-2-[2-(4-fluorophenyl)ethyl]-4-oxo-4H-pyrimidin-l-yl)acetate (Int B51) (lg) was dissolved in trifluoroacetic acid (10ml) and stirred for 3h at room temperature. The solution was concentrated under vacuum to a foam. Trituration with ether afforded the title compound as a colourless solid, (0.783g, 93%), 1H-NMR (DMSO) δ 1.05 (3H, t, J=7.5Hz), 2.24 (2H, q, J=7.5Hz), 2.79 (2H, m), 2.93 (2H, m), 4.79 (2H, s), 7.11 (2H, m), 7.30 (2H, m), 7.53 (IH, s) and 13.48 (IH, br. s). (APCI-) Found (M-l) = 303, Cι₆H₁₇FN₂0₃ requires 304.

The following 4-oxo-4H-pyrimidin-l-ylacetic acids were prepared from the corresponding lH-pyrimidin- 4-ones by alkylation with ethyl iodoacetate (as for Intermediate B50) followed by hydrolysis as for Intermediate CI, or by alkylation with t-butyl iodoacetate (as for Intermediate B51) followed by hydrolysis as for Intermediate C2.

No. Precursor Structure Name C3 B2 2-(2-(2-(2-trifluoromethyl-4-fluorophenyl)-ethyl)-4- oxo-4,5,6,7-tetrahydro-cyclopentapyrimidin-l-yl)- acetic acid

C4 B3

C5 B4

C6 B5

C9 B8 2-(2-(2-(3,4-difluorophenyl)-ethyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-acetic acid

CIO B9 2-(2-(2-(2-fluorophenyl)-ethyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-acetic acid

Cll BIO 2-(2-(2-(3-fluorophenyl)-ethyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-acetic acid

C12 Bl l 2-(2-(2-(3-chlorophenyl)-ethyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-acetic acid

C13 B12 2-(2-(2-(4-chlorophenyl)-ethyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-acetic acid

C14 B13 2-(2-(2-(4-methylphenyl)-ethyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-acetic acid

C15 B14 (2-(4-(trifluoromethyl)phenyl)-ethyl)-4-oxo- ,7-tetrahydro-cyclopentapyrimidin- 1 -yl)-acetic

C16 B15 2-(2-(2-(4-methoxyphenyl)-ethyl)-4-oxo-4,5,6,7- tetiahydro-cyclopentapyrimidin- 1 -yl)-acetic acid

C19 B18 2-(2-(2-phenyl-ethyl)-4-oxo-4,5,6,7-tetiahydro- cyclopentapyrimidin- 1 -yl)-acetic acid

2-(2-(2-(2-chlorophenyl)-ethyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-acetic acid

2-(2-(3-(4-fluorophenyl)-propyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-acetic acid

(£ 2-(2-(2-(4-fluorophenyl)-vinyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-acetic acid

C30 B41 2-(2-(2-phenylethyl)-5-methyl-4-oxo-4H-pyrimidin- l-yl)acetic acid

C31 B42 2-(5-ethyl-2-(3-(4-fluorophenyl)propyl)-4-oxo-4H- pyrimidin-l-yl)acetic acid

C32 B43 2-(2-(2-(4-fluorophenyl)ethyl)-5-(2,2,2- trifluoroethyl)-4-oxo-4H-pyrimidin- 1 -yl)acetic acid

C33 B44 2-(2-(2-(4-fluorophenyl)ethyl)-5,6-dimethyl-4-oxo- 4H-pyrimidin-l-yl)acetic acid

Intermediate C35 ^•2-(2-(2,3-DifluorophenyI)ethyl-4-oxo-4H-pyrido[2,3-<f]pyrimidin-l-yI)acetic acid

Example B53 (0.86g, 2.3mmol) was dissolved in EtOΗ (10ml). Water (3ml) and 2M NaOΗ (1.38ml, 2.76mmol) were added and the mixture was stirred for 15 min. The reaction mixture was concentrated, then water and EtOAc added. The pΗ was adjusted to 3.0 by the addition of 2M ΗC1. The resulting solid was collected by filtration, washed with water and EtOAc, and dried under vacuum to give 0.464 g of a 1.8:1 mixture ofthe title compound and (3-carbamoylpyridin-2-ylamino)acetic acid. ^I Η-NMR data of the title compound. ^JΗ-NMR (d₆-DMSO) δ 3.16 (4H,s), 5.25 (2H, s), 7.13-7.17 (IH, m), 7.24-7.30 (2H, m), 7.59 (IH, dd), 8.47 (IH, dd), 8.84 (IH, dd); MS (APCI") found (M-H₃0)" = 326; C17H13NF2 3O5 requires 345.

The following intermediates were prepared from Intermediate B52 and the amidines stated by the method of Intermediate B53 to give acetic acid derivatives after hydrolysis as for Intermediates C35 or CI.

No. Precursors Structure Name

C36 B52 +A108 2-(2-(4-Fluorophenyl)ethyl-4-oxo-4H- pyrido[2,3-£ ]pyrimidin- 1 -yl)acetic acid

C37 B52 +A113 2-(2-(2,3,4-Trifluorophenyl)ethyl-4-oxo-4H- pyrido[2,3-d]pyτimidin-l-yl)acetic acid

Intermediate C39 {2-[2-(2,3-Difluorophenyl)ethyl]-4-oxo-4Η-thieno[3,2-d]pyrimidin-l-yI}acetic acid.

Ethyl 2-(2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-4H-thieno[3,2-d]pyrimidin-l-yl)acetate (Int B57) (375mg) as a suspension in dioxan (2-3 ml) was treated with 0.5M solution of aqueous sodium hydroxide (1.98ml) at room temperature. After lh the solution was concentiated to a small volume and acidified with 2M hydrochloric acid. The precipitate was filtered off, washed with water and dried in vacuo at 40°C overnight. The title compound was obtained as a white solid (308mgs, 89%); ^!H-NMR (DMSO) δ 3.09 (4H, m), 5.19 (2H, s), 7.05-7.31 (3H, m), 7.49 (IH, d, J5.2Hz) and 8.14 (IH, d, J5.2Hz). (APCI+) Found (M+1) = 351, C₁₆H₁₂F₂N₂O3S requires 350. Intermediate C40 — 2-(2-[2-(4-FIuorophenyl)ethyl]-4-oxo-4H-thieno[3,2-d]pyrimidin-l-yl)acetic acid.

The above acetic acid derivative was prepared from Intermediates B55 and A108 by the procedures for Intermediates B56, B57 and C39.

Intermediate C41 — (6-(2-(2,3-Difluorophenyl)-ethyl)-2-methyl-4-oxo-2,4-dihydro-pyrazoIo- [3,4-</|pyrimidin-7-yl)-acetic acid

A solution of2-(6-[2-(2,3-difluorophenyl)-ethyl]-2-methyl-4-oxo-2,4-dihydro-pyrazolo[3,4-ύT|pyrimidin- 7-yl)-acetic acid ethyl ester (Int. B61) (600mg, 1.6mmol) in methanol (15ml) and 2M sodium hydroxide solution (1.0ml, 2mmol) was stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue dissolved in water (3ml). Acidification to pH 1 with 2M hydrochloric acid gave a solid that was filtered, washed with water and dried in vacuo to give the title compound as a cream solid (0.54g, 97%). Η-NMR (DMSO) δ 2.83 (2H, t), 3.31 (2H, t), 4.06 (3H, s), 5.24 (2H, s), 6.99-7.36 (3H, m), 8.80 (IH, s).

Intermediate C43 — 2-(2-(2-(2,3-Difluorophenyl)-ethyl)-4-oxo-4H-quinazolin-l-yl)-acetic acid

A solution of 2-(2-(2-(2,3-difluorophenyl)-ethyl)-4-oxo-4H-quinazolin-l-yl)-acetic acid ethyl ester (B65) (6.8g, 18.3mmol) in methanol (30ml) and 2M sodium hydroxide solution (18.0ml, 36mmol) was stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue dissolved in water (10ml). Acidification to pΗ 1 with 2M hydrochloric acid gave a solid that was filtered, washed with water and dried in vacuo to give the desired product (5.9g, 94%) as a white solid. Η-NMR (DMSO) δ 3.11-3.30 (4Η, m), 5.31 (2H, s), 7.16-7.33 (3H, m), 7.61 (IH, t), 7:68 (IH, d), 7.89 (IH, t), 8.18 (IH, d); MS (APCI+) found (M+1) = 345; C₁₈Hi4F₂N₂θ3 requires 344. The following 4-oxo-4H-quinazolin-l-yl-acetic acids (C44-C68) were prepared from acid chlorides and (2-carbamoylphenylamino)-acetic acid ethyl ester (or simple substituted derivatives prepared by the general method of Monatsh. Chem. 1986, 117(4), 499-509) in a two step procedure by the methods used for Intermediates B65 and C43.

No. Precursors Structure Name C48 A55 2-(2-(2-(3,4-Difluorophenyl)-ethyl)-4-oxo-4H- quinazolin-l-yl)-acetic acid

C49 A56 2-(2-(2-(2-Fluorophenyl)-ethyl)-4-oxo-4H- quinazolin-l-yI)-acetic acid

C50 , A57 2-(2-(2-(3-Fluorophenyl)-ethyl)-4-oxo-4H- quinazolin-l-yl)-acetic acid

C52 A59 2-(2-(2-(2,3,4-Trifluorophenyl)-ethyl)-4-oxo-4H- quinazolin-l-yl)-acetic acid

C53 A60 2-(2-(2-(2,3,5-Trifluorophenyl)-ethy])-4-oxo-4H- quinazolin-l-yl)-acetic acid

C62 A59 2-(6-Fluoro-2-(2-(2,3,4-trifluorophenyl)-ethyl)-4- oxo-4H-quinazolin- 1 -yl)-acetic acid

C66 A54 2-(2-(2-(2,3-Difluorophenyl)-ethyl)-8-methyI-4- oxo-4H-quinazolin-l-yl)-acetic acid

C67 A54 -yl)-acetic

C68 3-Phenyl- lin- 1 -yl)- propionyl chloride

C75 A54 2-(2-(2-(2,3-difluorophenyl)-ethyl)-7-methyl-4- oxo-4H-quinazolin- 1 -yl)-acetic acid

C76 A54 2-(2-(2-(2,3-difluorophenyl)-ethyl)-6,7-difluoro-4- oxo-4H-quinazolin- 1 -yl)acetic acid

C77 A54 2-(2-(2-(2,3-difluorophenyl)-ethyl)-7-fluoro-4-oxo- 4H-quinazolin-l-yl)acetic acid

C78 A54 2-(2-(2-(2,3-difluorophenyl)-ethyl)-6-fluoro-4-oxo- 4H-quinazolin-l-yl)acetic acid

Intermediate C69 — 2-(2-[2-(4-FIuoropheπyl)-ethyl]-4-oxo-4H-quinazoliπ-l-yI)-acetic acid

Ethyl 2-(2-[2-(4-fluorophenyl)-ethyl]-4-oxo-4H-quinazolin-l-yl)-acetate (Intermediate B68) was hydrolysed using the method for Example CI to give the title compound.

The following acetic acid intermediates were prepared using the general procedures of Examples B68 and CI.

No. Precursors Structure Name

C70 A95 2-(2-(2-phenyl-proρyl)-4-oxo-4H-quinazolin- 1 - yl)-acetic acid

C71 A98 2-(2-(2-(2,5-difluorophenyl)-ethyl)-4-oxo-4H- quinazolin-l-yl)-acetic acid

C72 B67, A108 2-(2-(2-(4-fluorophenyl)-ethyl)-5-methyl-4-oxo- 4H-thieno[2,3- ]pyimidin-l-yl)-acetic acid

Intermediate C80 2-(2-(2-(2,3-DifluorophenyI)-ethyl)-4-oxo-4H- pyrido[3,2-</]pyrimidin-l- yl)acetic acid

A mixture of 3-amino-pyridine-2-carboxylic acid amide (300mg, 2.2mmol), ethyl bromoacetate (0.24ml, 2.2mmol) and sodium hydrogen carbonate (185mg, 2.2mmol) in DMF (2ml) was heated at 70 °C for 4h. The mixture was evaporated to dryness and partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic phases washed with brine, dried (MgS0₄) and evaporated. The residue was purified by chromatography (lOg silica cartridge, dichloromethane-50% ethyl acetate / dichloromethane) to give the title compound as a white solid. This material was converted to the title compound in a two step procedure by the methods of Intermediates B65 and C43. Η-NMR (d6 DMSO) δ 3.13 (4H, brs), 5.20 (2H, s), 7.12-7.32 (3H, m), 7.83 (IH, dd), 8.13 (IH, d), 8.80 (IH, d), 13.70 (IH, brs); MS (APCI-) found (M-l) = 344; C₁₇H₁₃F2N3θ3 requires 345.

Intermediate Dl — 4-(4-Chlorophenyl)benzaldehyde

₀ -XX^a

(a) A mixture of 4-formylbenzeneboronic acid (2.50g, 2 equiv), 4-chloroiodobenzene (1.98g, 1 equiv), tetrakis(tiiphenylphosphine)palladium(0) (0.50g, 0.05 equiv), aqueous sodium carbonate (18ml, 2M solution, 2 equiv) and dimethoxyethane (50ml) was stirred at reflux under argon overnight, then cooled and diluted with ethyl acetate. The mixture was filtered as necessary to remove inorganic residues, then the organic layer was washed successively with aqueous citric acid and brine, dried and evaporated. The crude product was purified by chromatography (silica, 5% ethyl acetate in hexane); product fractions were evaporated to a white solid (1.32g, 72%). (b) A mixture of 4-chlorobenzeneboronic acid (19.4g, 1 equiv), 4-bromobenzaldehyde (22.9g, 1 equiv), palladium(II) acetate (1.4g, 0.05 equiv), aqueous sodium carbonate (30.3 g in 144ml solution, 2 equiv) and dimethoxyethane (500ml) was stirred at reflux under argon for 2.5h, then evaporated to low volume and diluted with dichloromethane. Workup continued as in (a) above to give identical material (25.2g, 94%). 'H-NMR (CDC1₃) δ 10.05 (IH, s), 7.96 (2H, d), 7.73 (2H, d), 7.57 (2H, d), 7.46 (2H, d); MS (AP+) found (M+1) = 217, C13H9CIO requires 216.

Intermediate D2 — 4-(4-Trifluoromethylphenyl)-benzaIdehyde

A 3 L 3 -neck flask fitted with top stirrer, condenser and argon inlet/outlet was charged with 4- trifluoromethybenzene boronic acid (90.0g, 0.474 mol), 4-bromobenzaldehyde (83.29g, 0.450 mol) and 1,2-dimethoxyethane (1.3 L), followed by 2M aqueous sodium carbonate (474ml) and palladium acetate (5.32g, 0.0237 mol). The stirring mixture was heated to reflux for 4h under argon, then allowed to cool to room temperature over 16h. The reaction mixture was filtered through hyflo. The filtrate was diluted with saturated brine and extracted 3x 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. 120g, crude). Flash chromatography (silica, 10-50% dichloromethane in pet. ether, 10% steps) gave a white solid which dissolved in hexane (500ml) on boiling. Crystallisation, finally in ice, gave the title compound as a solid which was filtered off, washed with ice cold hexane and dried, (86.33g, 77%). 'H-NMR (CDCI3) δ 7.77-8.03 (8H, m), 10.09 (IH, s).

Intermediate D3 — N-(2-Diethylaminoethyl)-4-(4-chlorophenyl)benzylamine

A mixture of Intermediate Dl (55.0g), N,N-diethylethylenediamine (35.6ml), 4A molecular sieve (37g), and dichloromethane (1100ml) was reacted at room temperature under argon for 16h, with occasional agitation. The solid was filtered off and washed with dichloromethane, and the combined filtrates evaporated to a yellow foam (72.4g). This intermediate imine was reduced with sodium borohydride (8.7g) in ethanol (850ml) as described for Intermediate D4, yielding the title compound as a yellow oil (72.7g). ¹ H-NMR (CDC1₃) δ 1.70 (2H, t), 2.22 (6H, s), 2.33 (2H, t), 2.69 (2H, br. m), 3.83 (2H, s), 7.37- 7.43 (4H, m), 7.52-7.56 (4H, m).

Intermediate D4 — N,N-diethyl-N'-(4'-trifluoromethyIbiphenyl-4-ylmethyl)-ethane-l,2-diamine)

4-(4-Trifluoromethylphenyl)benzaldehyde (85.43g, 0.3414 mol) (Int. D2) and 4A molecular sieve (400g, predried at 120°C) were suspended in dichloromethane (1.4 L), then N,N-diethylethylenediamine (47.97ml, 0.3414 mol) was added. The mixture was left at room temperature for 16h 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 (114.3g, 0.328 mol) in ethanol (1 L) was cooled in an ice bath, and sodium borohydride (12.41g, 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 16h. The solvent was removed in vacuo, water and brine were added, and the mixture was extracted 3x with dichloromethane. The combined extracts were dried over potassium carbonate and evaporated to give the title compound as a yellow solid, (112.1g, 98%). ! H-NMR (CDCI3) δ 7.66 (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+l)= 351, C₂oH₂₅F₃N₂ requires 350.

Intermediate D5 — N-Methyl-4-(4-trifluoromethylphenyl)benzylamine

A mixture of Intermediate D2 (4.57g, leq), methylamine (9.15mL of a 2M solution in THF) and anhydrous magnesium sulphate (4.4 lg, 2eq) was stirred at room temperature for 16h, filtered and the solid washed thoroughly with ethyl acetate. The combined filtrates were evaporated to a solid which was suspended in ethanol (90mL) and sodium borohydride (l.Olg, 1.5eq) added portionwise. The mixture stirred at room temperature for 3h and the solvent removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine, dried and evaporated to give the title compound as a white solid. -NMR (CDCI3) δ 7.68 (4H, m), 7.56-7.58 (2H, m), 7.43-7.45 (2H, m), 3.83 (2H, s), 2.50 (3H, s); MS(APCI+) found (M+l)= 266, C₁₅H₁ F₃N requires 265.

Intemediate D6 — 4-(4-TrifluoromethylphenyI)benzonitrile

Prepared by the method of intermediate D2 using 4-trifluoromethylbenzeneboronic acid and 4- bromobenzonitrile. Η-NMR (DMSO) δ 7.99-7.94 (6H, m) 7.86 (2H, d); MS(APCI+) found (M+l)=248, Cι₄H₈NF₃ requires 247. Intemediate D7 — 4-(4-TrifluoromethylphenyI)benzylamine, free base and hydrochloride salt

(a) A solution of intermediate D6 (75.5g, 0.306 mol) in anhydrous THF (500ml) was added dropwise to a solution of lithium aluminium hydride (460ml, 1.0M solution in THF) at 0°C under argon. The mixture was stirred at room temperature for 16h, then water (17ml), 10% aqueous sodium hydroxide solution

(10ml) and water (50ml) were carefully added dropwise over 8h under argon. The mixture was stirred for 16h, then filtered through celite and the filtrate evaporated. The residue was dissolved in dichloromethane (500ml) and washed with brine, dried and evaporated to give the title compound as a cream solid (66.3g, 86%). 'H-NMR (CDC1₃) δ 7.68 (4H, s), 7.57 (2H, d), 7.42 (2H, d), 3.94 (2H, s), 1.50 (2H, s); MS(APCI+) found (M-NH₂)=235, C_HH^N requires 251.

(b) To a solution of intermediate D6 (96.7 g, 0.39 mol) in absolute ethanol (5L) and concentrated hydrochloric acid (200ml) was added 10% palladium on charcoal (30.0g, 54% H₂0 paste). The mixture was stirred under 50psi hydrogen for 16h. Additional 10% palladium on charcoal (25. Og, 54% H₂0 paste) was added and the mixture was stirred under 50psi hydrogen for further 16h. The mixture was filtered through celite and the solvent evaporated to give the hydrochloride salt ofthe title compound as a cream solid (102.5g, 91%). "H-NMR (DMSO) δ 8.61 (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, Cι₄H₁₂F₃N requires 251.

Intermediate D8 — N-(l-Methyl-piperidin-4-yl)-4-(4-trifluoromethylphenyl)benzyIamine

A mixture of intermediate D7 hydrochloride salt (6.0g, 20.9mmol), l-methyl-piperidin-4-one (2.56ml, 20.8mmol), sodium triacetoxyborohyride (6.20g, 29.3mmol) and acetic acid (1.3ml) in dichloroethane (50ml) was stirred at room temperature under argon for 16h then poured into 2M sodium hydroxide solution (150ml). 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 (6.3g, 87%). 'H-NMR (CDC1₃) δ 7.68 (4H, s), 7.57 (2H, d), 7.42 (2H, d), 3.87 (2H, s), 2.82 (2H, m), 2.52 (IH, m), 2.27 (3H, s), 1.90-2.02 (4H, m), 1.45-1.51 (2H, m); MS(APCI+) found (M+l)=349, C₂0H23N2F3 requires 348.

Intermediate D9 — 4-(4-Bromophenyl)benzylaldehyde

H =\ =v ° ^

A solution of 4,4'-dibromobiphenyl (lOg, 32mmol) in tefrahydrofuran (250ml), was cooled to -78°C, and butyllithium (2.5M, 12.8ml, 32mmol) was added dropwise. After 15 min, dimethylformamide (50ml) was added, initially dropwise. The mixture was allowed to warm to room temperature and stirred for 2h, then water (250ml) was added and the product was extracted into ether. Drying and evaporation ofthe extracts, followed by chromatography (silica, toluene) yielded the title compound (7. lg, 85%). Η-NMR (CDCI₃) δ 7.49 (2H, d), 7.60 (2H, d), 7.71 (2H, d), 7.95 (2H, d), 10.08 (IH, s). Intermediate D10 — 4-(Thien-2-yl)benzyl acohol

A mixture of 4-bromobenzyl alcohol (2.09g, 11.2mmol), 2-(tributylstannyl)thiophene (5.0g, 13.4mmol), tetiakis(trphenylρhosphine)palladium (0.39g, 0.34mmol) and xylene (30ml) was stirred at 140°C for lh, then cooled and applied directly to a silica column. Elution with ethyl acetate/hexane gave the desired product (1.43g, 67%). *H-NMR (CDC1₃) δ 4.70 (2H, s), 7.07 (IH, m), 7.27 (IH, m), 7.30 (IH, m), 7.36 (2H, d), 7.60 (2H, d).

Intermediate Dll — 4-(5-Tributylstannyl-thien-2-yl)benzyl acohol

HQ n- ^■ S-

^X -<V Intermediate D10 (1.43g, 7.5mmol) was dissolved in THF (40ml) and cooled to -30°C. n-Butyllithium (16.5mmol) was added dropwise and stirring continued at -30°C for lh, then the mixture was cooled to -78°C and a solution of tributyltin chloride (4.47ml, 16.5mmol) in THF (10ml) was added. The mixture was allowed to warm to room temperature, then saturated aqueous ammonium chloride (15ml) was added with stirring, followed by water (10ml). The product was extracted into ether, dried, and the solvent evaporated. Chromatography (silica, 30% ethyl acetate in hexane) gave the desired product (3.29g, 92%). ^!H-NMR (CDCI3) δ 0.90 (9H, t), 0.13 (6H, m), 0.37 (6H, m), 1.63 (6H, m), 4.70 (2H, d), 7.14 (IH, m), 7.36 (2H, m), 7.42 (IH, m), 7.62 (2H, m).

Intermediate D12 — 4-(5-Iodothien-2-yl)benzyl acohol

A solution of intermediate Dl 1 (1.6g, 3.34mmol) in chloroform (40ml) was cooled to 0°C and a solution of iodine (0.805g, 3.17mmol) in chloroform (10ml) was added dropwise, followed by a solution of potassium fluoride (1.2 equiv) in methanol (4ml). After stirring for 2 mins water was added, then the organic layer was separated and applied directly to a silica column, which was eluted with ethyl acetate/hexane to obtain the title compound (0.84g, 80%). ^-NMR (CDCI3) δ 1.66 (IH, t), 4.70 (2H, d), 6.97 (IH, m), 7.21 (IH, m), 7.36 (2H, m), 7.51 (2H, m).

Intermediate D13 — 4-(5-Iodothien-2-yl)benzaldehyde

A mixture of intermediate D12 (0.40g) and manganese dioxide (l.lg, 10 equiv) in dichloromethane (20ml) was stirred under argon in the dark for 16h. Filtration through celite and evaporation ofthe solvent yielded the title compound (0.36g). ^!H-NMR (CDCI3) δ 7.11 (IH, m), 7.26 (IH, m), 7.64 (2H, m), 7.89 (2H, m), 10.00 (IH, s). Intermediate D14 — 4-(5-Trifluoromethylthien-2-yl)benzaldehyde

A mixture of intermediate D13 (0.772g, 2.46mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.36g, 12.3mmol), copper iodide (0.56g, 2.95mmol), N-methylpyrrolidone (1.18ml, 12.3mmol) and dimethylformamide (20ml) was stirred at 70°C for 7h, then further portions of methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (2.36g, 12.3mmol) and copper iodide (2.8g, 12.3mmol) were added, and heating was continued for a further 6h. Saturated aqueous ammonium chloride (30ml) was added with stirring, then the mixtured was diluted with water (20ml), filtered through celite, then extracted with ethyl acetate. The extracts were dried, evaporated, and purified by chromatography (silica, 15% ethyl acetate in hexane); yield 0.44 g (70%). * H-NMR (CDC1₃) δ 7.39 (IH, m), 7.46 (IH, m), 7.77 (2H, m), 7.94 (2H, m), 10.06 (IH, s).

Intermediate D15 — 4-(4-Pentafluorophenyl)benzaldehyde

VA ΓV

H ^=/ —^y

Pentafluoroethyl iodide (2ml, 16.9mmol) was added to copper (2.12g, 33.3mmol) and dimethylsulfoxide (13ml) at 0°C in a tube which was then sealed and heated to 110°C for 4h. A portion ofthe resulting organocuprate solution (3.2ml) was mixed with intermediate D9 (0.20g) and heated to 70°C for 3h. The remaining organocuprate was added, and heating continued for 20h. The mixture was poμred into a mixture of 2M hydrochloric acid and ethyl acetate, then the organic layer was dried and evaporated to obtain the title compound (0.22g). * H-NMR (CDCI3) δ 7.74 (6H, m), 7.97 (2H, m), 10.10 (IH, s). The following intermediates were made as described in WO 00/66567

No. Structure Name

D16 * /^=z /^X (2-(4-trifluoromethylphenyl)pyrimidine-5-carboxaldehyde

W // -CF,

D17 /⁼⁼\ /⁼⁼\ 5-Formyl-2-(4-trifluoromethylphenyl)pyridine

D18 H ²,N _\ /f~ /⁼⁼\ 4-(4-Chlorophenyl)benzylamine

5-(4-Chlorophenyl)furfural (Intermediate D19) was commercially available. The following intermediates were made by the method of Intermediate D 1 :

No. Precursors Name

D21 4-bromobenzaldehyde, . 4-(4-n-penrylphenyl)benzaldehyde

4-n-pentylbenzeneboronic acid

D22 5-bromothiophene-2-carboxaldehyde 5-(4-trifluoromethylphenyl)thiophene-2-

4-trifluoromethylbenzeneboronic acid carboxaldehyde

D23 4-bromobenzaldehyde 4-(2-chlorothien-5-yl)benzylaldehyde 5-chlorothiophene-2-boronic acid

D24 , 4-bromobenzaldehyde, 4-(4-methylphenyl)benzaldehyde ¹ ; 4-methylbenzeneboronic acid

■ D25 i 4-bromobenzaldehyde, 4-(4-ethylphenyl)benzaldehyde

. 4-ethylbenzeneboronic acid

D26 4-bromobenzaldehyde, 4-(4-methylthiophenyl)benzaldehyde

4-methylthiobenzeneboronic acid

D27 4-isopropyliodobenzene 4-(4-isopropylphenyl)benzaldehyde

4-formylbenzeneboronic acid

D28 4-iodobenzonitrile 4-(4-cyanophenyl)benzaldehyde

4-formylbenzeneboronic acid

D29 4-bromobenzaldehyde, 4-(4-methylsulfonylphenyl)benzaldehyde

4-methylsulfonylbenzeneboronic acid

D30 5-bromo-2-furaldehyde 5-(4-trifluoromethylphenyl)furfural

4-trifluoromethylbenzeneboronic acid

D31 5-bromothiophene-2-carboxaIdehyde 5-(5-chlorothien-2-yl)thiophene-2- 5-chlorothiophene-2-boronic acid carboxaldehyde

D91 1 -iodo-4-(piperidin- 1 -ylsulfonyl)benzene 4-(piperidin- 1 -ylsulfonylphenyl)benzaldehyde 4-formylbenzeneboronic acid

The following intermediates were made by the method of Intermediate D3 : Amine precursors were either commercially available, or readily prepared from commercially available materials by literature methods or minor modifications thereof.

No. Precur- Structure Name

N-(2-(piperidin- 1 -yl)ethyl)-4-(4-trifluoro- methylphenyl)benzylamine

N-(2-(/V-ethyl-t-butoxycarbonylamino)- ethyl)-4-(4-trifluoro- methylphenyl)benzylamine

N-(2-(ethylamino)-2-methyl-propyl)-4-(4- trifluoromethylphenyl)benzylamine

N-(2-(diethylamino)-2-methyl-propyl)-4-(4- trifluoromethylphenyl)-benzylamine

D36 Int. D2 N-(2-(dimethylamino)-2-methyl-propyl)-4-(4-

-CF, trifluoromethylphenyl)benzylamine

D40

D41

D42

D43

D44

D45

D46 Int. D2 N-(3 -(pyrrolidin- l-yl)-propyl)-4-(4-trifluoro- methylphenyl)benzylamine

D49 I Int. D2 (+/-)-N-(l-ethyl-pyrrolidin-2-ylmethyl)-4-(4- trifluoromethylphenyl)benzylamine

D50 Int. D21 ^' ^N , — , =v N-(2-diethylaminoethyl)-4-(4-pent-l-

^: Et₂N-^ — \_/ — , , ^C5^Hιι ylphenyl)benzylamine N-(2-diethylaminoethyl)-4- (ρhenyl)benzylamine . N-(3-diethylamino-propyl)-4-(4-trifluoro- methylphenyl)benzylamine

N-(2,2-dimethyl-3-dimethylamino-propyl)-4- (4-trifluoromethylphenyl)benzylamine

D58 Int. D25 N-(2-diethylaminoethyl)-4-(4-ethylphenyl)- benzylamine

D59 Int. D26 N-(2-diethylaminoethyl)-4-(4-methylthio- phenyl)benzylamine

D60 Int. D27 , _; N-(2-diethylaminoethyl)-4-(4-isopropyl- ^' phenyl)benzylamine

N-(2-diethylaminoethyl)-4-(4-cyanophenyl)-

benzylamine

D62 Int. D29 , N-(2-diethylaminoethyl)-4-(4-methylsulfonyl- phenyl)benzylamine

D63 Int. D9 N-(2-diethylaminoethyl)-4-(4-bromophenyl)- benzylamine

N-(2-methoxyethyl)-4-(4-trifluoromethyl- phenyl)benzylamine N-(t-butoxycarbonylmethyl)-4-(4-trifluoro- methylphenyl)benzylamine N-methyl-2-(4-trifluoromethylphenylpyrid-5- i ylmethylamine

. N-(2-diethylaminoethyl)-(2-(4-trifluoro- methylphenyl)pyrimid-5-ylmethylamine

D68 Int. D23 N-(2-diethylaminoethyl)-4-(2-chlorothien-5- yl)benzylamine

D69 Int. D22 ^; N-(2-diethyIaminoethyl)-5-(4-trifluoromethyI- phenyl)thien-2-ylmethylamine

D70 Int. D14 ' N-(2-diethylaminoethyl)-4-(5-tiifluoromethyl- thien-2-yl)benzylamine

The following intermediates were made by the method of Intermediate D8: Piperidone precursors were either commercially available, or readily prepared from commercially available materials by literature methods or minor modifications thereof.

D47 Int. D2 N-( 1 -ethyl-piperidin-4-y l)-4-(4-trifluoro- methylphenyl)benzylamine

D48 Int. D2 N-( 1 -/-SOpropyl-piperidin-4-yl)-4-(4- trifluoromethylphenyl)benzylamine

D83 Int. D18 N-(l-methylpiperidin-4-yl)-4-(4-chloro- phenyl)benzylamine

D84 Int. D18 N-(l-isopropylpiperidin-4-yl)-4-(4- chlorophenyl)benzylamine

D85 Int. D18 . N-(l-(2-methoxyethyl)piperidin-4-yl)-4- (4-chlorαphenyl)benzylamine

Example 1 — N-(2-Diethylaminoethyl)-2-(2-(2-(2,3-difluorophenyl)-ethyl)-4-oxo-4H-quinazolin-l- yI)-N-(4'-trifluoromethyl-biphenyI-4-ylmethyI)acetamide bitartrate

A solution of Ν-(2-(diethylamino)ethyl)-4-(4-trifluoromethylphenyl)benzylamine (Intermediate D4) (0.25g, 0.73mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (DEC) (0.28g, 1.45mmol), 1- hydroxybenzotriazole hydrate (0.10g, 0.73mmol), 2-(2-(2-(2,3-difluorophenyl)-ethyl)-4-oxo-4H- quinazolin-l-yl)-acetic acid (Int. C43) (0.25g, 0.73mmol) in dichloromethane (20ml) was stirred at ambient temperature overnight then diluted with dichloromethane, washed with aqueous sodium bicarbonate and evaporated. The residue was purified by chromatography (1 Og silica cartridge, 20% methanol in ethyl acetate) to give the title compound, as the free base, as a yellow foam (0.43g, 88%). 'Η-NMR (CDC1₃, rotamer mixture) δ 0.98-1.04 (6Η, m), 2.50-2.67 (6H, m), 2.85-3.02 (2H, m), 3.23-3.66 (4H, m), 4.71/4.85/5.28 (4H, 3x s), 6.86-7.53 (9H, m), 7.63-7.73 (5H, m), 8.34/8.40 (IH, 2x d); MS (APCI+) found (M+1) = 677; C3gH37F5N₄0₂ requires 676. A solution of cf-tartaric acid (0.94g, 0.62mmol) and the title compound as the free base (0.42g, 0.62mmol) in methanol (2ml) was evaporated to give a yellow foam which was triturated with ether, filtered, and dried in vacuo to yield the salt (0.49g, 96%). Η-NMR (CDCI3, rotamer mixture) δ 0.89-1.02 (6H, m), 2.55-3.50 (12H, m), 4.23 (2H, s), 4.64/4.88 (2H, 2x s), 5.29/5.53 (2H ,2x s), 7.10-7.86 (14H, m), 8.10 (IH, t). MS (APCI+) found (M+1) = 677; C3₈H3₇F₅N₄0 requires 676.

Example 2 — N-(2-Diethylaminoethyl)-2-(5-ethyl-2-[2-(4-fluorophenyI)ethyl]-4-oxo-4H-pyrimidin- l-yl)-N-(4'-trifluoromethyIbiphenyl-4-ylmethyl)acetamide bitartrate

2-(5-Ethyl-2-[2-(4-fluorophenyl)ethyl]-4-oxo-4H-pyrimidin-l-yl)acetic acid (Int. C2) (150mg), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(189mg), 1-hydroxybenzotriazole hydrate, (67mg) and N,N-diethyl-N'-(4^,-trifluoromethyIbiphenyl-4-ylmethyl)ethane-l,2-diamine (Int. D4) (173mg) were combined in dichloromethane (20ml) at room temperature and stirred for 24h. The solution was washed with saturated sodium bicarbonate, brine, dried and concentrated. The crude product was purified by column chromatography (silica gel,40% methanol/ethyl acetate). The title compound was obtained as a yellow foam, (277mg, 89%); *H-NMR (CDC1₃) ca 2:1 mixture of rotamers δ 0.94/0.99 (6H, t, J=7.1Hz), 1.14 (3H, m), 2.42-2.75 (10H, m), 3.07/3.15 (2H, t, J=8.3Hz), 3.25/3.59 (2H, t, J=4.8Hz), 4.34/4.66 (2H, s), 4.66/4.83 (2H, s) and 6.86-7.74 (13H, m). (APCI+) Found (M+1) = 637, C₃₆H₄oF₄N₄θ₂ requires 636. The bitartiate salt was prepared by treatment ofthe free base (270mg) in methanol (2ml) with d-tartaric acid,(64mg). The solution was concentiated to a yellow foam, and triturated with ether to give the title compound as a yellow solid, (314mg, 94%), 1H-NMR (DMSO) ca 2:1 mixture of rotamers δ 0.90/0.97 (6H, t, J=7.2Hz), 1.06 (3H, m), 2.27 (2H, m), 2.50 (2H, m), 2.68 (6H, m), 2.93 (2H, m), 3.37/3.45 (2H, t, J=6.0Hz), 4.21 (2H, s), 4.64/4.71 (2H, s), 4.99/5.15 (2H, s) and 7.06-7.85 (13H, m).

Example 3 — N-(2-DiethyIaminoethyl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4,5,6,7- tetrahydro-cycIopentapyrimidin-l-yl]-N-(4'-trifluoromethyI-biphenyI-4-ylmethyl)acetamide bitartrate

A solution of N,N-diethyl-N-(4^,-trifluoromethyl-biphenyI-4-ylmethyl)-ethane-l,2-diamine (Int D4) (0.50g, 1.44mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.56g, 1.45mmol), 1- hydroxybenzotriazole hydrate (0.12g) and 2-(2-[2-(2,3-difluorophenyl)-ethyl]-4-oxo-4,5,6,7-tetrahydro- cyclopentapyrimidin-l-yl)-acetic acid (Int CI) (0.48g, 1.44mmol) in dichloromethane (10ml) was stirred at ambient temperature overnight then diluted with dichloromethane (30ml), washed with aqueous sodium bicarbonate and evaporated. The residue was purified by chromatography (lOg silica cartridge, ethyl acetate-acetone) to give the title compound as a yellow foam (free base) (0.50g, 52%). Η-ΝMR (DMSO, rotamer mixture) δ 0.83-0.89 (6H, m), 1.98 (2H, m), 2.40 (4H, m), 2.45-2.82 (10H, m), 3.02 (2H, m), 4.64/4.75 (2H,2x s), 4.96/5.19 (2H,2x s), 7.11-7.40 (5H, m), 7.65 (2H, m), 7.84 (4H, m); MS (APCI+) found (M+1) = 667; C3₇H39F₅Ν4θ₂ requires 666. rf-Tartaric acid (0.09g, 0.60mmol) was added to a solution ofthe free base (0.40g, 0.60mmol) in methanol (10ml) with stirring. The resulting solution was evaporated to yield the salt (0.49g). Η-NMR (DMSO, rotamer mixture) δ 0.85-0.97 (6H, m), 1.91-2.00 (2H, m), 2.40-2.49 (4H, m), 2.54-2.82 (10H, m), 3.02- 3.46 (2H, m), 4.20 (2H, s), 4.64/4.75 (2H, 2x s), 4.97/5.18 (2H, 2x s), 7.11-7.40 (5H, m), 7.65 (2H, m), 7.84 (4H, m); MS (APCI+) found (M+1) = 667; C₃7H39F₅N₄0₂ requires 666. Example 4 — N-(2-Diethylaminoethyl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-thieno[3,2- d]pyrimidin-l-yI]- N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate

2-(2-[2-(2,3-Difluorophenyl)ethyl]-4-oxo-4H-thieno[3,2-d]pyrimidin-l-yl)acetic acid, (Int. C39) (150mg), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (164mg), 1- hydroxybenzotriazole hydrate (58mg) and N,N-diethyl-N'-(4'-trifluoromethylbiphenyl-4-ylmethyl)ethane- 1,2-diamine (Int. D4) (150mg) were combined in dichloromethane (5ml) at room temperature and stirred for 24h. The solution was washed with saturated sodium bicarbonate, brine, dried and concentiated. The crude product was purified by column chromatography on silica gel eluting with 40% methanol/ethyl acetate. The title compound was obtained as a yellow foam, (260mgs, 89%), H-NMR (CDCI3) ca 2:1 mixture of rotamers δ 1.00 (6H, t, J6.8Hz), 2.57 (4H, q, J6.8Hz), 2.64 (2H, m), 2.83/2.96 (2H, t, J8.4Hz), 3.24/3.30 (2H, t, J8.4Hz), 3.39/3.65 (2H, m), 4.68/4.82 (2H, s), 5.30 (2H, s), 6.95-7.06 (5H, m), 7.32/7.36 (IH, d, J8.4Hz), 7.52/7.60 (IH, d, J8.2Hz) and 7.62-7.72 (6H, m). (APCI+) Found (M+1) = 683, C₃₆H₃₅F₅N₄θ₂S requires 682.

The free base (260mg) in methanol (2ml) was treated with d-tartaric acid (57mg). The solution was concentrated to a colourless foam and triturated with ether to give the title compound as a colourless solid (304mg, 96%), * H-NMR (DMSO) ca 2:1 mixture of rotamers δ 0.90/0.98 (6H, t, J7.0Hz), 2.72-3.51 (10H, complex m), 4.22 (2H, s), 4.64/4.83 (2H, s), 5.34/5.55 (2H, s), 7.14-7.44 (6H, m), 7.65 (2H, m), 7.83 (4H, m) and 8.13/8.17 (IH, d, J5.4Hz).

Example 5 — 7V-(2-Diethylaminoethyl)-2-[6-(2-(2,3-difluorophenyl)ethyl)-2-methyl-4-oxo-2,4-

A solution of N,N-diethyl-N-(4'-trifluoromethyI-biphenyl-4-ylmethyI)-ethane-l,2-diamine (Int. D4) (0.54g, 0.73mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.58g, 3.04mmol), 1- hydroxybenzotriazole hydrate (0.03g), {6-[2-(2,3-difluorophenyl)-ethyl]-2-methyl-4-oxo-2,4-dihydro- pyrazolo[3,4-J]pyrimidin-7-yl} -acetic acid (Int. C41) (0.54, 1.52mmol) and NN-diisopropylethylamine (0.27ml, 1.55mmmol) in dichloromethane (6ml) was stirred at ambient temperature overnight then diluted with dichloromethane, washed with aqueous sodium bicarbonate and evaporated. The residue was purified by chromatography (lOg silica cartridge, dichloromethane-2% methanolic ammonia / dichloromethane) to give the title compound as a white solid (0.14g, 13%). Η-ΝMR (DMSO, rotamer mixture) δ 0.83-0.93 (6H, m), 2.22-2.58 (6H, m), 2.86-2.95 (2H, m), 3.06-3.15 (2H, m), 3.32-3.40 (2H, m), 3.97 (3H, s), 4.64/4.81 (2H, 2x s), 5.19/5.40 (2H, 2x s), 7.09-7.87 (1 IH, m), 8.37 (IH, 2x s); MS (APCI+) found (M+1) = 681; C3₆H₃₇F₅N₆θ2 requires 680.

<5?-Tartaric acid (0.03 lg, 0.21mmol) was added to a solution ofthe free base (0.14g, 0.21mmol) in methanol (5ml) with stirring. The resulting solution was evaporated to yield the salt (0.24g). Η-NMR (DMSO, rotamer mixture) δ 0.94-0.99 (6H, m), 2.51-2.93 (8H, m), 3.11 (2H, m), 3.74 (2H, m), 3.98 (3H,s), 4.18 (2H,s), 4.64/4.81 (2H,2x s), 5.22/5.40 (2H,2x s), 7.09-7.87 (11H, m), 8.39 (lH,s); MS (APCI+) found (M+1) = 681; C36H37F5N6O2 requires 680.

Example 6 — N-(2-Diethylaminoethyl)-(2-(2-(2,3-difluorophenyI)ethyl)-4-oxo-4H-pyrido[2,3- </]pyrimidin-l-yl)-N-(4-(4-trifluoromethylphenyl)phenyl)methylacetamide bitartrate

Intermediate C35 (0.33g) and intermediate D4 (0.37g) were stirred together in an ice bath under argon in dimethylformamide. Diisopropylethylamine (0.36ml) and O-^-azabenzotriazol-l-y -NjN^N'- tetiamethyluronium hexafluorophosphate (ΗATU) (0.43g) were added and stirred for 30 min. Solvent was removed under reduced pressure and the residue partitioned between dichloromethane and water, filtered through celite and the organic layer washed with further water and dried over K₂C0₃. The solvent was removed under reduced pressure and the residue chromatographed on silica gel, eluting with 5% methanol in dichloromethane, to give a solid. The celite pad was washed with methanol and concentrated. The residue was dissolved in 9: 1 dichloromethane:methanol and washed with water. Drying, evaporation and chromatography as above gave a material which was combined with the product from the previous chromatography (total yield = 0.2 lg). This material dissolved in methanol and a solution of tartaric acid (0.046g) in methanol added. The solvent was removed under reduced pressure and the residue triturated with Et₂0 to give the title compound (0.235g). Rotamers were present in the *Η-NMR (d₆-DMSO) δ 0.90-1.11 (6Η, m), 2.67-3.50 (m), 4.20 (2H, s), 4.64 & 4.87 (2H, 2s), 5.51 & 5.68 (IH, 2xbrs), 7.12-7.19 (IH, m), 7.24-7.36 (3H, m), 7.58-7.66 (3H, m), 7.80-7.93 (5H, m), 8.47-8.50 (IH, m), 8.85-8.89 (IH, m); MS (APCI+) found (free base M+1) = 678; C₃₇H₃₆ F₅N₅0₂ requires 677.

Example 7 — N-(l-Methylpiperidin-4-yl)-(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinazolin-l- yl)-N-(4-(4-trifluoromethylphenyl)phenyl)methylacetamide bitartrate

Intermediate C43 (0.2g) and intermediate D8 (0.2g) were stirred together in an ice bath under argon in dichloromethane. Diisopropylethylamine (0.23ml) and 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetiamethyluronium hexafluorophosphate (ΗATU) (0.26g) were added and stirred overnight. After diluting with dichloromethane, the mixture was washed with water and chromatographed on silica gel eluting with 6-13% methanol in dichloromethane. This gave a solid (0.26g) which was converted to the bitartrate salt (title compound) with tartaric acid as in example 6. Η-NMR (DMSO, rotamer mixture) δ 1.6-2.0 (4H, m), 2.2-2.5 (5H, m), 2.5-3.9 (6H, m), 4.0-4.1 + 4.25-4.4 (IH, 2xm), 4.56 + 4.85 + 5.1 + 5.58 (4H, 4xbr.s), 7.05-7.7 (9H, 2x br.m), 7.7-7.95 (5H, m), 8.1 (IH, t); MS (APCI+) found (M+1) = 675; C₃8H₃₅F₅N4O2 requires 674.

Example 8 — N-(l-Ethylpiperidin-4-yl)-(2-(2-(2,3-difluorojphenyl)ethyl)-4-oxo-4H-quinazolin-l- yl)-N-(5-(4-trifluoromethylphenyl)thien-2-yl)methyIacetamide bitartrate

The title compound was prepared from intermediates C43 + D77 in dimethylformamide using 0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetiame1hyluronium hexafluorophosphate (HATU) as a coupling agent, followed by bitartrate salt formation using the methods described in examples 6 and 7. Η-NMR (DMSO, rotamer mixture) δ 1.0-1.2 (3H, m), 1.6-2.2 (4H, m), 2.2-2.75 (4H, m), 2.75-3.9 (6H, m), 3.9-4.1 + 4.15- 4.35 (IH, 2xm), 4.15 (2H, s), 4.7 + 4.95 (2H, 2xbr.s), 5.3 + 5.5 (2H, 2xbr.s), 6.9-7.55 (8H, 2x br.s), 7.7- 7.95 (4H, m), 8.1 (IH, t); MS (APCI+) found (M+1) = 695; C₃₇H₃₅F₅N₄θ₂S requires 694.

Example 9 — N-(l-Ethylpiperidin-4-yl)-(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinazolin-l- yI)-N-(4-(5-trifluoromethylthien-2-yl)phenyl)methylacetamide bitartrate

The title compound was prepared from intermediates C43 + D79 in dimethylformamide using 0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) as a coupling agent, followed by bitartiate salt formation using the methods described in examples 6 and 7. Η-NMR (DMSO, rotamer mixture) δ 1.05-1.14 (3H, m), 1.70-2.00 (4H, m), 2.48-3.21 (10H, m), 4.09 (2H, s), 4.14/4.41 (IH, 2x br m), 4.41/4.84 (2H, 2x s), 5.11/5.60 (2H, 2x s), 7.09-8.12 (13H, m); MS (APCI+) found (M+1) = 695; C₃₇H₃₅F₅N4θ₂S requires 694. Example 10 — 7V-(l-Methylpiperidin-4-yl)-(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-pyrido[2,3- rf]pyrimidin-l-yl)-N-(4-(4-trifluoromethylphenyl)phenyl)methylacetamide bitartrate

The title compound was prepared from intermediates C35 + D8 in dimethylformamide using 0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) as a coupling agent, followed by bitartiate salt formation using the methods described in examples 6 and 7. Η-NMR (DMSO, rotamer mixture) δ 1.60-1.91 (4H, m), 2.37- 2.42 (5H, m), 3.04- 3.18 (6H, m), 4.09/4.26 (IH 2x br m), 4.14 (2H, s), 4.60/4.83 (2H, 2x s), 5.40/5.68 (2H, 2x s), 7.13-7.18 (IH, m), 7.25-7.33 (3H, m), 7.57-7.67 (3H, m), 7.78-7.92 (5H, m), 8.46-8.49 (IH, m), 8.88-8.93 (IH, m); MS (APCI+) found (M+1) = 676; C₃₇H₃₄F₅N₅θ2 requires 675.

Example 11 — N-(l-(2-Methoxyethyl)piperidin-4-yl)-(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H- pyrido [2,3-d] pyrimidin-1 -yl)-N-(4-(4-trifluoromethylphenyl)phenyl)methylacetamide bitartrate

The title compound was prepared from intermediates C35 + D80 in dimethylformamide using 0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (ΗATU) as a coupling agent, followed by bitartiate salt formation using the methods described in examples 6 and 7. Η-NMR (DMSO, rotamer mixture) δ 1.56-1.82 (4Η, m), 2.23- 2.37 (2H, m), 2.63-2.66 (2H, m), 3.02- 3.18 (6H, m), 3.20/3.23 (3H, 2x s), 3.40-3.46 (2H, m), 4.05/4.26 (IH 2x br m), 4.19 (2H, s), 4.61/4.83 (2H, 2x s), 5.39/5.68 (2H, 2x s), 7.13-7.17 (IH, m), 7.25-7.33 (3H, m), 7.57-7.66 (3H, m), 7.78-7.92 (5H, m), 8.45- 8.49 (IH, m), 8.88-8.93 (IH, m); MS (APCI+) found (M+1) = 720; 0₃₉^^₅0₃ requires 719.

The following amide Examples were prepared from the corresponding acetic acid and amine using l-(3- dimethylaminopropyl)-3-ethylcarbodiimide with or without 1-hydroxybenzotiiazole hydrate as coupling agent (as for Examples 1-5), though a few were prepared using 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) as a coupling agent (as for Examples 6 and 7), followed by treatment with d-tartaric acid to give the salt if indicated.

No. Precur Structure Name sors • N-(2-ethylamino-2-methyl-propyl)-2-(2- (2-(2,3-difluorophenyl)-ethyl)-4-oxo- 4,5,6,7-tetrahydro-cyclopentapyrimidin-l- yl)-N-(4'-trifluoromethyl-biphenyl-4- ylmethyl)acetamide bitartrate

N-(2-t-butylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-N- (4'-trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

N-( 1 -ethyl-piperidin-4-yl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4,5,6,7- tetiahydro-cyclopentapyrimidin- 1 -yl)-N- (4'-trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

N-(2-diethylaminoethyl)-2-(2-(2-(4- fluoro-2-(trifluoromethyl)phenyl)-ethyl)- 4-oxo-4,5,6,7-tetiahydro- . cyclopentapyrimidin- 1 -yl)-N-(4'- trifluoromethyI-biphenyI-4-ylmethyI)- acetamide bitartrate

C4 + N-(2-diethylaminoethyl)-2-(2-(2-(4- D4 fluoro-3-(trifluoromethyl)phenyl)-ethyl)- 4-oxo-4,5,6,7-tetrahydro- cyclopentapyrimidin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

C5 + N-(2-diethylaminoethyl)-2-(2-(2-(3- D4 chloro-4-fluorophenyl)-ethyl)-4-oxo- 4,5,6,7-tetiahydro-cyclopentapyrimidin-l- yl)-N-(4'-trifluoromethyl-biphenyl-4- ylmethyl)acetamide bitartrate

C6 + (+/-)-N-(2-diethylaminoethyl)-2- D4 (2phenyl-propyl)-4-oxo-4,5,6,7- tetiahydro-cyclopentapyrimidin- 1 -yl)-N- (4'-trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartrate

N-(2-diethylaminoethyl)-2-(2-(2-(4- chlorophenyl)-ethyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-N- (4'-trifluoromethyl-biphenyl-4-ylmethyl)- acetamide

N-(2-diethylaminoethyl)-2-(2-(2-(4- methylphenyl)-ethyl)-4-oxo-4,5,6,7- tetiahydro-cyclopentapyrimidin- 1 -yl)-N- (4'-trifluoromethyl-biphenyl-4-ylmethyl)- acetamide

N-(2-diethylaminoethyl)-2-(2-(2-(4- (trifluoromethyl)phenyl)-ethyl)-4-oxo- 4,5,6,7-tetrahydro-cyclopentapyrimidin- 1 - yl)-N-(4'-trifluoromethyl-biphenyl-4- ylmethyl)acetamide

N-(2-diethylaminoethyl)-2-(2-(2-(4- methoxyphenyl)-ethyl)-4-oxo-4,5,6,7- tetrahydro-cyclopentapyrimidin- 1 -yl)-N- (4'-trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartrate

N-(2-diethylaminoethyl)-2-(2-(2-(4- (trifluoromethoxy)phenyl)-ethyl)-4-oxo- 4,5,6,7-tetrahydro-cyclopentapyrimidin- 1 - yl)-N-(4'-trifluoromethyl-biphenyl-4- ylmethyl)acetamide bitartrate

N-(2-diethylaminoethyl)-2-(2-(2-(4- fluorophenyl)-ethyl)-4-oxo-4,5,6,7- tetiahydro-cyclopentapyrimidin- 1 -yl)-N- (4Vtrifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,4- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartiate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,6- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(3,5- difluorophenyl)-ethyI)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(3,4- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(2- fluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-yImethyl)acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(3- fluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(4- fluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,3,4- trifluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartiate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,3,5- trifluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yI)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,4,5- trifluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(3,4,5- trifluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartiate

N-(2-Diethylaminoethyl)-2-(2-(2-(3- cyanophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartiate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,3,6- trifluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyI- biphenyl-4-ylmethyl)acetamide bitartiate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,4,6- trifluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-tiifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-5-methyl-4-oxo- 4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-6-methyl-4-oxo- 4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-8-methyl-4-oxo- 4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyi-4-ylmethyl)- acetamide

N-(2-Diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-7-trifluoromethyl- 4-oxo-4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartrate

N-(2-Diethylaminoethyl)-2-(2-(2-phenyl- ethyl)-4-oxo-4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,3- difluoroρhenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(2-(4'- trifluoromethylphenyl)pyrid-5-yl- methyl)acetamide bitartiate

N-(2-Diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-chloro-biphenyl-4- ylmethyl)acetamide bitartrate

N-(2-piperidin- 1 -ylethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoro-biphenyl- 4-ylmethyl)acetamide bitartiate

N-(2-(N-ethyl-t-butoxycarbonylamino)- ethyl)-2-(2-(2-(2,3-difluorophenyl)- ethyl)-4-oxo-4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide

N-(2-Ethylamino-2-methylpropyl)-2-(2- (2-(2,3-difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartiate

N-(2-(Diethylamino)-2-methyl-propyl)-2- (2-(2-(2,3-difluorophenyl)-ethyl)-4-oxo- 4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

N-(2-(Dimethylamino)-2-methyl-propyl)- 2-(2-(2-(2,3-difluorophenyl)-ethyl)-4- oxo-4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

N-(2-(/-sOpropylamino)-2-methyl-propyl)- 2-(2-(2-(2,3-difluorophenyl)-ethyl)-4- oxo-4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide

N-(2-(t-butylamino)-ethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide

N-(2-(piperidin-l-yl)-2-methyl-propyl)-2- (2-(2-(2,3-difluorophenyl)-ethyl)-4-oxo- 4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide

N-(2-(morpholin-4-yl)-ethyl)-2-(2-(2- (2,3-difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartiate

90 C43 + N-(2-(mo holin-4-yl)-2-methyl-propyl)-

D41 2-(2-(2-(2,3-difluorophenyl)-ethyl)-4- oxo-4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

N-(2-(pyrrolidin-l-yl)-ethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide

N-(2-(pyrrolidin- 1 -yl)-2-methyl-propyl)- 2-(2-(2-(2,3-difluorophenyl)-ethyl)-4- oxo-4H-quinazolin- 1 -yl)-N-(4'- tiifluoromethyl-biphenyl-4-ylmethyl)- acetamide

N-(3-(piperidin- 1 -yl)-propyl)-2-(2-(2- (2,3-difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartiate

N-(3-(morpholin-4-yl)-propyl)-2-(2-(2- (2,3-difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-(3-(pyrrolidin-l-yl)-ρropyl)-2-(2-(2- (2,3-difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-( 1 -Ethyl-piperidin-4-yl)-2-(2-(2-(2,3- difluorophenyI)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartiate

N-( 1 -f5opropyl-piperidin-4-yl)-2-(2-(2- (2,3-difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

98 C43 + (+/-)-N-( 1 -ethyl-pyrrolidin-2-ylmethyl)-2-

D49 (2-(2-(2,3-difluorophenyl)-ethyl)-4-oxo- 4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartrate

99 , C43 + N-(2-(diethylamino)ethyl)-2-(2-(2-(2,3-

D50 difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-pent- 1 -yl- biphenyl-4-ylmethyl)acetamide bitartiate

100 C43 + N-(2-(diethylamino)ethyl)-2-(2-(2-(2,3-

D51 difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(biphenyl-4- ylmethyl)acetamide bitartrate

101 N-(3-(diethylamino)propyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethy 1- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-7-methyl-4-oxo- 4H-quinazolin- 1 -yl)-N-(4'- tiifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

106 C76 + N-(2-diethylaminoethyl)-2-(2-(2-(2,3-

D4 difluorophenyl)-ethyl)-6,7-difluoro-4- oxo-4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

N-(2-diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-7-fluoro-4-oxo- 4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartrate

N-(2-diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-6-fluoro-4-oxo- 4H-quinazolin- 1 -yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartiate

N-(l-ethylpiperidin-4-yl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- pyrido[2,3-c?]pyrimidin-l-yl)-N-(4'- trifluoromethyl-biphenyl-4-ylmethyl)- acetamide bitartrate

N-( 1 -ethylpiperidin-4-ylmethyl)-2-(2-(2- (2,3-difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-methyl-biphenyl-4- ylmethyl)acetamide bitartiate

N-(2-diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-ethyl-biphenyl-4- ylmethyl)acetamide bitartrate

N-(2-diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-methylthio- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-(prop-2 -yl)- biphenyl-4-ylmethyl)acetamide bitartrate

N-(2-diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyI)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-cyano-biphenyl-4- ylmethyl)acetamide bitartrate

N-(2-diethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-methylsulfony 1- biphenyl-4-ylmethyl)acetamide bitartiate

124 C43 + N-(2-methoxyethyl)-2-(2-(2-(2,3-

D64 difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide

N-(l-ethylpiperidin-4-yl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(2-(4-chlorophenyl)- fur-5-ylmethyl)acetamide bitartrate

N-(l-ethylpiperidin-4-yl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(2-(4-trifluoromethyl- phenyl)fur-5-ylmethyl)acetamide bitartrate

133 C43 + N-(2-diethylaminoethyl)-2-(2-(2-(2,3-

D63 difluorophenyl)-ethyl)-4-pxo-4H- quinazolin- 1 -yl)-N-(4'-bromo-biphenyl-4- ylmethyl)acetamide bitartrate

N-(l-ethyIpiperidin-4-yl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(2-(2-chlorothien-5- yl)thien-5-ylmethyl)acetamide bitartrate

N-( 1 -ethylpiperidin-4-yl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quninazolin- 1 -yl)-N-(4'-chloro-biphenyl- 4-ylmethyl)acetamide bitartiate

N-( 1 -methylpiperidin-4-yl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quninazolin- 1 -yl)-N-(4'-chloro-biphenyl- 4-ylmethyl)acetamide

p eny) enzyamne

(WO 00/66567)

142 C43 + N-(2-diethylaminoethyl)-2-(2-(2-(2,3- ■ D96 difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-(piperidin- 1 - ylsulfonyl)-biphenyl-4-ylmethyl)- acetamide

143 C43 + N-( 1 -t-butoxycarbonylpiperidin-4-y l)-2-(2- D95 (2-(2,3-difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide

The following compounds were prepared by the method of Intermediate C2 No. Precur- Structure Name sors

N-(hydroxycarbonylmethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- . biphenyl-4-ylmethyl)acetamide

N-(piperidin-4-yl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- : biphenyl-4-ylmethyl)acetamide

N-(2-Ethylaminoethyl)-2-(2-(2-(2,3- difluorophenyl)-ethyl)-4-oxo-4H- quinazolin- 1 -yl)-N-(4'-trifluoromethyl- biphenyl-4-ylmethyl)acetamide bitartiate

Biological Data

1. Screen for Lp-PLA₂ inhibition.

Enzyme activity was determined by measuring the rate of turnover ofthe artificial substrate (A) at 37 C in 50mM ΗEPES (Ν-2-hydroxyethylpiperazine-Ν'-2-ethanesulphonic acid) buffer containing 150mM NaCl, pΗ 7.4.

(A)

Assays were performed in 96 well titre plates.

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 ultra-filtration, the enzyme was stored at 6mg/ml at 4°C. Assay plates of compound or vehicle plus buffer were set up using automated robotics to a volume of 170μl. The reaction was initiated by the addition of 20μl of lOx substrate (A) to give a final substrate concentration of 20μM and 10 μl of diluted enzyme to a final 0.2 nM LpPLA2.

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.

Results

The compounds described in the Examples were tested as described above and had IC50 values in the range <0.1 to 200 nM.

Claims

Claims

1. A compound of formula (I):

in which:

R! is an aryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cπ. fyalkyl, Cπ.ζ\aϊkoxy, Cπ g-_jalkylthio, hydroxy, halogen, CN, to

fused 5-or 6-membered carbocyclic ring; or

R^ and R- together with the pyrimidone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from halogen, Cn -4)alkyl, cyano, Cn .g-_jalkoxy, Cn _g)alkylthio or mono to perfluoro-Cπ _4)alkyl;

R4 is hydrogen, Cn.g^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-(hydroxyCπ _g)alkyl)amino and N-hydroxyCπ .g^alkyl-N-Cπ .^alkylamino; or

R4 is Het-C(0-4)alkyl in which Het is a 5- to 7- membered heterocyclyl ring comprising N and optionally 0 or S, and in which N may be substituted by COR⁷, COOR⁷, CONR⁹R¹⁰, or C(i_₆)alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰ or NR⁹R¹⁰, for instance, piperidin-4-yl, pyrrolidin-3-yl;

R5 is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cπ_6)alkyl, Cn-.g\alkoxy, Cπ.g^alkylthio, arylCπ_6)alkoxy,

NRSJRIO _mono o perfluoro-Cπ .4)alkyl and mono to perfluoro-Cπ _4)alkoxy;

R> is 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

Cπ _1 g)alkoxy, Cπ _6)alkylthio, Cπ_6)alkylsulfonyl, arylCπ .g)alkoxy, hydroxy, halogen, CN, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁷COR⁸, S0₂NR⁹R¹⁰, NR⁷S0₂R⁸, NR⁹R¹⁰, mono to perfluoro-C(₁.₄)alkyl and mono to perfluoro-Cπ _4)alkoxy, or C(5_ι o)alkyl;

R⁷ is hydrogen or Cπ _ι₂)alkyl, for instance Cπ _4)alkyl (e.g. methyl or ethyl); R⁸ is hydrogen, OCπ .g^alkyl, or Cπ _ι₂)alkyl, for instance Cπ _4)alkyl (e.g. methyl or ethyl);

R⁹ and R^ which may be the same or different is each selected from hydrogen, or Cπ.ι₂)alkyl, or R⁹ and R^ together 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, Cπ _4)alkyl, Cπ . 4)alkylcarboxy, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine; and

X is C(₂_4)alkylene, optionally substituted by 1,2 or 3 substituents selected from methyl and ethyl, or CH=CH.

2. A compound of formula (I) as claimed in claim 1 in which R* is phenyl optionally substituted by halogen, Cn.^alkyl, trifluoromethyl, C^.g^alkoxy.

3. A compound of fomula (I) as claimed in claim 1 or 2 in which R^ is ethyl when R^ is hydrogen, or R^ and R3 together with the pyrimidine 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.

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

5. A compound of formula (I) as claimed in any of claims 1 to 4 in which R^ is phenyl or thienyl.

6. A compound of formula (I) as claimed in any of claims 1 to 5 in which R" is phenyl substituted by trifluoromethyl at the 4-position or R^ is thienyl substituted by trifluoromethyl at the 5-position.

7. A compound of formula (I) as claimed in any of claims 1 to 6 in which R^ and R° together 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.

9. A compound of formula (I) as claimed in any of claims 1 to 8 in which R is phenyl substituted by 1 to 3 fluoro; R^ is ethyl when R^ is hydrogen; R^ is 2-(diethylamino)ethyl, l-ethyl-piperidin-4-yl, 1- methylpiperidin-4-yl or l-(2-methoxyethyl)piperidin-4-yl; R^ is phenyl, thienyl or pyridyl; R" is phenyl substituted by trifluoromethyl at the 4-position, or thien-2-yl substituted by trifluoromethyl in the 5- position; and X is (CH₂)₂.

10. A compound of formula (I) as claimed in any of claims 1 to 9 in which R! is phenyl substituted by 2,3 difluoro; R^ and R^, together with the pyrimidine 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; R is 2-(diethylamino)ethyl, l-ethyl-piperidin-4-yl, l-methylpiperidin-4-yl or l-(2- methoxyethyl)piperidin-4-yl; R^ is phenyl, thienyl or pyridyl; R^ is phenyl substituted by trifluoromethyl at the 4-position, or thien-2-yl substituted by trifluoromethyl in the 5-position; and X is (CH₂)₂.

11. A compound of formula (I) as claimed in any of claims 1 to 10 in which R^ is phenyl substituted by 2,3 difluoro; R^ and R^, together with the pyrimidine ring carbon atoms to which they are attached, form a fused pyrido ring; R^ is l-methylpiperidin-4-yl or l-(2-methoxyethyl)piperidin-4-yl; R^ and R^ together form a 4-(phenyl)phenyl in which the remote phenyl ring is substituted by trifluoromethyl, preferably at the 4-position; and X is (CH₂)₂.

12. A compound of formula (I) as claimed in claim 1 and as named in any one of Examples 1 to 146.

13. A compound of formula (I) as defined in claim 1 selected from the group consisting of N-(l-methylpiperidin-4-yl)-(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-pyrido[2,3-rf]pyrimidin-l-yl)-N-

(4-(4-trifluoromethylphenyl)phenyl)methylacetamide;

N-(l-(2-methoxyethyl)piperidin-4-yl)-(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-pyrido[2,3- ]pyrimidin- l-yl)-N-(4-(4-trifluoromethylphenyl)phenyl)methylacetamide; or a pharmaceutically acceptable salt thereof, in particular the bitartrate salt.

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 ofthe enzyme Lp-PLA₂ which method involves treating a patient in need thereof with a therapeutically effective amount of a compound of formula (I) 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):

(II) in which X, R*, R^ and R^ are as hereinbefore defined, with an amine compound of formula (III):

R⁶-R⁵-CΗ₂ΝΗR⁴

(III) in which R⁴, R^ and R*> are 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 l-(3-dimethyl-aminopropyl)-3- ethylcarbodiimide (DEC), or 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), preferably in the presence of di-isopropylethylamine.