Field of the invention:
The pre^'ent invention relates to 2-phenyl-6-aminocarbonyJ-pynmidine derivatives and fiieir use as P2Yi2 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and otlicr mammals.
Background of the invention:
Hacmoslasis is referred to as the natural balance of maintaining the fluidity of the blood in the vascular system and preventing excessive blood loss subsequent to blood vessel injury by rapid formation of a solid blood clot. After vascular damage.'contraction of the vessels and platelet adhesion occur immediately followed by aggregation of the platelets, activation of the coagulation cascade and finally also of the fibrinolyiic system. Haemostatic abnormalities can lead to excessive bleeding or thrombosis, both life-threatening situations,
A series of antiplatelet agents have been developed over the past several years based on different mechanisms of action. The most widely used agent in antiplatelet therapy is aspirin, which irreversibly inhibits cyclooxygenase-1 and thereby affecting the thromboxane pathway. Although not optimally efficacious, treatment with aspirin remains the standard therapy against which new therapeutics are compared and judged.

-2-
Olher drugs like the phosphodiesterase inhibiiors dipyridamole and cilostazol, as well as the vitamin K antagonists (warfarin), are marketed bul do not show all desirable features for such drugs. Three intravenously applicable, poieni GPIIb/IlIa receptor antagonists (abciximab, epiifibatide, and tirofiban) blocking platelet aggregation are available on the market. Besides, some orally active GPIIb/Ula antagonists (eg, sibrafiban. xcmilofiban or orboflban) have not been successful in clinical development so far.
Adenosine 5'-diphosphate (ADP) is a key mediator in platelet activation and aggregation interfering with two platelet ADP receptors P2Yi and P2Yi2.
Antagonists of the platelet ADP receptor have been identified and display inhibition of platelet aggregation and antithrombotic activity. The most effective antagonists known so far are the thicnopyridincs ticlopidinc, clopidogrcl and CS-747, which have been used clinically as antithrombotic agents. It could be shown that these drugs, via their reactive metabolites, irreversibly block the ADP receptor subtype P2Yi2,
Some P2Yi2 antagonists like AR-C6993)MX (Cangrclor) or AZD6140 have reached phase II clinical studies. The.se inhibitors are selective platelet ADP receptor antagonists, which inhibit ADP-dependent platelet aggregation, and are effective in vivo.
Piperazino-carbonylmethylaminocarbonyl-naphtyl or -quinolyl derivatives have been described as ADP receptor antagonists in WO 02/098856 and WO 2004/052366.
However, only a few 2-phenyl-4-(carbonylmc1hylaminocarbonyl)-pyrimidine derivatives are known in the art: indeed, only IP 53073586 describes penicicillin derivatives possessing such a motif (as antibiotic agents).

Description of the invention:
The present invention firstly relates to the compounds of formula I

wherein
R' represents phenyl optionally substituted 1 to 3 times (preferably optionally substituted once
or twice and more preferably optionally substituted once) by substilucnls each independently
selected from the group consisting of halogen, methyl, methoxy,:lrifluoromethy! and
trifluoromethoxy;
R^ represents an alkoxyalkoxyalkyl group, a dihydroxyalkyl group, a diraethoxyalkyl group or
a (2,2-dimethyl-[l,3]dioxolan-4-y!)-alkyl group;
or R* represents a group of the formula

wherein
cither m is 1 and n is 2 or 3, or m is 2 and n is 2; and
X represents 0, S. NH, NR', SO or SOj;

-4-
R' represents alkyl or an,'lalkyl:
or also R^ represents 2.2,6/i-tctrametIiyKpipendin-4-yl:
each of R and R^ represents independently hydrogen or methyl;
R represents alkoxy; and
Y represents alkylene or phenyiaikyJene, and Z represents -OH, -COOH, cyano, tetrazoiyl or
-COOR', R' representing alkyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
The compounds of formula 1 may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of formula 1 may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be Separated in a manner known to a person skilled in the art.
The compoiind.s of formula I are P2Yj2 receptor antagonists. Accordingly, tjjey are usefai in therapy (including combination therapy), where they can be widely used as inhibitors of platelet activation, aggregation and degranulation, as promoters of platelet disaggregation or as "anti-thrombotic agents.
The following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention. Said definitions arc intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader or narrower definition.
•> The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably to fluorine, chlorine or bromine and more preferably to fluorine.
•> Unless specified otherwise, the term "alkyl" (whether used alone or in combination) refers to a straight or branched chain alkyl group containing I to 7 carbon atoms (e.g. methyl, ethyl, propyl, isa-propyl butyi, fso-butyU sec-buty], ferl-buty), fr-ps:ntyU neopentyJ, /io-pcntyl, /7-hcxy!, (i'y-hexyl, u-hcptyl or ;"io-hcptyl), and more preferably 1 to 4 carbon atoms.
•> Unless specified otherwise, the term "alkoxy" (whether used alone or in combination) refers to a saturated straight or branched chain alkoxy group containing 1 to 6 carbon

-:> -
atoms {e.g. methoxy, ethoxy, propoxy, /ra-propoxy. butoxy, 750-butoxy. 5^c-butoxy, ferf-hutoxy, «-pentoxy, neopenlyloxy. ;>o-peiit\'Ioxy, jj-hexyloxy or /.vo-hexyloxy), and preferably I to 4 carbon atoms,
•:• The term "ajkoxyalkoxyalkyt", as used herein, refers lo a straight or branched chain alkyl group of I to 4 carbon atoms wherein one hydrogen atom has been replaced by a straight or branched chain alkoxy group of 1 to 3 carbon atoms, the latter being itself substituted by a straight or branched chain alkoxy group of 1 to 3 carbon atoms. Methoxyalkoxyalkyl groups (an example thereof being 2-(2-mcthoxy-ethoxy)-ethyl) are preferred among alkoxyalkoxyalkyl groups.
<• The term "dihydroxyalkyf, as used herein, refers to an alkyl group as previously defined wherein two hydrogen atoms attached to different atoms of the alkyl group have been replaced by hydroxy (i.e. -OH) groups. Examples of dihydroxyaikyi include, but are not limited to, 2,3-dihydroxy-propyl.
♦ The term "dimethoxyalkyl", as used herein, refers to an aikyl group as previously defined
wherein two hydrogen atoms attached to different atoms of the alkyl group have been
replaced by methoxy (i.e. -OCH3) groups. Examples of dimethoxyalkyl include, but are
not limited to, 2,3-dimethoxy-propyl.
<• The term "(2,2-dimethyl-[l,3]dioxoian-4-yl)-alkyf' as used herein, refers to a straight or branched chain aJkyJ group of 1 to 4 carbon aloms wherein one hydrogen atom has been replaced by a 2.2-dimethyl-[l ,3]dioxolan-4-yl group. Examples of (2.2-dimethyl-[l,31dioxolan-4-yl)-alkyl include, but are not limited to, (/;)-2,2-dimethyl-[l,3]dioxotan-4-ylmelhyl and (5)-2,2-dimethyl-[l,3]dioxolan-4-ylmethy! (and in particular (/?)-2,2-dimcthyl-[l,3]dioxolan-4-ylmethyl).
♦ The term "aryl" refers to an aromatic cyclic group with one, two Or three rings, having
from 6 to M carbon ring-atoms and preferably from 6 to 10 carbon ring-atoms, for
example to phenyl or naphthyl groups (and notably to phenyl groups); in addition, the term
"aryl" may also refer to the indanyl (e.g. indan-1-yl or indan-2-yl), tetrahydronaphtalene.
biphenyl-4-yl and benzo[!.3]dJoxolyl groups. Any aryJ group (and in particular any phenyl
group) as defined herein may be substituted with one, two or more substitucnts (preferably

-6-
with one to three substituents, more preferably with one or [wo substi'ments and notably
with one substituent), each independently selected from the group consisting of halogen,
aJkyl. alkoxy, hydroxymctljyJ, acetyl, mclhancsuIfon\'i, (rifluoromcthyl. trifluoromcthoxy,
carboxy, alkoxycarbonyl, amino, cyano and nitro. Specific examples of ar>'l groups are
phenyl, bipheiiyl-4-yl, 2-fluorophenyl, 3-fIuorophenyl. 4-fIuorophenyl, 2-chlorophenyJ,.
3-chlorophenyl, 4-chlorophenyl. 2-meihoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,
2-mcthylphcnyl, 3-m'clhylphcnyl, 4-mcthyJphcny), 2-trifl uorornctfiylphcnyl.
3-trifluoromethylphenyl, 4-Irifluoromethylphenyl. 4-!rifluoromedioxy-phenyl,
2,4-diiluoropheny], 3,4-diflliorophenyl, 2,4-dimethoxyphcnyI,; 3-carboX'yphen3'l,
4-carboxy phenyl, 4-hydroxy methyl-pheny!, 5-amino-2,4-difluorophenyl and
2,4-dimeihy]phenyl. g
<• The term "arylalkyl", as used herein, alone or in any combination, refers to an aryl group appended to the parent molecular moiety through an alky! group wherein however Ihc ar>'l group may be unsubstitutcd or substituted with 1 to 3 substiments selected independently from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl and trifluoromethoxy. Representative examples of aralkyl include, but are not limited to, benzyl, 2-phenylcthyl, 3-phenylpropyl and 2-naphth-2-ylcfhyl.
<• The term "alkylene", used alone or in combination, refers to a straight and branched divalent saturated hydrocarbon chain group with one lo six carbon atoms and preferably one to four carbon atoms. Representative examples of alkylene include, but are not limited to, methylene {-CH2-), ethylene (-CH2-CH2-), n-propylei^e (-CH2-CHj-CH2-) and JW-propylene (-CHrCHCCHs)-).
*;• The term "phenylalkylene", as used herein, refers to an unsubstitutcd divalent phenylalkyl group wherein the alkyl is as previously defined, said divalent group being attached to the rest of the molecule by, on the one side, one of the carbon atoms of the phenyl group and by, one the other side, one of the carbon atoms of the alky! group.
•:• The term "phenylalkyl", as used herein, refers to an alkyl group as previously defined wherein one hydrogen atom has been replaced by an unsubstitutcd phenyl group.

-7-
Representative examples of phenylalkyl include, but are not limited to, benzyl, 2-phenylethyl and 3-phenylpropyl.
Moreover, the sign "*" placed near an atom will be used to designate the point of attachment of a radical to the rest of a molecule. For example;
designates the tetrahydropyran-4-yL
Besides, the following paragraphs provide definitions of various other terms. Said definitions are intended to apply uniformly throughout the specification and claims unless an othei^wise expressly set out definition provides a broader or narrower definition.
The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. /■/laraj. (1986), 33, 201-217.
The term "room temperature" as used herein refers to a temperature of 25°C.
Unless used regarding temperatures, the term "about" placed before a numerical value "X" refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5%) of X to X plus 5% of X. In the particular case of temperatures, the term "about" (or alternatively the term "around") placed before a temperature "Y" refers in the current application to an interval extending from the temperature Y minus 10 "C to Y plus ICC, and preferably to an interval extending from Y minus 5 "C to Y plus 5 "C.

-8-
The compounds of formula I will in particular be compounds of formula ICF.
0'
<-^«

ICE
wherein
R represents phenyl opiionally substituted once by halogen or methyl;
R represents a mefhoxyalkoxyalkyl group, a dihydrosyaJky] group, a djmeihoxyalkyi group
or a (2,2-dimcthy]-[l,3]d!OXolan-4-yl)-alkyl group;
or R represents a group of the formula

wherein
cither mis I and n is 2 or 3, or m is 2 and n is 2; and X represents O, S, NH or NR^ (and preferably O, NH or NR"); } R^ represents alkyl orphenylalkyl;
or also R^ represents 2,2,6,6-tetramethyl-piperidin-4-yl;
one of R'' and R^ represeiifs h}'drogcn or mclhy! and the other represents hydrogen;
R represents alkoxy; and

-9-
Y represents alkylene or phenylalkylene, and Z represents -OH, -COOH, cyano, tetrazolyl or -COOR , R' representing al] R^ represents an alkoxyalkoxyalkyl group or a (2,2-dimethyl-[1.3]dioxolan-4-yi)-alkyl group;

- iO-
orR represents a group of the formula

wherein
either m is 1 and n is 2 or 3. or m is 2 and n is 2; and
X represents 0, NH or NR^
R represents alkyl or phenylalkyl;
or slso R^ represents 2,2,6,5-IetramethyJ-piperidin-4-y];
<• Y represents alkylene or phenyl alkylene, and Z represents -OH, -COOH or telrazoiyl (and notably -OH or -COOH);
•> one of R'' and R^ represents hydrogen or methyl and the other represents hydrogen;
♦ R represents alkoxy of! to 3 carbon atoms.
Even more preferred compounds of formula I will be those wherein at least one of the following characteristics is present:
•> R' represents phenyl optionally substituted once by halogen or methyl;
♦ R represents a group of the formula

wherein
either m is 1 and n is 2 or 3, or m is 2 and n is 2; and
X represents O, NH or NR^
R"' represents alkyl or phenylalkyl;
or also R' represents 2,2,6,6-tetramethyl-piperidin-4-yl;
<• Y represents alkylene or phenylalkylcne and Z represents -COOH;

-11 -
<• one of R and R represents hydrogen or methyl and the other represents hydrogen;" *^ R represents alkoxy of 1 to 3 carbon atoms.
Particularly prefeiTed compounds of formula I will be those wherein at least one of the' following characteristics is present:
<• R' represents phenyl;
•*• R^ represents a group of the formula

wherein
either m is 1 and n is 2 or 3, or m is 2 and n is 2; and
X represents 0, NH or NR"';
R" represents alkyl or phenylalkyl;
•> Y represents alkylene and Z represents -COOH;
•;• each of R"* and R^ represents hydrogen;
♦ R'^ represents elboxy.
Besides, when R" represents a group of the formula
([^ >^

as defined in formula 1, R^ will preferably be selected from the group consisting of tetrahydropyran-4-yl, tetrahydrothiopyran-4-y!, 1 -methyl-pipeTidin-3-yl, l-benzyl-piperidin-4-yl and tetrahydrofuran-3-yl (R^ hcing notably tetrahydropyran-4-yl, l-methyl-piperidinT3-yU. 1-benzyl-piperidin-4-yl or tetrahydrofuran-3-yl, in particular tetrahydrofuran-3-yO'

- 12-
Moreover, in a general manner, R'^ will preferably represent an alkoxy of 1 to 5 carbon atoms, especially an alkoxy of 2 to 4 carbon atoms. More preferably, when R^ represents an alkoxy of more than 3 carbon atoms, the alkoxy chain will be linear; for example, when R^ is an alkoxy of 4 carbon atoms, R* being «-butoxy will be preferred.
The following main embodiments of compounds of formula 1 (or of salts thereof, in particular of pharmaceutically acceptable salts thereof) are particularly preferred.
According to one main embodiment of this invention, the compounds of formula 1 will be such (hat R^ represents an alkoxyalkoxyalkyl group, a dihydroxyalkyl group, a dimcthoxyalkyl group or a(2,2-dimethyl-[],3]dioxolan-4-yl)-alkyl group; such compounds will be collectively designated by "compounds of formula li" throughout the specification and claims. In such case, the compounds of formula 1L will preferably be such that;
R' represents phenyl optionally substituted once or twice by substiments each
independently selected from the group consisting of halogen, methyl, methoxy,
trifluoromethyl and trifluoromethoxy;
R' represents an alkoxyalkojivalkyl group, a dihydroxyalkyl group, a dimethoxyalkyi
group or a (2,2-dimethyl-[i,3]dioxolan-4-yl)-alkyl group;
each of R* and R^ represenls independently hydrogen or melhyl:
R^ represents alkoxy; and
Y represents aJkyleiie or phenyialkyiene, and Z represenls -OH, -COOH. cyano, tetrazolyl
or -COOR^ R'' representing alkyl.
Preferably, the compounds of formula 1L will at least have one of the following characteristics:
♦ R' represents phenyl optionally substituted once by a substituent selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl and trifluoromethoxy;
•:• R^ represents an alkoxyalkoxyalkyl group, a dihydroxyalkyl group or a (2,2-dimcthyl-[ 1,3]dioxolan-4-yl)-alkyl group;
•:• one of R.'' and R^ represents hydrogen and the other represents hydrogen or methyl;
*i* R* represents aikoxy of I to 4 carbon atoms;

•:■ Y represents alkylene or phcnylalkylene, and Z represents -OH, -COOH. cyano or tctrazolyl (and preferably Y represents alkylene, and Z lepresents -OH, -COOH or tctrazolyl).
More preferably, the compounds of formula 1L will at least have one of the following characteristics:
•:• R represents phenyl optionally substituted once by a substituent selected from the group consisting of halogen, methyl and methoxy (and notably unsubstituted phenyl);
•:• R^ represents an alkoxyalkoxyalkyl group or a (2.2-dimcthyl-[li]dioxolan-4-y!)-alkyl group;
<• each of R'' and R^ represents hydrogen;
•*• R^ represents afkoxy of 1 to 3 carbon atoms (in particular cthoxy);
•:* Y represents alkylene (preferably -CH2-, -CH;-CH2- or -CH2-CH2~CH2- and more preferably -CH2--CH2-) and Z represents -COOH.
According to another main embodiment of this invention, the compounds of formula I will be such that R' represents group of the formula

or such that R^ represents 2,2.6.6-tctramethyl-piperidin-4-yl; such compounds will be collectively designated by "compounds of formula IK" throughout the specification and claims. In such case, the compounds of formula IR will preferably be such that R' represents phenyl optionally sobstituted once or tivice by substituenis each independentfy selected from (he group consisting of halogen, methyl, methoxy, trifluoromethyl and trifluoromethoxy.
Preferably, the compounds of formula IR will at least have one of the following characteristics:
♦ R' represents phenyl optionally substituted once by a substituent selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl and trifluoromethoxy;

- 14-
•'• R^ represents a group of tiie formula

wherein
either m is 1 and ii is 2 or 3. or m is 2 and n is 2; and
X represents O, S, NH or NR^
R" represents alkyl or arylalkyl;
or also R^ represents 2,2.6,6-tetramethyl-piperidin-4-yl;
:• one of R"" and R^ represents hydrogen and the other represents hydrogen or methyl;
> R represents alkoxy of 1 to 4 carbon atoms;
** y represents alkylene or phenyl alkylene, and Z represents -OH, -COOH, eyano or tetrazolyl (and preferably Y represents alkylene. and Z represents -OH or -COOH).
AoTC preferably, the compounds of formula IK will at least have one of the following characteristics:
> R' represents phenyl optionally substituted once by a substituent selected from the group
consisting of halogen, methyl and methoxy (and notably unsubstitutcd phenyl);
'^ R^ represents a group of the formula
(rte ><

wherein
either m is I and n is 2 or 3, or m is 2 and n is 2; and
X represents O. NH o^NR^
R" represents alkyl or phenylalkyi;
♦ each of R"* and R represents hydrogen;

<• R represents alkoxy of I to 3 carbon atoms (in particular ethoxy);
•:• Y rqjresents alkylene (preferably -CH2-, -CH2-CH2- or -CH2-CH2-CH2- and more preferably -CH2-CH2-) and Z represents -COOH,
The following compounds of general formula I are especially preferred: -4-[(5)-4-carboxy-2-((6-[2-(2-methoxy-elhoxy)-ethoxy]-2--phenyI-pynmidine-4-carbonyl}-amino)-butyryl]-piperazine-l-carboxylic acid ethyl ester;
-4-((i')-4-carboxy-2-{[6-((^)-2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-2-phenyl-pyrimidine-4-carbonyl]-aminoJ-butyi-yl)-piperazine-l-carboxyl!C acid ethyl ester; -4-((5)-4-carboxy-2-{[6-((5)-23-dihydroxy-propoxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyi7l)-piperazine-l-carboxylic acid ethyl ester;
-4-((5)-4-cai-boxy-2-{[6-((^)-2,3-dimethoxy-propoxy)-2-pheiiyl-pyrimid!ne-4-carbonyl]-amino}-butyryl)-piperazine-I-carboxylic acid ethyl ester;
- 4-((50-4-carboxy-2- {[2-phenyl-6-(tetrahydro-pyran-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-l-carboxylic acid ethyl ester;
- 4-((5^-4-carboxy-2-{[6-(l-methyl-piperidin-3-yloxy)-2-phenyl-pyriraidine-4-carbonyl]-aminO|-butyryl)-pipera2ine-I-carboxylic acid ethyl ester;
- 4-((5)-2- {[6-( 1 -benzyl-piperidin-4-yloxy)-2-phenyl-pyrimidine-4-carbonyl]-araino}-4-carboxy-butyryl)-piperazine-]-carboxylic acid ethyl ester;
-4-((5)'4-carboxy-2-{[2-(4-fluoro-phenyl)-6-(tetrahydro-fiiran-3-yloxy)-pynmid!ne-4-carbonyl]-amino}-butyiyl)-piperazine-l -carboxylic acid ethyl ester; -((,S)-4-carboxy-2-{[6-(tctrahydro-furan-3-yloxy)-2-/j-tolyl-pyrimidinc-4-carbonyl]-amino}-
butyry])-piperazine-l-carboxylic acid ethyl ester;
- ((5)-4-carboxy-2-{[2-phenyl-6-(tetrahydro-fiiran-3-yloxy)-pyrimidine-4-carbonyl]-amino}-
butyryl)-3-methyl-piperazine-l-carboxylic acid ethyl ester;
-4-[(S)-3-(4-carboxy-phenyl)-2-((2-phenyl-6-[(tetrahydro-furan-3-yI)oxy]-pyrimidinc-4-carbonyl}-amino)-propionyl]-piperazine-l-carboxylic acid ethyl ester; -4-((y)-4-carboxy-2-{[2-phenyl-6-(piperidin-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-l-carboxylic acid ethyl ester;
- 4-((y)-4-carboxy-2- {[2-phenyl-6-(2,2,6,6-tetramethyl-piperidin-4-yloxy)-pynmidine-
4-carbonyl]-amino;-butyryl)-piperazine-l-carboxylic acid ethyl ester;

-16-
-4-[(^-4-cyano-2-({2-plieny]-6-[(telrahydi-o-furan-3-yl>oxy]-pyrimidine-4-carbonyl)-amino)-butyry]]-piperazine-1 -carboxylic add ethyl ester; .
- 4-((S^-4-carboxy-2- {[2-phcnyl-6-(tcfrahydro-fLiran-3-yloxy)-pyrimidinc-4-carbonyl]-amino}-butyry])-piperazine-l-carboxylic acid ethyl ester;
- 4-[{5)-3-hydroxy-2-({2-phenyl-6-[(tetrahydro-furan-3-yl)oxy]-pyiiinidine-4-carbonyl}-amino)-propionyl]-piperazine-l-carboxylic acid ethyl ester;
- 4-[(iS')-2-{[2-phenyl-6-(tctrahydr6-furan-3-yloxy)-pynmidinc-4-carbonyl]-amino}-4-(lH-tetrazol-5-yl)-butyry!]-piperazine-]-carboxylic acid ethyl ester;
- 4-((5)-4-/erf-butoxycarbonyl-2-f[2-phenyi-6-(tetrahydro-pyran-4-yloxy)-pyrimidine-4-carbonylJ-amino) -butyryl)-piperazine-1 -carboxylic acid ethyl ester;
- 4-((5)-4-te:>-/-biitoxycarbonyl-2-{f6-(]-meEhyl-pipendin-3-yloxy}-2-pheny)-pynmidine-4-carbonyl]-amino}-butyryl)-pipcrazinc-l-carboxylic acid ethyl ester; , ,
- 4-({5)-2-{[6-(l-benzyl-piperidin-4-yloxy)-2-phenyl-pynmidine-4-carbonyl]-amino}-4-fert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester;
- 4-[{iS)-3-(4-to-f-butoxycarbonyt-phenyl)-2-({2-phenyl-6-[(tetrahydro-fiiran-3-yl)oxy]-pyrimidine-4-carbooyl}-ainiro)-propionyl]-piperazine-l-carboxylic acid ethyl ester;
- ((,6')-4-fe)V-butoxycarbonyl-2-{[2-phenyl-6-(piperidin-4-yloxy)-pyrimidinc-4-carbonyl]-aminoj-butyryO-piperazine-I-carboxylic acid ethyl ester;
-4-((5)-4-te/7-butoxycarbonyl-2-{[2-phenyl-6-(2,2,6,6-tetramethyl-piperidin-4-yloxy')-pyrimidine-4-carbony]]-3mijj[>}-butyiy])-piperazine-l-carboxylic acid ethyl ester;
- 4-{(,?)-4-c.arbnxy-2-1 [fi-(3-hydroxy-2-hydroxymethyl-propoxy)-2-phcnyl-pyrimidinc-
4-carbonyl]-amino}-butyryl)-piperazine-l-carboxylic acid ethyl ester;
- 4-((S)-4-carboxy-2-{[2-phenyl-6-(tetrahydro-thiopyran-4-yloxy)-pyrimidine-4-carbonyl]-
amiiio}-butyryl)-piperazine-j-carboxylic acid ethyl ester;
- 4-[(5)-4-carboxy-2-( (2-phenyl-6-[(i?)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl} -
aTnino)-butyryl]-piperazine-1-carboxylic acid ethyl ester;
'4-[(J>4-carboxy-2-({2-phcnyl-6-[(^-(ictrahydro-fiiran-3-y0oxy]-pyrimidinc-4-carbonylf-
amino)-butyryl]-piperazine-l-carboxylic acid ethyl ester;
- 4-[{5)-4-carboxy-2-({2-pbenyl-6-[tetrahydro-furan-3-yloxy]-pyrimidine-4-carbonyli-
amino)-butyryl]-piperazine-l-carboxylic acid ethyl ester;

- 17-
-4-[(i)-4-carboxy-2-({2-phenyi-6-peIrahydro-furan-3-yloxy]-pyrimidine-4.carbor)yE;-aiTiino)-butyryl]-pipcrazine-l-carboxylic acid butyl ester;
-4-[(5)-4-carboxy-2-({2-phcnyl-6-[C5)-(tclrahydro-furan-3-yl)oxy]-pynmidinc-4-carbonyl}-amino)-butyryl]-pipcrazine-l -carboxylic acid butyl ester;
-4-[(5)-4-carboxy-2-{{2-phenyl-6-[(y;)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-ainiiio)-butyry]]-pipcrazine-l-carboxy]ic acid butyl esler;
-4-{(i')-4-/t-'r/-butoxycarbonyl-2-{[6-(2,2-dimcthyl-[l,3]dioxan-5-ylmcthoxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-i-carboxyHc acid ethyl ester; ■4-((i)-4-;g'/7-biiloxycarbonyl-2-J[2-pheH)']-6-(iefrahydro-tbiopyran-4-yloA-y)-pyriijjJdjne-4-carbonyl]-amino|-butyryl)-piperazine-!-carboxy!ic acid elhy! ester; ■4-[(5)-4-rer/-bi)toxycarbonyl-2-({2-phenyl-6-[(5)*(tclraliydro-furan-3-yl)oxy]-pyrimidine-4-carbony[}-amino)-buiyryIj-pipcrazinc-I-carboxylic acid ethyl ester;
- 4-[(5)-4-r«f7-butoxycarbonyl-2-({2-phenyl-6-[(5)-(teirahydro-fi!ran-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazinc-l-carboxylic acid butyl ester;
- 4-[(5^-4-fe77-butoxycarbonyl-2-({2-phcnyI-6-[{y?)-(tetrahydro-furan-3 yl)oxy]-pyriinidine-4-carbonyt}-amino)-butyryl]-piperazinc-l-carboxylic acid butyl ester;
- 4-{{5)-4-carboxy-2-{[2-phcnyl-6-(pipcridin-4-yloxy)-pyrimidinc-4-carbonyl]-amino}-butyryl)-piperazine-l-carboxylic acid butyl ester;
-4-((i')-4-rer/-butoxycarbonyi-2-{[2-phcnyl-6-{piperidin-4-yloxy)-pyrimidine-4-carbonyll-amino}-buIyryJ)-piperazine-J-carbo.\yJic acid butyl ester;
as well as ihc salts thcrcnf {in particular the pharmaccutically acceptable salts ihercof).
The following compounds of general formula I are more especially preferred; -4-[(^-4-carboxy-2-({6-[2-(2-methoxy-cthoxy)-ethoxy]-2-phcnyl-pyrimi0ine-4-carbonyl}-
am!no)-butyryl]-pipcrazine-l-carboxylic acid ethyl ester;
-4-((^-4-carboxy-2-{[6-((>?)-2,2-dimcihyJ-[],3]dioxolan-4-yImclhoxy)-2-phcnyJ-pynmidinc-
4-carbonyl]-amino}-butyryl)-piperazine-l-carboxylicacid ethyl ester;
. 4-((5^-4-carboxy-2- {[6-((iS)-2,3-dihydroxy-propoxy)-2-phenyl-pyrimidinc-4-carbonyl]-
amino}-butyryl)-piperazine-l-carhoxylic acid ethyl ester;
.4-((^-4-carboxy-2-{[6-{(/?)-2,3-dimethoxy-propoxy)-2-phenyl-pyrimidine-4-carbonyl]-
amino}-butyryl)-piperazine-l-carboxylic acid ethyl esler;

-jS-
-4-((5')-4-caiboxy-2-i[2-phenyl-6-(tetrahydro-pyian-4-yloxy)-pynmidine-4-carbonyI]-aniino)-butyryn-piperazine-I-carboxylic acid elhyl ester;
-4-((6')-4-carboxy-2-{[6-(l-mcthyi-pipt;ndin-3-yloxy)-2-phcnyl-pyrimidinc-4-carbonyl]-
amino}-butyryl)-pipei-azine-l~carboxylic acid ethyl ester; ,. . ■
-4-((^-2-([6-(l'benzyl-pipendin-4-yloxy)-2-phenyI-pyrfmidine-4-carbonyl]-araino|-' 4-carboxy-butyryl)-piperazine-l-caiboxylic acid ethyl ester;
- 4--((5)-4-carboxy-2-{[2-{4-f!uoro-phcnyl)-6-(tctiahydro-furaii-3-yloxy)-pyriniidinc-
4-cai-bonyl]-amino}-fautyryl)-piperazine-l-carboxylic acid ethyl ester;
-((^-4-carboxy-2-{[6-{tetrahydro-furan-3-yloxy)-2-/7-tolyl-pyrimidine-4-carbonyl]-amino}-.. butyry])-piperazine-l-carboxyIic acid ethyl ester;
- ((5)-4-carboxy-2-{[2-phenyl-6-(tetrahydro-furan-3-yloxy)-pyrimidine-4-carbonyl]-amino}-
butyryl)-3-mcthyl-pipcrazinc-l-carboxylic acid ethyl ester;
-4-[(S)-3-(4-carboxy-phenyl)-2-(i2'phenyl-6-[(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbony])-amino)-propionyl]-piperazine-l-carboxylic acid ethyl ester;,
- 4-((5)-4-carboxy-2-{[2-phenyl-6-(piperidin-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-pip6razine-l-carboxylic acid ethyl ester;
- 4-((5)-4-carboxy-2-{[2-phcnyl-6-(2,2,(),6-tctramcthyl-pipcridin-4-yloxy)-pyrimidinc-4-carhony}]-amino]-butyryiypipcrazine-l-carboxylic acid ethyl ester; .^
- 4-[{S)-4-cyano-2-({2-pheny]-6-[(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonylS-amino)-butyryl]-piperazine-l-carboxylic acid ethyl ester;
- 4-('(Sl-4-carboxy-2-{[2-phcnyl-6-ftctrahydro-fiiran-3-yloxy)-pyrimidinc-4-carbonyl]-amino)-butyryl)-piperazine-l-carboxylic acid ethyl ester;
-4-[(,?)-3-hydroxy-2-({2-phenyl-6-[(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbony!}-
amino)-propionyl]-piperazine-l-carboxylic acid ethyl ester; - •
--4-[(5)-2-{[2-phenyK6-(tetrahydro-ftiran-3-yloxy)-pyrimidine-4-carbonyl]-aminoi- .' 4-(l/f-tetrazol-5-yl)-butyryl]-piperazine-l-carboxylic acid ethyl ester; -4-((5)-4-/e;-/-butoxycarbonyl-2-{[2-phcnyl-6-{tctrahydro-pyran-4-yioxy)-pyrimidinc-4-carbonyl]-amino}-butyryl)-piperazine-l-carboxylic acid ethyl ester; ■ -4-((5)-4-fa-f-butoxycarbonyl-2-([6-(l-methyl-piperidin-3-yloxy)-2-phenyl-pyrimidine-4-carbonyl]-amiiio} -butyryl)-piperazine-l -carboxylic acid ethy! ester;

- 19-
-4-((5)-2-{[6-(l-henzyl-piperidin-4-yloxy)-2-phenyl-pyrimidine-4-cai-bonyl]-aminoj-
4-fe;-/-butoxycarbonyl-butyryl)-pipei-azine-l-carboxyhc acid ethyl ester;
- 4-[(5')-3-(4-to'/-butoxycarbonyl-phcnyl)-2-({2-phcnyl-6-[(tctrahydro-f-uran-3-yl)oxy]-
pyrJmidine-4-carbonyl}-amino)-propionyf}-piperazine-!-ca/-boxylic acid ethyl ester,
-((5)-4-/e;7-bufoxycarbonyl-2-{[2-phenyl-6-(piperidin-4-yloxy)-pyriniidine-4:carbonyi]-
amirio}-butyry])-piperazine-I-carboxylic acid ethyl ester; -
-4-{(5)-4-(t'j-/-butoxycarbonyi-2-([2-phcnyl-6-(2,2,6,6-tctramclhyl-pipcridiii-4-yloxy)-
pyrimidine-4-carbonyJ]-amiDo}-butyryl)-piperaziiJe-l-carboxylic acid ethyl ester;
as well as the salts thereof (in particular the pharraaceutically acceptable salts thereof).
A further object of the invention is the compounds of formula 1 (or of formula I^H) or their pharmaceutically acceptable salts as medicaments.
The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parental administration.
The invention thus also relates to pharmaceutical compositions containing at least one compound according to this invention (notably a compound, of formula 1 or let), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. Tn particular, the invention relates to pharmaceutical compositions containing at least one compound of formula I (or of formula ICE) and a pharmaceutically acceptable carrier, diluent or excipient.
The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible sohd or Uquid carrier materials and, if desired, usual pharmaceutical adjuvants.

- 20 -
<• The compounds according to formula I and the pharmaceutically acceptable salt thereof may be used for the preparation of a medicament, and are suitable: for the treatment or prophylaxis of diseases including stable angina, unstable angina, myocardial infarction, embolism (including comph'cations of atherosclerosis, notably embolic stroke), arterial thrombosis (including primar>' arterial thrombotic complications of atherosclerosis, notably thrombotic stroke), venous thrombosis (notably deep vein thrombosis), thrombosis secondary to vascular damage or to inflammation (including vasculitis, arteritis and glomemloncphritis), venoocclusive diseases, transient ischaemic attacks, peripheral vascular diseases, myocardial infarction with or without thrombolysis, myeloproliferative disease, thrombocythaemia, sickle cell disease, inflammatory bowel disease, thrombotic thrombocytopaenie purpura, haemolytic uraemic syndrome;
<• for preventing thrombotic complications of septicaemia, aduh respiratory distress syndrome, anti-phospholipid syndrome, hcparin-indueed thrombocytopaenia and prc-eclampsi a/eclampsia;
•I* for preventing cardiovascular complications after certain surgery procedures (notably coronary revascularisation like angioplasty (PTCA), other vascular graft surgery, endarterectoray or stent placement) or after accidental trauma;
•t* for preventing organ graft rejection.
Therefore, a particular object of this invention is the use of a compound of formula 1 (or of formula Ice), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the uses listed above, and for the manufacture of a medicament for the treatment of occlusive vascular disorders in genera).
More generally, the invention reiates to the use of a compound of formula I (or of formula ICG), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of occlusive vascular disorders as well as to the use of a compound of formula \ (or of formula JCK) for the manufacture of a medicament for the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals.

-21 -
Among (he above-mentioned uses of compounds of fonnula 1 (or of formula ICE) or of
pharmaceuticaliy acceptable salts thereof for the manufacture of medicaments, the uses for
manufacturing medicaments for the treatment or prophylaxis of myocardial infarction, arterial
thrombosis (notably thrombotic stroke), transient ischaemic attacks,' peripheral vascular
disease and stable and unstable angina will be preferred, '^
The invention further relates to the use of a compound of formula 1 (or of formula ICE), or of a pharmaceuticaliy acceptable sati thereof, for the preservation of blood products in vitro (e.g. the preser\'ation of platelet concentrates). Or for the prevention of occlusion in extra-corporeal blood or blood product treatment machines (such as renal dialysis machines or plasmapheresis machines).
The invention also relates to methods of treatment for said disorders, said methods comprising the administration to a patient in need thereof of an effective amount of a compound of formula I (or of formula ICE) or of a pharmaceuticaliy acceptable salt thereof.
The preference.^ indicated for the compoi^nd.'; of formula I of course apply muUiiia mutandis lo the compounds of formula ICE, as well as to the salts and pharmaceuticaliy acceptable salts of the compounds of formula 1 or of formula ICE- The same applies to these compounds as medicaments, to pharmaceutical composifiom containing these compounds as active principles or to the uses of these compounds for the manufacture of a medicament for the treatment of the diseases according to this invention.
According to the invention, the compounds of formula] (or of formula ICE) can be prepared by the process described below.

-22-
PREPARATION OF THE COMPOUNDS OF FORMULA I
Abbreviations:
Tlie foUowin g abbreviations are used throughout the specification and the examples:
abs. anhydrous
Ac acetyl
aq. aqueous
CC column chromatography
cone. concentrated
DCC 1,3-dicyclohexylcarbodiimide
DCM dichloro methane
DIPEA diisopropyl ethyl amine
DME 1,2-dimethoxyethane
DMF A''J\'-dimethylformamide
EA ethyl acetate
EDCl ,V-(3-dimcthylaminopropyl)-A''-cthylcarbodiimidc
Et ethyl
Hept heptane
Hex hexane
HOBT 1 -hydroxybenzotri azoic
HV high vacuum
MCPBA me;a-ch!oroperbenzoic acid
Me methyl
n-BuLi «-bulyl lithium
org. organic
Pd/C palladium on carbon
Ph phenyl
PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate
TEA trifluoro acetic acid
THE tcirahydrofuran

-T,-

TLC RT

thin layer chromatography room temperature retention time

The various compounds of formula I can be prepared using the general routes summarized in Scheme I hereafter.



RV .N. ,J
o
(II)

i H
O
R'
^-?
V°
RV ,N
R=
O
(I.1):Z' = C00R'
(Z' = O-PG^)
(1.2): Z' = CN (1.3): Z' = O-PG^

° H (f ^^
RV ^N. J Y^ o
o
R= // tf
H (1.5)

(1.6)

Scheme

-24-
Tlic compounds of fomiula 1 wherein Z represents COOR' (i.e. the compounds of general formula I.l in which Y, R', R'. R\ R' and R^ are as.defined in formula I and Z' represents COOR^), wherein Z represents CN (i.e. the compounds of general formula 1.2 in which Y. R', R , R , R and R are as defined in formula 1 and Z' represents CN) or wherein Z represents 0-PG , PG being a suitable protecting group for an alcohol function (i.e. (he compounds of general formula 1.3 in which Y. R\ R^ R\ R^ and R* are as defined in formula I and Z' represents 0-PG') can be prepared (Scheme 1) by converting a compound of formula II wherein R , R , R , R , Y and Z' have the same meanings as in formula 1,1, 1.2 or 1.3 by aromatic substitution reaction with an alcohol of formula HOR^ in the presence of a suitable base such as NaH, the reaction being carried out in a suitable solvent such as THF, MeCN or DMF and preferably at a temperature between RT and 80°C.
The compounds of formula 1,4 can then be obtained (Scheme 1) by hydrolysis of the corresponding compounds- of formula J.) wherein Z' Is -COOR' (R' being a)kyl) under standard conditions well known to one skilled in the art.
The letrazolc derivatives of formula 1.5 can be prepared (Scheme 1) by conversion of the corresponding cyano derivatives of formula 1.2 wherein Z' is -CN using the well-known methodology with sodium azide, oplionalfy in the presence of ZnBr2.
The compounds of formula 1.6 can be prepared (Scheme I) by deprotection of the corresponding compounds of formula 1.3 wherein Z' is ~0-PG and PG is a suitable protecting group for an alcohol function. Suitable alcohol fiinciion protection groups and protection and deproteclion methods are well known to one skilled in the art (see notably "Protective groups in organic synthesis", Greene T. W. and Wuts P. G. M., Wiley-Intcrscicnce, 1999).
Preparation ofjhe_yarjous_s^^^ PreparaHon of the compounds of formula II
The compounds of formula 11 can be prepared (Scheme 2) by coupling the piperazine derivatives of formula III wherein Y, Z\ R*, R^ and R'' have the'same meanings as in

-2>-
formula II with the compounds of formula IV wlievein R' has the same meaning as in
formula II using standard peptide coupling methods such as
PyBOP, in the presence of a suitable base such as NEl?, DIPEA or A'-mcthylmorpholinc and in a suitabie solvent such as DCM, THF or DMF. preferably at a temperature around RT.


R'
0

o
(III)

NH,
•r

Scheme 2
Preparation of the compounds of formula HI
The compounds of formuia Hi can be prepared (Scheme 3) by coupling the piperazine
derivative of formula V wherein R'', R^ and R'' have the same meanings as in formula III with
a compound of formula VI wherein Y and Z' have the same meanings as in formula 111, using
standard peptide coupling methods such as
HOBT, EDCI. DCC, PyBOP, benzotriazole-l-y]-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate, optionally in the presence of a suitable base such as NEti, DIPEA or A'-mcthylmorpholine and in a suitable solvent such as DCM, THF or DMF, preferably at a temperature around RT. The resulting intermediates of formula VII are then deprotected using standard methods (see e.g. "Protective groups in organic synthesis", Greene T. W. and Wuts P. G. M., Wiley-Interscience, 1999) to yield the compounds of formula 111.

NH2 Z'
NH
R" (III)

o
O
O
R= (VII)
(V)
(VI)
Scheme 3

.- 26 -
Prepai-alion of the compounds of formula IV
The carboxypyrimidiiic derivatives of formula IV can be prepared as summarised in Scheme 4 hereafter.

HO

R„

o o
(viri)

NH
NH,
(IX)

OH N
(X)

CI
N _
N^R-
(XI)

CI N
(XII)


Scheme 4
The acetoacefate derivalive of formuJa VIH (wherein R is alkyJ) is reacted with an amidine of formula IX, optionally in the presence of a suitable base such as MeONa, in a suitable solvent such as EtOH, the mixture being preferably heated at a temperature between 60 and 90°C. The compound of formula X may be chlorinated using standard conditions (e;g, phosphoryl chloride at reflux). The compound of formula XI may then be demethylated using standard reagents such as BBrj, in a suitable solvent such as DCM, preferably at a temperature between -10 and 10°C; the intermediate alcohol of formula XII thus obtained can then be oxidised, using standard oxidising agents such as KMn04. in a suitable solvent such as water, dioxane, ■ and preferably al a temperature around RT.
Preparation ofihe compounds of formula V
Three situations have to be distinguished for the preparation of compounds of formula V, namely the case wherein R" and R^ are both hydrogen (Scheme 5), the cases wherein one of R and R' is hydrogen whereas the other is methyl (Scheme 5a) and eventually the case wherein R'' and R^ are both methyl.

27-

■ PG^ „6_nr,_r'i ,-...,PG^
N'"~" R'-CO-CI r-^N' r^NH

O O
(XIII) (XIV) (V)
Scheme 5
The compounds of formula V wherein R" and R^ are both hydrogen can be prepared (Scheme 5) by reacting the piperazine derivative of formula XT!T (wherein PG"' is a suitable protecting group for' an amine function) with the chloro derivative of formula R -CO-Cl (wherein R has the same meaning as in formula V) in the presence of a suitable base such as NEtj, DIPEA, A'-methylmorpholine, in a suitable solvent such as DCM, THF or DMF, at a temperature preferably around RT, The intermediates of formula XIV are converted into the compounds of formula V by cleaving off the protecting group PG' using standard conditions for the deprotection of amines, and preferentially Pd/C in a suitable solvent such as MeOH, EtOH, THF or EA, or TFA or hydrochloric acid in a suitable solvent such as DCM, Et20, dioxanc or EA.
-NH R'-CO-CI >-NH
HN

O

(V.1)

NH r ^N'''^ R^-CO-CI r^N'^^* _ r ^NH
HN. J HN^ "^^V^T '^^V^'T
(XV) ' (XVI) {V.2)
Scheme 5a

-:s-
The two cases wherein one of R'' and R^ is hydrogen whereas the other is methyl are_
represented in Scheme 5a above:
•> The compounds of formula V.l can be prepared (top of Scheme 5a} by direct coupling with a chlOTO derivative of formula R^'-CO-Cl,
•*• In the case of the compounds of formula V.2 (bottom of Scheme 5a), a protection by an amine protecting group PG'' is first carried out. The intermediate of formula XV thus obtained is then coupled with a chloro derivative of formula R^-CO-Cl and the coupling product of formula XVI is then deprotected as described above for the compounds of formula XIV.
For the particular case wherein R*" and R^ are both methyl, the disubslituted piperazine may be coupled to the chloro derivative R'^-CO-Cl according to a procedure described by M.J. Bishop et al. in J. Med. Chem. (2003), 623-633, yielding the corresponding piperazine derivative of formula V.
Preparation of the compounds of formula V!
If nol commerciany available, these compounds can be prepared according lo standard methods by the skilled artisan from commercially available compounds.
Particular embodiments of the invention arc described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in any way.

-29-
EXAMPLES
Charaderization meihoih used:
The LC-MS retention limes have been obtained using the folJowing eliition conditions:
A Zorbax column (Agilent SB.Aq Sjim, 4,6x50mm) was used. The two clution solvents were as follows: solvent A = water + 0.05% TFA; solvent B = aceionitrile. The eJuent flow rate was 4,5 ml/min and the characteristics of tlie cfufing mixture proportion in fiinction of the tiinct from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):

t (min) 0 1 1,45 " 1,55
Solvent A (%) 95" .5 5 95 ■
Solvent B (%) 5 95 95 5'
Preparative LC-MS methods used:
The purifications by preparative LC-MS have been performed using the conditions described hereafter.
A ZorbaxK columii (FrqillT SB,Aq 5r.iin, 2!.2x50nim) "-:^r. used. The t'.vo clution solvents were as follows: solvent A = water + 0.2% fonnic acid; solvent B = acetonitrile + 0,2% fonnic acid. The elucnt fiow rate was 95 ml/min and the characteristics of the cluting mixnire proportion in function of the time t from start of the elution are summarized ,in the tables below (a linear gradient being used between two consecutive time points):

I) Preparative LC-MS (5): "
t (min) 0 2 4 5 5,2 5.4 6,5 .
Solvent A (%) 60 60 50 5 ■ 5 60 .60
Solvent B (%) 40 40 50 95 95 " 40 40

-30-
I?) Preparative LC-MS (11):

t (min) 0 0.6 3.3 3.9 4.5 5,1 5.2 6
Solvent A (%) 79 79 58 58 0 n 79 79
Solvent B (%) 21 21 42 42 100 100 21 21
111) Preparative LC-MS (III):
t (min) 0 0.6 3,3 3.9 4.5 5.1 5.2 6
Solvent A (%) 68.5 68.5 42 42 0 0 68-5 68.5
Soh'cm 8 (%) 3L5 31.5 58 5S 100 100 31.5 31.5
IV) Preparative LC-MS (IV):
t (min) 0 0.6 3.3 3-9 4.5 5.1 5.2 6
Solvent A (%) 58 58 31.6 31.6 0 0 58 58
Solvent B (%) 42 42 68.4 68.4 100 100 42 42
V) Preparative LC-MS (V):
t (min) 0 0.6 3.3 3.9 4.5 5.1 5.2 6
Solvent A (%) 42 42 21 21 0 0 42 42
Solvent B (%) 58 58 79 79 iOO IOO 58 58

-3i -

VI) preparative I X-MS (Vl):
t (min) 0 2 4 5 5.2 5.4 6.5
Solvent A (%) 55 55 45 5 5- - 55 ■55
Solvent B (%) 45 45 55 95 95 45 '45
Example 1: 4-f(5}-4-carbox.v-2-{{6-[2-(2-methoxy-ethoxy)-etho\y]-2-phenyl-pyrimidine-4)-2-phcnyl-pyrimi(iine-4-carbonyl]-aniino}-butjTj'l)-piperazine-]-carboxylic acid etiiyl ester:
TFA (3 [il) was added to a solution of Example 2 (7 mg") in THF (56 MO and water (14 [il). The mixture was stirred overnight at RT. The solvents were evaporated off and the residue was purified by preparative LC-MS (11). LC-MS; IR - 0.78 min; [M+H]*: 560.58.
Example 4: 4-((5)-4-carboxy-2-{|6-((ff)-23-dimethoxy-propoxy)-2-phenyl-pyriiiiidine-4-carbonyl]-ainino}-butyryl)-piperazine-l-carboxyiic acid ethyl ester:
4J. {2.3-dimelhoxy-propoxymelhyl)-be.nze.iie:
NaH (384 mg) was added to a solution of (±)-3-benzyloxy-1,2-propanediol {0.659 ml) in THF (15 mi). The mixture was stirred for 30 min at RT and iodomclhane (0.606 in]) was added. The reaction mixture was stirred on at RT. McOH was added, then water and the mixture was extracted with DCM. The org. phases were dried (t^ajSOi) and evaporated off to afford 841 mg of the desired compound, LC-MS; tR = 0.84 min; [M-HH]*; 21.1.29.
4.2. 2.3-dimethoxy'propan-l-oh
This compound was prepared using a method anaiogous to that of Example 1, step 1.2, intermediate 4.) replacing intermediate 1.1.
'H-NMR (CDCI;): 3.70 (m, I H); 3.60 (m, IH); 3.46 (m, 2H); 3.43 (s, 3H); 3.38 (m, IH);
3.33 (s,3H). i,
43. 4-((S)-4-carboxy-2-{[6-((R)-2.3-dimelhoxy-propoxy)--2-phei-iy!-pyrimiilin&-4-cui-bunyI]-amino}-bulyryl)-piperazine-l-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example I, step 1.8, intermediate 4.2 replacing 2-{2-mcthoxyethoxy)ethanol. The title compound was however purified by preparative TLC (DCM/MeOH/AeOH 96/4/0.1), followed.by preparative LC-MS (method (V) followed by method (VJ)),

-35-LC-MS: tR = 0.91 rnin; [M+H]*: 588.57.
Examples: 4-((5)-4-carboxj'-2-{|2-phenyl-6-(letrahy(lro-pyraii-4-yloxy)-pyrimidiiie-4-carbonyl|-amino}-butyi-yl)-piperazine-l-carboxylic acid ethyl ester:
.5.7. 4-((S)-4-tert-hu1oxycarhonyl-2-{[2'phenyl-6-(lelrahydro-pyran-4-yJaxy)'pyrimidine-4'Carbonyl]-amino}-bulyryl)-piperazine.-l-C(vboxylic acid ethyl ester:
To a solution of tetrahydro-2//-pyran-4-ol (0.255 ml) in THF (10 ml) was added NaH (64 mg) and the mixture was stirred at RT for 15 min, Jntennediate 1.7 (300 mg) was added and the mixture was stirred al RT for 3 h. A NH4CI solulion was added and the mixture was extracted with EA. The org. phases were dried (Na;S04) and evaporated off to afford 600 mg of crude material, which was used without further purification, LC-MS:IR= 1.08 min; [M-HHj^ 626.54.
5.2. 4-((S)-4-carboxy-2-{f2-phenyJ-6-(lefrahydro-pyran-4-yloxy)-pynmidine-4-carboi]yl]' aminOj'-bulyiyl)-piperazine-]-carboxylic acid sihyl esler:
A solulion of imennediate 5.1 (600 mg) in TFA/DCM (1/2, 15 ml) was stirred at RT for 4 h. The solvents were removed and the crude was purified by CC (DCM to DCM/McOH R5/15) to afford 70 mg of the desired compound. LC-MS: tR- 0.93 min; [M+H]^: 570.43.
Example 6: 4-((5)-4-carboxy-2-|[6-(]-mcthyI-piperiiIJn-3-ylosy)-2-phc3yl-pyrimidinc-4-carbonyll-amino!-butyryl)-piperazine-l-carboxylic acid ethyl ester trifluoroacetate salt:
6.1. 4-((S)-4-tei-t-butoxycarbonyl-2-{[6-(}-melhyl-piperidin-S-yioxy)-2-phenyl-pynmicline-4-carbonyl]-amino}-buiyiyl)'piperazine-}-carboxylk- acid elhyl esler:
This compound was prepared using a method analogous to that of Example 5, step 5.1, 3-hydroxy-l-methylpipcridinc replacing lctrahydro-2/y-pyran-4-ol. LC-MS: tR = 0.86 min; [M+H]^: 639.59.

-3f.-
6.2. 4'((S)-4-cayboxy-2-[[6-(i-me.ihyl-pipendin-S-ylnyy)-2-phenyl~pynmidine-4-ccirbor)yl]-amino}-hiify'y})-pipera2ine-}-carhoxyIic acid elhyl ester:
This compound was prepared using a method analogous to that of Example 5, step 5.2, infermediate 6.1 replacing intermediate 5.1, LC-MS; iR = 0.76 min; [M+Hf; 583.45,
Example 7: 4-((5')-2-{[6-(1-benz>'1-piperidin-4-yloxy)-2-phenyl-pyrimidine-4-carbonyI]-amino}-4-carboxy-biitj'ryl)-piperazine-l-carboxyUc acid ethyl ester trifluoroacetate salt:
7.!. 4-((S)-2-{[6-(l-be.nzyl-pipendin-4~ylQxy)~2-pheny}-pynmidine-4-carbonyl]-amino}' 4-rert-hulnxycarhonyl'hiity}yl}-pipsiazine-!-CQrboxylic acid ethyl exler:
This compound was prepared using a method analogous to that of Example 5, step 5.1, A'-benzyl-4-hydroxypiperidine replacing tetrahydro-2H-pyran-4-ol. LC-MS: tR - 0,90 min; [M+H]"": 715.54.
7.2. 4-((S)-2-{[6-(]-benzyl-pipendin'4-yloxy)-2-pheny}-pyhmidine-4-carhonyl}-amino}-4-carboxy-l)ulyiyl)-piperazine-]-carboxy!ic add ethyl ester trifluoroacetate salt:
Thiy compound was prepared using a method analogous to that of Example 5, step 5.2, intermediate 7.1 replacing intermediate 5,1. LC-MS: tR - 0.83 min; [M+H]"": 659,51.
Example 8: 4-{(S)-4-carboxy'2-{{2-{4-(\uoro-pbeny])-6~(tetrahydro-furan~3-y\o\y}-pyrimidine-4-carbonylI-amino)-but>Tyl)-piperazinc-l-carboxylic add ethyl ester:
8.L 4-fluoro-benzamidine:
To an iee-cold solution of hexamethyldisilazane (7 ml) in EtjO (40 ml) was added n-BuLi (I.6W in hexanes, 20.6 ml), followed by a solution of 4-fluorofaenzonftriie (2 g) in EtjO (10 ml). After stirring at 0°C for 10 min, the mixture was allowed to warm to RT and was stirred at RT for 20 h. The mixture was acidified to pH 1 by adding a \M HCl solution and was washed with CHCI3, The aqueous layer was then basjficd to pH 14 by adding Na2C0j and

-37-
NaOH and was extracted twice with CHCl.;. The org, layers were dried (NaTSOj) and evaporaieci off to afford i .59 g of the desired compound. LC-MS:!|( = 0.33min;[M+H]^ 139.21.
H.2. 2-{4~Jluoro-phenyl)'6-jjie!hoxymethy!-pynmidin-4-o!:
This compound was prepared using a method analogous to that of Example 1, Klep 1.3, intermediate 8.1 replacing benzamidinc. LC-MS: tR- 0.72 min; [M+Hf: 235.31.
8.3. 4-chloro-6-me!hoxymelhyl-2-(4'Jluoi-o-phe-nyl)-pyrimidine:
This compound was prepared using a method analogous to that of Example 1, step 1.4, intermediate 8.2 replacing iniermcdiale 1.3. LC-MS: tR = 1.04 min; [M+H]*: 253,27.
8.4. [6-chloro-2-(4-J}uoro-phenyl)-pynmidin-4'yIJ-iiielhonol:
This compound was prepared using a method analogous to that of Example I, sicp 1.5, intermediate 8.3 replacing intermediate 1.4. LC-MS: tK = 0.92 min; [M+H]*; 239.25.
8.5. 6-chloro-2-(4-/Iuoro-pheT7yl)-pynmidine'4'Carboxylic acid:
This compound was prepared using a method analogous to thai of Example 1, step \.6, intermediate 8.4 replacing intermediate 1.5. LC-MS: tR = 0.90 min; [M+HJ*: 253.24.
8.6. 4-((S)-4-lerl-huloxycarbonyl-2-{[6~ch}oro-2-(4-J}uoro-phenyl)-pyrimidme-4-carbony!]-
amino}-huryryl)-piperazine-1 -carboxylic acid eihyf esler:
This compound was prepared using a method analogous to that of Example. 1, step 1.7, intermediate 8.5 replacing intermediate ! .6. LC-MS: tK= 1.09 min; [M+H]*: 578.4L

-3S-
8.7. 4-((S)'4'Carboxy-2-{[2-(4-jluow-phmyl)-6-(ien-ahyd}-o-furan-i-y}o>;y)-pyniii!dine-4-cai-bony}]-cimino}-bulyryl)-piperazine-I-carboxyHc acid ethyl esler:
This compound was prepared using a method analogous to that of Example 1, step 1,8, intermediate 8.6 replacing intermediate 1.7 and 3-hydroxytetrahydrofurane replacing 2-(2-melhoxyethoxy)ethanol. The reaction mixture was however not worked up but was directly purified by preparative LC-MS (Hi), followed by preparative TLC (DCM/MeOH/AcOH 9/i/O.l). LC-MS: tR = 0,93 min; [M-i-H]^ 574.41.
Example 9: ((iS)-4-carboxy-2-j[6-(tetrahy(lro-furaii-3-yIoxy)-2-77-tolyl-pyrmiidine-4-carbonyl)-aniino}-butj'r>'l)-piperazine-l-carboxylic acid ethyl ester:
P. /. 6-nielhoxymelhy!-2-p-loly/-pyrimidin-4-o!:
This compound was prepared using a method analogous (o that of Example I, step 1.3, 4-melhylbenzamidine replacing benzamidine. LC-MS: IR = 0.76 min; [M-HH]^ 231.34.
9.2. 4-chloro-6-melhoxynieiliyl-2-p-lolyl-pynmidine:
This compound was prepared using a method analogous to that of Example 1, step 1.4, intermediate 9,1 replacing intermediate 1.3. LC-iviS: fR= i.05 min; [ivi+H]'; 249.29.
9.3. (6-chloro-2-p-lolyl-pynmidin-4-yl)-melhano!:
This compound was prepared using a method analogous to that of Example 1, step 1.5, intermediate 9.2 replacing intermediate 1.4. LC-MS: tR = 0.93 min; [M4-H]^ 235.28.
9.4. 6-cliloro-2-p-lo/yl-pyn'niidine-4-carboxylicacid:
This compound was prepared using a method analogous to that of Example 1, step 1.6, intermediate 9.3 replacing intermediate 1.5.

-39-LC-MS: TR= 0.93 min: [iVl-fH]^: 249.2^,
9.5. 4-{(S)-4-ie.rl-huloxycarbonyl-2-[(6-cbhrO'2~p-io!yl-pynnn(iine-4-carbonyl)-amino]-
bu!yry]}-pipp.raz}ne-1 -carboxylic acid ethyl esler:
This compound was prepared using a method analogous to that of Example 1, step 1.7, iniennediale 9.4 replacing intermediate ! .6-LC-MS: tR = 1.11 min; [M-HH]' : 574.42.
9.6. ({S)'4-carboxy-2-{[6-(ietrahydro-fui-an-3-yloxy)'2'p-tolyl-pynmidihe-4-carbony}]~
OJ7iii2o}-hu!yiyl)-piperazine-J-cai'hoxylic- acid ethyl esler:
This compound was prepared using a method analogous to that of Example 8, step 8.7, intenncdiaie 9.5 replacing intermediate 8.6. LC-MS: tR= 0.94 min; [M+H]*; 570.44.
Example tO: ((5)-4-carbox>'-2-Jt2-phenyl-6-(fetrahydro-furan-3-yloxy)-pyrimidine-4-carbonyl]-aniino}-butyry])-3-methyl-piperaziiie-l-carboxyIic acid ethyl ester:
10.}. 3-melhyl-piperazine-J-carboxylic acid ethyl ester:
To a solution of 2-mcthylpiperazinc (1 g) in MeOH (12 ml) was added AcOH (1.8 ml). The mixture was cooled down to 0°C, ethyl chloroformate (0.95 ml) was added over a 60 min period. The mixture was allowed to warm to TIT and was stirred overnight. Water was added and McOI-I was evaporaicJ uIT. The riisiJue wa> c\lraclcJ vvilli toluene and the erg. layers were washed with water. The combined aq. layers were basifled to pH 14 with an aq, NaOH (2Af) solution and extracted with toluene. The combined org, layers were washed with brine, dried over NajSOj and evaporated off to give 936 mg of the desired compound. 'H-NMR (CDCb): 4.1 (q, 2H); 3.95 (br s, 2H); 2.9 (d, 1H); 2.75 (m, 3H); 2.4 (t, 1H); 1,6 (br s, IH); 1.25 (t.3H); 1,05 (t.3H).

-40-
10.2. 4-((S)-2~benzy]oyycayhony}amino-4'ierl-bu1oxycai-bonyl-bu!yiyl)-i->ne!hyl-pipera2!iie-
l-carbosylic acid ethyl ester:
This compound was prepared using a method analogous to thai of Example 1, step 1.1, intermediate 10.1 replacing I -(cthoxycarbonyl)piperazine. The compound was used in the next step without characterization.
10.3. 4-((S)~2-ai!U']0-4-lerl-buioxycarbony!-bulyiyl)'3-nielhyl-piperazine-!-c(]rho.\ylic acid
ethyl ester:
This compound was prepared using a method analogous To that of Example I, step 1.2, intermediate 10.2 replacing intermediate 1.1.
'H-NMR (CDCh); 4.66 (m, IH); 4.0« (br s, 2H); 3.80 (br s. 2H); 3.68 (br s, IH); 3.25 (m, IH); 2.94 (in,3H); 2.44 {m. lH);2.27(m, IH); 1,8 (m, IH); 1,55 (m, IH); 1.36 (s,9H); L19 (t,3H); 1.07(brs, 3H).
10-4. 4-{(S)-4-terl-buloxycarbonyl-2-[(6-chloro-2-phenyl-pyrimicl!ne-4-c^rbonyl)-auunoJ-buiyiylJ-3-melhyl-piperazine-J-carboxylic acid elhyl esler:
This compound was prepared using a method analogous lo Ihal of Example 1, step 1.7, intermediate 10.3 replacing intermediate 1.2. LC-MS: tR = 1.10 min; [M+H]*: 574,43.
!0.5- ((S)-4-curbo:;y-2-l[2'phcnyl 6'(tclralrydro-fin-tin-3-y!oxy)-py!in^.id!rie-4-carbonyl]--amino}~bulyiy!)-3-'ne!hyl-piperazine-]-carboxylic acid ethyl ester:
I TTiis compound was prepared using a method analogous to that of Example 8, step 8.7, intermediate 10.4 replacing intermediate 8.6. LC-MS: tR = 0.93 min; [M+H]*: 570.45.

-4] -
Example 11: 4-|{5)-3-(4-c3rbDx,v-pbenyl)-2-({2-pliei),yl-6-|(tetr3h>'dro-furan-3-yl)os7'}-l>yriniidine-4-carbonyl}-amiiio)-|)ropionyl|-piperazine-l-carboxylic acid ethyl ester;
//./. [(S)-2-henzyh>ycarbonylamino-3-(4-lert-hulox}'cai-horiyl-phe.nyl)-propinnylJpipei-azi)-te' l-carboxylic acid eihy! esler:
To a solution of Z-p-carboxy-(L)Phc(OtBu)-OH (5 g) in DCM (100 ml) were added at RT H0BT{2.n g), EDCl (2,5 g) and DIPEA (4.4 ml). After 15 min stirring" at RT, 1-etho-xycarbonylpiperazine (2 g) was added and the stirring was continued at RT overnight. 150 ml of EA and 60 ml of a NaHCO? solution were added to the reaction mixture and the phases were separated. The org. phase was washed with an aq. NaHS04 (l^■f) solution and with brine, dried over Na2S04 and evaporated off. After HV drying, erl-buloxycarbony}-phenyJ)-2-({2-pheny]-6-[(!eU-ahydro-jurau-^-yl)ox^^ pynniieline-4-carhonyl}-amii]o)-propioiiyl]-piperazine-I-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 8, siep 8.7, intermediate 11.3 replacing intermediate 8.6. The compound was however purified by preparative TLC (DCM/MeOH/AcOH 9.5/0.5/0.1, and EA/Hcpt. 1/1). ;■ LC-MS: tR = 1,13 min; [M+H]': 674.70.
}1.5. 4'[(S)-3'(4-cai-boxy-phenyl)-2-((2-phenyI-6-[(tetrahydvo-fwan-i-yl)oxy]-pyiimidine-4-caiboiiyl}-am!no)-propionyl]-piperazine-}-cai'hoxyUc acid ethyl exter:
This compound was prepared u,sing a method analogous to that of Example 5, step 5.2, intermediate 11,4 replacing intennediate 5.1. The compound was however not purified, LC-MS: IK = 0.96 min; [M+H]': 618.65.
Example 12: 4-((S}-4-carboxy-2-Jl2-phenyl-6-(pipericlin-4-ylox>)-pyrimicline-4-carbonyl|-animo}-butyr\'l)-piperazine-1-carboxy)ic acid ethyl ester:
12J. ((S)-4-tert-buioxycarbonyl-2-{[2-pheiiyl-6-(piperidin-4-y!oxy)-pyi-imidine'4-carbonyl]-amino}-bu(yiy/)-pipeiazine-l-carboxylic acid elhyl ester:
This compound was prepared using a method analogous to that of Example i, step 1.2, intermediate 7.1 replacing intermediate 1.1. LC-MS: tK = 0.85 min; [M+H]': 625,54.
12.2. ((S)-4-c.ai'boxy~2-{[2-phenyJ-6-(piperidin-4-yloxy)'pyrimidine.-4-carbonyI]-amino}-hu!y>yI)-piperazine~I-carboxylic acid elhyl ester:
This compound was prepared using a method analogous to that of Example 5, step 5.2,
intermediate 12.1 replacing intermediate 5.1. The compound was however worked up by
diluting the residue in EA/water and adding a Na2C03 solution until pH 7. The org. layers
were dried over Ma2S04 and evaporated off. The crude was purified by CC (DCM to
DCM/MeOH9/l).
LC-MS: tR = 0,74 min; [M+H]*: 569.43.

-43-
Example 13: 4~((S)-4heny}-6-(2.2,6.6-tetrametbyi'piperidin-4'y}oxy)-pyrimidine-4-carbonyl)-aminoJ-but>Tyl)-piperazine-l-carboxylic acid ethyl ester:
13.!. 4-((S)-4-ieii-buioxycai-bonyl-2-{/2-phenyl-6-(2.2.6.6-te.lianiethyI-pipentiiii-4-y!oxy)-pyrimidine-4-carbony}]'amino}-bulyiyl)-pipeiazine'}-caiboxyUcadd ethyl e.'^ler:
This compound was prepared using a method analogou^s to that of Example 5, step 5.!, 4-hydroxy-2,2,6,6-tetramethylpiperidine replacing tetrahydro-2//-pyran-4-ol. The compound was however purified by CC (DCM/MeOH 9/1). LC-MS: tR = 0.90 min; [M+H]^: 686.60.
]3.2. 4-((S)-4'carboxy-2-{[2-pheny!-6-(2.2.6.6-lelraiJic'lhyl-p!pendin-4-ylo,\y)-py)-imiclin(i-4-cai-bonyl]-amuio}-hulyryi)-piperazine-}-c.a!-boxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 5, step 5.2, intermediate 13,1 replacing intermediate 5.1, LC-MS: fR = 0.79 mm; [M+HJ*: 625.52.
Example 14: 4-|(5)-4-cyano-2-(i2-phenyl-6-|(tetrahydro-ruran-3-yl)oxyl-pyriniidine-4-carbonyJ)-amino)-bu(yryI|-piperazfne-l-carbOKyJic acid ethyl ester:
]4.}. 4-((S)-2-benzyloxyc-arbonylamino-4-C-ai-bamoyl-bulyiyl)-p}perazme-l-carboxyiic.acid ethyl esler:
This compound was prepared using a aiclhod analogous tu uiai uf C.xaiViplc 1, sicji!.', Z-(L)-GIn-OH replacing 2-(L)-Glu(0tBu)-0H. LC-MS: tR = 0.74 min; [M+H]^: 421.50.
14.2. 4-((S)-2-benzyloxycarbonyiamino-4-cyano-huiyiyI)-pipera2i>]e-Ucai-boxylic acid ethyl enter:
Benzencsulfonyl chloride (19 g) was added to a solution of intermediate 14.1 (37,4 g) in dry pyridine (29.5 ml). The mixture was heated at 50°C for 1 h, and neutralized (pH 7) by adding a 2M HCl solution. The mixture was extracted three times with EA. The combined org. phases

-44-
were washed with a iiW HCI solution, a NaKCOi solution and with wafer, dried over UaiSO^ and evaporated to afford 30g of the desired compound. I-C-MS: 1R= 0.85 min; [M+Hf: 403.48.
14.3. 4-((S)-2-amino-4-cyano-hulyiy!)-piperaziiie-1 -carhoxylic add elhyl esler:
This compound was prepared using a method analogous to that of Example 1, step 1.2. intermediate 14.2 replacing intermediate l.I. LC-MS: tR = 0.74 min; [M+H]*: 421.50.
14.4. 4-{(S)-2-[{6-chhro-2-phenyi-pyrimidme-4-carbonyI)-am!no]-4-cyano-hulyiyl}-
pipercizine-1-carhoxylic acid eihyl esler: ,i
This compound was prepared using a method analogous to that of Example 1, step J .7,
intermediate 14,3 replacing intermediate 1.2. '
LC-MS: t„ = 0,99 min; [M+H]*; 485,33.
J4.5. 4-[(S)-4-cyano-2-({2-phenyI~6'[(S)-(te!rahydi-0'furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-bulyiyl]'piper(izine-l-ciirboxylic acid elhyl esler:
This compound was prepared using a method anaiogous to that of Example 8, step 8,7, inlcrmediatc 14.4 replacing intermediate 8,6. The compound was however purified by CC (EA/Hepl, 0/1 to EA/Hept. I/O). LC-MS: tR = 0.97 min; [M+H]*: 537.38.
Example IS: 4-((i}-4-carboxy-2-{[2-pheny]-6-(tetrahydro-ruran-3-yloxy)-pyrimidine-4-carbonyIl-aniino}-but>'ryl)-piperazine-l-carboxy]ic acid ethyl esler:
This compound was prepared using a method analogous to that of Example 8, step 8,7, intermediate L7 replacing intermediate 8,6. The compound was however purified by CC (DCM/McOH/AcOH 95/5/O.J), LC-MS: tR = 0.92 min; [M+H]*: 556,67.

-45-
Example 16: 4-[(LS)-3-hydroxy-2-({2-phenyl-6-[{letiahydro-fiiran-3-yl)oxyl-pyrimidine-4-carbonyl}-amino)-propionyl|-piperazinD-l-carboxyIic acid ethyl ester:
16.}. 4-((S)-3-henzyloxy-2-rerl-buloxycarbonylamino-propioiiy!)-piperazine-l-carhoxyljc acid ethyl enter:
This compound was prepared asing a method analogous to that of Example 1. ^tep 1.1. Boc-0-bcnzyl-(L)-Scrinc replacing Z-(L)Glu(OtBu)-OH. LC-MS: tR- 0.96 min; [M+Hf: 436.55.
16.2. 4-((S)-2-amino-3-benzy}oxy'propionyl)-piperazine-l-carboxylic acid ethyl ester
hydrochloride:
Intermediate 16.1 (2.5 g) was dissolved in a 3JW HCl solution in EA (15 ml) and the mixture was stirred for 3 h at RT. The solvent was removed and the crude (2,68 g) was used in the next step without purification. LC-MS: tR - 0.68 min; [M+H]*; 336.45.
16.3. 4-{(S)-3-benzyloxy-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-propionyl}-
piperazine-]-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.7, fntermedTate 16.2 replacfng fntermedfate 1.2. TTie compound was however purified by CC (EA/'Hepl. 2/lj. LC-MS: tR= L09 min; [M-HHr: 552.35.
16.4. 4-((S)-3-benzyloxy-2-{[2-phenyl-6-(tetrahydro-furan-3-ylnxy)-pyrimidine-4-carhony}]-
amino}-propionyl)-piperazine-}-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 8, step 8.7, intermediate 16.3 replacing inlermediate 8,6. The compound was however purified by preparative LC-MS (IV). LC-MS: tR = 1,07 min; [M+H]*: 604.63.

-46-
■J
16.5. 4-[(S)'3-hydroxy-2-({2-phenyl-6'[(R)-(ielrahydro-furan-S-y!)r)xy]-pyrinudlne.-4-carhony!j'-amino)-propionylJ-piperazine-]-cai-hoxylic acid ethyl ester:
This compound was prepared using a method analogous to thai of Example 1, step i.2, intermediale 16,4 replacing intermediate i.l. The compound was however purified by preparative LC-MS (III). LC-MS: tR - 0.90 min; [M+Hf; 514.58.
Example 17: 4-|(5)-2-J|2-phen.vl-6-(tetrahy(!ro-furan-3->'loxy)-pyrimidine-4-carbon>'ll-amino}-4-(lW-tetrazol-5-yl)-but\'ryl|-piperazine-l-carboxyIic acid ethyl ester:
To a microwave vial was added intermediale 14.5 (200 mg), sodium azide (27 mg), zinc dibromide (84 mg). Water (2 ml) was added and the mixture was heated at 100°C overnight. The mixture was evaporated off and the residue was purified by CC (DCM/McOH 95/5) followed by preparative LC-MS (V), LC-MS: 1R = 0.91 min; [M-t-Hf; 5F0.63.
The compounds of Examples JS lo 23 were prepared using a method analogous lo ihal of the Example indicated between bi-ackels. except ihcil the last slep of the corresponding Example was noi carried out.
Example 18: 4-((5)-4-i'ert-bntoxycarbonyl-2-![2-phenyl-6-(tetraliydro-pyran-4-yloxy)-pyrimidine-4-carboiiyl|-amino}-but>Tyl)-pipera/ine-l-carboxy)ic acid eihyi ester:
(Example 5). LC-MS: IR = ! M min; [M-l-H]*: 626.54.
Example 19: 4-((iS)-4-tert-butoxycarbonyl-2-j[6-(l-methyl-piperidin-3-yloxy)-2-phenyl-pyrimlillne-4-carbonyll-amiiio}-butyryl)-piperazine-J-carboxylic acid ethyl ester:
(Example 6). LC-MS: tR - 0.8(S min; [M-HH]*: 639.59.

-47-
Exaniple20: 4-((5)-2-{i6-(l-benzyl-piperidin-4-yloxy)-2-pheny1-pyriniidine-4-carbonyl]-amiiio}-4-to7-butoxyc3rboiiy]-buty'r>))-piperazijie-]-carbo.vv)ic acid elhyJ ester:
(Example 7). LC-MS: IR = 0.90 min; [M+H]': 715.54.
Example 21: 4-[(5)-3-(4-fert-.butoxycarbonyl-phenyl)-2-(!2-phenyl-6-[(tetraliydro-ruran-3-yl)oxy|-pyriniidine-4-carbonyl}-amino)-propiony]]-piperazine-l-carboxylic acid ethyl ester:
(Example 11). LC-MS: 1R = 1.13 mm; [M+H]^; 674.70.
Example 22: ((5')-4-/^/T-butoxycarbonyl-2-{l2-phcnyI-6-(piperidirt-4-yloxy)-pyrinii(Iine-4-carbonyl]-aminoj-but>'ryl)-piperazliie-I-carboxylic acid elhyl ester:
(Example 12), LC-MS: XR = 0.85 min; [M+H]^: 625.54.
Example 2,1: 4-((5)-4-rert-butoxycarbonyl-2-{[2-phenyl-6-(2,2,6,6-tetrametliyl-piperidin-4-yloxy)-pyrimidine-4-carbonyl|-amino}-butyryl)-piperazine-l-carboxylic acid elhyl ester;
(Example 13). LC-MS: IR = 0.90 min; [M+H]*: 686.60.
Example 24: 4-((5)-4-carboxy-2-{(6-(3-hydroxy-2-hydroxymethyl-propoxy)-2-pheiiyl-pyrimidine-4-carbonyIl-amino}-butyryl)-piperazine-l-carboxylic acid ethyl ester:
24.]. (2,2-dimelhyl-[I,i]dioxan-5'yl)-meihanol:
To a mixture of 2-hydroxymethylpropane-l,3-diol (200 mg) in THF {1 ml) was added 2,2-dimethoxypropane (0,278 ml) and p-toluenesulfonic acid monohydrate (11 mg). The mixture was stirred at RT for 4 h. NEt^ (262 p.1) was added and the mixture was stirred for further 15 min. The solvent was removed and the residue was purified by CC (DCM to DCM/MeOH 95/5) to afford 220 mg of the desired compound. .

-48-
'H-MMR (CDCI.O; '^.O? (d, IH); 4.02 (d. IH); 3.82 (d, IH); 3.79 (m, 3H): 1.87 (ni. IH); 1.47 (s,3H); 1.43 (s,3H).
24.2. 4-((S)'4-!err-buioxyc.arbony]-2-{[6-(2.2'dime.ihyl-[iJ]dwxan-5-ylnielhoxy)-2'phenyi-pyrimidine-4-carbonyl]-amino}-huty>yl)-piperazine-1 -carhoxyJic acid ethyl esler:
This compound was prepared using a method analogous to that of Example 5, step 5.1,
inlermediate 24.1 replacing tetrahydro-2//-pyran-4-ol. The compound was however purified
■j by CC (DCM to DCM/MeOH 8/2).
LC-MS: tR= 1.09; [M+Hf: 670.51.
243. 4'((S)-4-carboxy-2~{[6-(3-hyd)-uxy-2-hydroxynwihyI-prapoxy)-2-phe-nyl-pyrimidine.-4-carboiiylJ-amino}-butyryI)-piperazine-I-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 5, step 5.2, intermediate 24.2 replacing intermediate 5.1. The compound was however purified by CC (DCM/MeOH 8/2). LC-MS: tR = 0.79 min; [M+H]*: 574.43.
Example 25: 4-((5)-4-carboxy-2-j|2-pheiiyl-6-(leliahydro-lhiopyran-4-yloxy)-pyrimidine-4-carbonyl|-amino]-butyryl)-|>i|ierazine-l-carboxylic acid ethyl ester:
25. J. 4-((S)-4-!e/-l-buloxycarbonl-2-{[2~pheny!-6-(te!rahydro-!hiopyya!7-4-yloxy)-pyr}i}]id!iie-4-carko!-!ylJ-:!!:!ir.cJ-bu!y!y!)-p!p(.'ruzi!K'-!-c(!rhox)'!ic-(ind ahyl cslcr:
This compound was prepared using a method analogous to that of Example 5, step 5.1, tetrahydro-2//-lhiopyran-4-ol replacing tetrahydro-2//-pyran-4-ol and using DMF instead of THF. The compound was however purified by CC (EA/Hept 3/7). LC-MS: tR = 1.13 min: [M+H]^: 642.41.

-49-
25.2. 4-((S)'4-caiboxy-2-i[2-phenyl--6-(!e!rahydiO-!hiopyi-an-4-yhsy)-pynmidine-4-carbonyl]-amino}-bu!yiyl}-pipercizine-l-carboxyric acid el/iyl ester:
This compound wa"s prepared using a method analogous to !liat of Example 5, step 5.2, intermediate 25.1 replacing intermediate 5.1. The compound was however purified by preparative LC-MS (IV). LC-MS; tR = 0.99 min; [M+H]': 586,26.
Example 26: 4-|(5)-4-carboxy-2-({2-phcnyl-6-|(ft)-(tetrahydro-fiiran-3-yI)oxy|-pyrimidine-4-carbonyl}-amino)-butyryi]-pipera/jne-l-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example i, step 1.8, (ff)-(-)-3-hydroxytetrahydrofurane replacing 2-(2-methoxyethoxy)ethanol. The title compound was however purified by preparative LC-MS (111). LC-MS: tR= 0.90 min; [M+H]': 556.28.
Example 27: 4-|(5)-4-carboxy-2-(S2-phenyl-'6-|(5)-(tetraliydro-furan-3-yl)oxy|-pyrimidine-4-carbonyl}-aniino)-bulj'ryl|-piperazine-l-carboxylic acid ethyl ester:
27.1. 4-((S)-4-lerl-buiox-ycaihonI-2-{[2-phenyl-6-(letiahydro-thiopyran-4-yIoxy)-pynmidine-
4'CarbonyI]-amino}-bulyiyl)-piperazme-]-carboxylic acid elhyl esler:
This compound was prepared using a method analogous to that of Example 5, step 5.1, (5)-(+)-3-hydroxyIetrahydrofurane replacing lclrahydro-2//-pyran-4-ol and using DMF instead of THF, The compound was however purified by CC (EA/Hept 3/7). LC-MS; IR = ] .06 min; [M+H]^: 612.39.
27.2. 4-f{S)-4-carboxy-2-f{2-pfienyl--6-f(S)-(ieirahydro-furan-3-y/)oxyJ-pyi'imidiiie-
4-carbonyl}-amino)-buryiylJ-piperazine-J-carboxylic acid elhyl ester:
This compound was prepared using a method analogous to that of Example 5, step 5.2, intermediate 27.1 replacing intermediate 5.1. The compound was however taken up in toluene and the solvent was evaporated off to remove residua! TFA. LC-MS: tK = 0.9!min; [M+H]'; 556.40.

-50-
Ex2niple28: 4-[(5^-4-carboxy-2-({2-plicnyl-6-[tetrahydro-furan-3-yloxyl-pyriniii1iiie-4-carbon>l}-amino)-butyryl)-piperazine-i-carboxylic acid ethyl es(er:
28.1. 4-((S)'2'henzyIoxycai-bory/cjniiiio-3''e.r!'huroxycarho''iy!-piopioiiyI)-piperazii!e-]-corhoxylic acid ethyl ester:
This compound was prepared using a method analogoa^ to that of Example 1, step l.I, 2-(L)-Asp(0tBu)-0H replacing Z-(L)-Asp(OlBu)-OH. LC-MS: tR= 0.96 min; [M+H]*: 464,36.
28-2. 4-((SJ-2-mijhw-3-ierr-huloxycarhoiiy/-piopiony!)-piperazine-J-carhoxylicackl ethyl enter:
This compound was prepared using a method analogous to that of Example 1, step !.2, intermediate 28.1 replacing intermediate l.I and usingEA instead ofElOH. 'H-NMR (CDC\3)-. 4.15 (q, 2H); 4,05 (dd, IH); 3.& to 3.4 (m, m); 2.6 (dd, IH); 2,4 (dd, IH); 1.6(s, 2H); 1.45 {s,9H); 1.25 (t,3H).
28.3. 'l'{(S)-3-lerI-buloxycarbonyl-2-[(6-chhro-2-phenyl-pyrimiilii7e-'i-ceirbonyl)-amino]-
prnpinny!}-piperazine- l-carhoxylic acid ethy! ester:
This compound was prepared using a method analogous to that of Example 1, step].?, intermediate 28.2 replacing intermediate 1.2. The compound was however purified by CC (EA/Hept 3/7). LC-MS: IR = 1.06 min; [M-^H]': 546.42,
28.4. 4-[(S)-4-c-arboxy-2-({2-phenyJ-6-[le.lrahydro-furan-3-yhxy]-pyi-irri!dine'4'Ca}bonyl}-
aminn)-butytyl]-piperazine-l-cayhoxylic odd ethy] ester:
This compound was prepared using a method analogous to that of Example 1. step 1.8, intermediate 28.3 replacing intermediate 1.7 and 3-hydroxytetrahydrofuranc replacing 2-(2-methoxycthoxy)elhanoi. The compound was however purified by preparative CC (DCM/MeOH/AcOH 95/4.5/0.5). LC-MS: tR = 0.88 min; [M+H]*: 542.40.

-5i -
Example 29: 4-[(iS)-4-cai-boxy-2-({2-plienyl-6-ttetrahydro-furan-3-yloxy]-pyi-imidine-4-carboiiyl}-amino)-butyry'l|-piperaziiie-l-carboxylic acid butyl ester:
29.1. 4-be.nzyl'piperazine-1 -carboxylic acid bulyl.esier:
To a solution of l-benzyl-piperazine (1,97 ml) andNEtj (1.9 ml) in DCIV1 (100 ml) was added n-butyl chloroforraate (1,47 ml). The mixture was stirred at RT for 2 h. Water was added; the org, phase separated, dried (Na:S04) and evaporated off to give 3,13 g of a yellow oil, LC-MS: tR = 0.73 min; [M+H]^: 277,42.
29.2. Piperazine-l-carhoxyJic acid butyl ester: ■■
This compound was prepared using a method analogous to that of Example 1, step 1.2, intermediate 29.1 replacing intermediate 1.1. LC-MS: tR = 0.54 min; [M+H+MeCN]*: 226.39.
29.3. 4-(lS)-2-benzyloxycavbony}am!nO'4-le!-l-bu!o>:ycarhony}-buly}y})'piperaz})7e-]-
carboxylic acid buXy] ester: ,'.
This compound was prepared using a method analogous to that of Example 1, step 1.1,
intermediate 29.2 replacing 1-ethoxycarbonylpipcrazinc and using DCM instead of
DCMA'HF. ■ ..
LC-MS: tii - 1.04 min; [M+H]"": 506.49, ■ . ^ ■
29.4. 4-('{S)-2-u}ui^o-4-!er!-bl^ioj:ycarbGr,y!-bl!ly!y!}-pipcraz:rc-!<■cr■bo^y!!cnc:d bith:/ csti'.'-
acetic acid salt:
This compound was prepared using a' method analogous to. that of Example 1, step 1.2, intermediate 29,3 replacing intermediate 1.1 and using EtOH/AcOH (100/1) instead of EtOH. LC-MS; tR = 0-75 min; [M+H]": 372.49.

.',?.
29.5. 4-{(S)-4-lerl-bLaoxycarhonyl-2-[(6 1,13 min; [M+H]': 588.49.
29.6. 4-[(S)-4-cayboxy-2-({2-phenyl-6-[lelrahydyo-furan-i-yloxy]-pyi-imidine'4'Carbony}}-
amuio)-buiyiy}]-pipei-azme-l-carhoxylic acid butyl esler:
This compound was prepared using a method analogous to that of Example I, step 1.8, intermediate 29.5 replacing intermediate ],7 and 3-hydroxytctrahydrofuranc replacing 2-(2-mcthoxycthoxy)cthanol. The compound was however fiinhcr processed as follows: water and DCM were added to the reaction mixture, TFA was added to the org. phase and after I h stirring, the solvents were removed. The residue was purified by preparative LC-MS (IV) to afford the desired compound. LC-MS: tR = 0,97 min; {M+H]': 584.54.
Example 30; 4-|(5)^-carboxy-2-(j2-phenyl-6-[(5)-(te(rahydro-furan-3-yl)ox>]-pyriniidinc-4-carbon.vl}-amino)-bulyrj'l)-piperazine-l-carboxylic acid butyl ester:
?0.!. 4-f(S)'4-lerf-h^JU?y^>corhnrJyl-2-({2-ph('nyl-f^-[fS)-(l(■h7lhydrl>-flll•an-!i-yl)nyy]-pynmidine'4'Cai-bonyl}-amino)-bu!yiyl]-piperazine-I-carboxyUc acid butyl ester:
This compound was prepared using a method analogous to that ofrExample 5, step 5.1, intermediate 29.5 replacing intennediate 1.7, (5)-(-f-)-3-hydroxytetrahydrof\!ranc replacing teIraiiydro-2W-pyran-4-ol and using DMF instead of THF. The compound was however purified by CC {EA/Hept 2/i? to EA). LC-MS: tK ^ 1.16 min; [M-HH]*: 639.50.

-53-
S0.2. 4'[(S)'4-carboxy-2-({2-pheuyl-6-[(S)-(!e!rahydyo-furan-i-yl)oxy]-pynmidine-4-carbonyl}-amino}-butyryl]-piperazine-l-carboxylic acid bu/yl ester:
This compound was prepared using a method analogous to that of Example 5, step 5.2, intermediate 30.1 replacing intermediate 5.1. The compound was however purified by CC (EA toEA/MeOH 10/1). LC-MS: IR-1.03 mill, [M+H]': 584.13.
Example 31: 4-|(5^-4-carboxy-2-(|2-pheiiyl-6-[(«)-((etrahydro-fiiran-3-yl)oxy|-pyrimidine-4-carbonylS-amino)-bulyry)]-piperazine-1-carboxylic acid but>l ester:
This compound was prepared using a method analogous to thai of; Example 1, step 1.8. inlermediatc 29.5 repiacing intermediate !.7 and (/?)-(-)-3-hydroxytetrahydrofurane replacing 2-{2-methoxyethoxy)ethanol. The compound was however purified by CC (EA/Hept 3/t, EA, EA/MeOH 9/1 then 7/3). LC-MS: tR = 0.99 min; [M+H]': 584,29,
The compounds of Examples 32 to 35 were prepared using a method analogous to that of the Example indicated between brackets, except that she last step of the corresponding Example was not carried out.
Example 32: 4-((5^-4-/carbonyl-2-i[6-(2,2-dimelhyl-|I31dioxan-5-yImethoxy)-2-phenyl-pyrimidine-4-carbonyl|-amino}-bulyryI)-piperazine-I-carboxyIic acid ethyl ester:
(Example 24). LC-MS: tR = 1.09; [M+H]^ 670.51.
Example 33; 4-((5)-4-ter/-butoxycarbonyl-2-{[2-phenyl-6-(tetrahydro-thiopyran-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-I-carboxylic acid ethyl ester:
(Example25). LC-MS: tR= 1.13 min; [M+H]^: 642-41.

-54-
Exaniple34: 4-|(5)-4-/(7cf-butoxycai-boiiyl-2-({2-pheiiyl-6-l(5')-(tctrahycIro-fiiran-3-yl)o\yj-pyrinii(line-4-carbonyl}-amino)-but\'n,l]-piperazine-l-carboxylicacid ethyl esler:
(Example 27). LC-MS: IR= 1.06min: [M+H]': 612.39,
Example 35: 4-|(5)-4-/^r/-butoxycarbonyl-2-({2-pheny[-6-|(Sl-(te(rahydro-furan-3-yl)oxy)-pyrimidiiie-4-carbonyl!-amino)-but>Tyl]-piperazine-l-carboxylic acid butyl ester:
(Example 30). LC-MS; tR= 1.16 min; [M+H]^: 639.50.
Example 36: 4-|(5)-4-j'^/'Nbutoxycarbonyl-2-({2-phenyl-6-[(ff)-(tetrahydro-fiii-a)i-3-yl)oxyl-pyrimidine-4-carbonyl}-amino)-butyryll-piperazine-l-carboxylic acid bi'tyl ester:
This compound was obtained as secondary product during the reaction performed for the
synthesis of Example 31.
LC-MS (A); IR = 1.12 min; [M+H]': 640.37.
Example 37: 4-((5)-4-carboxy-2-{|2-phenyl-6-(piperidin-4-yIox'}')-pyrimidine-4-carbonyl]-amino}-butj'ryl)-piperazine-l-carboxyIic acid butyl ester:
37.J. 4~(2-{[6-{}-benzyl-piperidin-4-yloxy)-2-phenyl'pynniHline-4-carbonyl]-amino}' (S)-'}-len-buJoxycarbonyl-bulyryI)-piperazine-1 -carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 5, step 5.1, Mbenzy 1-4-hydroxy pi peridine replacing tetrahydro-2//-pyran-4-ol and intermediate 29.5 replacing intermediate 1,7. LC-MS (A): tR= 1.00 min; [M+H]': 743.09.

-3J -
J7.2. 4-((S)-4-lert-bi(ioxycarbouyl-2-{[2-pheny!-6-(piperidin-4-y!oxy)-pynmidine-4-carbonylJ-aininoj-bulyry/)-pipero2ine-l-carboxy!ic acid bulyl ester:
This compound was prepared using a method analogous to ihal of Example 1, step 1.2, intermediate 37.1 replacing intermediate 1.1 and using McOH instead of EtOH, LC-MS (A): tR - 0,94 min; [M+Hf: 653.14.
57.5. 4-((S)-4-caiboxy-2-{[2-pheny}-6-(piperidin-4-yioxy)-pyrimidi>ie-4 carbonyl]-amino}-buty>yl)-piperazine-l-caiboxylic acid buly! esler:
This compound was prepared using a method analogous to that of Example 5, step 5.2, intermediate 37.2 replacing intermediate 5.1. The compound was however worked up as follows: the reaction mixture was evaporated off, the residue was taken up in EA and a Na^CO? solution was added until pH 8; the phases were separated and the aq. phase was brought to pH 7 by adding a iM HCI solution; upon addition of EA, the compound precipitated out and was filtered off and dried under HV. LC-MS (A): IR = 0.84 min; [M+H]*: 597.18.
Example 38: 4-({5)-4-j'err-butOJ.7Carbonyl-2-{|2-plicnyl-6-(piperidin-4-yloxy)-pyriniidine-4-carbonyl|-amino}-bulyryI)-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 37, except that the
last 'Jten was not carried onl,
LC-MS (A): tR = 0.94 min; [M+H]*; 653.14,

-56-Biolotiical tests
P2Yi2 receptor binding assay
Pj.'ocedyi-e
Chinese Hamster Ovary (CHO) cells with recombinant expression of the human P2Yi2 receptor were cultured in 24 well ccU-cultairc plafcs. Cells were washed three times with binding buffer (50 mM Tris pH 7.4, 100 mM NaCl. l.mM EDTA, 0.5 % BSA). The cells were then incubated with 0,5 ml per well binding buffer containing tritiuni-labcted 2-methyl-thio-adenosinc 5'-diphosphate {2-methyl-S-ADP) (between lOO'OOO and 300'000 dpm per well) and various concentrations of test compounds. After incubation at room temperature for 2 hours, cells were washed three times with binding buffer. Then, cells were sohibilized by addition of 0.5 ml solubilization buffer (SDS, NaOH, EDTA). The content of each well was then transfcn-ed into beta-counter vials and 2,0 ml of Uhima Gold Scintillation liquid was added. After quantification of the cell-associated signal, extent, of inhibition was calculated relative to maximal possible inhibition demonstrated by addition of excess of cold 2-methyl-S-ADP.
Using the procedure described above for the P2yi3 receptor binding assay. ICsnS ranging from 12 nM to 1045 nM, with a mean value of about 190 nM, were measured for the compounds of the Examples I to 17. 24(o3l and 37.

-57-
For example, llie following results could be obtained for the Example compounds using the procedure described above for the P2Yi; receptor binding assay:

oS-Claims:
1. A compound of formula 1

I
wherein
R represents phenyl optionally substituted 1 to 3 times by subslilucnts each independently
'=:elccted from the. group consisting of halogen, methyl, methoxy, trifl'.inrome'hyl and
trifluoromethoxy;
R represents an alkoxyalkoxyalkyl group, a dihydroxyalkyl group, a dimethoxyalkyl group or
a (2,2"dimcthyi-[l,3]dioxolan-4-yl)-alkyl group;
or R^ represents a group of the formula
(Ete X
J ^)-

-59-
wherein
either m is I and n is 2 or 3, or m is 2 and n is 2; and
X represents 0, S, NH, NR-\ SO or SO;; .
R represents alkyl or arylalkyi;
or also R^ represents 2,2,6,f>-tctramelhyl-piperidin-4-yi;
each of R'' and R^ represents independently hydrogen or methyl;
R^ represents aikoxy; and
Y represents atkylene or phenylalkvlene, and Z represents -OH, -COOH, cyano, tetr^zolyl or
-COOR', R' representing alkyl;
or a salt of such a compound.
2. A compound according to claim 1, wherein R' represents phenyl optionally substituted once by halogen, methyl, methoxy, trifluoromethyl and trifluoromelhoxy.
3. A compound according to claim L wherein R^ represents an alkoxyalkoxyalkyl group, a dihydroxyalkyl group, a dimethoxyalkyl group or a (2,2-dimethyl-[l,3]dioxolan-4-yl)-alkyl group.
4. A compound according to claim I, wherein R" represents group of the formula

or R represents 2.2,6,6-tetramethyl-piperidin-4-yl.
5. A compound according to claim 1, wherein one of R* and R* represents hydrogen and the other represents hydrogen or methyl.
6. A compound according to claim 1, wherein Y represents alkylcnc or phcnylalkylcnc, and Z represents -OH or -COOH or tctrazolyi.
7. A compound according to claim 6, wherein Y represents -CH2-, -CH2-CH2- or -CH?-CH2-CH3-, and Z represents -COOH.

-60-
8. A compound according to claim 1. which is selected from the group consisting of: -4-[(5)-4-carboxy-2-((6-[2-(2-mfMhoxy-ethoxy)-ethoxy]-2-phcnyl-pyrimidine-4-carbony!!-amino)-butyi7l]-pipcrazLnc-] -carboxylic acid clhyl cslcr;
-4-((5)-4-carboxy-2-{[6-({/t)-2,2-dimethyl-[l,3]dioxolaii-4-ylniethoxy)-2-pheiiyI-pyrimidine-4-carbonyI]-amino}-butyryl)-pipcraziiie-l-carboxylic acid ethyl ester;
- 4-((5)-4-carboxy-2-{[6-{CiS)-2,3-dihydroxy-propoxy)-2-pheiiy!-pyrimidine-4-carbonyl]-ainif]o}-butyryl)-pipcrazi!ic-!-carboxylLc acid ethyl cslcr;
- 4-((5)-4-carboxy-2-{[6-((/?)-2,3-dimethoxy-propoxy)-2-phenyl-pyrimLdine-4-carbonyI]-amino}-but}'ryl)-piperazine-l-carboxylic acid ethyl ester;
- 4-((5')-4-carboxy-2-![2-phenyl-6-(letrahydro-pyran-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazirie-l-carboxylic acid ethyl ester;
- 4-((iS')-4-carboxy-2- i [6-(l -mclhyl-pipcridin-3-yloxy)-2-phcnyl-pyrimidinc-4-carbonyl]-amino}-butyryl)-piperazinc-l-carboxylic acid ethyl ester;
■ 4-((5')-2-[[6-(l-bcn2yl-p!pcridin-4-yloxy)-2-phenyl-pyn!Tiidine-4-carbonyl]-amino}-4-carboxy-butyryl)-p!perazine-l-carboxylicacid ethyl ester;
- 4-((5)-4-carboxy-2- {[2-(4-{luoro-phenyl)-6-{tetrahydro-furan-3-yioxy)-pyrimidine-
4-carbonyl]-amino}-butyryl)-pipcra2inc-l-carboxylic acid clhyl ester;
-((5)-4-carboxy-2-{[6-(tetrahydro-furan"3-yloxy)-2-p-tolyl-pyrimidine-4-carbonyl]-amino}-butyryl}-piperazine-l-carboxylic acid ethyl ester;
-((5)-4-carboxy-2-{[2-phcnyl-6-(tctrahydro-furan-3-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-3-methyl-pipera2ine-l-carboxylie acid ethyl ester;
-4-[(5)-3-(4-carboxy-phenyl)-2-{{2-phenyl-6-[(tetrahydro-fiiran-3-yl)oxy]-pyrimidine-4-carbonyl(-amino)-propionyl]-pipcrazine-l-carboxylic acid ethyl ester;
- 4-((S)-4-carboxy-2- {[2-phenyl-6-(piperidin-4-y]oxy)-pyrimidinc-4-carbonyl]-am!no} -
butyryi)-piperazine-l-carboxyIic acidethyi ester; -4-((5)-4-carboxy-2-{[2-phcnyl-6-(2,2,6,6-tetramethyl-pipcridin-4-yloxy)-pyrimidine-
4-carbonyl]-ainino}-butyryI)-pipcrazinc-l-carboxylic acid ethyl ester;
-4-[(5)-4-cyano-2-({2-phcnyl-6-[(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazire-] -carboxylic acid ethyl ester;
- 4-((5')-4-carboxy-2- j [2-phenyl-6-(tetrahydTO-furan-3-y!oxy)-pyrimidinc-4-carboiiyl]-
amino}-butyryl)-pipcrazinc-I-carboxylic acid ethyl ester;

- 61 -
-4-[(5)-3-hydroxy-2-(i2-phenyl-6-[(telrabydro-furan-3-yl)oxy]-pyrimidine-4-c2rbonyl}-
aTnino)-propionyl]-piperazine-l-carboxylic acid ethyl ester;
-4-[(5)-2-{[2-phcnyl-6-(lctrahydro-ruran-3-yloxy)-p>'rimidmc-4-carbonyl]-amino}-
4-(l//-tetrazol-5-yn-butyryl]-piperazine-1-carboxylic acid ethyl ester;
-4-((5)-4-/e/-/-butoxycarbonyl-2-{[2-phenyl-6-(tetrahydro-pyran-4-yloxy)-pyrimidine-
4-carbonyi]-amino}-bulyry])-pipera2ine-l-carboxylic acid ethyl eater;
- 4-((5)-4-te7-buloxycarbonyi-2-{[6-(l-mcthyl-pipcridin-3-yloxy)-2-phcnyl-pyrimidinc-
4-carbonyll.amino}-butyryl)-pipcrazine-l-carboxylic acid ethyl ester;
-4-((5)-2-{[6-{ I-benzyl-piperidin-4-yloxy)-2-phenyl-pyrimidine-4-carbonyl]-aniino}-
4-?ert-butoxycarbonyl-butyryl)-piperazine-1 -carboxylic acid ethyl ester;
-4-[(5)-3-(4-fe;7-butoxycarbonyl-phenyl)-2-C!2-phenyl-6-[('eirahydro-ftiraii-3-y))oxy]-
pyriinidinc-4-carbonyl}-amino)-propionyl]-p!pcrazinc-1-carboxylic acid ethyl csier;
-((5)-4-fe/7-butoxycarbonyl-2-{[2-phenyl-6-{pipEridin-4-yloxy)-pyrimidine-4-carbonyl]-
aminoj-butyryl)-piperazine-l-carboxylic acid ethyl ester;
-4-((5)-4-fe/7-butoxycarbonyl-2-{[2-phenyl-6-(2.2,6,6-tetramethyl-piperidin-4-yloxy)-
pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-l-carboxylic acid ethyl ester;
-4-((5}-4-carboxy-2-{[6-(3-hydroxy-2-hydroxymcthyl-propoxy)-2-phcnyl-pyrimid!nc-
4-carbonyI].aniino}-butyryI)-piperazine-1-carboxylic acid ethyl ester;
-4-((5^-4-carboxy-2-{[2-phenyI-6-(tetrahydro-thiopyran-4-yloxy)-pyrimiditie-4-carbonyl]-
aminoj-butyryl)-piperazinc-)-carboxylic acid ethyl ester;
-4-[(5)-4-carboxy-2-({2-phcnyl-6-[{^)-(lctrahydro-rTjran-3-yl)oxy]-pyrimidinc-4-carbonyl}-
amino)-butyryl]-piperazine-i-carboxylic acid ethyl ester;
-4-[(y)-4-carboxy-2-({2-phcny!-6-[(^-(te!rahydro-ft)ran-3-y))o.i(y]-pyrimidjne-4-carbonyl}-amino)-butyryl]-piperazine-!-carboxylic acid ethyl ester; -4-[{5)-4-carboxy-2-{i2-phenyl-6-[tetrahydro-furan-3-y!oxy]-pyrimidine-4-carbonyl}-
amino)-butyryl]-piperazine-l-carboxylic acid ethyl ester; -4-[(,5)-4-carboxy"2-({2-phcnyl-6-[tclrahydro-foran-3-yloxy]-pyrimidinc-4-carbonyl}-
amino)-butyryl]-piperazinc-l -carboxylic acid butyl ester; -4-[{5)-4-carboxy-2-{{2-pheny]-6-[(S)-{tetrahydro-furan-3-yl)oxy]-pyrimidiiie-4-carbonyl}-
amino)-butyryl]-piperazine-l-carboxylic acid butyl ester;

- (■:2 -
-4-[(5)-4-carboxy-2-({2-pheiiyi-6-[(fl)-(tetrahydro-faran-3-yl)oxy]-pyni-nidine-4-carbony])-amino)-butyrylj-piperaziiie-l -carboxylic acid butyl ester;
-4-((S)-4-(w(-bmoxycai-bonyl-2-{[6-t2,2-dime1hyl-[l,3]dioxan-5-ylmclhoxy)-2-phcnyl-pyrimidine-4-carboTiyl]-amino)-biityryl)-piperazine-l-carboxylicacidediyl ester; -4-((S;)-4-;er/-butoxycarbonyl-2-i[2-phenyl-6-(tetrahydro-thiopyran-4-yloxy)-pyriinidjne-4-carbonyl]-ammo}-butyryl)-pipera2ine-l-carboxy!ic acid ethyl ester; -4-[(LS')-4-/f;'/-butoxycarbonyl-2-({2-phcnyI-6-[(5)-{tctrahydro-furan-3-yl)oxy]-pyrimidinc-4-carbonyl|-amino)-butyryl]-piperazine-l-carboxylic acid ethyl ester; -4-[(5)-4-/ei7-butoxycarbonyl-2-((2-phenyl-6-[(5)-(teti-ahydro-furan-3'yI)oxy]-pyniTiidine-4-carbonyl|-amino)-butyiyl]-piperazine-l-carboxylic acid butyl ester; -4-[(6^-4-to'/-butoxycarbonyl-2-({2-phenyl-6-[{y?)-(telrahydro-furan-3 yljoxyj-pyrimidine-4-carbonyl}-amino)-butyryl]-pipcrazinc-l-carboxyhc acid butyl ester;
- 4-((i')-4-carboxy-2- {[2-phenyl-6-(piperidin-4-y!oxy)-pyriniidiiie-4-carboiiyl]-amino5 -butyryl)-piperazine-l-carboxylic acid butyl ester; and
- 4-((lS^-4-fe^^butoxycarbony!-2-i[2-phenyl-6-(piperidin-4-yloxy)-pyrimidme-4-ca^boIlyl]-amino}-biityryl)-piperazine-I-carboxylic acid butyl ester;
or a phamiaccutically acceptable salt of such a compound.
9, A compound according to claim I, which is selected from the group consisting of:
- 4-[(y)-4-carboxy-2-({6-[2-(2-methoxy-ethoxy)-cthoxy]-2-phenyl-pyrimidine-4-carbo)iyl}-
aniino)-butyryl]-piperazine-l-carboxylic acid ethyl ester;
-4-((^)-4-caiboxy-2-i[6-(i^if)-2,2-dimethyl-[i,3]dioxoian-4-ylmethoxyj-2-phenyi-]>yriiuidine-
4-carbony]]-amino}-butyry])-piperazine-l-carboxylic acid ethyl ester;
- 4-((5')-4-carboxy-2-{[6-({5)-2,3-dihydroxy-propoxy)-2-phenyl-pyrimidine-4-carbonyl]-
amino}-butyryl)-piperazine-i-carboxyIic acid ethyl ester;
.4.((5).4.carboxy-2-i[6-f(/?>2,3-dimcthoxy-propoxy)-2-phcnyl'pyrimid!nc-4-carbonyl]-ainino}-butyryl)-piperazine-I-carboxylic acid ethyl ester; -4.((5)-4.carboxy-2-{[2-pheiiyl-6-(tetrahydro-pyran-4-y]oxy)-pyrimidine-4-carbonyl]-
amiiioj-butyryl)-piperazine-l-carboxylic acid ethyl ester; -4-((5)-4-carboxy-2-{[6-(l-methyl-piperidin-3-yloxy)-2-phenyl-pyrimidine-4-carbonyl]-
aminO|-butyryl)-piperazine-l-earboxylic acid ethyl ester;

-63-
-4-((^-2-([6-(l-berizy|.pfperfdTn-4-yloxy)-2-pheny(-pyrimidinc-4-carbonyiJ-amino[-4-Garboxy-bulyryl)-])iperazine-1 -carboxylic acid ethy! cslcr;
-4-{(5)-4-carboxy-2-([2-(4-fluoro-phcnyl)-6-(tclrahydro-f\lran-3-yloxy)-pyrimidinc-4-carbonyl]-aminoj-butyryl)-piperaziiie-)-carboxylic acid ethyl ester; -{(5)-4-carboxy-2-{[6-(teIrahydro-furan-3-yloxy)-2-/?-tolyl-pyrimidine-4-carbonyi]-amino)-bufyryl)-piperazine-! -carboxylic acid eihyl ester;
-((6^-4-carboxy-2-{[2-phcnyi-6-{lclrahydro-fiiran-3-yloxy)-pyrimidinc-4-carbonyl]-aminoj-butyryl)-3-methyl-piperazine-l-carboxylic acid ethyl ester;
-4-[(5)-3-{4-carboxy-phcnyl)-2-({2-phenyl-6-[(tetrahydro-fiiran-3-yl)oxy]-pyrimidine-4-carbony]j-amino)-propionyil-piperazine-l-carboxylic acid ethyl ester; -4-((5)-4-carboxy-2-|[2-phenyl-6-(piperidin-4-yloxy)-pyrimidine-4-carbonyl]-aminoJ-bufyryl)-pipcrazine-l -carboxylic acid cihyl cslcr;
-4-((5}-4-carboxy-2-{[2-phcnyl-6-(2,2,6,6-tclraniethyl-piperidin-4-yloxy)-pyrimidine-4-carbonylJ-am(rTo)-butyryO-prperazine-1-carboxylic acid ethyl esler;
- 4-[(5)-4-cyano-2-{{2-phenyl-6-[(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-
butyryl]-piperazine-l -carboxylic acid elhyl esler;
-4-((5)-4-carboxy-2-{[2-phenyl-6-(tclrahydro-furan-3-y]oxy)-pyrimidinc-4-carbonyl]-amino}-butyryl)-piperazir)c-l-carboxy!ic acid elhyl ester;
-4-[(S)-3-hydroxy-2-({2-phenyl-6-[(telrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-propionyl]-piperazine-l-carboxy]ic acid elhyl ester;
- 4-[(5)-2- j [2-pbcnyl-6-(tctrahydro-ruran-3-yloxy)-pyrimidinc-4-carbony]]-aminol -
4-(l//-tetrazol-5-y])-butyryl]-piperazine-1-carboxylic acid ethyl ester;
-4-((5)-4-/e/7-biJtoxycarbonyl-2-{[2-phenyl-6-(tctrahydro-pyran-4-yloxy)-pyrimidinc-
4-carbonyl]-amino}-butyryl)-piperazine-!-carboxylic acid ethyl ester;
-4-((S')-4-/erf-buloxycarbonyl-2-{[6-(l-methy!-piperidin-3-yloxy)-2-phcnyl-pyrimidine-
4-carbonyl]-amino} -butyryl)-pipcrazine-1 -carboxylic acid ethyl ester; -4-((i')-2-|[6-(I-bcnzyl-p(pcridin-4-y]oxy)-2-phcjjyI-pynmidJnc-4-carbony)]-am)no)-4-;e/Y-butoxycarbonyl-bijtyryl)-pipcrazine-l -carboxylic acid ethyl ester; -4-[(5)-3-(4-/err-butoxycarbonyl-phenyl)-2-((2-phenyl-6-[(letrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-propionyl]-p!pcra2inc-l -carboxylic acid ethyl ester;

■ - 64 -
- ({5)-4-/e/'f-butoxycarbonyl-2-![2-phenyl-6-(piperidin-4-yloxy)-pyrimidine-4-carbonyl]-aminoi-butyry!)-piperazine-]-carboxylic acid ethyl ester; and
- 4-({5')-4-/CTV-butoxyc3rbonyl-2-([2-phcnyl-6-(2,2,6,6-lctramethyUpiperidin-4-y]oxy)-pyrimidine-4-carbonyl]-amino}-butyryi)-piperazine-l-carboxylic acid ethyl ester;
or a pharmaceuticaily acceptable salt of such a compound.
10. As a medicament, a compound of formula I as defined in claim 1, or a pharmaceuticaily acceptable salt thereof
11. A pharmaceutical composition conlaining at least one compound of formula I as defined in claim 1, or a pharmaceutieally acceptable salt thereof, and a phannaceuticaily acceptable carrier, diluent or excipienl.
12. Use of a compound of formula I as defined in claim 1, or of a pliarmaccutically acceptable salt thereof for the manufacture of a medicament for Ihc treatment of occlusive vascular disorders.

(ARINDAM PAUL)
Of De Penning & De Pemiing
Agent for the Applicants
Dated this 18 day of May 2009