PHOSPHONIC ACID DERIVATES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
Field of the invention:
The present invention relates to certain phosphonic acid derivatives and their 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 other mammals.
Background of the invention:
Haemostasis 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 fibrinolytic 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.
Other drugs like the phosphodiesterase inhibitors dipyridamole and cilostazol, as well as the vitamin K antagonists (warfarin), are marketed but do not show all desirable features for such drugs. Three intravenously applicable, potent GPIIb/llla receptor antagonists (abciximab, eptifibatide, and tirofiban) blocking platelet aggregation are available on the market. Besides, some orally active GPIIb/llla antagonists (e.g. sibrafiban, xemilofiban or orbofiban) 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 thienopyridines ticlopidine, clopidogrel 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-C69931MX(Cangrelor) orAZD6140 have reached phase II clinical studies. These 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.
WO 2006/114774 describes 2-phenyl-4-(carbonylmethylaminocarbonyl)-pyrimidine derivatives as P2YJ2 receptor antagonists. However these compounds do not contain any phosphonic acid or phosphonate motif.
Description of the invention:
The inventors have now found that the phosphonic acid derivatives according to the present invention surprisingly show significantly improved biological properties compared to the corresponding carboxylic acid derivatives previously known to one skilled in the art.
Various embodiments of the invention are presented hereafter:
1) The present invention firstly relates to the compounds of formula I

formula I
wherein
R represents phenyl, wherein the phenyl is unsubstituted or substituted 1 to 3 times (preferably unsubstituted or
substituted once or twice, more preferably unsubstituted or substituted once and most preferably unsubstituted)
by substituents each independently selected from the group consisting of halogen, methyl, methoxy,
trifiuoromethyl and trifluoromethoxy;
W represents a bond, and R2 represents alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl or heteroaryl; or
W represents -O- and R2 represents alkyl, cycloalkyl, hydroxyalkyl or heterocyclyl; or
W represents -NR3-, R2 represents alkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl,
heterocyclyl, cycloalkyl, aryl or aralkyl and R represents hydrogen or alkyl; or W represents -NR - and R and R
form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7 members wherein the members
needed to complete said - A - heterocyclic ring are each independently selected from -CH2-, -CHRX-, -O-, -S-, -
CO- and -NRy-, it being understood however that said heterocyclic ring does not contain more than one member
selected from the group consisting of-CHRX-, -O-, -S-, -CO- and -NRy-, Representing hydroxy, hydroxymethyl,
alkoxymethyl or alkoxy and Ry representing hydrogen or alkyl;
or W represents -NR3- and R2 and R3 form, together with the nitrogen that carries them, an imidazolyl, pyrazolyl,
1,2,3-triazolyl or 1,2,4-triazolyl ring, which ring may be substituted by an alkyl group (especially by a methyl
group);
Ra represents hydrogen or methyl;
Rb represents hydrogen or methyl;
R4 represents alkoxy;
n represents 0, 1, 2 or 3, V represents a bond, and m represents 0; or
n represents 0 or 1, V represents phenyl, and m represents 0; or
n represents 1 , V represents phenyl, and m represents 1 ;
R5 and R8 are identical and represent each hydroxy, unsubstituted phenyloxy, unsubstituted benzyloxy, a group -
0-(CHR6)-0-C(=0)-R7, a group -0-(CHR6)-0-C(=0)-0-R7 a group -0-(CHR6)-C(=0)-0-R9, a group -NH-
(CHR10)-C(=O)-O-R9 or a group -NH-C(CH3)2- C(=0)-0-R9; or
R5 represents hydroxy or unsubstituted phenyloxy, and R8 represents a group -0-(CH2)-0-C(=0)-R9 or a group -
NH-CH(CH3)-C(=0)-0-R9; or
P(0)R R represents a group selected from the following structures

wherein the arrow marks the point of attachment to the remaining part of compounds of formula I;
q represents 1 or 2;
R6 represents hydrogen or (Ci-C3)alkyl;
R7 represents (Ci-C4)alkyl or unsubstituted (C3-Ce)cycloalkyl;
R9 represents (Ci-C4)alkyl;
R10 represents hydrogen, (Ci-C4)alkyl, unsubstituted phenyl or unsubstituted benzyl;
R11 represents hydrogen, (Ci-C4)alkyl or (Ci-C4)alkoxy;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
The compounds of formula I may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of formula I 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 compounds of formula I are P2Yi2 receptor antagonists. Accordingly, they are useful 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 are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader or narrower definition.
V The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably to fluorine, chlorine or bromine and more preferably to fluorine.
V The term "alkyl", used alone or in combination, refers to a saturated straight or branched chain alkyl group containing 1 to 7 carbon atoms (e.g. methyl, ethyl, A-propyl, cb0-propyl,
«-butyl, cbo-butyl, sec-butyl, tert-butyl, «-pentyl, neopentyl, /so-pentyl, «-hexyl, cbo-hexyl,
«-heptyl or cb0-heptyl), and preferably 1 to 4 carbon atoms. Representative examples of preferred alkyl groups include methyl, ethyl, A-propyl, cbo-propyl, «-butyl, cbo-butyl, sec-butyl and tert-butyl. The term "(Cx-Cy)alkyl" (x and y being integers) refers to a straight or branched chain alkyl group containing xto y carbon atoms.
V The term "alkoxy", 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, cbo-propoxy, «-butoxy, cbo-butoxy, sec-butoxy, tert-butoxy, «-pentoxy, neopentyloxy, cbo-pentyloxy, «-hexyloxy or cbo-hexyloxy), and preferably 1 to 4 carbon atoms. Representative examples of preferred alkoxy groups include methoxy, ethoxy, «-propoxy, cbo-propoxy, «-butoxy, cbo-butoxy, sec-butoxy and tert-butoxy. The term "(Cx-Cy)alkoxy" (x and y being integers) refers to a straight or branched chain alkoxy group containing x to y carbon atoms.
V The term "hydroxy alkyl", as used herein, refers to an alkyl group as previously defined wherein one hydrogen atom has been replaced by a hydroxy (i.e. -OH) group. Examples of hydroxy alkyl groups include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 2-hydroxy-l -methyl-ethyl, 2-hydroxy-1 , 1 -dimethyl-ethyl, 1 -hydroxy- propyl, 3-hydroxy -propyl, 1 -hydroxy -butyl, 3-hydroxy-butyl, 4-hydroxy -butyl, 3-hydroxy-pentyl and 3-hydroxy-3-methyl-butyl (and preferably hydroxymethyl, 2-hydroxy-ethyl and 3 -hy droxy-butyl).
V The term "alkoxyalkyl", as used herein, refers to an alkyl group as previously defined wherein one hydrogen

atom has been replaced by an alkoxy group as previously defined. Examples of alkoxyalkyl groups include, but are not limited to, 3-methoxy-propyl, methoxymethyl and 2-methoxy-ethyl (and notably methoxymethyl and 2-methoxy-ethyl). In analogy, the term "alkoxymethyl" means for example methoxymethyl or 2-methoxy- ethyl.
V The term "cycloalkyl", as used herein, alone or in any combination, refers to a saturated cyclic hydrocarbon
moiety containing 3 to 7 carbon atoms which may be unsubstituted or substituted once by hydroxy,
hydroxymethyl, alkoxymethyl (preferably methoxymethyl or ethoxymethyl and more preferably methoxymethyl) or
alkoxy (preferably methoxy or ethoxy and more preferably methoxy). Representative examples of cycloalkyl
groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-hydroxy-cyclohexyl, 2-
hydroxy-cyclohexyl, 2-hydroxymethyl-cyclopropyl and 2- methoxymethyl-cyclopropyl (in particular cyclopropyl, 2-
hydroxymethyl-cyclopropyl and
2-methoxymethyl-cyclopropyl).
V The term "alkoxycarbonylalkyl" refers to an alkyl group as previously defined wherein one hydrogen atom has
been replaced by an alkoxycarbonyl group, that is, a -C(=0)- group itself substituted by an alkoxy group as
previously defined. Representative examples of alkoxycarbonylalkyl groups include, but are not limited to, 2-
ethoxycarbonyl-ethyl and
2-methoxycarbonyl-ethyl.
V The term "carboxyalkyl" refers to an alkyl group as previously defined wherein one hydrogen atom has been
replaced by a carboxy group (that is, by a -COOH group). Representative examples of carboxylalkyl groups
include, but are not limited to,
2-carboxy-ethyl and 3-carboxy-propyl.
V The term "aryl" refers to an aromatic cyclic group with one, two or three rings, having from 6 to 14 carbon ring-
atoms and preferably from 6 to 10 carbon ring-atoms, for example to phenyl or naphthyl groups (and notably to
phenyl groups). Any aryl group (and in particular any phenyl group) as defined herein may be unsubstituted or
substituted with one, two or more substituents (preferably with one to three substituents, more preferably with
one or two substituents and notably with one substituent), each independently selected from the group consisting
of halogen, alkyl and alkoxy. Specific examples of aryl groups are phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-
fluorophenyl, 2-chlorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,4-dimethoxyphenyl and 2,4-dimethylphenyl (preferably phenyl and 4-methoxyphenyl).
V The term "aralkyl", as used herein, alone or in any combination, refers to an aryl group appended to the parent molecular moiety through an alkyl group wherein however the aryl group may be unsubstituted or substituted with 1 to 3 substituents selected independently from the group consisting of halogen, alkyl and alkoxy. Representative examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl and 2-naphth-2-ylethyl. Preferred aralkyl groups are the phenylalkyl groups.
V The term "phenylalkyl", as used herein, alone or in any combination, refers to an unsubstituted phenyl group appended to the parent molecular moiety through an alkyl group. Representative examples of phenylalkyl groups include, but are not limited to, benzyl, 2-phenylethyl and 3-phenylpropyl. Preferred is benzyl.
V The term "heteroaryl", as used herein, alone or in combination, refers to a mono-, bi- or tricyclic aromatic ring system containing up to 14 ring atoms wherein at least one of the rings contains at least one heteroatom independently selected from the group consisting of nitrogen, oxygen and sulfur; in addition, the term "heteroaryl" may also refer to 1-oxy- pyridinyl groups. The heteroaryl group can be unsubstituted or substituted with 1 to 3 substituents (preferably 1 to 2 substituents and more preferably 1 substituent) selected independently from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl and trifluoromethoxy. Representative examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, pyridinyl, 1 -oxy-4-pyridinyl, l-oxy-3 -pyridinyl, 1 -oxy-2-pyridinyl, pyrimidinyl, quinolinyl, benzimidazolyl, benzo thiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, indolyl, carbazolyl, phenothiazinyl and phenoxazinyl (preferably thienyl, pyrazolyl and 4-methyl- pyrazolyl).
V The term "monocyclic heteroaryl", as used herein, refers to a monocyclic aromatic ring system containing 5 or 6 ring atoms among which 1 or 2 may be heteroatoms selected from O, N and S. The monocyclic heteroaryl group can be unsubstituted or substituted with 1 to 2 substituents (preferably 1 substituent) selected independently from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl and trifluoromethoxy. Representative examples of monocyclic heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, pyridinyl and pyrimidinyl.
V The term "heterocyclyl", as used herein, alone or in any combination, refers to an unsubstituted saturated monocyclic moiety of 3 to 7 ring members containing 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur, it being however understood that (i) a heterocyclyl group is not attached to the rest of the molecule by a nitrogen atom, (ii) a heterocyclyl group of 3 or 4 ring members contains only one heteroatom which is a nitrogen atom and (iii) a heterocyclyl group does not contain 2 sulfur atoms. The sulfur atom of a heterocyclyl group may be in an oxidised form, i.e. as a sulfoxide or sulfonyl. Representative examples of heterocyclyl groups include, but

are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl (preferably tetrahydrofuran-3-yl).
In this patent application, variably attached bonds may be used for substituents or groups. In such case it is meant that the substituent or group is attached to either atom linked by the bond into which the variably attached bond is drawn into. For example, the compound drawn below
Besides, the following paragraphs provide definitions of various other terms. Said definitions are intended to apply uniformly throughout the specification and claims unless an otherwise 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. Pharm. (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 fromX 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 10 °C, and preferably to an interval extending from Y minus 5 X to Y plus 5 X
2) In particular, the invention relates to compounds of formula I that are also compounds of formula ICE
formula ICE
wherein
R represents phenyl, wherein the phenyl is unsubstituted or monosubstituted with halogen, methyl or
trifluoromethyl;
W represents a bond, and R2 represents alkyl, hydro xyalkyl (notably 3-hydroxy-butyl), alkoxyalkyl (notably 3-
methoxy-propyl), a cycloalkyl group of 3 to 7 carbon atoms (preferably of 3 to 6, more preferably of 3 to 5 carbon
atoms and most preferably of 3 carbon atoms) which may be substituted once by hydroxymethyl or alkoxymethyl
(preferably methoxymethyl or ethoxymethyl and more preferably methoxymethyl), a phenyl group which is

unsubstituted or monosubstituted with alkoxy, or an unsubstituted monocyclic heteroaryl group; or
W represents -O- and R2 represents alkyl (notably methyl), cycloalkyl (notably cyclopentyl), hydroxyalkyl (notably
2-hydroxyethyl) or heterocyclyl (notably tetrahydrofuran-3-yl); orW represents -NR3-, R2 represents alkyl,
alkoxycarbonylalkyl [notably 2-(ethoxycarbonyl)-ethyl], carboxyalkyl (notably 2-carboxy-ethyl), hydroxyalkyl
(notably 2-hydroxy-ethyl), alkoxyalkyl, heterocyclyl (notably teterahydrofuran-3-yl), cycloalkyl (notably
cyclopropyl), phenyl or phenylalkyl (notably benzyl) and R represents hydrogen or alkyl (notably methyl); orW
represents -NR3- and R2 and R3 form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7
members (preferably 4 to 6 members) wherein the members needed to complete said heterocyclic ring are each
independently selected from -CH2-, -CHRX-, -O-and -NRy-, it being understood however that said heterocyclic
ring does not contain more than one member selected from the group consisting of-CHRX-, -O- and -NRy-,
Rx representing hydroxy, hydroxymethyl, alkoxymethyl (notably methoxymethyl) or alkoxy (notably methoxy) and
Ry representing alkyl (especially methyl);
or W represents -NR3- and R2 and R3 form, together with the nitrogen that carries them, a pyrazolyl ring which
may be unsubstituted or monosubstituted by an alkyl group (especially by a methyl group);
Ra represents hydrogen or methyl;
R4 represents alkoxy (preferably ethoxy or «-butoxy);
n represents 0, 1, 2 or 3, V represents a bond, and m represents 0; or
n represents 0 or 1, V represents phenyl, and m represents 0; or
n represents 1 , V represents phenyl, and m represents 1 ;
R and R are identical and represent each hydroxy, unsubstituted phenyloxy, unsubstituted benzyloxy, a group -
0-(CHR6)-0-C(=0)-R7, a group -0-(CHR6)-0-C(=0)-0-R7 a group -0-(CHR6)-C(=0)-0-R9, a group -NH-
(CHR10)-C(=O)-O-R9 or a group -NH-C(CH3)2- C(=0)-0-R9; or
R5 represents hydroxy and R8 represents a group -0-(CH2)-0-C(=0)-R9; or
R5 represents unsubstituted phenyloxy and R8 represents a group -NH-CH(CH3)-C(=0)-0-R9; or
P(0)R5R8 represents a group selected from the following structures
wherein the arrow marks the point of attachment to the remaining part of compounds of formula ICE;
q represents 2 ;
R6 represents hydrogen or (Ci-C3)alkyl (preferably hydrogen or methyl);
R7 represents (Ci-C4)alkyl or unsubstituted (C3-Ce)cycloalkyl;
R9 represents (Ci-C4)alkyl;
R10 represents hydrogen, (Ci-C4)alkyl, unsubstituted phenyl or unsubstituted benzyl;
R11 represents hydrogen, (Ci-C4)alkyl or (Ci-C4)alkoxy;

3) According to one preferred embodiment, the invention relates to compounds of formula I that are also
_2
formula Ip
wherein
R1 represents phenyl optionally substituted 1 to 3 times (preferably optionally substituted once or twice and moi
preferably optionally substituted once) by substituents each independently selected from the group consisting o
halogen, methyl, methoxy, trifiuoromethyl and trifluoromethoxy;
W represents a bond, and R2 represents alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl or heteroaryl; or
W represents -O- and R2 represents alkyl or heterocyclyl; or
W represents -NR3-, R2 represents alkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl,
heterocyclyl, cycloalkyl, aryl or aralkyl and R represents hydrogen or alkyl; or
W represents -NR3- and R2 and R3 form, together with the nitrogen that carries them, a heterocyclic ring of 4 to members wherein the members needed to complete said heterocyclic ring are each independently selected froi -CH2- -CHRX-, -O-, -S-, -CO- and
-NRy-, it being understood however that said heterocyclic ring does not contain more than one member selectei from the group consisting of-CHRX-, -O-, -S-, -CO- and -NRy-, Rx representing hydroxy, hydroxymethyl, alkoxymethyl or alkoxy and Ry representing hydrogen or alkyl;
or also W represents -NR - and R and R form, together with the nitrogen that carries them, an imidazolyl,
pyrazolyl, 1 ,2,3-triazolyl or 1,2,4-triazolyl ring, which ring may be substituted by an alkyl group (especially by a
methyl group);
Ra represents hydrogen or methyl;
Rb represents hydrogen or methyl;
R4 represents alkoxy;
n represents 0, 1 or 2;
R5 represents hydroxy or a group -0-(CHR6)-0-C(=0)-R7 wherein R6 represents hydrogen or
(Ci-C3)alkyl and R7 represents (Ci-C4)alkyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
4) In particular, the invention relates to compounds of formula Ip that are also compounds of formula ICEP

formula ICEP
wherein
, 1
R represents phenyl optionally substituted once or twice by substituents independently selected from the group
consisting of halogen, methyl, methoxy, trifiuoromethyl and trifluoromethoxy (and preferably optionally substituted
once or twice by substituents independently selected from the group consisting of halogen, methyl and
trifiuoromethyl, especially optionally substituted once by halogen, methyl or trifiuoromethyl);
W represents a bond, and R2 represents alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, a phenyl group optionally
substituted once by alkoxy, or also an unsubstituted monocyclic heteroaryl group; or
W represents -O- and R2 represents alkyl (notably methyl) or heterocyclyi (notably tetrahydrofuran-3-yl); or
W represents -NR3-, R2 represents alkyl, alkoxycarbonylaikyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl,
heterocyclyi, phenyl or phenylalkyl, or a cycloalkyl group of 3 to 7 carbon atoms (preferably of 3 to 6 and more
preferably of 3 to 5 carbon atoms) which may be substituted once by hydroxymethyl or alkoxymethyl (preferably
methoxymethyl or ethoxymethyl and more preferably methoxymethyl), and R represents hydrogen or alkyl (and
notably hydrogen or methyl); or
W represents -NR - and R and R form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7
members (and notably of 5 to 6 members) wherein the members needed to complete said heterocyclic ring are
each independently selected from -CH2-, -CHRX-, -O- and -NRy-, it being understood however that said
heterocyclic ring does not contain more than one member selected from the group consisting of-CHRX-, -O- and
-NRy-, Rx representing hydroxy, hydroxymethyl or alkoxy (notably methoxy) and Ry representing alkyl (especially
methyl);
or also W represents -NR3- and R2 and R3 form, together with the nitrogen that carries them, a pyrazolyl ring
which may be substituted by an alkyl group (especially by a methyl group); Ra represents hydrogen or methyl;
Rb represents hydrogen;
R4 represents alkoxy;
n represents 0, 1 or 2;
R5 represents hydroxy or a group -0-(CHR6)-0-C(=0)-R7 wherein R6 represents hydrogen or (Ci-C3)alkyl and
R7 represents (Ci-C4)alkyl;
and to salts (in particular pharmaceutically acceptable salts) of compounds of formula ICE- 5) Preferably, the
compounds of formula I as defined in embodiment 1) or 2) above or their salts (among which the
pharmaceutically acceptable salts will be preferred) will be such that they are also compounds of formula ISTI and
have the stereochemistry drawn below

formula ISTI
6) According to another preferred embodiment of this invention, the compounds of formula I as defined in embodiment 1) or 2) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that they are also compounds of formula IST2, wherein n represents 1 or 3, and have the stereochemistry drawn below
formula IST2
7) According to one preferred embodiment of this invention, the compounds of formula I as defined in embodiment 1), 2) or 5) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that V represents a bond.
8) According to another preferred embodiment of this invention, the compounds of formula I as defined in embodiment 1), 2) or 5) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that V represents phenyl.
9) According to a preferred embodiment of this invention, the compounds of formula I as defined in embodiment 1), 2), 5) or 7) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that when V represents a bond, then m represents 0 and n represents 1, 2 or 3.

10) According to a preferred embodiment of this invention, the compounds of formula I as defined in embodiment 1), 2), 5) or 8) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that when V represents phenyl, then m represents 0 and n represents 0 or 1.
11) According to a preferred embodiment of this invention, the compounds of formula I as defined in embodiment 1), 2), 5) or 8) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such

that when V represents phenyl, then m represents 1 and n represents 1.
12) According to a preferred embodiment of this invention, the compounds of formula I as defined in any one of embodiments 1), 2), 5), 7) or 9) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that when n represents 2, V represents a bond and m represents 0, then R represents (C4-Ce)alkoxy, especially linear (C4-Ce)alkoxy and in particular «-butoxy.
13) According to one preferred embodiment of this invention, the compounds of formula Ip as defined in embodiment 3) or 4) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that when n represents 2, then R represents (C4-Ce)alkoxy, especially linear (C4-C(3)alkoxy and in particular «-butoxy.
14) According to one particular embodiment of this invention, the compounds of formula I as defined in any one of embodiments 1) to 5), 7), 8) or 10) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that n represents 0.
15) According to another particular embodiment of this invention, the compounds of formula I as defined in any one of embodiments 1 ) to 11) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that n represents 1.
16) According to yet another particular embodiment of this invention, the compounds of formula I as defined in any one of embodiments 1) to 5), 7), 9) or 12) to 13) ortheir salts (among which the pharmaceutically acceptable salts will be preferred) will be such that n represents 2.
17) According to yet another particular embodiment of this invention, the compounds of formula Ip as defined in embodiment 3) or 4) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that n represents 2.
18) According to yet another particular embodiment of this invention, the compounds of formula I as defined in embodiment 1), 2), 5), 6), 7) or 9) or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that n represents 3.
19) Preferably, the compounds of formula I as defined in any one of embodiments 1) to 18) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R4 represents (C4-Ce)alkoxy, especially linear (C4-Ce)alkoxy and in particular n-butoxy.
20) Preferably, the compounds of formula Ip as defined in embodiment 17) above ortheir salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R represents (C4-Ce)alkoxy, especially linear (C4-Ce)alkoxy and in particular «-butoxy.
21) Preferably, the compounds of formula Ip as defined in embodiment 17) or 20) above ortheir salts (among which the pharmaceutically acceptable salts will be preferred) will be such that they have the stereochemistry drawn below

(among which the pharmaceutical^ acceptable salts will be preferred) will be such that R represents phenyl optionally substituted once by halogen, methyl, methoxy, trifiuoromethyl ortrifluoromethoxy (notably phenyl optionally substituted once by halogen, methyl or trifiuoromethyl and especially phenyl optionally substituted once by fluorine, methyl or trifiuoromethyl).
23) More preferably, the compounds of formula I as defined in one of embodiments 1) to 22) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R1 represents unsubstituted phenyl.
24) According to one variant of this invention, the compounds of formula I as defined in one of embodiments 1) to 23) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that W represents a bond.
25) Preferably, the compounds of formula I as defined in embodiment 24) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R represents alkyl (notably methyl and isopropyl and especially methyl), hydroxyalkyl (especially 3 -hydroxy -butyl), alkoxyalkyl (especially 3-methoxy -propyl), cycloalkyl (especially cyclopropyl optionally substituted once by hydroxymethyl or alkoxymethyl), a phenyl group optionally substituted once by alkoxy, or also an unsubstituted monocyclic heteroaryl group (especially thiophen-3-yl).
26) More preferably, the compounds of formula I as defined in embodiment 25) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that
R represents hydroxyalkyl, alkoxyalkyl or cycloalkyl (especially cyclopropyl optionally substituted once by alkoxymethyl or alkoxy and more especially cyclopropyl optionally substituted once by alkoxymethyl).
27) According to another variant of this invention, the compounds of formula I as defined in one of embodiments
1), 2), 5) to 12), 14) to 16), 18) to 20), 22) or 23) above or their salts
(among which the pharmaceutically acceptable salts will be preferred) will be such that W represents -O- and R represents alkyl (notably methyl), cycloalkyl (notably cyclopentyl), hydroxyalkyl (notably 2-hydroxyethyl) or heterocyclyl (notably tetrahydrofuran-3-yl).
28) According to another variant of this invention, the compounds of formula I as defined in one of embodiments 1) to 23) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such thatW represents -O-.
29) Preferably, the compounds of formula I as defined in embodiment 28) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R represents methyl or heterocyclyl (e.g. tetrahydrofuran-3-yl), and notably heterocyclyl (especially tetrahydrofuran-3-yl).
30) According to a further variant of this invention, the compounds of formula I as defined in one of embodiments 1), 3) or 5) to 23) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that W represents -NR -, R represents alkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl, heterocyclyl, cycloalkyl, aryl or aralkyl and R3 represents hydrogen or alkyl, or such that W represents -NR - and R2 and R3 form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7 members wherein the members needed to complete said heterocyclic ring are each independently selected from -CH2-, -CHRX-, -O-, -S-, -CO- and -NRy-, it being understood however that said heterocyclic ring does not contain more than one member selected from the group consisting of-CHRX-, -O-, -S-, -CO- and -NRy-, Rx representing hydroxy, hydroxymethyl, alkoxymethyl or alkoxy and Representing hydrogen or alkyl or also such that W represents -NR
- and R and R form, together with the nitrogen that carries them, either an imidazolyl, pyrazolyl, 1,2,3-triazolyl or
1,2,4-triazolyl ring, which ring may be substituted by an alkyl group (especially by a methyl group).
31) According to a further variant of this invention, the compounds of formula I as defined in one of embodiments
1) to 3) or 5) to 23) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will
be such that W represents -NR -, R represents alkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl,
heterocyclyl, cycloalkyl, phenyl or phenylalkyl and R represents hydrogen or alkyl; or such that W represents -NR
- and R and R form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7 members (preferably
4 to 6 members) wherein the members needed to complete said heterocyclic ring are each independently
selected from -CH2-, -CHRX-, -O-and -NRy-, it being understood however that said heterocyclic ring does not
contain more than one member selected from the group consisting of-CHRX-, -O- and -NRy-, Rx representing
hydroxy, hydroxymethyl, alkoxymethyl or alkoxy (notably methoxy) and Ry representing alkyl (especially methyl)
or also such that W represents -NR - and R and R form, together with the nitrogen that carries them, a pyrazolyl

ring which may be unsubstituted or monosubstituted by an alkyl group (especially by a methyl group);
32) According to one subvariant of said further variant, the compounds of formula I as defined in embodiment 30) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that W represents -NR -, R represents alkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl, heterocyclyl, cycloalkyl, aryl or aralkyl and R3 represents hydrogen or alkyl (notably hydrogen or methyl).
33) Preferably, the compounds of formula I as defined in embodiment 31) or 32) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that W represents -NR -, R represents alkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl, heterocyclyl, cycloalkyl or phenylalkyl and R represents hydrogen or alkyl (notably hydrogen or methyl).
34) More preferably, the compounds of formula I as defined in embodiment 31) or 32) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that W represents -NR3-,
R2 represents (Ci-C4)alkyl, (Ci-C2)alkoxy-carbonyl-(Ci-C4)alkyl, carboxy-(Ci-C4)alkyl, (Ci-C4)hydroxyalkyl, (Ci-C2)alkoxy-(Ci-C4)alkyl, heterocyclyl, cycloalkyl or phenylalkyl (and in particular methyl, ethyl, cbo-propyl, 2-ethoxycarbonyl-ethyl, 2-carboxy-ethyl, 2-hydroxyethyl, 2-methoxy-ethyl, tetrahydrofuran-3-yl, cyclopropyl or benzyl) and R3 represents hydrogen or methyl (and notably hydrogen).
35) According to another subvariant of said further variant, the compounds of formula I as defined in embodiment 30) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that W represents -NR3- and R and R3 form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7 members wherein the members needed to complete said heterocyclic ring are each independently selected from -CH2-, -CHRX-, -O-, -S-, -CO- and -NRy-, it being understood however that said heterocyclic ring does not contain more than one member selected from the group consisting of -CHRX-, -O-, -S-, -CO- and -NRy-, Rx representing hydroxy, hydroxymethyl, alkoxymethyl or alkoxy and Ry representing hydrogen or alkyl (notably hydrogen or methyl).
36) Preferably, the compounds of formula I as defined in embodiment 31) or 35) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that W represents -NR - and R and R form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7 members (and notably of 4 to 6 members and especially of 5 to 6 members) wherein the members needed to complete said heterocyclic ring are each independently selected from -CH2-, -CHRX-, -O- and -NRy-, it being understood however that said heterocyclic ring does not contain more than one member selected from the group consisting of-CHRX-, -O- and -NRy-, Rx representing hydroxy, hydroxymethyl, alkoxymethyl or alkoxy (and notably hydroxy, hydroxymethyl or alkoxy) and Representing alkyl (especially methyl).
37) More preferably, the compounds of formula I as defined in embodiment 31) or 35) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that W represents -NR3- and R2 and R3 form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 6 members (and especially of 5 to 6 members) wherein the members needed to complete said heterocyclic ring are each independently selected from -CH2-, -CHRX-, -O- and -NRy-, it being understood however that said heterocyclic ring does not contain more than one member selected from the group consisting of-CHRX-, -O- and -NRy-, Rx representing hydroxy, hydroxymethyl, methoxymethyl or methoxy (especially hydroxy, hydroxymethyl or methoxy) and Ry representing methyl (and especially such that R and R form, together with the nitrogen that carries them, 3-methoxymethyl-azetidin-l-yl, pyrrolidin-1-yl, morpholin-4-yl, 4-methyl-piperazin-1 -yl, 3-methoxy-pyrrolidin-l-yl, 3-hydroxy-pyrrolidin-1 -yl or 2-hydroxymethyl-piperidin-l-yl and in particular such that R and R form, together with the nitrogen that carries them, pyrrolidin-1-yl, morpholin-4-yl, 4-methyl-piperazin-1 -yl, 3-methoxy-pyrrolidin-l-yl, 3-hydroxy-pyrrolidin-l-yl or 2-hydroxymethyl-piperidin-l-yl).
38) According to yet another subvariant of said further variant, the compounds of formula I as defined in embodiment 30) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that W represents -NR - and R and R form, together with the nitrogen that carries them, an imidazolyl, pyrazolyl, 1 ,2,3-triazolyl or 1 ,2,4-triazolyl ring, which ring may be substituted by an alkyl group (especially by a methyl group).
39) Preferably, the compounds of formula I as defined in embodiment 31) or 38) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R and R form, together with the nitrogen that carries them, a pyrazolyl ring which may be substituted by a methyl group (and in particular such that R and R form, together with the nitrogen that carries them, pyrazoi-1-yl or 4-methyl-pyrazol-l-yl).
40) Besides, the compounds of formula I as defined in one of embodiments 1) to 11), 14) to 18) or 21) to 39) above (among which the pharmaceutically acceptable salts will be preferred) will preferably be such that R

represents (C2-C4)alkoxy, especially linear (C2-C4)alkoxy, in particular ethoxy or «-butoxy.
41) According to a preferred variant of embodiment 40), the compounds of formula I (among which the pharmaceutically acceptable salts will be preferred) will be such that R represents ethoxy.
42) According to another preferred variant of embodiment 40), the compounds of formula I as defined in one of embodiments 1) to 39) above (among which the pharmaceutically acceptable salts will be preferred) will be such that R represents «-butoxy.
43) One main embodiment of this invention relates to the compounds of formula lp as defined in embodiment 3) that are also compounds of formula IPD
IPD
wherein
R1 represents phenyl optionally substituted 1 to 3 times (preferably optionally substituted once or twice and more
preferably optionally substituted once) by substituents each independently selected from the group consisting of
halogen, methyl, methoxy, trifiuoromethyl and trifluoromethoxy;
W represents a bond, and R represents alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl or heteroaryl; or
W represents -O- and R represents alkyl or heterocyclyl; or
W represents -NR -, R represents alkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl, heterocyclyl,
cycloalkyl, aryl or aralkyl and R3 represents hydrogen or alkyl; or
W represents -NR3- and R2 and R3 form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7 members wherein the members needed to complete said heterocyclic ring are each independently selected from -CH2- -CHRX-, -O-, -S-, -CO- and
-NRy-, it being understood however that said heterocyclic ring does not contain more than one member selected from the group consisting of-CHRX-, -O-, -S-, -CO- and -NRy-, Rx representing hydroxy, hydroxymethyl, alkoxymethyl or alkoxy and Ry representing hydrogen or alkyl;
or also W represents -NR - and R and R form, together with the nitrogen that carries them, an imidazolyl,
pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl ring, which ring may be substituted by an alkyl group (especially by a
methyl group);
Ra represents hydrogen or methyl;
Rb represents hydrogen or methyl;
R4 represents alkoxy;
n represents 0, 1 or 2;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
44) Another main embodiment of this invention relates to the compounds of formula lp as defined in embodiment 3) that are also compounds of formula IP_PDG

wherein
R1 represents phenyl optionally substituted 1 to 3 times (preferably optionally substituted once or twice and more
preferably optionally substituted once) by substituents each independently selected from the group consisting of
halogen, methyl, methoxy, trifiuoromethyl and trifluoromethoxy;
W represents a bond, and R2 represents alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl or heteroaryl; orW
represents -O- and R2 represents alkyl or heterocyclyl; or
W represents -NR -, R represents alkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyj^ heterocyclyl,
cycloalkyl, aryl or aralkyl and R3 represents hydrogen or alkyl; or W represents -NR3- and R2 and R form,
together with the nitrogen that carries them, a heterocyclic ring of 4 to 7 members wherein the members needed
to complete said heterocyclic ring are each independently selected from -CH2-, -CHRX-, -O-, -S-, -CO- and -NRy-,
it being understood however that said heterocyclic ring does not contain more than one member selected from
the group consisting of-CHRx-, -O-, -S-, -CO- and -NRy-, Rx representing hydroxy, hydroxymethyl, alkoxymethyl
or alkoxy and Ry representing hydrogen or alkyl;
or also W represents -NR3- and R2 and R3 form, together with the nitrogen that carries them, an imidazolyl,
pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl ring, which ring may be substituted by an alkyl group (especially by a
methyl group);
Ra represents hydrogen or methyl;
Rb represents hydrogen or methyl;
R4 represents alkoxy;
n represents 0, 1 or 2;
R5 represents a group -0-(CHR6)-0-C(=0)-R7 wherein R6 represents hydrogen or (Ci-C3)alkyl and R7 represents
(CrC4)alkyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
45) Preferably, the compounds of formula Ip as defined in embodiment 44) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R represents hydrogen (and notably such that R5 represents 2,2-dimethyl-propionyloxymethoxy or isobutyryloxymethoxy).
46) According to a preferred embodiment, the compounds of formula I as defined in any one of embodiments 1) to 43) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R5 and, if present, R8 are identical and represent hydroxy.
47) According to another preferred embodiment, the compounds of formula I as defined in any one of embodiments 1), 2), 5) to 12), 14) to 16), 18), 19) or 22) to 42) above or their salts (amona which the pharmaceutically acceptable salts will be preferred) will be such that R5 and, if present, R are identical and represent each unsubstituted phenyloxy, unsubstituted benzyloxy, a group -0-(CHR6)-0-C(=0)-R7, a group -O-(CHR6)-0-C(=0)-0-R7, a group -0-(CHR6)-C(=0)-0-R9, a group -NH-(CHR10)-C(=O)-O-R9 or a group -NH-C(CH3)2-C(=0)-0-R9
48) According to a more preferred embodiment, the compounds of formula I as defined in embodiment 47) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R5 and, if present, R8 are identical and represent -0-(CHR6)-0-C(=0)-R7 (and most preferably -0-(CH2)-0-C(=0)-R7).
49) According to another preferred embodiment, the compounds of formula I as defined in embodiment 47) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that

Rb and, if present, R are identical and represent -0-(CHR )-0-C(=0)-0-R' (and most preferably -0-(CH2)-0-C(=0)-0-R7).
50) According to another preferred embodiment, the compounds of formula I as defined in embodiment 47) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R5 and, if present, R are identical and represent -NH-(CHR )-C(=0)-0-R9 or -NH-C(CH3)2-C(=0)-0-R9.
51) According to still another preferred embodiment, the compounds of formula I as defined in any one of embodiments 1), 2), 5) to 12), 14) to 16), 18), 19) or 22) to 42) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R represents hydroxy and R represents a group -0-(CH2)-0-C(=0)-R (and notably -0-(CH2)-0-C(=0)-CH3).
52) According to still another preferred embodiment, the compounds of formula I as defined in any one of embodiments 1), 2), 5) to 12), 14) to 16), 18), 19) or 22) to 42) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R represents unsubstituted phenyloxy and R represents a group -NH-CH(CH3)-C(=0)-0-R (and notably -NH-CH(CH3)-C(=0)-0-CH2CH3).
53) According to still another preferred embodiment, the compounds of formula I as defined in any one of embodiments 1), 2), 5) to 12), 14) to 16), 18), 19) or 22) to 42) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that P(0)R5R8 represents a group selected from the following structures
wherein the arrow marks the point of attachment to the remaining part of compounds of formula I, q represents 1 or 2 (and preferably 2), R9 represents (Ci-C4)alkyl (and preferably methyl or tert-butyl) and R . 11 represents hydrogen, (Ci-C4)alkyl or (Ci-C4)alkoxy.
54) Another preferred embodiment of this invention relates to the compounds of formula I as defined in
embodiment 1), wherein
R1 represents phenyl;
W represents -NR3- and R2 and R3 form, together with the nitrogen that carries them, a heterocyclic ring of 5
members wherein the members needed to complete said heterocyclic ring are each independently selected from

-CH2- and -CHRX-, it being understood however that said heterocyclic ring does not contain more than one -
CHRX- group, Rx representing alkoxy (and preferrably W represents -NR - and R2 and R3 form, together with the
nitrogen that carries them, a 3-methoxy-pyrrolidin-l-yl group);
Ra represents hydrogen;
Rb represents hydrogen;
R4 represents alkoxy;
n represents 1 or 2, V represents a bond, and m represents 0;
R5 and R8 are identical and represent each a group -0-(CHR6)-0-C(=0)-R7, a group -O- (CHR6)-0-C(=0)-0-
R7 or a group -NH-(CHR10)-C(=O)-O-R9; or
P(0)R R represents a group selected from the following structures
wherein the arrow marks the point of attachment to the remaining part of compounds of formula I;
q represents 2;
R6 represents hydrogen;
R7 represents (Ci-C4)alkyl;
R9 represents (Ci-C4)alkyl;
R10 represents hydrogen, (Ci-C4)alkyl or unsubstituted phenyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
55) The following compounds of formula I as defined in embodiment 1) to 4) are particularly preferred: 4-((i?)-2- {[6-((5)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} - 3-phosphono-propionyl)-piperazine-l-carboxylic acid ethyl ester;
4-((i?)-2- {[6-((5)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} - 3-phosphono-propionyl)-piperazine-l-carboxylic acid butyl ester;
4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}- 3-phosphono-propionyl)-piperazine-l-carboxylic acid ethyl ester;
4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-1 -carboxylic acid ethyl ester;
4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l -carboxylic acid butyl ester;
4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}- 3-phosphono-propionyl)-piperazine-l -carboxylic acid butyl ester;
4- {(5)-2-[(2-phenyl-6-pyrazol-1 -yl-pyrimidine-4-carbonyl)-amino]-4-phosphono-butyryl} -piperazine-1 -carboxylic acid butyl ester;
4-((5)-2-{[6-(4-methyl-pyrazol-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l -carboxylic acid butyl ester;
4-[(5)-2-({2-phenyl-6-[(5)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-4-phosphono-butyryl]-piperazine-1 -carboxylic acid butyl ester;
4- {(5)-2-[(2-phenyl-6-pyrrolidin-1 -yl-pyrimidine-4-carbonyl)-amino]-4-phosphono-butyryl} -piperazine-1 -carboxylic acid butyl ester;
4-{(5)-2-[(6-isopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-4-phosphono-butyryl}-piperazine-1 -carboxylic acid butyl ester;
4-{(5)-2-[(6-morpholin-4-yl-2-phenyl-pyrimidine-4-carbonyl)-amino]-4-phosphono-butyryl}-piperazine-1 -carboxylic acid butyl ester;
4-((5)-2-{[6-(4-methyl-piperazin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l -carboxylic acid butyl ester;
4-{(i?)-2-[(6-methylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1 -carboxylic acid butyl ester;
4-{(i?)-2-[(6-dimethylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl} -piperazine-1-carboxylic acid butyl ester;
4-{(i?)-2-[(6-ethylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1-carboxylic acid butyl ester;
4-{(i?)-2-[(6-isopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl} -piperazine-1-carboxylic acid butyl ester;

4-((5)-2-{[2-(4-fluoro-phenyl)-6-((5)-3-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-1 -carboxylic acid butyl ester;
4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-p-tolyl-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-1 -carboxylic acid butyl ester;
4-((5)-2-{[2-(2-fluoro-phenyl)-6-((5)-3-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l -carboxylic acid butyl ester;
4-((5)-2-{[2-(3-fluoro-phenyl)-6-((5)-3-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l -carboxylic acid butyl ester;
4-{(i?)-2-[(6-methoxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1 -carboxylic acid butyl ester;
4-{(i?)-2-[(6-methyl-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1 -carboxylic acid butyl ester;
4-{(i?)-2-[(6-cyclopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl} -piperazine-1 -carboxylic acid butyl ester;
4-{(i?)-2-[(2-phenyl-6-phenylamino-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1-carboxylic acid butyl ester;
4-{(i?)-2-[(6-benzylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1 -carboxylic acid butyl ester;
4-[(i?)-2-({2-phenyl-6-[(i?)-(tetrahydro-furan-3-yl)amino]-pyrimidine-4-carbonyl}-amino)- 3-phosphono-propionyl]-piperazine-l -carboxylic acid butyl ester;
4-((i?)-2-{[6-(3-hydroxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}- 3-phosphono-propionyl)-piperazine-l -carboxylic acid butyl ester;
4-[(i?)-2-({6-[(2-methoxy-ethyl)-methyl-amino]-2-phenyl-pyrimidine-4-carbonyl}-amino)-3-phosphono-propionyl]-piperazine-1 -carboxylic acid butyl ester;
4-((i?)-2- {[6-(2-ethoxycarbonyl-ethylamino)-2-phenyl-pyrimidine-4-carbonyl]-amino} - 3-phosphono-propionyl)-
piperazine-l -carboxylic acid butyl ester;
4-((i?)-2-{ [6-(2-carboxy-ethylamino)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-
piperazine-l-carboxylic acid butyl ester;
4- {(i?)-2-[(2,6-diphenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl} -piperazine-1-carboxylic acid
butyl ester;
4-{(i?)-2-[(2-phenyl-6-thiophen-3-yl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-carboxylic
acid butyl ester;
4-((i?)-2- {[6-(4-methoxy-phenyl)-2-phenyl-pyrimidine-4-carbonyl]-amino} -3-phosphono-propionyl)-piperazine-1
-carboxylic acid butyl ester;
4-{(i?)-2-[(6-cyclopropyl-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1 -carboxylic
acid butyl ester;
4-{(i?)-2-[(6-butyl-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1 -carboxylic acid
butyl ester;
4-[(i?)-2-({2-phenyl-6-[(5)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)- 3-phosphono-propionyl]-
piperazine-l -carboxylic acid butyl ester;
4-((i?)-2- {[6-((5)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} - 3-phosphono-propionyl)-2-
methyl-piperazine-l -carboxylic acid ethyl ester;
4-((i?)-2- {[6-((5)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} -4-phosphono-butyryl)-
piperazine-l -carboxylic acid ethyl ester;
4-((i?)-2- {[6-((5)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} - 4-phosphono-butyryl)-
piperazine-l -carboxylic acid butyl ester;
4-((i?)-2-{[6-((i5',25)-2-methoxymethyl-cyclopropyl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-
propionyl)-piperazine-l -carboxylic acid butyl ester;
4-((i?)-2-{ [6-((i5',25)-2-hydroxymethyl-cyclopropyl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-
propionyl)-piperazine-l -carboxylic acid butyl ester;
4-((i?)-2-{ [6-(2-hydroxy-ethylamino)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-
piperazine-l -carboxylic acid butyl ester;
4-((i?)-2- {[6-(2-hydroxymethyl-piperidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino } -3-phosphono-propionyl)-
piperazine-1 -carboxylic acid butyl ester;
4-((i?)-2-{ [6-(3-methoxy-propyl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-l-carboxylic acid butyl ester;
4-((i?)-2-{ [6-(3-hydroxy-butyl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-l-carboxylic acid butyl ester;
4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-(3-trifluoromethyl-phenyl)-pyrimidine- 4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l-carboxylic acid butyl ester;
4-((5)-4-[8cjb-(2,2-dimethyl-propionyloxymethoxy)-phosphoryl]-2-{[6-((5)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino } -butyryl)-piperazine-1 -carboxylic acid butyl ester; 4-((5)-4-(8cjb-isobutyryloxymethoxy-phosphoryl)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)- 2-phenyl-pyrimidine-4-

carbonyl]-amino}-butyryl)-piperazine-l -carboxylic acid butyl ester;
4-((5)-4- {8cjb-[(2,2-dimethyl-propionyloxy)-ethoxy]-phosphoryl} -2- {[6-((5)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino } -butyryl)-piperazine-1 -carboxylic acid butyl ester;
4-((i?)-3-[8cjb-(2,2-dimethyl-propionyloxymethoxy)-phosphoryl]-2-{[6-((5)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((i?)-3- {bis-[ 1 -(2,2-dimethyl-propionyloxy)-ethoxy]-phosphoryl} -2- {[6-((5)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -propionyl)-piperazine-1 -carboxylic acid butyl ester; 4-((i?)-3-[8cjb-(l-isobutyryloxy-ethoxy)-phosphoryl]-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino } -propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((i?)-3-[8cjb-(l-propionyloxy-ethoxy)-phosphoryl]-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-l -carboxylic acid butyl ester; 4-((i?)-3-(8cjb-isobutyryloxymethoxy-phosphoryl)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-l -carboxylic acid butyl ester;
4-(2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-2-phosphono-acetyl)-piperazine-l -carboxylic acid butyl ester;
wherein it is well understood that any stereogenic center of any above listed compound, which is not explicitly assigned, may be in absolute (R)- or (A-configuration;
as well as the salts (in particular pharmaceutically acceptable salts) thereof.
56) Further preferred compounds of formula I as defined in embodiment 1) or 2) are selected from the group consisting of:
4-((R)-2-{[6-(2-Hydroxy-ethoxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((S)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-5-phosphono-pentanoyl)-piperazine-l -carboxylic acid butyl ester;
4-[(S)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-(4-phosphono-phenyl)-propionyl]-piperazine-l -carboxylic acid ethyl ester;
4-[(S)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-(4-phosphono-phenyl)-propionyl]-piperazine-l -carboxylic acid butyl ester;
4-[(S)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-(4-phosphonomethyl-phenyl)-propionyl]-piperazine-l -carboxylic acid ethyl ester;
4-[(S)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-(4-phosphonomethyl-phenyl)-propionyl]-piperazine-1 -carboxylic acid butyl ester;
4-((R)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-5-phosphono-pentanoyl)-piperazine-l -carboxylic acid butyl ester;
4-{(R)-2-[(6-lsopropyl-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1 -carboxylic acid butyl ester;
4-((R)-2-{[6-(3-Methoxymethyl-azetidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-l -carboxylic acid butyl ester;
4-{(R)-2-[(6-Cyclopentyloxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l -carboxylic acid ethyl ester;
4-[(S)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-(4-phosphono-phenyl)-propionyl]-piperazine-l -carboxylic acid ethyl ester;
4-[2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-2-(4-phosphono-phenyl)-acetyl]-piperazine-l -carboxylic acid ethyl ester;
4-[2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-2-(4-phosphono-phenyl)-acetyl]-piperazine-l -carboxylic acid butyl ester;
4-[2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-2-(3-phosphono-phenyl)-acetyl]-piperazine-l-carboxylic acid ethyl ester;
4-[2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-2-(3-phosphono-phenyl)-acetyl]-piperazine-l-carboxylic acid butyl ester;
4-[2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-2-(2-phosphono-phenyl)-acetyl]-piperazine-l -carboxylic acid butyl ester;
4-((R)-2-{[6-(4-Methyl-piperazin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-l-carboxylic acid butyl ester;
4-{(R)-2-[(6-Morpholin-4-yl-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1 -carboxylic acid butyl ester;
N,N'-Bis-(ethoxycarbonylmethyl)-3-{(S)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-4-oxo-4-(4-butoxy-carbonyl-piperazin-l-yl)-butyl-phosphonic acid diamide; 4-((R)-3-(Bis-acetoxymethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-

amino } -propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((R)-3-(Bis-propionyloxymethoxy-phosphoryl)-2- {[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino } -propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((R)-3-(Bis-butyryloxymethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino }-propionyl)-piperazine-1 -carboxylic acid butyl ester; N,N'-Bis-(ethoxycarbonylmethyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide;
N,N'-Bis-((S)-l-ethoxycarbonylethyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide;
N,N'-Bis-(methoxycarbonylmethyl)-2- {(R)-[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide;
N,N'-Bis-((S)-l-methoxycarbonyl-2-methyl-propyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-oxo-3-(4-butoxy-carbonyl-piperazin-l-yl)-propyl-phosphonic acid diamide;
N,N'-Bis-(tert-butyloxycarbonylmethyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -3-oxo-3-(4-butoxy-carbonyi-piperazin-1 -yl)-propyl-phosphonic acid diamide;
N,N'-Bis-((S)-l-methoxycarbonylpropyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide; N,N'-Bis-((S)-l-methoxycarbonyl-2,2-dimethyl-propyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide; N,N'-Bis-((S)-l-tert-butyloxycarbonylethyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide; N,N'-Bis-((S)-l-methoxycarbonyl-2-phenyl-ethyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)- 2-phenyl-pyrimidine-4-carbonyl]-amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide; N,N'-Bis-((S)-methoxycarbonylphenylmethyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide; N,N'-Bis-((S)-l-methoxycarbonylethyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yi)-propyl-phosphonic acid diamide; N,N'-Bis-(propyloxycarbonylmethyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide;
N,N'-Bis-(isopropyloxycarbonylmethyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide;
N,N'-Bis-(2-ethoxycarbonyl-prop-2-yl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yi)-propyl-phosphonic acid diamide;
4-((R)-3-(Bis-methoxycarbonyloxymethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino } -propionyl)-piperazine-1 -carboxy lie acid butyl ester;
4-((R)-3-(Bis-ethoxycarbonyloxymethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino } -propionyl)-piperazine-1 -carboxy lie acid butyl ester;
4-((R)-3-(Bis-isopropoxycarbonyloxymethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-l-carboxylic acid butyl ester; 4-((R)-3-(Bis-tert-butoxycarbonyloxymethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-l-carboxylic acid butyl ester;
4-((R)-3-[Bis-(l-ethyloxycarbonyloxy-ethoxy)-phosphoryl]-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-l-carboxylic acid butyl ester;
4-((R)-3-[Bis-(l-isopropyloxycarbonyloxy-ethoxy)-phosphoryl]-2-{[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((R)-3-[Bis-(l-cyclohexyloxycarbonyloxy-ethoxy)-phosphoryl]-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-l -carboxylic acid butyl ester;
4-((R)-3-(Diphenoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino }-propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((R)-3-[Bis-(5-methyl-2-oxo-[l,3]dioxol-4-ylmethoxy)-phosphoryl]-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-l -carboxylic acid butyl ester; 4-[(R)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-(2-oxo-4H-2A5-benzo[l,3,2]dioxaphosphinin-2-yl)-propionyl]-piperazine-l -carboxylic acid butyl ester;
4-[(R)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-(2-oxo-l,4-dihydro-2H-2A5-benzo[d][l,3,2]oxazaphosphinin-2-yl)-propionyl]-piperazine-l-carboxylic acid butyl ester;
4-[(R)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-(8-methyl-2-oxo-l,4-dihydro-2H-2A5-benzo[d][l,3,2]oxazaphosphinin-2-yl)-propionyl]-piperazine-1-carboxylic acid butyl ester; 4-((R)-3-[Bis-(3-oxo-l,3-dihydro-isobenzofuran-l-yloxy)-phosphoryl]-2-{[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -propionyi)-piperazine-1 -carboxylic acid butyl ester; 4-((R)-3-(Bis-ethoxycarbonylmethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-

carbonyl] -amino } -propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((R)-3-[Bis-((S)-l-ethoxycarbonyl-ethoxy)-phosphoryl]-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino } -propionyl)-piperazine-1 -carboxylic acid butyl ester;
N-[(S)-l-Ethoxycarbonyl-ethyl]-0-phenyl-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} -3-oxo-3-(4-butoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid amide; 4-[(R)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-(2-oxo-2A5-[l,3,2]dioxaphosphinan-2-yl)-propionyl]-piperazine-l -carboxylic acid butyl ester; 4-[(R)-2-{[6-((S)-3-Methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-(8-methyl-2-oxo-4H-2A5-benzo[l,3,2]dioxaphosphinin-2-yl)-propionyl]-piperazine-l -carboxylic acid butyl ester;
4-((R)-3-(8-lsopropyl-2-oxo-4H-2A -benzo[l,3,2]dioxaphosphinin-2-yl)-2-{[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino } -propionyl)-piperazine-1 -carboxylic acid butyl ester; 4-((R)-3-(8-Methoxy-2-oxo-l,4-dihydro-2H-2A5-benzo[d][l,3,2]oxazaphosphinin-2-yl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((R)-3-[(5-tert-Butyl-2-oxo-[l,3]dioxol-4-ylmethoxy)-hydroxy-phosphoryl]-2-{[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl]-amino } -propionyl)-piperazine-1 -carboxylic acid butyl ester; 4-((R)-3-(Bis-benzyloxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino} -propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((R)-3-(Acetoxymethoxy-hydroxy-phosphoryl)-2- {[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino } -propionyl)-piperazine-1 -carboxylic acid butyl ester;
4-((S)-3-(Bis-acetoxymethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino } -propionyl)-piperazine-1 -carboxylic acid ethyl ester;
4-((S)-3-(Bis-butyryloxymethoxy-phosphoryl)-2- {[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino } -propionyl)-piperazine-1 -carboxylic acid ethyl ester;
N,N'-Bis-((S)-l-ethoxycarbonylethyl)-2-{(S)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -3-oxo-3-(4-ethoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide; 4-((S)-3-(Bis-ethoxycarbonyloxymethoxy-phosphoryl)-2- {[6-((S)-3-methoxy-pyrrolidin-1 -yl)- 2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-l -carboxylic acid ethyl ester;
4-((R)-3-(Bis-acetoxymethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino } -propionyl)-piperazine-1 -carboxylic acid ethyl ester;
4-((R)-3-(Bis-butyryloxymethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino }-propionyl)-piperazine-1 -carboxylic acid ethyl ester;
N,N'-Bis-((S)-l-ethoxycarbonylethyl)-2-{(R)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino} -3-oxo-3-(4-ethoxy-carbonyl-piperazin-1 -yl)-propyl-phosphonic acid diamide;
4-((R)-3-(Bis-ethoxycarbonyloxymethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino } -propionyl)-piperazine-1 -carboxylic acid ethyl ester;
4-((S)-3-[4-(Bis-butyryloxymethoxy-phosphoryl)-phenyl]-2- {[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino } -propionyl)-piperazine-1 -carboxylic acid ethyl ester;
N,N'-Bis-((S)-l-ethoxycarbonylethyl)-4-[2-{(S)-[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-
amino} -3-oxo-3-(4-ethoxy-carbonyl-piperazin-1 -yl)-propyl]-phenyl-phosphonic acid diamide; and
4-((S)-3-[4-(Bis-ethoxycarbonyloxymethoxy-phosphoryl)-phenyl]-2-{[6-((S)-3-methoxy-pyrrolidin-1 -yl)-2-phenyl-
pyrimidine-4-carbonyl] -amino} -propionyl)-piperazine-1 -carboxylic acid ethyl ester;
wherein it is well understood that any stereogenic center of any above listed compound, which is not explicitly
assigned, may be in absolute (R)- or (A-configuration;
as well as the salts (in particular pharmaceutically acceptable salts) thereof.
57) A further object of the invention is the compounds of formula I (or of formula ICE) as defined in one of
embodiments 1) to 56) above, 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.
58) The invention thus also relates to pharmaceutical compositions containing at least one compound according
to one of embodiments 1) to 56) above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, diluent or excipient. In particular, the invention relates to pharmaceutical compositions
containing at least one compound of formula I (or of formula ICE) and one or more pharmaceutically acceptable

The production of the pharmaceutical compositions can be effected in a manner 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 solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
59) The compounds according to formula I as defined in embodiments 1) to 56) above and the pharmaceutically
acceptable salts thereof may be used for the preparation of a medicament, and are suitable:
V for the treatment or prophylaxis of diseases including stable angina, unstable angina, myocardial infarction, embolism (including complications of atherosclerosis, notably embolic stroke), arterial thrombosis (including primary 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 glomerulonephritis), venoocclusive diseases, transient ischaemic attacks, peripheral vascular diseases, myocardial infarction with or without thrombolysis, myeloproliferative disease, thrombocythaemia, sickle cell disease, inflammatory bowel disease, thrombotic thrombocytopaenic purpura, haemolytic uraemic syndrome;
V for preventing thrombotic complications of septicaemia, adult respiratory distress syndrome, anti-phospholipid syndrome, heparin-induced thrombocytopaenia and pre- eclampsia/eclampsia;
V for preventing cardiovascular complications after certain surgery procedures (notably coronary revascularisation like angioplasty (PTCA), other vascular graft surgery, endarterectomy or stent placement) or after accidental trauma;
V for preventing organ graft rejection.

60) Therefore, a particular object of this invention is the use of a compound of formula I (or of formula ICE) as defined in one of embodiments 1) to 56) above, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the uses listed in embodiment 59) above, and for the manufacture of a medicament for the treatment of occlusive vascular disorders in general.
61) More generally, the invention relates to the use of a compound of formula I (or of formula ICE) as defined in one of embodiments 1) to 56) above, 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 I (or of formula ICE) 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.
62) Among the above-mentioned uses of compounds of formula I (or of formula ICE) or of pharmaceutically acceptable salts thereof for the manufacture of medicaments according to embodiment 59) above, 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.
63) The invention further relates to the use of a compound of formula I (or of formula ICE) according to one of embodiments 1) to 56) above, or of a pharmaceutically acceptable salt thereof, for the preservation of blood products in vitro (e.g. the preservation 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).
64) The invention also relates to methods of treatment for the disorders mentioned in embodiment 59) above, 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) according to one of embodiments 1) to 56), or of a pharmaceutically acceptable salt of such a compound.
Any reference to a compound of formula I, ICE, Ip, ICEP, ISTI, IST2, IPD or IP_PDG in this text is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient. The preferences indicated for the compounds of formula I of course apply mutatis mutandis to the compounds of formula ICE, the compounds of formula Ip, the compounds of formula ICEP, the compounds of formula ISTI, the compounds of formula IST2, the compounds of formula IPD and the compounds of formula Ip-PDG, as well as to the salts and pharmaceutically acceptable salts of the compounds of formula I, of formula ICE, of formula Ip, of formula ICEP, of formula ISTI, of formula IST2, of formula IPD or of formula IP-PDG- The same applies to these compounds as medicaments, to pharmaceutical compositions 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.
PREPARATION OF THE COMPOUNDS OF FORMULA I
Abbreviations:
The following abbreviations are used throughout the specification and the examples:
Ac acetyl
anh. anhydrous
aq. aqueous
Boc te/t-butoxycarbonyl
br. broad
Cbz benzyloxycarbonyl
CC column chromatography
cHex cyclohexane
cone, concentrated
Cremophor-EL® compound with the Chemical Abstracts registry No. 61791-12-6
CV column volume
DCC 1 ,3-dicyclohexylcarbodiimide
DCM dichloromethane
DCMC N,N'-dicyclohexyl-4-morpholinecarboxamidine
DIPEA diisopropylethylamine
DME 1 ,2-dimethoxyethane
DMF N,N-dimethylformamide
DMPU iV.iV-diraethylpropyleneurca
EA ethyl acetate
EDCI 7V-(3-dimethylaminopropyl)-7V-ethylcarbodiimide Eq equivalent
Et ethyl
Fmoc 9H-fluoren-9-ylmethoxycarbonyl
HATU 2-(7-aza-1 H-benzotriazole-1 -yl)-1,1,3 ,3-tetramethyluronium
hexafluorophosphate
Hept heptane
Hex hexane
HOBT 1 -hydroxybenzotriazole
Hse L-homoserine
HV high vacuum
LC-MS Liquid Chromatography - Mass Spectrometry
MCPBA met0-chloroperbenzoic acid
Me methyl
«-BuLi «-butyl lithium
NMP 7V-methy Ipyrro lidone
org. organic
Pd/C palladium on carbon
PEG400 polyethylene glycol with a molecular weight of 400 g/mol
PG polypropylene glycol
Ph phenyl
PyBOP benzotriazole-1 -yl-oxy-tris-pyrrolidino-phosphonium
hexafluor opho sphate
RT room temperature
sat. saturated
TEAtriethylamine
TFA trifluoroacetic acid
THF tetr ahy dro furan
TLC thin layer chromatography
tR retention time
Z benzyloxycarbonyl Gener al preparation routes;
A further aspect of the invention is a process for the preparation of compounds of formula (I) (or formula ICE).
Compounds of formula (I) of the present invention can be prepared according to the general sequence of
reactions outlined in the schemes below wherein V, W, R1, R , R3, R4, R5, R , R7, R8, R9, R10, n, m and q are as
defined for formula (I). The compounds obtained may also be converted into pharmaceutically acceptable salts
thereof in a manner known per se.
In general, all chemical transformations can be performed according to well-known standard methodologies as

The various compounds of formula I can be prepared using the general routes summarized in Scheme 1 hereafter.
Scheme 1 The compounds of formula ID can be prepared by treating the compounds of formula II with HCI optionally in the presence of water, in a suitable organic solvent such as THF, EA, dioxane or Et.20 and preferably at a temperature around RT, or with trimethylsilyl bromide ortrimethylsilyl iodide in a suitable solvent such as DCM or MeCN and preferably at a temperature around RT.
The compounds of formula IPDG (R and R t OH) can be prepared by the reaction between a phosphonic acid of formula lD and an appropriate halide derivative of formula X-(CHR )-0-C(=0)-R7, X-(CHR6)-0-C(=0)-0-R7, X-(CH2)-C(=0)-0-R9 or 3-bromophthalide, X being chloride, bromide or iodide, in the presence of a suitable base (e.g. NEt.3, DIPEA, DCMC) in a suitable solvent such as DMF, NMP or DMPU, optionally in the presence of Nal and preferably at a temperature between 45 and 90°C.
Alternatively, the compounds of formula IPDG (R and/or R tOV\) can be prepared by the reaction between a phosphonic acid of formula ID and an appropriate a-amino acid alkyl ester of formula NH2-(CHR10)-C(=O)-O-R9 01 NH2-C(CH3)2-C(=0)-0-R9 in the presence of a suitable base (e.g. NEt.3) and an activating mixture of reagents such as a combination of 2,2'-dipyridyl disulfide and PPh3 in a suitable solvent such as anhydrous pyridine and preferably at a temperature of about 60°C.
Alternatively, the compounds of formula IPDG (R5 and/or R81 OH) can be prepared by the reaction between a phosphonic acid of formula ID and an appropriate alcohol of formula HO-(CHR6)-C(=0)-0-R9, HO-CH2-(CH2)q-OH, phenol, benzyl alcohol, 4-hydroxymethyl-5-methyl-[l,3]dioxol-2-one, 2-hydroxybenzyl alcohol being unsubstitued or substituted on the phenyl ring, 2-aminobenzyl alcohol being unsubstitued or substituted on the phenyl ring in the presence of a condensing reagent (e.g. PyBOP) and a suitable base (e.g. NEt.3, DIPEA) in a suitable solvent such as DMF and preferably at a temperature between RT and 45°C.
Alternatively, when R5 represents phenyloxy and R represents a group of formula NH-(CHR10)-C(=O)-O-R9 or NH-C(CH3)2-C(=0)-0-R9, the respective compounds of formula IPDG can be prepared in a three-step procedure starting from the respective phosphonic acid of formula b: 1. a coupling reaction is performed with a phenol in the presence of a condensing reagent (e.g. PyBOP) and a suitable base (e.g. NEt.3, DIPEA) in a suitable solvent such as DMF and preferably at a temperature between RT and 45°C;
2. a saponification reaction is performed using standard conditions such as NaOH in a mixture of water and a suitable organic solvent such as MeOH or EtOH; and finally
3. a coupling reaction is performed with an appropriate a-amino acid alkyl ester of formula NH2-(CHR10)-C(=O)-O-R9 or NH2-C(CH3)2-C(=0)-0-R9 in the presence of a suitable base (e.g. NEt.3) and an activating mixture of reagents such as a combination of 2,2'-dipyridyl disulfide and PPh3 in a suitable solvent such as anhydrous

Alternatively, when R5 represents hydroxy and R8 represents a group -0-(CH2)-0-C(=0)-R9, the compounds of formula IPDG can be prepared in a two-step procedure starting from the respective phosphonic acid of formula I:
1. a coupling reaction is performed with benzyl alcohol in the presence of a suitable base (e.g. NEt.3) and an activating mixture of reagents such as a combination of 2,2'-dipyridyl disulfide and PPh3 in a suitable solvent such as anhydrous pyridine and preferably at a temperature of about 60°C to give the mono-benzylated intermediate; and
2. a substitution reaction is performed with an appropriate halide derivative of formula X-(CH2)-0-C(=0)-R9, X being chloride, bromide or iodide, in the presence of a suitable base (e.g. NEt.3, DIPEA, DCMC) in a suitable solvent such as DMF, NMP or DMPU and preferably at a temperature between 45 and 90°C. The benzyl cleavage occured simultaneously.
Preparation of the various synthesis intermediates;
Preparation of the compounds of formula II
The compounds of formula II can be prepared using the routes summarized in Scheme 2 and Scheme 2a hereafter.
The compound of formula V can be obtained (Scheme 2) by coupling a compound of formula III with a compound of formula IV using standard peptide coupling methods such as PyBOP, in the presence of a suitable base such as NEt.3, DIPEA or N-methylmorpholine and in a suitable solvent such as DCM, THF or DMF, preferably at a temperature around RT.
The resulting intermediate of formula V can then be converted into a compound of formula II wherein W is -NR3-by aromatic substitution reaction with an amine of formula HNR2R3 optionally in the presence of a suitable base such as NEt.3, DIPEA or N-methylmorpholine, the reaction being carried out in a suitable solvent such as DCM, THF, MeCN or DMF and preferably between RT and 70°C.
The intermediate of formula V can also be converted into a compound of formula II wherein W is -O- by aromatic substitution reaction with an alcohol of formula R2OH in the presence of a suitable base such as NaH, the reaction being carried out in a suitable solvent such as MeOH, THF, MeCN or DMF and preferably around RT.
The intermediate of formula V can furthermore be converted into a compound of formula II wherein W is a bond, using a reagent of formula R2-B(OR)2, R being hydrogen or alkyl, using standard conditions for a Suzuki reaction, and preferably using a boronic acid or ester derivative R -B(OR)2 in the presence of a suitable base such as K3P04 or K2C03, in the presence of a suitable palladium catalyst such as
tetrakis(triphenylphosphine)palladium or tris(dibenzylideneacetone)dipalladium, optionally in the presence of a suitable ligand such as triphenylphosphine in a suitable solvent such as dioxane or a toluene/EtOH mixture, and preferably heating between 8O0C and 100 C. Besides, the intermediate of formula V can also be converted into a compound of formula II wherein W is a bond, using a reagent of formula R2-SnBu3, using standard conditions for

a Stille reaction, and preferably using a tributylstannane derivative R2-SnBu3 in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium in a suitable solvent such as toluene, and preferably heating at about 110°C. Alternatively, the intermediate of formula V can also be converted into a compound of formula II wherein W is a bond, using a magnesium derivative of formula R -MgBr, in the presence of a suitable iron catalyst such as iron(lll)acetylacetonate, in a suitable solvent such as THF and at a temperature preferably around RT (see Furstner A. et al. in J. Am. Chem. Soc. (2002), 13856-13863).
Alternatively, the intermediate of formula V can also be converted in a two step procedure into a compound of formula II wherein W is a bond, using a reagent of formula R-CECH (R equals RCH2CH2), using standard conditions for a Sonogashira reaction, and preferably using an alkyne derivative R-CECH in the presence of a suitable base such as NEt.3, in the presence of a suitable palladium catalyst such as bis-(triphenylphosphine) palladium(ll)-dichloride, in the presence of a suitable copper catalyst such as copper(l) iodide, in a suitable solvent such as DMF, and at RT. In a second step, the obtained intermediate can be converted into a compound of formula II by reducing the triple bond to the single bond in the presence of a suitable catalyst such as Raney Nickel, in a suitable solvent such as MeOH, at a temperature preferably around RT under a hydrogen atmosphere.
Scheme 2a
Alternatively, the compounds of formula II can be prepared as described in Scheme 2a by coupling a compound of formula III with a compound of formula VI using standard peptide coupling methods such as PyBOP, HOBT, EDCI hydrochloride, lA-dicyclohexylcarbodiimide, HATU, optionally in the presence of a suitable base such as NEt.3, DIPEA or 7V-methylmorpholine and in a suitable solvent such as DCM, THF or DMF, preferably at a temperature around RT.
Preparation of the compounds of formula III
The compounds of formula III wherein n is 1 , V represents a bond and m is O can be prepared using the route summarized in Scheme 3 hereafter.
Scheme 3
The compounds of formula VIII can be obtained in three steps starting from Boc-3-iodo-L-Ala-OMe or Boc-3-iodo-D-Ala-OMe: an Arbuzov reaction is performed (e.g. using P(OEt)3 at reflux) followed by a saponification reaction using standard conditions such as NaOH or LiOH in a mixture of water and a suitable organic solvent such as THF, MeOH or EtOH; finally the obtained acid intermediate is coupled with a compound of formula VII using standard peptide coupling methods such as those described for the synthesis of compounds of formula II (see Scheme 2a). The compounds of formula III can then be obtained by standard acidic conditions forthe removal of

a Boc group that are well known to one skilled in the art.
The compounds of formula III wherein n is 2, V represents a bond and m is O can be prepared using the route summarized in Scheme 3a hereafter.
Scheme 3a
L-Homoserine or D-homoserine is first protected on the nitrogen atom with a Z group using standard conditions known to one skilled in the art. The dicyclohexylamine salt of the obtained molecule is prepared and the methyl ester is formed using Mel in DMF at a temperature around RT. The hydroxy function is then substituted by a bromide using standard conditions such as PPH3 and CBr4, in a suitable solvent such as DCM, preferably between O0C and RT. The next three steps leading to the compounds of formula IX are performed using conditions such as those already described for the synthesis of the compounds of formula VIII (see Scheme 3). The compounds of formula III can then be obtained by cleaving the Z protecting group using standard conditions known to one skilled in the art (e.g. hydrogenation with Pd/C in EtOH).
The compounds of formula III wherein n is 0, V represents a bond and m is 0 can be prepared using the route summarized in Scheme 3b hereafter.
Scheme 3b
The compounds of formula X can be obtained in two steps starting from commercially available (3 solution thu offering the compound of formula III.
The compounds of formula III wherein n is 0, V represents phenyl and m is 0 can be prepared using the route summarized in Scheme 3f hereafter.
Scheme 3/
The compounds of formula III can be prepared in six steps starting from the commercially available DL-bromo-phenylglycines using conditions such as those already described for the synthesis of the compounds of formula III in Scheme 3d.
Preparation of the compounds of formula IV
The compounds of formula IV can be prepared using the route described in WO 2006/114774 (see general preparation routes, preparation of the compounds of formula IV, Scheme Aa).
Preparation of the compounds of formula VI
The compounds of formula VI can be prepared using the reaction shown in Scheme 4 hereafter.

(IV) (VI) Scheme 4
The intermediate of formula IV can be converted into a compound of formula VI wherein W is a bond, using a reagent of formula R2-B(OR)2, R being hydrogen or alkyl, using standard conditions for a Suzuki reaction such as those described for the synthesis of compounds of formula II wherein W is a bond (see Scheme 2). Alternatively, the intermediate of formula IV can be converted into a compound of formula VI wherein W is -NR - by aromatic substitution reaction with an amine of formula HNR2R3 using conditions such as those described for the synthesis of compounds of formula II wherein W is -NR - (see Scheme 2).
Preparation of the compounds of formula VII
The compounds of formula VII can be prepared using the route described in WO 2006/114774 (see general preparation routes, preparation of the compounds of formula V, Schemes 5 and 5 a).
Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in anyway.
EXAMPLES
Characterization methods used:
H-NMR: The NMR spectra were measured on a 400 MHz Brucker Avance.
The LC-MS retention times have been obtained using the following elution conditions:
LC-MS (A): A Zorbax column (Agilent SB.Aq 5um, 4.6x50mm) was used. The two elution solvents were as follows: solvent A = water + 0.04% TFA; solvent B = MeCN. The eluent flow rate was 4.5 ml/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):
LC-MS (B): AX-terra® column (MS C18 5 urn, 2.1x50mm) was used. The two elution solvents were as follows: solvent A = water + 0.06% formic acid; solvent B = MeCN + 0.06% formic acid. The eluent flow rate was 3 ml/min and the characteristics of the eluting mixture proportion in function of the timet from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):
LC-MS (C): A Zorbax® column (Extend-C18 5 urn, 4.6x50mm) was used. The two elution solvents were as follows: solvent A = water + 0.1% cone. aq. ammonia; solvent B = MeCN. The eluent flow rate was 4.5 ml/min and the characteristics of the eluting mixture proportion in function of the timet from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):

The purifications by preparative LC-MS have been performed using a Phenomenex® column unless otherwise specified in the relevant Example description, with the general conditions described hereafter.
A Phenomenex® column (Gemini 10u CI 8 HOA Ax 50x21.2 mm) or a X-Terra® column (Prep MS CI 8 OBD™ 10u 30x75 mm) was used. The two elution solvents were as follows: solvent A = water + 1% formic acid; solvent B = MeCN + 1% formic acid. The eluent flow rate was 50 mL/min for the Phenomenex®column and 100 mL/min for the X-Terra® column. The characteristics of the eluting mixture proportion in function of the timet from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

propionyl)-piperazine-l-carboxylic acid ethyl ester:
1.1. (R)-2-tert-butoxycarbonylamino-S-(diethoxy-phosphoryl)-propionic acid methyl ester:
Boc-3-iodo-L- Ala-OMe (9.4 g) was dissolved in triethyl phosphite (100 ml_). The mixture was heated at 130°C overnight and evaporated to dryness to give a yellow oil (8.37 g). The compound was used in the next step without further purification. LC-MS (A): tR = 0.85 min; [M+H]+: 340.09.
1.2. (fyA-tert-butoxycarbonylamino-S-idiethoxy-phosphoryfy-propionic acid:
An aq. solution of lithium hydroxide hydrate (2.07 g in 5 mi) was added to a solution of intermediate 1.1 (8.37 g) in THF (99 ml_). The reaction mixture was stirred at RT overnight and DCM and a \M HCI solution (60 ml_) were added. The phases were separated and the aq. phase was extracted three times with DCM. The org. phases were combined, dried (Na2SOA and evaporated off to give 5.8 g of the desired product as a white powder. LC-MS (A): tR = 0.77 min; [M+H]+: 326.13.
1.3. 4-[(R)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionyl]-piperazine-1-carboxylic acid ethyl
ester:
HOBT hydrate (98 mg) and EDCI hydrochloride (123 mg) were added to a solution of intermediate 1.2 (200 mg) and DIPEA(0.42 ml_) in THF/DCM (0.6 mL/2.4 ml_). After stirring at RTfor 10 min, 1 -ethoxycarbonylpiperazine (97 mg) was added and the stirring was continued overnight at RT. DCM and an aq. NaHCCbsolution were added to the mixture and the phases were separated. The aq. phase was extracted with DCM and the combined org. phases were washed with a NaCI solution, dried (Na2SOA and evaporated off. The crude was purified by CC (eluent: gradient from EAto EA/MeOH 25/1). After HV drying, the desired compound was obtained as a colourless resin (194 mg). LC-MS (A): tR = 0.86 min; [M+H]+: 466.05.
1.4. 4-[(R)-2-amino-S-(diethoxy-phosphoryl)-propionyl]-piperazine-l-carboxylic acid ethyl ester hydrochloride salt:
Intermediate 1.3 (192 mg) was dissolved in EA (0.2 mL) and a 4M HC1 solution in dioxane (0.4 mL). The reaction
mixture was stirred at RT for 4.5 h and evaporated off. After HV drying, the desired compound was obtained as a
colourless resin (199 mg).
LC-MS (A): tR = 0.65 min; [M+H]+: 366.04.
1.5. (S)-S-hydroxypyrrolidine-l-carboxylic acid tert-butyl ester:
Di-tert-butyl-dicarbonate (27.5 g) was added portionwise to a solution of (5)-3-hydroxypyrrolidine (10 g) and NEt.3 (32 mL) in DCM (240 mL). The reaction mixture was stirred overnight at RT. Water was added and the org. phase was separated. It was washed with sat. aq. NH4CI, sat. aq. NaHCC>3 and sat. aq. NaCI. The org. phase was dried (Na2SOA and evaporated off to afford the desired compound (21.4 g). 1H-NMR (CDCI3): 8 = 4.43 (br. s, IH); 3.40 (m, 4H); 2.70 (m, IH); 1.93 (m, 2H); 1.46 (s, 9H).
1.6. (S)-3-methoxy-pyrrolidine-l-carboxylic acid tert-butyl ester:
To an ice-cold solution of intermediate 1.5 (22 g) in THF (300 mL) was added NaH (7.7 g, 55% dispersion in mineral oil) portionwise. The reaction mixture was stirred for 30 min at RT, cooled down to 0°C and Mel (11 mL) was added dropwise. Stirring was continued for additional 2 h at RT. Water and ethanolamine (14 mL) were added to the reaction mixture that was stirred for 15 min. The org. phase was separated and the aq. phase was extracted with DCM three times. The combined org. phases were washed with sat. aq. NaCI, dried (Na2SOA and evaporated off to afford a yellow oil (27.5 g). 1H-NMR (CDCI3): 8 = 3.94 (br. s, IH); 3.44 (m, 4H); 3.35 (s, 3H); 1.99 (m, 2H); 1.48 (s, 9H).
1.7. (S)-3-methoxy-pyrrolidine hydrochloride salt:
Intermediate 1.6 (27.5 g) was dissolved in IM HCI in EA (30O mL) and 3M HCI in EA (50 mL) was added. The reaction mixture was stirred overnight at RT and the solvent was evaporated off. The residue was taken up in Et.20 (500 mL) and the compound precipitated out. The suspension was stirred for 1 h, filtered off and the powder washed with Et.20. HV drying afforded the desired hydrochloride salt (13.9 g). 1H-NMR (CDCI3): 8 = 9.84 (br. s, IH); 4.10 (br s, IH); 3.43 (m, 4H); 3.33 (s, 3H); 2.19 (m, IH); 2.04 (m, IH).
1.8. 6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carboxylic acid:
6-chloro-2-phenyl-pyrimidine-4-carboxylic acid (14.3 g; prepared as described in WO 2006/114774, Example 24, intermediate 24.3), intermediate 1.7(10 g) and DIPEA (23 mL) were dissolved in THF (191 mL). The reaction mixture was stirred at 60°C for 48 h. Water and DCM were added and the phases were separated. The aq. phases were washed with DCM and the combined org. phases were dried (Na2SOA and evaporated off. CC (DCM/MeOH 9/1) of the crude yielded the desired compound (13.2 g).

LC-MS (A): tR = 0.74 min; [M+H]+: 300.42.
1.9. 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidineA-carbonylj-aminoj-
propionyfy-piperazine-l-carboxylic acid ethyl ester:
To a solution of intermediate 1.8(135 mg) in THF/DCM (0.4 mL/1.6 ml_) were sequentially added DIPEA (0.305 ml_), HOBT hydrate (83 mg) and EDCI hydrochloride (104 mg). After stirring at RTfor 5 min, intermediate 1.4 (194 mg) was added and the stirring was continued overnight at RT. DCM and an aq. NaHCC>3 solution were added to the mixture and the phases were separated. The org. phase was dried (Na2SOA and evaporated off. The crude was purified by CC (eluent: gradient from EA/MeOH 100/1 to EA/MeOH 9/1). After HV drying, the desired compound was obtained as a colourless resin (131 mg). LC-MS (A): tR = 1.00 min; [M+H]+: 646.95.
1.10. 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino}-3-phosphono-propionyl
piperazine-l-carboxylic acid ethyl ester:
To an ice-cold solution of intermediate 1.9 (129 mg) in anhydrous MeCN (0.6 mL) was added trimethylsilyl bromide (0.516 mL) dropwise. The reaction mixture was allowed to warm to RT and was stirred at RT until completion. Water (1 mil) was added. After stirring at RT for 3 h, water was added and the mixture was extractet 5 times with DCM. The combined org. phases were dried (Na2SCA) and evaporated off. The crude was purified by CC (reverse phase; eluent: gradient from water/TFA 100/1 to MeCN/TFA 100/1). After HV drying, the desired compound was obtained as a colourless resin (94 mg). LC-MS (A): tR = 0.82 min; [M+H]+: 590.97.
Example 2: 4-((i?)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidiiie- 4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-l-carboxylic acid butyl ester:
2.1. 4-benzyl-piperazine-l-carboxylic acid butyl ester:
To a solution of 1 -benzyl-piperazine (1.97 ml) and NEt3(1.9 ml) in DCM (100 ml) was added « -butyl chloroformate (1.47 ml). The mixture was stirred at RTfor 2 h. Water was added, the org. phase separated, driei (Na2SCA) and evaporated off to give a yellow oil (3.13 g). LC-MS (A): tR = 0.73 min; [M+H]+: 277.42.
2.2. Piperazine-1-carboxylic acid butyl ester:
Intermediate 2.1 (3.1 g) was hydrogenated in EtOH (100 ml) with Pd/C (wet, 5%, 480 mg) for 24 h. The mixture was filtered through celite and evaporated off. HV drying afforded the desired compound as a pale yellow liquid (2.04 g). LC-MS (A): tR = 0.54 min; [M+H+MeCN]+: 226.39.
2.3. 4- [(R)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionyl] -piperazine-1-carboxylic acid butyl
ester:
This compound was prepared using a method analogous to that of Example 1, step 1.3, intermediate 2.2 replacing 1-ethoxycarbonylpiperazine. LC-MS (A): tR = 0.94 min; [M+H]+: 494.18.
2.4. 4-[(R)-2-amino-3-(diethoxy-phosphoryl)-propionyl]-piperazine-l-carboxylic acid butyl ester hydrochloride salt:
This compound was prepared using a method analogous to that of Example 1, step 1.4, intermediate 2.3
replacing intermediate 1.3.
LC-MS (A): tR = 0.73 min; [M+H]+: 394.08.
2.5. 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidineA-carbonylj-aminoj-
propionylj-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.9, intermediate 2.4
replacing intermediate 1.4.
LC-MS (A): tR = 1.05 min; [M+H]+: 675.14.
2.6. 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-
piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 2.5
replacing intermediate 1.9.
LC-MS (A): tR = 0.88 min; [M+H]+: 618.96.
Example 3: 4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-l-carboxylic acid ethyl ester:

3.1. (S)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionic acid methyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.1, Boc-3-iodo-D-Ala-OMe replacing Boc-3-iodo-L-Ala-OMe. LC-MS (A): tR = 0.84 min; [M+H]+: 340.32.
3.2. (S)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionic acid:
This compound was prepared using a method analogous to that of Example 1, step 1.2, intermediate 3.1
replacing intermediate 1.1.
LC-MS (A): tR = 0.77 min; [M+H]+: 326.29.
3.3. 4-[(S)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionyl]-piperazine-1-carboxylic acid ethyl
ester:
This compound was prepared using a method analogous to that of Example 1, step 1.3, intermediate 3.2
replacing intermediate 1.2.
LC-MS (A): tR = 0.85 min; [M+H]+: 466.21.
3.4. 4-[(S)-2-amino-3-(diethoxy-phosphoryl)-propionyl]-piperazine-l-carboxylic acid ethyl ester hydrochloride salt:
This compound was prepared using a method analogous to that of Example 1, step 1.4, intermediate 3.3
replacing intermediate 1.3.
LC-MS (A): tR = 0.66 min; [M+H]+: 366.12.
3.5. 4-((S)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidineA-carbonylj-aminoj-
propionyfy-piperazine-l-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.9, intermediate 3.4
replacing intermediate 1.4.
LC-MS (A): tR = 0.98 min; [M+H]+: 647.23.
3.6. 4-((S)-2-{ [6-((S)-3-methoxy-pyrrolidin-l -yl)-2-phenyl-pyrimidine-4-carbonyl] -amino}-3-phosphono-propionyl)-
piperazine-l-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 3.5
replacing intermediate 1.9. The product was however purified by CC (eluent: gradient from CHCI3 to CHCbMeOH
1/1).
LC-MS (A): tR = 0.81 min; [M+H]+: 591.18.
Example 4: 4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l-carboxylic acid ethyl ester:
4.1. (S)-2-benzyloxycarbonylamino-4-hydroxy-butyric acid:
To an ice-cooled solution of H-Hse-OH (3 g) in dioxane/2M NaOH (100 ml_/25 mL) was added benzyl chloro formate (4 mL) dropwise over 15 min. The reaction mixture was allowed to warm to RT and was stirred overnight at RT. The solvent was evaporated off and the aq. residue was extracted with Et.20 and acidified with a 2M HCI solution. The aq. phase was extracted with DCM. The DCM layers were combined, dried (Na2SOA and evaporated off to give the desired product as a white powder (4.13 g). LC-MS (A): tR = 0.72 min; [M+H]+: 254.36.
4.2. (S)-2-benzyloxycarbonylamino-4-hydroxy-butyric acid dicyclohexylamine salt:
To a solution of intermediate 4.1 (8.9 g) in EtOH (77 mL) was added dropwise dicyclohexylamine (7 mL). The solvent was removed and the white powder was suspended in Et.20. The suspension was filtered off and the white solid (12.1 g) was dried in vacuo. LC-MS (A): tR = 0.71 min.
4.3. (S)-2-benzyloxycarbonylamino-4-hydroxy-butyric acid methyl ester:
Mel (2.1 mL) was added dropwise to a suspension of intermediate 4.2 (12.1 g) in anhydrous DMF (196 mL). The reaction mixture was stirred overnight at RT. 1 more equivalent of Mel was added, and after 6 h stirring 2 more equivalents were added. The reaction mixture was stirred overnight and the solvent was removed. The residue was taken up in EA/water and the org. phase was washed with a NaCI solution, dried (Na2SCM) and evaporated off. The crude was purified by CC (Et^O) to give the desired compound as a colourless resin (4.2 g). LC-MS (A): tR = 0.79 min; [M+H]+: 268.30.
4.4. (S)-2-benzyloxycarbonylamino-4-bromo-butyric acid methyl ester:
PPI13 on resin (1.6 mmol/g, 12.4 g) was added to an ice-cooled solution of intermediate 4.3 (2.4 g) and CBr4 (6.7 g) in anhydrous DCM (120 mL). The reaction mixture was stirred at 0°C for 2 h and was allowed to warm to RT.

The resin was filtered off and the solution evaporated off. The crude was purified by CC (EA/Hept 1/3) to give the desired compound as a colourless resin (1.7 g). LC-MS (A): tR = 0.86 min; [M+H]+: 331.89.
4.5. (S)-2-benzyloxycarbonylamino-4-(diethoxy-phosphoryl)-butyric acid methyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.1, intermediate 4.4 replacing Boc-3-iodo-L-Ala-OMe. The compound was however purified by CC (EA/Hept 1/3 to 1/0). LC-MS (A): tR = 0.90 min; [M+H]+: 388.24.
4.6. (S)-2-benzyloxycarbonylamino-4-(diethoxy-phosphoryl)-butyric acid:
This compound was prepared using a method analogous to that of Example 1, step 1.2, intermediate 4.5
replacing intermediate 1.1.
LC-MS (A): tR = 0.83 min; [M+H]+: 374.36.
4.7. 4-[(S)-2-benzyloxycarbonylamino-4-(diethoxy-phosphoryl)-butyryl]-piperazine-1-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.9, intermediate 4.6
replacing intermediate 1.8 and 1-ethoxycarbonylpiperazine replacing intermediate 1.4. The compound was
however purified twice by CC (EA).
LC-MS (A): tR = 0.91 min; [M+H]+: 514.24.
4.8. 4- [(S)-2-amino-4-(diethoxy-phosphoryl)-butyryl]-piperazine- 1-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 2, step 2.2, intermediate 4.7 replacing intermediate 2.1, however using MeOH instead of EtOH. LC-MS (A): tR = 0.66 min; [M+H]+: 380.32.
4.9. 4-((S)-4-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-
butyryl)-piperazine- 1-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.3, intermediate 4.8 replacing 1-ethoxycarbonylpiperazine and intermediate 1.8 replacing intermediate 1.2. The product was however purified by CC (eluent: gradient from Heptto EA followed by gradient from EAto EA/MeOH 1/1), followed by preparative TLC (EA/MeOH 30/1). LC-MS (A): tR = 1.01 min; [M+H]+: 660.304.
4.10. 4-((S)-2-{[6-((S)-S-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino}-4-phosphono-butyryl)-
piperazine- 1-carboxylic acid ethyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 4.9 replacing intermediate 1.9. The crude was purified by CC (eluent: gradient from CHCMo CHCb/MeOH 1/1).
LC-MS (A): tR = 0.85 min; [M+H]+: 605.03.
Example 5: 4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l-carboxylic acid butyl ester:
5.1. 4-[(S)-2-benzyloxycarbonylamino-4-(diethoxy-phosphoryl)-butyryl]-piperazine-1-carboxylic acid butyl ester: This compound was prepared using a method analogous to that of Example 1, step 1.9, intermediate 4.6 replacing intermediate 1.8 and intermediate 2.2 replacing intermediate 1.4. The product was however purified twice by CC (eluent: gradient from EA/MeOH 10/1 to EA/MeOH 1/1, then gradient from EAto EA/MeOH 95/5). LC-MS (A): tR = 0.96 min; [M+H]+: 542.29.
5.2. 4- [(S)-2-amino-4-(diethoxy-phosphoryl)-butyryl]-piperazine- 1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 2, step 2.2, intermediate 5.1 replacing intermediate 2.1, however using MeOH instead of EtOH. LC-MS (A): tR = 0.69 min; [M+H]+: 408.18.
5.3. 4-((S)-4-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-
butyryl)-piperazine- 1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1 step 1.3, intermediate 5.2 replacing 1-ethoxycarbonylpiperazine and intermediate 1.8 replacing intermediate 1.2. The crude was however purified by CC (eluent: gradient from EAto EA/MeOH 9/1). LC-MS (A): tR = 1.06 min; [M+H]+: 689.24.

5.4. 4-((S)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonylJ -amino}-4-phosphono-butyryl)-piperazine- 1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 5.3 replacing intermediate 1.9.
LC-MS (A): tR = 0.91 min; [M+H]+: 633.13.
Example 6: 4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-l-carboxylic acid butyl ester:
6.1. 4-[(S)-2-tert-butoxycarbonylamino-S-(diethoxy-phosphoryl)-propionyl]-piperazine-1-carboxylic acid butyl
ester:
This compound was prepared using a method analogous to that of Example 1, step 1.3, intermediate 3.2 replacing intermediate 1.2 and intermediate 2.2 replacing 1 -ethoxycarbonylpiperazine. LC-MS (A): tR = 0.94 min; [M+H]+: 494.26.
6.2. 4-[(S)-2-amino-3-(diethoxy-phosphoryl)-propionyl]-piperazine-l-carboxylic acid butyl ester hydrochloride salt:
This compound was prepared using a method analogous to that of Example 1, step 1.4, intermediate 6.1
replacing intermediate 1.3.
LC-MS (A): tR = 0.74 min; [M+H]+: 394.18.
6.3. 4-((S)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-
propionyl)-piperazine- 1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1 step 1.9, intermediate 6.2
replacing intermediate 1.4.
LC-MS (A): tR = 1.05 min; [M+H]+: 675.13.
6.4. 4-((S)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] '-aminoj-3-phosphono-propionyl)-
piperazine- 1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 6.3 replacing intermediate 1.9. The crude was purified by CC (eluent: gradient from CHCMo CHCb/MeOH 1/1). LC-MS (A): tR = 0.88 min; [M+H]+: 619.12.
Example 7: 4-{(5)-2-[(2-phenyl-6-pyrazol-l-yl-pyrimidine-4-carbonyl)-amino]-4-phosphono-butyryl}-piperazine-l-carboxylic acid butyl ester:
7.1. 4-[(S)-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-4-(diethoxy-phosphoryl)-butyryl] -piper azine-1-
carboxylic acid butyl ester:
To a solution of 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid (334 mg) in DCM (10 mL) was added PyBOP (815 mg), intermediate 5.2 (580 mg) and DIPEA (0.268 mL). The solution was stirred at RTfor24 h. It was diluted with DCM (50 mL) and washed with 2M Na2C03, \M NaHS94 and sat. aq. NaCI. The org. phase was dried (Na2SOA and evaporated off. The crude was purified by CC (DCM/acetone 1/0 to 6/3) to afford the desired product as brownish foam (680 mg). LC-MS (A): tR = 1.08 min; [M+H]+: 623.96.
7.2. 4-{(S)-4-(diethoxy-phosphoryl)-2-[(2-phenyl-6-pyrazol-l-yl-pyrimidine-4-carbonyl)-amino] -butyryl}-piper azine-
1-carboxylic acid butyl ester:
Pyrazole (7 uL) was added to a suspension of NaH (60% dispersion in mineral oil, 5.3 mg) in THF (0.5 mL). The suspension was stirred at RT for 30 min and a solution of intermediate 7.1 (55 mg) in THF (0.5 mL) was added. The reaction mixture was stirred at RT for 48 h. Water and DCM were added, the phases were separated and the org. phase was dried (Na2SOA and evaporated off to afford the crude compound (30 mg). No further purification was performed. LC-MS (B): tR= 1.17 min; [M+H]+: 656.35.
7.3. 4-{(S)-2-[(2-phenyl-6-pyrazol-l-yl-pyrimidine-4-carbonyl)-amino]-4-phosphono-butyryl}-piper azine-1-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 7.2 replacing intermediate 1.9. The crude was purified by preparative LC-MS (I). LC-MS (A): tR = 0.94 min; [M+H]+: 599.96.
Example 8: 4-((5)-2-{[6-(4-methyl-pyrazol-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l-carboxylic acid butyl ester: 8.1. 4-((S)-4-(diethoxy-phosphoryl)-2-{[6-(4-methyl-pyrazol-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-l-carboxylic acid butyl ester: This compound was prepared using a method analogous to that of Example 7, step 7.2, 4-methylpyrazole

replacing pyrazole.
LC-MS (B): tR = 1.20 min; [M+H]+: 670.40.
8.2. 4-((S)-2-{[6-(4-methyl-pyrazol-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino}-4-phosphono-butyryl)-piperazine-
l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 8.1
replacing intermediate 1.9. The crude was purified by preparative LC-MS (I). LC-MS (A): tR = 0.97 min; [M+H]+:
613.94.
Example 9: 4-[(S)-2-({2-phenyl-6-[(S)-(tetrahydro-furan-3-yl)oxy]-pyrimidiiie-4-carbonyl}-amino)-4-phosphono-butyryl]-piperazine-l-carboxylic acid butyl ester:
9.1. 4-[(S)-4-(diethoxy-phosphoryl)-2-({2-phenyl-6-[(S)-(tetrahydro-furan-S-yl)oxy]-pyrimidine-4-carbonyl}-amino)-
butyryl]-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 7, step 7.2, (5)-(+)-3-hydroxytetrahydrofurane replacing pyrazole, however using DMF instead of THF. LC-MS (A): tR = 1.07 min; [M+H]+: 675.91.
9.2. 4-[(S)-2-({2-phenyl-6-[(S)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-4-phosphono-butyryl] -
piper azine-1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 9.1 replacing intermediate 1.9. The crude was purified by preparative LC-MS (I). LC-MS (A): tR = 0.92 min; [M+H]+: 619.97.
Example 10: 4-{(5)-2-[(2-phenyl-6-pyrrolidin-l-yl-pyrimidine-4-carbonyl)-amino]-4-phosphono-butyryl}-piperazine-l-
carboxylic acid butyl ester: 10.1. 4-{(S)-4-(diethoxy-phosphoryl)-2-[(2-phenyl-6-pyrrolidin-l-yl-pyrimidine-4-
carbonyl)-amino] -butyrylj-piperazine-1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 7, step 7.2, pyrrolidine replacing
pyrazole. The compound was however not purified.
LC-MS (A): tR = 1.09 min; [M+H]+: 659.05.
10.2. 4-{(S)-2-[(2-phenyl-6-pyrrolidin-l-yl-pyrimidine-4-carbonyl)-amino]-4-phosphono-butyryl}-piper azine-1-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 10.1
replacing intermediate 1.9. The crude was purified by preparative LC-MS (I).
LC-MS (A): tR = 0.97 min; [M+H]+: 602.95.
Example 11:4- {(5)-2- [(6-isopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino] -4-phosphono-butyryl}-piperazine-l-carboxylic acid butyl ester:
11.1. 4-{(S)-4-(diethoxy-phosphoryl)-2-[(6-isopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino] -butyrylj-
piperazine-1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.8, isopropylamine replacing intermediate 1.7 and intermediate 7.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid. The product was however not purified. LC-MS (A): tR = 1.08 min; [M+H]+: 646.99.
11.2. 4-{(S)-2-[(6-isopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-4-phosphono-butyryl}-piperazine-l -
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 11.1 replacing intermediate 1.9. The crude was purified by preparative LC-MS (I). LC-MS (A): tR = 0.93 min; [M+H]+: 591.05.
Example 12:4- {(5)-2- [(6-morpholin-4-yl-2-phenyl-pyrimidine-4-carbonyl)-amino] -4-phosphono-butyryl}-piperazine-l-carboxylic acid butyl ester:
12.1. 4-{(S)-4-(diethoxy-phosphoryl)-2-[(6-morpholin-4-yl-2-phenyl-pyrimidine-4-carbonyl)-amino] -butyrylj-piperazine-1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1 step 1.8, morpholine replacing intermediate 1.7 and intermediate 7.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid. The compound was however not purified.

LC-MS (A): tR = 1.06 min; [M+H]+: 674.96.
12.2. 4-{(S)-2-[(6-morpholin-4-yl-2-phenyl-pyrimidine-4-carbonyl)-amino]-4-phosphono-butyryl}-piperazine-l -
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 12.1
replacing intermediate 1.9. The crude was purified by preparative LC-MS (I).
LC-MS (A): tR = 0.91 min; [M+H]+: 618.89.
Example 13: 4-((5)-2-{[6-(4-methyl-piperazin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l-carboxylic acid butyl ester:
13.1. 4-((S)-4-(diethoxy-phosphoryl)-2-{[6-(4-methyl-piperazin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-
butyryl)-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1 step 1.8, 1-methylpiperazine replacing intermediate 1.7 and intermediate 7.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid. The compound was however not purified. LC-MS (A): tR = 0.87 min; [M+H]+: 688.04.
13.2. 4-((S)-2-{[6-(4-methyl-piperazin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino}-4-phosphono-butyryl)-
piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 13.1 replacing intermediate 1.9. The crude was purified by preparative LC-MS (I). LC-MS (A): tR = 0.77 min; [M+H]+: 631.98.
Example 14: 4-{(i?)-2-[(6-methylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-carboxylic acid butyl ester:
14.1. 4- [(R)-2- [(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino] -S-(diethoxy-phosphoryl)-propionyl] -piper
azine-1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 7, step 7.1, intermediate 2.4 replacing intermediate 5.2. The compound was however purified by CC (eluent: gradient from Hept to EA). LC-MS (A): tR = 1.07 min; [M+H]+: 609.88.
14.2. 4-{(R)-S-(diethoxy-phosphoryl)-2-[(6-methylamino-2-phenyl-pyrimidine-4-carbonyl)-amino] -propionylj-piper
azine-1-carboxylic acid butyl ester:
Intermediate 14.1 (67 mg) was dissolved in a solution of methylamine in THF (2M, 0.55 mL). The reaction mixture was stirred at 50°C overnight. It was quenched with sat. aq. NaHCC>3 and DCM and sat. aq. NaCI were added. The org. phase was dried (Na2SCA) and evaporated off to afford the desired product as a beige foam (47 mg). LC-MS (A): tR = 1.01 min; [M+H]+: 604.97.
14.3. 4-{(R)-2-[(6-methylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-S-phosphono-propionyl}-piperazine-l-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1 step 1.10, intermediate 14.2 replacing intermediate 1.9. The crude was however purified by CC (reverse phase; eluent: gradient from water/TFA 100/1 to MeCN/TFA 100/1). LC-MS (A): tR = 0.83 min; [M+H]+: 548.98.
Example 15 : 4-{(R)-2- [(6-dimethylamino-2-phenyl-pyrimidine-4-carbonyl)-amino] -3-phosphono-propionyl}-piperazine-l-carboxylic acid butyl ester:
15.1. 4-{(R)-3-(diethoxy-phosphoryl)-2-[(6-dimethylamino-2-phenyl-pyrimidine-4-carbonyl)-amino] -propionylj-
piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 14, step 14.2, dimethylamine (2Min THF) replacing methylamine (2Min THF). LC-MS (A): tR = 1.05 min; [M+H]+: 618.97.
15.2. 4-{(R)-2-[(6-dimethylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-S-phosphono-propionyl}-piperazine-l-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 15.1 replacing intermediate 1.9. The crude was purified by CC (reverse phase; eluent: gradient from water/TFA 100/1 to MeCN/TFA 100/1).

Example 16: 4-{(i?)-2-[(6-ethylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-carboxylic acid butyl ester:
16.1. 4-{(R)-3-(diethoxy-phosphoryl)-2-[(6-ethylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-propionyl}-
piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 14, step 14.2, ethylamine (2Min THF) replacing methylamine (2Min THF). LC-MS (A): tR = 1.04 min; [M+H]+: 618.96.
16.2. 4-{(R)-2-[(6-ethylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 16.1 replacing intermediate 1.9. The crude was purified by CC (reverse phase; eluent: gradient from water/TFA 100/1 to MeCN/TFA 100/1). LC-MS (A): tR = 0.87 min; [M+H]+: 562.80.
Example 17: 4-{(R)-2-[(6-isopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-carboxylic acid butyl ester:
17.1. 4-{(R)-3-(diethoxy-phosphoryl)-2-[(6-isopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino] -propionylj-
piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.8, isopropylamine (10 equivalents) replacing intermediate 1.7 and intermediate 7.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid, using no DIPEA and heating at 50°C instead of 60°C. The compound was however not purified. LC-MS (A): tR = 1.02 min; [M+H]+: 633.25.
17.2. 4-{(R)-2-[(6-isopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-S-phosphono-propionyl}-piperazine-l-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1 step 1.10, intermediate 17.1 replacing intermediate 1.9. The crude was purified by CC (reverse phase, eluent A: water/TFA 100/1; eluent B: MeCN/TFA 100/1; gradient: 5% B/l CV; 5% to 70% B/20 CV; 70% B/4 CV). LC-MS (A): tR = 0.90 min; [M+H]+: 576.59.
Example 18: 4-((5)-2-{[2-(4-fluoro-phenyl)-6-((5)-3-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l-carboxylic acid butyl ester:
18.1. 4-fluoro-benzamidine:
To an ice-cold solution of hexamethyldisilazane (7 mL) in Et.20 (40 mL) was added «-BuLi (1.6M in hexanes, 20.6 mL), followed by a solution of 4-fluorobenzonitrile (2 g) in Et^O (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 HCI solution and was washed with CHCI3. The aq. layer was then basified to pH 14 by adding Na2CC>3 and NaOH and was extracted twice with CHCI3. The org. layers were dried (Na2SOA and evaporated off to afford the desired compound (1.59 g).
LC-MS (A): tR = 0.33 min; [M+H]+: 139.21.
18.2. 6-chloro-2-(4-fluoro-phenyl)-pyrimidine-4-carboxylic acid:
This compound was prepared in 4 steps from intermediate 18.1 using methods analog to those described in WO 2006/114774 (see Example 1, step 1.3 and Example 24, steps 24.1, 24.2 and 24.3). LC-MS (A): tR = 0.90 min; [M+H]+: 253.24.
18.3. 2-(4-fluoro-phenyl)-6-((S)-S-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carboxylic acid:
This compound was prepared using a method analogous to that of Example 1, step 1.8, intermediate 18.2 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid. The product was however not purified. LC-MS (A): tR = 0.77 min; [M+H]+: 318.16.
18.4. 4-((S)-4-(diethoxy-phosphoryl)-2-{[2-(4-fluoro-phenyl)-6-((S)-3-methoxy-pyrrolidin-l-yl)-pyrimidine-4-
carbonyl]-amino}-butyryl)-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 7, step 7.1, intermediate 18.3

replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid. The compound was however purified by preparative
LC-MS (IV).
LC-MS (A): tR = 1.08 min; [M+H]+: 706.95.
18.5. 4-((S)-2-{[2-(4-fluoro-phenyl)-6-((S)-3-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carbonyl]-amino}-4-phosphono-
butyryl)-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 18.4
replacing intermediate 1.9. The crude was purified by preparative LC-MS (II).
LC-MS (A): tR = 0.94 min; [M+H]+: 650.94.
Example 19: 4-((5)-2-{[6-((5)-3-methoxy-pyrrolidin-l-yl)-2-/j-tolyl-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l-carboxylic acid butyl ester:
19.1. 6-chloroA-p-tolyl-pyrimidineA-carboxylic acid:
This compound was prepared in 4 steps from 4-methyl-benzamidine using methods analog to those described in WO 2006/114774 (see Example 1, step 1.3, Example 24, steps 24.1, 24.2 and 24.3). LC-MS (A): tR = 0.93 min; [M+H]+: 249.28.
19.2. 6-((S)-3-methoxy-pyrrolidin-l-yl)-2-p-tolyl-pyrimidine-4-carboxylic acid:
This compound was prepared using a method analogous to that of Example 1, step 1.8, intermediate 19.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid. The product was however not purified. LC-MS (A): tR = 0.79 min; [M+H]+: 314.08.
19.3. 4-((S)-4-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-p-tolyl-pyrimidineA-carbonylj-aminoj-
butyrylj-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 7, step 7.1, intermediate 19.2 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid. The product was however purified by preparative LC-MS (IV). LC-MS (A): tR = 1.08 min; [M+H]+: 703.40.
19.4. 4-((S)-2-{[6-((S)-3-methoxy-pyrrolidin-l-yl)-2-p-tolyl-pyrimidine-4-carbonyl] -amino}-4-phosphono-butyryl)-
piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 19.3 replacing intermediate 1.9. The crude was purified by preparative LC-MS (II). LC-MS (A): tR = 0.93 min; [M+H]+: 646.90.
Example 20: 4-((5)-2-{[2-(2-fluoro-phenyl)-6-((5)-3-methoxy-pyrrolidin-l-yl)-pyrimidineA-carbonylj-aminojA-phosphono-butyryA-piperazine-l-carboxylic acid butyl ester:
20.1. 2-fluoro-benzamidine:
This compound was prepared using a method analogous to that of Example 18, step 18.1, 2-fiuorobenzonitrile
replacing 4-fluorobenzonitrile.
LC-MS (A): tR = 0.25 min; [M+H+MeCN]+: 180.35.
20.2. 6-chloro-2-(2-fluoro-phenyl)-pyrimidine-4-carboxylic acid:
This compound was prepared in 4 steps from intermediate 20.1 using methods analog to those described in WO 2006/114774 (see Example 1, step 1.3 and Example 24, steps 24.1, 24.2 and 24.3). LC-MS (A): tR = 0.88 min; [M+H]+: 252.95.
20.3. 2-(4-fluoro-phenyl)-6-((S)-S-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carboxylic acid: This compound was
prepared using a method analogous to that of Example 1, step 1.8, intermediate 20.2 replacing 6-chloro-2-
phenyl-pyrimidine-4-carboxylic acid. The product was however not purified.
LC-MS (A): tR = 0.74 min; [M+H]+: 318.14.
20.4. 4-((S)-4-(diethoxy-phosphoryl)-2-{[2-(2-fluoro-phenyl)-6-((S)-3-methoxy-pyrrolidin-l-yl)-pyrimidine-4-
carbonyl]-amino}-butyryl)-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 7, step 7.1, intermediate 20.3 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid. The product was however purified by preparative LC-MS (IV).

20.5. 4-((S)-2-{[2-(2-fluoro-phenyl)-6-((S)-3-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carbonyl]-amino}-4-phosphono-
butyryl)-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 20.4
replacing intermediate 1.9. The crude was purified by preparative LC-MS (I).
LC-MS (A): tR = 0.89 min; [M+H]+: 650.98.
Example 21: 4-((5)-2-{[2-(3-fluoro-phenyl)-6-((5)-3-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carbonyl]-amino}-4-phosphono-butyryl)-piperazine-l-carboxylic acid butyl ester:
21.1. 3-fluoro-benzamidine:
This compound was prepared using a method analogous to that of Example 18, step 18.1, 3-fiuorobenzonitrile
replacing 4-fluorobenzonitrile.
LC-MS (A): tR = 0.30 min; [M+H+MeCN]+: 180.35.
21.2. 6-chloro-2-(S-fluoro-phenyl)-pyrimidine-4-carboxylic acid:
This compound was prepared in 4 steps from intermediate 21.1 using methods analog to those described in WO 2006/114774 (see Example 1, step 1.3 and Example 24, steps 24.1, 24.2 and 24.3). LC-MS (A): tR = 0.96 min; [M+H]+: 286.05.
21.3. 2-(S-fluoro-phenyl)-6-((S)-S-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carboxylic acid:
This compound was prepared using a method analogous to that of Example 1, step 1.8, intermediate 21.2 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid. The product was however not purified. LC-MS (A): tR = 0.77 min; [M+H]+: 318.16.
21.4. 4-((S)-4-(diethoxy-phosphoryl)-2-{[2-(S-fluoro-phenyl)-6-((S)-S-methoxy-pyrrolidin-l-yl)-pyrimidine-4-
carbonyl]-amino}-butyryl)-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 7, step 7.1, intermediate 21.3 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid. The product was however purified by preparative LC-MS (IV). LC-MS (A): tR = 1.11 min; [M+H]+: 706.94.
21.5. 4-((S)-2-{[2-(3-fluoro-phenyl)-6-((S)-3-methoxy-pyrrolidin-l-yl)-pyrimidine-4-carbonyl]-amino}-4-phosphono-
butyryl)-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 21.4 replacing intermediate 1.9. The crude was purified by preparative LC-MS (I). LC-MS (A): tR = 0.89 min; [M+H]+: 650.95.
Example 22: 4-{(i?)-2-[(6-methoxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-carboxylic acid butyl ester:
22.1. 4-{(R)-3-(diethoxy-phosphoryl)-2-[(6-methoxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-propionyl}-
piperazine-l-carboxylic acid butyl ester:
NaH (36 mg, 55% dispersion in mineral oil) was suspended in MeOH (0.5 mL). The resulting sodium methylate solution was added to a solution of intermediate 14.1 (102 mg) in MeOH (0.5 mL). The reaction mixture was stirred at RT for 2 h. Sat. aq. NH4CI and DCM were added and the phases were separated. The aq. phase was extracted with DCM and the combined org. phases were dried (Na2SOA and evaporated off to afford the desired compound (71 mg). LC-MS (A): tR = 1.06 min; [M+H]+: 605.97.
22.2. 4-{(R)-2-[(6-methoxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 22.1 replacing intermediate 1.9. The crude was purified by CC (reversed phase; eluent: gradient from water/TFA 100/1 to MeCN/TFA 100/1). LC-MS (A): tR = 0.90 min; [M+H]+: 549.94.
Example 23 : 4-{(R)-2- [(6-methyl-2-phenyl-pyrimidine-4-carbonyl)-amino] -3-phosphono-propionyl}-piperazine-l-

carboxylic acid butyl ester:
23.1. 4-{(R)-3-(diethoxy-phosphoryl)-2-[(6-methyl-2-phenyl-pyrimidine-4-carbonyl)-amino]-propionyl}-piperazine-l-
carboxylic acid butyl ester:
Intermediate 14.1 (114 mg), methylboronic acid (17 mg), tetrakis(triphenylphosphine)palladium (11 mg) and potassium phosphate (80 mg) were suspended in anhydrous dioxane (1 ml) under argon. The mixture was stirred overnight at RT under argon, then overnight at 50°C. Methylboronic acid (45 nig),
tetrakis(triphenylphosphine)palladium (108 mg) and potassium phosphate (198 mg) were added to the mixture and it was further stirred for 4.5 h at 50°C. Water and DCM were added, the aq. phase was extracted with DCM and the combined org. phases were dried (Na2SCA) and evaporated off. The crude was purified by CC three times (CC No. 1 : eluent: gradient from EAto EA/MeOH 9/1; CC No. 2: eluent: gradient form EAto EA/MeOH 100/1; CC No. 3: reverse phase, eluent: gradient from water/TFA 100/1 to MeCN/TFA 100/1) to give the desired compound as a colourless resin (22 mg). LC-MS (A): tR = 1.03 min; [M+H]+: 589.95.
23.2. 4-{(R)-2-[(6-methyl-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1-carboxylic
acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 23.1 replacing intermediate 1.9. The crude was purified by CC (reversed phase; eluent: gradient from water/TFA 100/1 to MeCN/TFA 100/1). LC-MS (A): tR = 0.86 min; [M+H]+: 533.96.
Example 24 : 4-{(R)-2- [(6-cyclopropylaminoA-phenyl-pyrimidineA-carbonyA-amino] -3-phosphono-propionylJ-piperazine-l-carboxylic acid butyl ester:
24.1. 4-[(R)-2-[(6-cyclopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-(diethoxy-phosphoryl)-propionyl] -
piperazine-1 -carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.8, cyclopropylamine replacing intermediate 1.7, intermediate 14.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid and heating at 70°C instead of 60°C. The product was however not purified. LC-MS (A): tR = 1.04 min; [M+H]+: 631.04.
24.2. 4-{(R)-2-[(6-cyclopropylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 24.1 replacing intermediate 1.9. The crude was purified by preparative LC-MS (II). LC-MS (A): tR = 0.88 min; [M+H]+: 574.84.
Example 25: 4-{(i?)-2-[(2-phenyl-6-phenylamino-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-carboxylic acid butyl ester:
25.1. 4-{(R)-S-(diethoxy-phosphoryl)-2-[(2-phenyl-6-phenylamino-pyrimidine-4-carbonyl)-amino] -propionylj-
piperazine-1 -carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.8, aniline (10 equivalents) replacing intermediate 1.7, intermediate 14.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid and heating at 70°C instead of 60°C. The product was however not purified. LC-MS (A): tR = 1.09 min; [M+H]+: 666.99.
25.2. 4-{(R)-2-[(2-phenyl-6-phenylamino-pyrimidine-4-carbonyl)-amino]-S-phosphono-propionylj-piperazine-l-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 25.1 replacing intermediate 1.9. The crude was purified by preparative LC-MS (III). LC-MS (A): tR = 0.96 min; [M+H]+: 610.88.
Example 26: 4-{(i?)-2-[(6-benzylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-carboxylic acid butyl ester:
26.1. 4-[(R)-2-[(6-benzylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-(diethoxy-phosphoryl)-propionyl]-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.8, benzylamine replacing intermediate 1.7, intermediate 14.1 replacing 6-chloro-2-phenyl- pyrimidine-4-carboxylic acid and heating at 70°C instead of 60°C. The product was however not purified.

LC-MS (A): tR = 1.09 min; [M+H]+: 681.01.
26.2. 4-{(R)-2-[(6-benzylamino-2-phenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionylj-piperazine-l-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 26.1
replacing intermediate 1.9. The crude was purified by preparative LC-MS (III).
LC-MS (A): tR = 0.95 min; [M+H]+: 624.94.
Example 27: 4-[(i?)-2-({2-phenyl-6-[(i?)-(tetrahydro-furan-3-yl)amino]-pyrimidiiie-4-carbonyl}-amino)-3-phosphono-propionyl]-piperazine-l-carboxylic acid butyl ester:
27.1. 4- [(R)-3-(diethoxy-phosphoryl)-2-({2-phenyl-6- [(R)-(tetrahydro-furan-3-yl)amino) '-pyrimidine-4-carbonyl}-
amino)-propionyl] -piper azine-1-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.8, (i?)-(+)-3-aminotetrahydrofurane toluene-4-sulfonate replacing intermediate 1.7, intermediate 14.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid and heating at 70°C instead of 60°C. The product was however not purified. LC-MS (A): tR = 1.01 min; [M+H]+: 661.01.
27.2. 4- [(R)-2-({2-phenyl-6- [(R)-(tetrahydro-furan-3-yl)amino] -pyrimidine-4-carbonyl}-amino)-3-phosphono-
propionyl]-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 27.1 replacing intermediate 1.9. The crude was purified by preparative LC-MS (II). LC-MS (A): tR = 0.86 min; [M+H]+: 604.95.
Example 28: 4-((i?)-2-{[6-(3-hydroxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carboiiyl]-amino}-3-phosphono-propionyl)-piperazine-l-carboxylic acid butyl ester:
28.1. 4-((R)-S-(diethoxy-phosphoryl)-2-{[6-(S-hydroxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-
propionyi)-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1 step 1.8, 3-pyrrolidinol replacing intermediate 1.7, intermediate 14.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid, and heating at 70°C instead of 60°C. The product was however not purified. LC-MS (A): tR = 0.97 min; [M+H]+: 661.01.
28.2. 4-((R)-2-{[6-(3-hydroxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl] -amino}-3-phosphono-propionyl)-
piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 28.1 replacing intermediate 1.9. The crude was purified by preparative LC-MS (I). LC-MS (A): tR = 0.81 min; [M+H]+: 604.93.
Example 29 : 4- [(R)-2-({6- [(2-methoxy-ethyl)-methyl-amino] -2-phenyl-pyrimidine-4-carbonyl}-amino)-3-phosphono-propionyl]-piperazine-l-carboxylic acid butyl ester:
29.1. 4-[(R)-3-(diethoxy-phosphoryl)-2-({6-[(2-methoxy-ethyl)-methyl-amino]-2-phenyl-pyrimidine-4-carbonyl}-
amino)-propionyl]-piperazine-l-carboxylic acid butyl ester::
This compound was prepared using a method analogous to that of Example 1, step 1.8, 7V-(2-methoxyethyl)methylamine replacing intermediate 1.7, intermediate 14.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid and heating at 70°C instead of 60°C. The product was however not purified. LC-MS (A): tR = 1.05 min; [M+H]+: 663.01.
29.2. 4- [(R)-2-({6- [(2-methoxy-ethyl)-methyl-amino] -2-phenyl-pyrimidine-4-carbonyl}-amino)-S-phosphono-
propionyl]-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 29.1 replacing intermediate 1.9. The crude was purified by preparative LC-MS (II). LC-MS (A): tR = 0.89 min; [M+H]+: 606.81.
Example 30: 4-((i?)-2-{[6-(2-ethoxycarbonyl-ethylamino)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-l-carboxylic acid butyl ester:
30.1. 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-(2-ethoxycarbonyl-ethylamino)-2-phenyl-pyrimidineA-carbonylj-aminoj-
propionyij-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.8, ethyl 3-aminopropanoate

hydrochloride replacing intermediate 1.7, intermediate 14.1 replacing 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid and heating at 70 C instead of 60°C. The product was however not purified. LC-MS (A): tR = 1.04 min; [M+H]+: 690.97.
30.2. 4-((R)-2-{[6-(2-ethoxycarbonyl-ethylamino)-2-phenyl-pyrimidine-4-carbonyl] -amino}-3-phosphono-
propionyi)-piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.10, intermediate 30.1
replacing intermediate 1.9. The crude was purified by preparative LC-MS (II).
LC-MS (A): tR = 0.90 min; [M+H]+: 634.91.
Example 31: 4-((i?)-2-{[6-(2-carboxy-ethylamino)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-l-carboxylic acid butyl ester:
The compound of Example 30 (42 mg) and NaOH (26 mg) were dissolved in MeOH (1 mL). After stirring at RT for 2 h, the reaction mixture was acidified with a \M HCI solution and extracted with EA. The org. layers were dried (Na2SOA and evaporated off. The crude was purified by preparative LC-MS (I) to afford the desired compound (0.2 mg). LC-MS (A): tR = 0.80 min; [M+H]+: 606.80.
Example 32 : 4-{(R)-2- [(2,6-diphenyl-pyrimidine-4-carbonyl)-amino] -3-phosphono-propionylj-piperaziiie-l-carboxylic acid butyl ester:
32.1. 4-{(R)-S-(diethoxy-phosphoryl)-2-[(2, 6-diphenyl-pyrimidine-4-carbonyl)-amino]-propionyl}-piperazine-l-
carboxylic acid butyl ester:
Intermediate 14.1 (150 mg), phenylboronic acid (45 mg), tetrakis(triphenylphosphine)palladium (14 mg) and potassium phosphate (104 mg) were dissolved in anhydrous dioxane (1 ml) under argon. The mixture was heated at 80°C overnight and water was added. The mixture was extracted with EA and the org. phase was dried (Na2SOA and evaporated off. The crude was purified by CC (eluent: gradient from Hept to EA, followed by MeOH) to give the desired compound (86 mg). LC-MS (A): tR = 1.12 min; [M+H]+: 651.99.
32.2. 4-{(R)-2-[(2, 6-diphenyl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-1-carboxylic acid
butyl ester:
Intermediate 32.1 (86 mg) was dissolved in 3 M HCI in EA(1.5 mL) and H2O(0.15 mL). After stirring at RT for 2 h, toluene was added and the solvents were evaporated off. The crude was purified by preparative LC-MS (III) to give the desired compound as a white solid (34 mg). LC-MS (A): tR = 0.98 min; [M+H]+: 595.90.
Example 33: 4-{(i?)-2-[(2-phenyl-6-thiophen-3-yl-pyrimidine-4-carbonyl)-amiiio]-3-phosphono-propionyl}-piperazine-l-carboxylic acid butyl ester:
33.1. 2-phenyl-6-thiophen-3-yl-pyrimidine-4-carboxylic acid:
This compound was prepared using a method analogous to that of Example 32, step 32.1, 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid replacing intermediate 14.1 and thiophene- 3-boronic acid replacing phenylboronic acid. The crude was however crystallized (EtOHZH20
2/1).
LC-MS (A): tR = 1.03 min; [M+H]+: 283.03.
33.2. 4-{(R)-3-(diethoxy-phosphoryl)-2-[(2-phenyl-6-thiophen-3-yl-pyrimidine-4-carbonyl)-amino] -propionylj-
piperazine-l-carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 1, step 1.3, intermediate 33.1 replacing intermediate 1.2 and intermediate 2.4 replacing 1-ethoxycarbonylpiperazine. During the work-up, the org. phases were additionally washed with an aq. NaHS94 solution. The crude was not purified. LC-MS (A): tR = 1.11 min; [M+H]+: 657.93.
33.3. 4-{(R)-2-[(2-phenyl-6-thiophen-3-yl-pyrimidine-4-carbonyl)-amino]-3-phosphono-propionyl}-piperazine-l-
carboxylic acid butyl ester:
This compound was prepared using a method analogous to that of Example 32, step 32.2, intermediate 33.2 replacing intermediate 32.1. The product was however purified by preparative LC-MS (V) using a X-Terra column.