OA20308A

OA20308A - New amino-pyrimidonyl-piperidinyl derivatives, a process for their preparation and pharmaceutical compositions containing them.

Info

Publication number: OA20308A
Application number: OA1202100170
Authority: OA
Inventors: Didier DEMARLES; Olivier Geneste; James Brooke MURRAY; Andrea Fiumana; Csaba WÉBER; Attila Vasas; Alba Macias; Lisa IVANSCHITZ; Balázs MOLNÁR; Kristóf HEGEDÜS; Tibor SOÓS; 2117 Árpád KISS; András Kotschy; Péter SPRÁNITZ
Original assignee: Les Laboratoires Servier; Vernalis (R&D) Limited
Priority date: 2018-10-19
Publication date: 2022-05-10

Abstract

Compounds of formula (I):

Description

NEW AMINO-PYRIMIDONYL-PIPERIDINYL DERIVATIVES, A PROCESS FOR THEIR PREPARATION

AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The présent invention relates to new amino-pyrimidonyl-piperidinyl dérivatives, to a process 5 for their préparation and to pharmaceutical compositions containing them.

The compounds of the présent invention are new and hâve very vaiuable pharmacological characteristics in the field of apoptosis and oncology.

Ubiquitination is a process controlling essential cellular functions such as protein turnover and homeostasis, protein activation and localisation. Ubiquitin is a 76 amino acids 10 polypeptide which is covalently attached to postranslationnaly modified protein substrates via an isopeptide bond. Deubiquinating enzymes (DUBs) are in majority cysteine proteases that cleave the ubiquitin-ubiquitin bond or ubiquitin-protein bond at the Cter glycine of Ubiquitin. Approximately 100 DUBs regulate the thousands ubiquitinated proteins and then some redundancy of deubiquitinase substrates régulation are observed.

Dysrégulation of DUBs hâve been associated with several diseases such as neurodegenerative and infectious diseases (Edelman et al., Expert Rev. Mol. Med. 2011, 13, 1-17) and human malignancies (Pal et al., Cancer Res. 2014, 74, 4955-4966). Accordingly, overexpression of DUBs or increase of their activity hâve been associated to numerous types of cancers (Luise et aL, Plos One 2011, 6, e 15891; Rolen et al., Mol. Carcinog. 2006, 45, 20 260-269) and poor prognosis.

Ubiquitin Spécifie Protease 7 (USP7), also known as Herpes-virus-Associated UbiquitinSpecific Protease (HAUSP), belongs to the deubiquitinating family. USP7 has been reported to stabilize numerous oncogenes involved in survival and proliférations via cell cycle progression, apoptosis, DNA repair, DNA réplication and epigenetic factors régulation 25 (Nicholson et al., Cell Biochem. Biophys. 2011, 60, 61-68). In addition, USP7 has been shown to regulate immune response via inflammation and Treg modulation (Van Loosdregt et aL, Immunity 2013, 39, 259-27; Colleran et al., Proc. Natl. Acad. Sci. USA 2013, 110, 618623). USP7 has also been implicated in other pathologie States such as neurodevelopmental disorder (Hao et aL, Mol. Cell 2015, 59, 956-969) and viral infection (Holowaty et al.,

-2Biochem. Soc. Trans. 2004, 32, 731-732).

USP7 overexpression has been associated with late stages of cancers and poor prognosis in lung, neuroblastoma, myeloma, prostate, colon and breast cancers. Numerous USP7 inhibitors hâve been recently published in the literature (Turnbull et al., Nature 2017, 550, 481-486; Kategaya et al., Nature 2017, 550, 534-538; Gavory et al., Nat. Chem. Biol. 2018, 14, 118-125; O’Dowd et ACS Med. Chem. Lett. 2018, 9, 238-243; Pozhidaeva et al., Cell Chem. Biol. 2017, 24, 1501-1512; Lamberto et al., Cell Chem. Biol. 2017, 24, 1490-1500; PCT/EP2017/064062; PCT/EP2017/064067) and, particularly, pyrimidonyl dérivatives claimed as USP7 inhibitors hâve been disclosed in PCT/GB2017/053175. However, PCT/GB2017/053175 shows that 5,6-disubstituted pyrimidonyl dérivatives provide compounds with weakest affinity on USP7. Despite an intense research in the field, no USP7 inhibitors hâve entered the clinic (Kemp et al., Progress in Médicinal Chemistry 2016, 55, 149-192; Wuet al., J. Med. Chem. 2018, 61,422-443). There is, therefore, a therapeutic need for compounds that inhibit the activity of the protein USP7.

In addition to being new and very potent on their target, the compounds of the présent invention hâve pro-apoptotic and/or anti-proliferative properties making it possible to use them in pathologies involving a defect in apoptosis, such as, for example, in the treatment of cancer and of immune and auto-immune diseases.

The présent invention relates more especially to compounds of formula (I):

wherein:

♦ Q represents an oxygen atom or a sulphur atom, ♦ Ri represents a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, ♦ R2 represents an aryl group or a heteroaryl group, ♦ R₃ represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched halo(Ci-Cô)alkyl, a linear or branched hydroxy(Ci-C6)alkyl group, a -C(O)-R8 group, a -C(O)-ORs group, a -C(O)-NH-R8 group, or a group, ♦ R4 represents a hydrogen atom or a halogen atom, ♦ R5 represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched halo(Ci-C6)alkyl group, or an aryl(Ci-Cô)alkyl group, ♦ n is an integer equal to 0, 1 or 2, ♦ J represents a -C(O)- group, a -CH(R6)- group, a -SO2- group, a -C(X)-N(R₇)- group, a -CH₂-C(O)-N(R₇)- group, or a group, ♦ Rô represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, or a -C(O)-OR8 group, ♦ R7 represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group, ♦ Rs represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, or a linear or branched halo(Ci-C6)alkyl group, ♦ K represents a bond or a-Cyi-group, ♦ L represents a linear or branched (Ci-C6)alkyl group, a -Cy2 group, or a -C(R9)2-Cy2 group, ♦ X represents an oxygen atom or a sulphur atom, ♦ R₉ represents a hydrogen atom or a halogen atom, ♦ Cyi represents a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, which is linked to the group J and to the group L, ♦ Cy2 represents a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, it being understood that:

- “aryl” means a phenyl, naphthyl, or indanyl group,

- “heteroaryl” means any mono- or fused bi-cyclic group composed of from 5 to 10 ring

-4members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,

- “cycloalkyl” means any mono- or fused bi-cyclic non-aromatic carbocyclic group containing from 3 to 7 ring members,

- “heterocycloalkyl” means any non-aromatic mono- or fused bi-cyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined to be substituted by from 1 to 4 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched (C2-Cë)alkenyl, linear or branched (C2-Cô)alkynyl, linear or branched halo(CiCô)alkyl, -Yi-OR’, -Yi-NR’R”, -Yi-S(O)_m-R’, oxo, A-oxide (where appropriate), pentafluorosulfide, nitro, -Υι-CN, -C(O)-R’, -C(O)-OR’, -O-C(O)-R’, -Yi-C(O)-NR’R”, -Yi-NR’-C(O)-R”, -Yi-NR’-C(O)-OR”, halogen, cyclopropyl and pyridinyl which can be substituted by a linear or branched (Ci-C6)alkyl group, it being understood that:

- Yi represents a bond, a linear or branched (Ci-C4)alkylene group, or a linear or branched halo(Ci-C4)alkylene group,

- R’ and R” independently of one another, represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a linear or branched (Ci-Ce)alkoxy group, a linear or branched halo(Ci-C6)alkyl, a linear or branched hydroxy(Ci-C6)alkyl group, a linear or branched (Ci-Ce)alkoxy(Ci-C6)alkyl group, a formyl group, a phenyl group, a benzyl group, a cyclopropyl group, a cyclopropylmethyl group, a tetrahydropyranyl group, or the pair (R’, R”) together with the nitrogen atom to which they are attached forms a non-aromatic ring composed of from 4 to 7 ring members, which may contain in addition to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by from 1 to 2 groups representing a hydrogen atom or a linear or branched (Ci-C6)alkyl group,

- m is an integer equal to 0, 1 and 2,

-5their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

In a preferred embodiment of the invention, the présent invention relates to compounds of formula (I) wherein:

♦ Q represents an oxygen atom, ♦ Ri represents an aryl group or a heteroaryl group, ♦ R₂ represents an aryl group, ♦ R₃ represents a hydrogen atom, a linear or branched hydroxy(Ci-C6)alkyl group, a -C(O)-ORs group, a -C(O)-NH-Rs group, or a group, ♦ Rs represents a hydrogen atom, ♦ Rô represents a hydrogen atom or a -C(O)-ORs group, ♦ Rs represents a linear or branched (C 1 -Cô)alky 1 group or a linear or branched halo(C 1 Cô)alkyl group, ♦ Cyi represents a cycloalkyl group, an aryl group, or a heteroaryl group, which is linked to the group J and to the group L, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined to be substituted by from 1 to 4 groups selected from linear or branched (Ci-C6)alkyl, linear or branched haIo(Ci-C6)alkyl, -Yi-OR’, -Yi-NR’R”, oxo, -Yi-CN, -Yi-NR’-C(O)-OR”, halogen, or cyclopropyl, it being understood that R’ and R’ ’ independently of one another, represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched halo(Ci-Ce)alkyl, or the pair (R’, R”) together with the nitrogen atom to which they are attached forms a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by from 1 to 2 groups representing a hydrogen atom, or a linear or branched (Ci-Cô)alkyl group.

Among the pharmaceutically acceptable acids there may be mentioned, without implying

-6any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, terZ-butylamine etc.

Among the heteroaryl groups there may be mentioned, without implying any limitation, pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl (also known as pyridyl), pyrazinyl, pyridazinyl, pyrimidinyl, pyridinonyl, indolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, dihydrocyclopentathienyl, benzothienyl, tetrahydrobenzothienyl, benzofuranyl, imidazopyridinyl, benzotriazolyl, benzodioxolyl, dihydrobenzodioxinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, dihydroquinoxalinyl, dihydrothienodioxinyl, quinazolinonyl, pyrrolopyridazinyl, pyrrolopyridinyl, dihydropyrrolizinyl, tetrahydroindolizinyl, etc.

Among the cycloalkyl groups there may be mentioned, without implying any limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

Among the heterocycloalkyl groups there may be mentioned, without implying any limitation, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, etc.

Advantageously, the compounds of formula (I) display a trans configuration as follows:

wherein Ri, R2, R3, R4, Rs, Q and n are as defined for formula (I).

More preferably, the compounds of formula (I) display a trans configuration as follows:

wherein Ri, R2, R3, R4, Rs, Q and n are as defined for formula (I).

In another embodiment, when R4 represents a halogen atom and n is an integer equal to 1 or

2, a new asymmetric carbon is created providing two possible isomers as follows:

or

wherein Ri, R₂, R₃, Rs, Q and n are as defined for formula (I) and R₄ is as defined hereinbefore.

Preferably, when R₄ represents a halogen atom and n is an integer equal to 2, having the 5 following formula:

the preferred isomer has the ^-configuration as follows:

wherein Ri, R₂, R₃, R₅ and Q are as defined for formula (I) and R₄ is as defined hereinbefore.

Q advantageously represents an oxygen atom.

Ri preferably represents an aryl group or a heteroaryl group. More preferably, Ri represents a phenyl group or a pyridinyl group. Even more preferably, Ri represents a phenyl group. In a preferred embodiment of the invention, Ri represents a phenyl group which is substituted by from 1 to 2 groups selected from linear or branched halo(Ci-C₆)alkyl, -Yi-OR’, -Yi-NR’R”, -Υι-CN, -Yi-NR’-C(O)-OR”, halogen, cyclopropyl, in which Yi, R’ and R” are as defined for formula (I). More advantageously, 5 Ri represents a phenyl group which is substituted by from 1 to 2 groups selected from fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, aminomethyl or tert-butoxycarbonylaminomethyl.

R2 preferably represents an aryl group. More preferably, R2 represents a phenyl group.

R3 preferably represents a hydrogen atom, a linear or branched hydroxy(Ci-C6)alkyl, a -C(O)-OR₈ group, a -C(O)-NH-R₈ group, or a group.

More preferably, R₃ represents a group.

Advantageously, R4 represents a hydrogen atom or a fluorine atom. More preferably, R4 represents a hydrogen atom. In another embodiment, when R4 represents a fluorine atom and n is equal to 2, both fluorine atoms preferably represent a gem-difluoro group.

Preferably, Rs represents a hydrogen atom.

Preferably, Rô represents a hydrogen atom or a -C(O)-ORs group. More preferably, Rô represents a hydrogen atom.

In the preferred compounds of the invention, J represents a -C(O)- group, a -CH2- group, a -CH[C(O)-O-CH₂-CH₃]- group, a -SO₂- group, a -CH₂-C(O)-N(R₇)- group a -C(X)-N(R₇)- group, or a

group.

Preferably, J represents a -C(O)- group, a -CH₂- group, a -SO2- group, or a -C(O)-NH- group.

More preferably, J represents a -C(O)- group. Advantageously, J represents a -CH2- group. In another preferred embodiment, J represents a -C(O)-NH- group.

K preferably represents a bond or a -Cyi- group selected from a phenyl group, a pyrrolyl group, a thienyl group, athiazolyl group, an oxazolyl group, an imidazolyl group, a pyrazolyl 5 group, a pyridinyl group, a pyrimidinyl group, a dihydrothienodioxinyl group, a cyclopropyl group, or a cyclobutyl group. More preferably, K preferably represents a bond or a -Cyigroup selected from a phenyl group, a thienyl group, a thiazolyl group, an imidazolyl group, a pyridinyl group, a pyrimidinyl group, or a dihydrothienodioxinyl group.

Preferably, Cyi represents a cycloalkyl group, an aryl group, or a heteroaryl group. 10 Preferably, Cyi represents a cycloalkyl group, an aryl group, or a heteroaryl group which are substituted by 1, 2 or 3 groups selected from linear or branched (Ci-Cejalkyl, linear or branched haIo(Ci-C6)alkyl, -Yi-OR’, -Yi-NR’R”, oxo, halogen, in which R’ and R” independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group, or the pair (R’, R”) together with the nitrogen atom to which they are attached forms 15 a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by a linear or branched (Ci-C6)alkyl group. Preferably, Cyi represents a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyrazolyl group, a pyridinyl 20 group, a pyrimidinyl group, a dihydrothienodioxinyl group, a cyclopropyl group, or a cyclobutyl group, said groups are substituted by 1, 2 or 3 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched halo(Ci-C6)alkyl, -Yi-OR’, -Yi-NR’R”, oxo, halogen, in which R’ and R” independently of one another represent a hydrogen atom, a linear or branched (Ci-Côjalkyl group, or the pair (R’, R”) together with the nitrogen atom 25 to which they are attached forms a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by a linear or branched (Ci-Ce)alkyl group. Even more preferably, Cyi represents a phenyl group, a thienyl group, a thiazolyl group, an imidazolyl group, a 30 pyridinyl group, a pyrimidinyl group, or a dihydrothienodioxinyl group, said groups are substituted by 1, 2 or 3 groups selected from linear or branched (Ci-C6)alkyl, linear or branched halo(Ci-C6)alkyl, -Yi-OR’, -Yi-NR’R”, oxo, halogen, in which R’ and R” independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group, or the pair (R’, R”) together with the nitrogen atom to which they are attached forms a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition 5 to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by a linear or branched (Ci-C6)alkyl group. Advantageously, Cyi represents a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyrazolyl group, a pyridinyl group, a pyrimidinyl group, a dihydrothienodioxinyl group, a cyclopropyl group, or a 10 cyclobutyl group, said groups are substituted by 1, 2 or 3 groups selected from methyl, fluorine or chlorine. More advantageously, Cyi represents a phenyl group, a thienyl group, a thiazolyl group, an imidazolyl group, a pyridinyl group, a pyrimidinyl group, or a dihydrothienodioxinyl group, said groups are substituted by 1, 2 or 3 groups selected from methyl, fluorine or chlorine.

Advantageously, L represents a linear or branched (Ci-C6)alkyl group, a -Cy2 group, a -CH2-Cy2 group, or a -CF2-Cy2 group. More advantageously, L represents a -Cy2 group. Preferably, Cy2 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a piperidinyl group, a tetrahydropyranyl group, a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, a dihydroindolyl group, a isoquinolinyl group, a dihydrothienodioxinyl group, a benzothiazolyl group, or a quinazolinonyl group. More preferably, Cy2 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a tetrahydropyranyl group, a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, a isoquinolinyl group, or a quinazolinonyl group.

Preferably, Cy2 represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group which are substituted by 1, 2 or 3 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched halo(Ci-C6)alkyl, -Yi-OR’, -Yi-NR’R”, oxo, halogen, in which R’ and R” independently of one another represent a hydrogen atom, a linear or branched (Ci-Ce)alkyl group, or the pair (R’, R”) together with the nitrogen atom to which

- 12they are attached forms a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by a linear or branched (Ci-C6)alkyl group. More preferably, Cy₂ represents a cyclobutyl group, 5 a cyclopentyl group, a cyclohexyl group, a piperidinyl group, a tetrahydropyranyl group, a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, a dihydroindolyl group, a isoquinolinyl group, a dihydrothienodioxinyl group, a benzothiazolyl group, or a quinazolinonyl group, said groups 10 are substituted by 1, 2 or 3 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched halo(Ci-Ce)alkyl, -Yi-OR’, -Yi-NR’R”, oxo, halogen, in which R’ and R” independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group, or the pair (R’, R”) together with the nitrogen atom to which they are attached forms a non-aromatic ring composed of from 5 to 7 ring members, which may 15 contain in addition to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by a linear or branched (Ci-Cô)alkyl group. Even more preferably, Cy₂ represents cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a tetrahydropyranyl group, a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl 20 group, a pyridazinyl group, an indolyl group, a isoquinolinyl group, or a quinazolinonyl group, said groups are substituted by 1, 2 or 3 groups selected from linear or branched (CiCô)alkyl, linear or branched halo(Ci-C6)alkyl, -Yi-OR’, -Yi-NR’R”, oxo, halogen, in which R’ and R” independently of one another represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, or the pair (R’, R”) together with the nitrogen atom to which they are 25 attached forms a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by a linear or branched (Ci-C6)alkyl group. Advantageously, Cy₂ represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a piperidinyl group, a tetrahydropyranyl group, a 30 phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, a dihydroindolyl group, a isoquinolinyl group, a

- 13 dihydrothienodioxinyl group, a benzothiazolyl group, or a quinazolinonyl group, said groups are substituted by 1, 2 or 3 groups selected from fluorine, bromine, iodine, chlorine, methyl, trifluoromethyl, methoxy, ethoxy, oxo and

-Yi-NR’R” wherein Yi is a bond and R’ and R” represent a methyl group or the pair 5 (R’, R”) together with the nitrogen atom to which they are attached forms a piperazinyl group, more preferably a 4-methyl-piperazinyl group, a morpholinyl group or a pyrrolidinyl group. More advantageously, Cy2 represents cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a tetrahydropyranyl group, a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a 10 pyridazinyl group, an indolyl group, a isoquinolinyl group, or a quinazolinonyl group, said groups are substituted by 1, 2 or 3 groups selected from fluorine, bromine, iodine, chlorine, methyl, trifluoromethyl, methoxy, ethoxy, oxo and -Yi-NR’R” wherein Yi is a bond and R’ and R” represent a methyl group or the pair (R’, R”) together with the nitrogen atom to which they are attached forms a piperazinyl group, more preferably a 15 4-methyl-piperazinyl group, a morpholinyl group or a pyrrolidinyl group.

In some preferred embodiment of the invention, K represents a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyrazolyl group, a pyridinyl group, a pyrimidinyl group, a dihydrothienodioxinyl group, a cyclopropyl group, or a cyclobutyl group and L represents a cyclobutyl group, a cyclopentyl group, a 20 cyclohexyl group, a piperidinyl group, a tetrahydropyranyl group, a phenyl group, a benzyl group, a pyrrolyl group, a thienyl group, or a pyridinyl group. More preferably, K represents a phenyl group, a thienyl group, a thiazolyl group, an imidazolyl group, a pyridinyl group, a pyrimidinyl group or a dihydrothienodioxinyl group, and L represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a tetrahydropyranyl group, a phenyl group, a benzyl 25 group, a pyrrolyl group, or a pyridinyl group, said groups may be substituted by 1 or 2 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched halo(Ci-C6)alkyl, -YiNR’R”, halogen, in which R’ and R” independently of one another represent a hydrogen atom or a linear or branched (Ci-Cô)alkyl group. Even more preferably, K represents a phenyl group, a thienyl group, a 30 thiazolyl group, an imidazolyl group, a pyridinyl group, a pyrimidinyl group or a dihydrothienodioxinyl group, and L represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a tetrahydropyranyl group, a phenyl group, a benzyl group, a pyrrolyl group, or a pyridinyl group, said groups may be substituted by 1 or 2 groups selected from fluorine, chlorine, methyl, trifluoromethyl and -Yi-NR’R” wherein Yi is a bond and R’ and R” represent a methyl group.

In a preferred embodiment, K represents a thienyl group and L represents a pyridinyl group, said groups may be substituted by 1 or 2 groups selected from linear or branched (CiCôjalkyl, linear or branched halo(Ci-C6)alkyl, -Yi-NR’R”, halogen, in which R’ and R” independently of one another represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group.

In another preferred embodiment, K represents a pyridinyl group and L represents a phenyl group, a pyrrolyl group or a pyridinyl group, said groups may be substituted by 1 or 2 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched halo(Ci-C6)alkyl, -YiNR’R”, halogen, in which R’ and R” independently of one another represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group.

In another preferred embodiment, K represents a pyrimidinyl group and L represents a phenyl group or a pyridinyl group, said groups may be substituted by 1 or 2 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched halo(Ci-Cô)alkyl, -Yi-NR’R”, halogen, in which R’ and R” independently of one another represent a hydrogen atom or a linear or branched (Ci-Cô)alkyl group.

In another preferred embodiment, K represents a thiazolyl group and L represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a tetrahydropyranyl group, a phenyl group, a benzyl group, or a pyridinyl group, said groups may be substituted by 1 or 2 groups selected from linear or branched (Ci-C6)alkyl, linear or branched halo(Ci-C6)alkyl, -Yi-NR’R”, halogen, in which R’ and R” independently of one another represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group.

In another preferred embodiment, K represents an imidazolyl group and L represents a pyridinyl group, said groups may be substituted by 1 or 2 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched halo(Ci-Ce)alkyl, -Yi-NR’R”, halogen, in which R’ and R” independently of one another represent a hydrogen atom or a linear or branched 30 (Ci-C6)alkyl group.

In another preferred embodiment, K represents a phenyl group and L represents a pyridinyl group, said groups may be substituted by 1 or 2 groups selected from linear or branched (Ci20308

- 15 Côjalkyl, linear or branched halo(Ci-C6)alkyl, -Yi-NR’R”, halogen, in which R’ and R” independently of one another represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group.

In another preferred embodiment, K represents a dihydrothienodioxinyl group and 5 L represents a pyridinyl group, said groups may be substituted by 1 or 2 groups selected from linear or branched (Ci-C6)alkyl, linear or branched halo(Ci-C6)alkyl, -Yi-NR’R”, halogen, in which R’ and R’ ’ independently of one another represent a hydrogen atom or a linear or branched (Ci-Cô)alkyl group.

Other compounds of the invention to which preference is given are those wherein 10 K represents a bond and L represents a phenyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, a dihydroindolyl group, a isoquinolinyl group, a dihydrothienodioxinyl group, a benzothiazolyl group, or a quinazolinonyl group.

More preferably, K represents a bond and L represents a phenyl group, a thienyl group, a 15 thiazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, a isoquinolinyl group, or a quinazolinonyl group, each said group may be substituted by 1 or 2 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched halo(Ci-C6)alkyl, -Yi-OR’, -Yi-NR’R”, halogen, in which R’ and R” independently of one another represent a linear or branched (Ci-Cô)alkyl group, or the pair 20 (R’, R”) together with the nitrogen atom to which they are attached forms a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by a linear or branched (Ci-Cô)alkyl group. Even more preferably, K represents a bond and L represents a phenyl group, a thienyl group, a 25 thiazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, a isoquinolinyl group, or a quinazolinonyl group, each said group may be substituted by 1 or 2 groups selected from fluorine, bromine, iodine, chlorine, methyl, trifluoromethyl, methoxy, ethoxy, oxo and -Yi-NR’R” wherein Yi is a bond and the pair (R’, R”) together with the nitrogen atom to which they are attached forms a 30 piperazinyl group, more preferably a 4-methyl-piperazinyl group, a morpholinyl group or a pyrrolidinyl group.

- 16In a preferred embodiment, the -J-K-L group linked to the piperidinyl ring is defined such as J represents a -C(O)- group, K represents a -Cyi- group and L represents a -Cy2 group.

In another preferred embodiment, the -J-K-L group is defined such as J represents a -CH₂- group, K represents a bond and L represents a -Cy2 group.

In another preferred embodiment, the -J-K-L group is defined such as J represents a -C(O)- group, K represents a bond and L represents a -Cy2 group.

In another preferred embodiment, the -J-K-L group is defined such as J represents a -CH2- group, K represents a -Cyi- group and L represents a -Cy₂ group.

In another preferred embodiment, the -J-K-L group is defined such as J represents a -C(O)NH- group, K represents a bond and L represents a -Cy2 group.

In another preferred embodiment, the -J-K-L group is defined such as J represents a -C(O)NH- group, K represents a -Cyi- group and L represents a -Cy2 group.

In another preferred embodiment, the -J-K-L group is defined such as J represents a -SO2- group, K represents a bond and L represents a -Cy2 group.

In a preferred embodiment of the invention, the présent invention relates to compounds of formula (I-a):

wherein Ri, R4, J, K, L and n are as defined for formula (I).

In another preferred embodiment of the invention, the présent invention relates to compounds of formula (I-b):

(I-b) wherein Ri, J, K and L are as defined for formula (I) and R4 represents a halogen atom, more preferably, a fluorine atom.

Preferably, Rs represents a linear or branched (Ci-C6)alkyl group or a linear or branched 5 halo(Ci-C6)alkyl group. More preferably, Rs represents a Zeri-butyl group or a 2,2,2-trifluoroethyl group.

Preferred compounds of the invention are:

- 5-amino-3 - {[(45)-3,3-di fluoro-4-hydroxy-1 - {(3R,4R)-1 - [(2-methy Ipyrim idin-4- yl)methyl]-3-phenylpiperidine-4-carbonyl}piperidin-4-yl]methyl}-6-(410 fluorophenoxy)pyrimidin-4(3Z/)-^one;

5-amino-6-(4-chlorophenoxy)-3-[(4-hydroxy-1 - {(3R,4R)-1 -[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3/Z)-one;

5-amino-6-(3-chloro-5-methoxyphenoxy)-3-[(4-hydroxy-l-{(37?,47?)-l-[4-methyl15 2-(6-methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(377)-one;

- 5-amino-6-(4-chloro-3-fluorophenoxy)-3-[(4-hydroxy-l-{(3.Æ,4À)-l-[4-methyI-2(6-methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3Z7)-one;

- 5-amino-6-(4-fluoro-3-methoxyphenoxy)-3-[(4-hydroxy-l-{(37?,4Æ)-l-[4-methyl-2(6-methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(37/)-one;

- 5-amino-3-[(4-hydroxy-l-{(3Æ,4Æ)-l-[4-methyl-2-(6-methylpyridin-3-yl)-l,320308

- Ιδιο thiazole-5-carbonyl]-3-phenyIpiperidine-4-carbonyl}piperidin-4-yl)methyl]-6-[3(trifluoromethyl)phenoxy]pyrimidin-4(3//)-one;

5-amino-3-[(4-hydroxy-l-{(32?,4J?)-l-[4-methyl-2-(6-methylpyridin-3-yl)-l,3thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}piperidin-4-yl)methyl]-6-[3(trifluoromethoxy)phenoxy]pyrimidin-4(3//)-one;

5-amino-3 -( {1 - [(3À,4A)-1 -(2-bromo-4-methyl-1,3 -thiazole-5 -carbony l)-3phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(37?)-one;

5-amino-3-({l-[(3À,4.Æ)-l-(benzenesulfonyl)-3-phenylpiperidine-4-carbonyl]-4hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3f/)-one;

5-amino-3-({l-[(3À,4À)-l-(3-bromobenzoyl)-3-phenylpiperidine-4-carbonyl]-4hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3//)-one;

5-amino-3-({l-[(37?,47?)-l-(5-bromopyridine-3-carbonyl)-3-phenylpiperidine-4carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3Z7)one;

- 5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(3A,47î)-l-(6'-methyl[3,3'bipyridine]-5-carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4yl}methyl)pyrimidin-4(377)-one;

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(37?,47?)-3-phenyl-l-(5phenylpyridine-3-carbonyl)piperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin4(377)-one;

5-amino-3-({l-[(3À,47?)-l-benzoyl-3-phenylpiperidine-4-carbonyl]-4hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3//)-one; 5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(37î,47?)-l-(l-methyl-lff-indole-2carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin-4(3/7)one;

-amino-3-( {1 - [(3À,47?)-1 -(3 -fluoro-5-iodothiophene-2-carbony l)-3 phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(377)-one;

5-amino-3-[(l-{(3À,47î)-l-[3-fluoro-5-(6-methylpyridin-3-yl)thiophene-2carbonyl]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-6-(4fluorophenoxy)pyrimidin-4(317)-one;

5-amino-3-({(45)-l-[(37/,47/)-1-(2-bromo-4-methyl-l,3-thiazole-5-carbonyI)-3phenylpiperidine-4-carbonyl]-3,3-difluoro-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(3/7)-one;

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(37/,47/)-1-{4-methyl-2-[6(trifluoromethyl)pyridin-3-yl]-l,3-thiazole-5-carbonyl}-3-phenylpiperidine-4carbonyI]piperidin-4-yl}methyl)pyrimidin-4(377)-one;

5-amino-3-({l-[(37/,47/)-l-{2-[6-(dimethylamino)pyridin-3-yl]-4-methyl-l,3th iazole-5 -carbonyl} -3 -pheny ipiperidine-4-carbony 1] -4-hydroxypiperidin-4yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(377)-one;

5-amino-3-{ [(45)-3,3-difluoro-l-{(37/,47/)-1-[2-(4-fluorophenyl)-4-methyl-1,3thiazole-5-carbonyI]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4yl]methyl}-6-(4-fluorophenoxy)pyrimidin-4(377)-one;

5-amino-3-{[(45)-3,3-difluoro-4-hydroxy-l-{(37/,47/)-l-[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl]methyl}-6-(4-fluorophenoxy)pyrimidin-4(377)-one; 5-amino-3-[(4-hydroxy-l-{(37/,47/)-l-[4-methyl-2-(6-methylpyridin-3-yl)-l,3thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}piperidin-4-yl)methyl]-6phenoxypyrimidin-4(377)-one;

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(37/,47/)-1-[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(377)-one;

5-amino-6-(4-fluorophenoxy)-3-[(l-{(37/,47/)-1-[2-(4-fluorophenyl)-4-methyl-1,3thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4yl)methyl]pyrimidin-4(377)-one;

5-amino-3-[[l-[(3R,4R)-l-[(2-bromothiazol-5-yl)methyl]-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one; 5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(37/,47/)-l-{[2-(6-methylpyridin-3yl)-l,3-thiazol-5-yI]methyl}-3-phenylpiperidine-4-carbonyl]piperidin-4yl} methyl)pyrimidin-4(377)-one;

- 5-amino-6-(4-fluorophenoxy)-3-[(l-{(37/,47/)-l-[(2-fluorophenyl)methyl]-3phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]pyrimidin-4(377)- one;

-20- 5-amino-3-({(45)-3,3-difluoro-4-hydroxy-l-[(37?,4/?)-l-{[2-(6-methylpyridin-3-yl)l,3-thiazol-5-yl]methyl}-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)-6(4-fluorophenoxy)pyrimidin-4(37/)-one;

- 5-amino-3-{[(4S)-3,3-difluoro-l-{(3R,4À)-l-[(2-fluorophenyl)methyl]-35 phenylpiperidine-4-carbonyl} -4-hydroxypiperidin-4-yl]methyl} -6-(4fluorophenoxy)pyrimidin-4(377)-one;

5-amino-3-({l-[(3.Æ,4À)-l-(3-ethoxybenzoyl)-3-phenylpiperidine-4-carbonyl]-4hydroxypiperidm-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3//)-one; 5-amino-3-({l-[(37?,4R)-l-(2-benzyl-4-methyl-l,3-thiazole-5-carbonyl)-310 phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(3//)-one;

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3R,47?)-3-phenyl-l-[(pyridin-3yl)methyl]piperidine-4-carbonyI}piperidin-4-yl)methyl]pyrimidin-4(37/)-one; 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3À,47?)-l-[4-methyl-215 (morpholin-4-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(377)-one;

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l -{(3Λ,4Λ)-1 -[4-methyl-2-(pyrrolidinl-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}piperidin-4yl)methyl]pyrimidin-4(3/7)-one;

- 5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-1 -[(3À,47?)-1 -(4-methyl-2-phenyl-1,3thiazoIe-5-carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4yI}methyl)pyrimidin-4(377)-one;

-amino-6-(4-fluorophenoxy)-3- [(4-hydroxy-1 - {(3R,4R)-1 -[7-(6-methy lpyridin-3 yl)-2,3-dihydrothieno[3,4-6][l,4]dioxine-5-carbonyl]-3-phenylpiperidine-425 carbonyI}piperidin-4-yl)methyl]pyrimidin-4(3//)-one;

(3R,4À)-4-(4-{[5-amino-4-(4-fluorophenoxy)-6-oxopyrimidin-l(6.Z7)-yl]methyl}-4hydroxypiperidine-1 -carbony l)-A'-(4-methoxy pheny l)-3 -pheny Ipiperidine-1 carboxamide;

(3À,4À)-4-(4-{[5-amino-4-(4-fluorophenoxy)-6-oxopyrimidin-l(617)-yl]methyl}-430 hydroxypiperidine-l-carbonyl)-3-phenyl-./V-[3-(trifluoromethyl)phenyl]piperidine1-carboxamide;

(3À,47?)-4-(4-{[5-amino-4-(4-fluorophenoxy)-6-oxopyrimidin-l(6/7)-yl]methyl}-420308 hydiOxypiperidine-l-carbonyl)-7V-(3-bromophenyl)-3-phenylpiperidine-lcarboxamide;

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-N-[3-(6-methyl-3-pyridyI)phenyl]-3-phenylpiperidine-1 -carboxamide;

5-am ino-6-(4-fluorophenoxy)-3-( {4-hydroxy-1 - [(3R,4R)-1 -(5 -methylpyrid ine-3 carbonyl)-3 -phenylpiperidine-4-carbony 1] piperidin-4-y 1} methy l)pyrim id in-4(3/7)one;

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l -{(3Λ,47?)-1 -[1 -methyl-2-(6methylpyridin-3-yl)-17/-imidazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(377)-one;

5-amino-3-({l-[(3R,47?)-l-(2,6-dimethylpyridine-4-carbonyl)-3-phenylpiperidine4-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin4(3/7)-one;

5-amino-3-({l-[(3R,4.K)-l-(3-bromo-5-fluorobenzoyl)-3-phenylpiperidine-4carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3/7)one;

5-amino-6-(4-fluorophenoxy)-3-({4-hydiOxy-l-[(3R,47?)-l-(isoquinoline-5carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin-4(377)one;

- 5-amino-3-({(45)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-{4-methyl-2-[6(trifluoromethyl)pyridin-3-yl]-l,3-thiazole-5-carbonyl}-3-phenylpiperidine-4carbonyl]piperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3//)-one; 5-amino-3-{ [(45)-3,3-difluoro-l-{(3R,4R)-1-[3-fluoro-5-(6-methylpyridin-3yl)thiophene-2-carbonyl]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4yl]methyl}-6-(4-fluorophenoxy)pyrimidin-4(3/7)-one;

5-amino-3-[(l-{(3R,4R)-l-[5-chloro-3-fluoro-4-(6-methylpyridin-3-yl)thiophene-2carbonyl]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-6-(4fluorophenoxy)pyrimidin-4(377)-one;

5-amino-3-{ [(45)-3,3-difluoro-4-hydroxy-l-{(3R, 4R)-1 -[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl]methyl}-6-phenoxypyrimidin-4(377)-one;

-225-amino-3-[(l-{(3Æ,47?)-l-[3-fluoro-5-(6-methylpyridin-3-yl)benzoyl]-3phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-6-(4fluorophenoxy)pyrimidin-4(3/7)-one;

6-[(37?,47?)-4-(4-{[5-amino-4-(4-fluorophenoxy)-6-oxopyrimidin-1(627)yl]methyl}-4-hydroxypiperidine-l-carbonyl)-3-phenylpiperidine-l-carbonyl]-3methylquinazolin-4(377)-one;

5-amino-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-[6-(trifluorornethyl)-3pyridyI]thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyI]methyl]6-[3-(trifluoromethyl)phenoxy]pyrimidin-4-one;

5-amino-3-[[l-[(3R,4R)-l-[2-[6-(dirnethylamino)-3-pyridyl]-4-methyl-thiazole-5carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-[3(trifluoromethyl)phenoxy]pyrimidin-4-one;

- 5-amino-3-[[l-[(3R,4R)-l-(3-chloro-l-methyl-indole-2-carbonyl)-3-phenylpiperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

- 5-amino-3-[[l-[(3R,4R)-l-(3,5-difluorobenzoyl)-3-phenyl-piperidine-4-carbonyl]4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

- 5-amino-3-[[l-[(3R,4R)-l-(3,5-dichlorobenzoyl)-3-phenyl-piperidine-4-carbonyl]4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[4-hydroxy-l-[(3R,4R)-l-[4-rnethyl-2-(6methyl-3-pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

5-amino-3-[[l-[(3R,4R)-l-(5-chloropyridine-3-carbonyl)-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one; 5-amino-6-(4-fluorophenoxy)-3-[[l-[(3R,4R)-l-(5-fluoropyridine-3-carbonyl)-3phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]pyrimidin-4-one; 5-amino-6-(4-chloro-3-fluoro-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[(5-methylpyrazin-2-yl)methyI]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(5-methylpyrazin-2yl)rnethyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluoro-3methoxy-phenoxy)pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-(5-methylpyridine-3carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[l-[(3R,4R)-l-(2-cyclohexyl-4-methyl-thiazole-5-carbonyl)-3-phenylpiperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-[3-(6-methyl-3pyridyl)phenyl]sulfonyl-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

5-amino-3-[[(4S)-l-[(3R,4R)-l-[(2-chloropyrimidin-4-yl)methyl]-3-phenylpiperidine-4-carbonyl]-3,3-difluoiO-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

- 5-amino-3-[[l-[(3R,4R)-l-(2-cyclopentyl-4-methyl-thiazole-5-carbonyl)-3-phenylpiperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

- 5-amino-3-[[l-[(3R,4R)-l-(3-chloro-5-rnethyl-benzoyl)-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

- 5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-1 -[(3R,4R)-3-pheny 1-1 -(5-pyrrol-1 ylpyridine-3-carbonyl)piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one; 5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[[6-(6-methyl-3pyridyl)pyrimidin-4-yl]methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

- 5-amino-3-[[l-[(3R,4R)-l-(2-cyclobutyl-4-methyl-thiazole-5-carbonyl)-3-phenylpiperidine-4-carbony 1] -4-hydroxy-4-p iperidy l]methyl] -6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-6-(4-chlorophenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(2methylpyrimidin-4-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

5-amino-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3-pyridyl)thiazole-5carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyI]methyl]-6-(3pyridyloxy)pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[[2-(6-methyl-320308

-24pyridyl)pyrimidin-4-yl]methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-[(2phenylpyrimidin-4-yl)methyl]piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4- fluorophenoxy)pyrimidin-4-one;

-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]6-(4-fluoro-3-methoxy-phenoxy)pyrimidin-4-one;

5-amino-6-(4-chloro-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l10 [(3R,4R)-l-[(2-methylpyrimidin-4-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

5-amino-6-(4-chloro-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[(5-methylpyrazin-2-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

- 5-amino-6-(4-chloro-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[4-rnethyl-2-(6-methyl-3-pyridyl)thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-[6-methyl-5(trifluoromethyl)-3-pyridyl]thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]20 4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

- 5-amino-3-[[l-[(3R,4R)-l-[2-(3,3-difluorocyclobutyl)-4-methyl-thiazole-5carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[(4S)-l-[(3R,4R)-l-[2-(3,3-difluorocyclobutyl)-4-methyl-thiazole-525 carbonyl]-3-phenyl-piperidine-4-carbonyl]-3,3-difluoro-4-hydroxy-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-(4-methyl-2tetrahydropyran-4-yl-thiazole-5-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

- 5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(5-methylpyrazin-2yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyrazin-2ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(6-methylpyrazin-25 yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[4-methyl-2-(6-methyl-3-pyridyl)thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyI]-4-piperidyl]methyl]pyrimidin-4-one;

- 5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(3-methylpyrazin-2yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyrimidin-4ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(415 fluorophenoxy)pyrimidin-4-one;

5-amino-6-(4-chlorophenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(5methylpyrazin-2-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[(4S)-l-[(3R,4R)-1-(3,520 dichlorobenzoyl)-3-phenyl-piperidine-4-carbonyl]-3,3-difluoiO-4-hydroxy-4piperidyl]methyl]pyrimidin-4-one.

The invention relates also to a process for the préparation of compounds of formula (I), which process is characterized in that there is used as starting material the compound of formula (II):

wherein R4 and n are as defined for formula (I),

-26which is subjected to coupling with a compound of formula (III):

(III) wherein R₂ is as defined for formula (I), and PG représente a protecting group of the amine function.

to yield the compound of formula (IV):

wherein R₂, R4, n and PG are as defined hereinbefore, compound of formula (IV) which is further converted to an epoxide compound of formula (V):

(V) wherein R₂, R4, n and PG are as defined hereinbefore, compound of formula (V) which is further subjected to coupling with compound of formula (VI):

(VI) wherein Ri, R5 and Q are as defined for formula (I), to yield the compound of formula (VII):

(VII) wherein Ri, R2, R4, Rs, Q, n and PG are as defined hereinbefore, compound of formula (VII) which is subjected to a réaction removing the protecting group PG, to yield compound of formula (I-a), a particular case of compound of formula (I):

(I-a) wherein Ri, R2, R4, Rs, Q and n are as defined hereinbefore, compound a formula (I-a), a particular case of compound of formula (I), which is further subjected to substitution reaction on piperidine’s nitrogen to yield the compound of formula (I-b):

wherein Ri, R2, R4, Rs, Q and n are as defined hereinbefore and R3’ represents a linear or branched (Ci-C6)alkyl group, a linear or branched halo(Ci-C6)alkyl, a linear or branched hydroxy(Ci-C6)alkyl group, a -C(O)-Rs group, a -C(O)-ORs group, a -C(O)-NH-Rs group, or a

group, compound of formula (I-a) and compound of formula (I-b), which constitute the totality of compounds of formula (I), may then be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

In another embodiment of the invention, compounds of formula (I) may be obtained using an alternative process, which process is characterized in that there is used as starting material the compound of formula (VIII):

(VIII) wherein R2 is as defined for formula (I), and PG represents a protecting group of the

-29carboxylic acid function, which is subjected to substitution reaction on piperidine’s nitrogen to yield the compound of formula (IX):

(ix) wherein R₂ and R3 are as defined for formula (I), and PG represents a protecting group of the carboxylic acid function, compound of formula (IX) which, after a reaction removing the protecting group PG, is further subjected to coupling with a compound of formula (II), to yield the compound of formula (X):

wherein R₂, R3, R4 and n are as defined hereinbefore, compound of formula (X) which is further converted to an epoxide compound of formula (XI):

(xi) wherein R₂, R3, R4 and n are as defined hereinbefore,

-30compound of formula (XI) which is further subjected to coupling with compound of formula (VI):

wherein Ri, Rs and Q are as defined for formula (I), to yield the compound of formula (I), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) ofthe starting reagents or ofthe synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

The compounds of formulae (II), (III), (VI) and (VIII) are either commercially available or can be obtained by the person skilled in the art using conventional Chemical reactions described in the literature.

Pharmacological studies of the compounds of the invention hâve shown pro-apoptotic and/or anti-proliferative properties. The ability to reactivate the apoptotic process in cancerous cells is of major therapeutic interest in the treatment of cancers and of immune and auto-immune System diseases.

Among the cancer treatments envisaged there may be mentioned, without implying any limitation, treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukemia, cancer of the colon, esophagus and liver, lymphoblastic leukemia, acute myeloid leukemia, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer. More especially, the compounds according to the invention will be useful in the treatment of chemo-, targeted therapy- or radio-resistant cancers.

The présent invention relates also to pharmaceutical compositions comprising at least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients. In particular, these pharmaceutical compositions are interesting for use as proapoptotic and/or anti-proliferative agents, particularly, in the treatment of cancers and of auto-immune and immune System diseases. Preferably, these pharmaceutical compositions can be used in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukemia, cancer of the colon, esophagus and liver, lymphoblastic leukemia, acute myeloid leukemia, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parentéral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.

The pharmaceutical compositions according to the invention comprise one or more excipients or carriers selected from diluents, lubricants, binders, disintegration agents, stabilisers, preservatives, absorbents, colorants, sweeteners, flavourings etc.

By way of non-limiting example there may be mentioned:

♦ as diluents·. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol, ♦ as lubricants·. silica, talc, stearic acid and its magnésium and calcium salts, polyethylene glycol, ♦ as binders: magnésium aluminium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, ♦ as disintegrants: agar, alginic acid and its sodium sait, effervescent mixtures.

-32The dosage varies according to the sex, âge and weight of the patient, the administration route, the nature of the therapeutic indication, or of any associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in one or more administrations.

Furthermore, the présent invention relates also to the combination of a compound of formula (I) with anti-cancer agents selected from genotoxic agents, mitotic poisons, antimetabolites, protéasome inhibitors, kinase inhibitors, protein-protein interaction inhibitors, immunomodulators, E3 ligase inhibitors, chimeric antigen receptor T-cell therapy and antibodies, and also to pharmaceutical compositions comprising that ty pe of combination and their use in the manufacture of médicaments for use in the treatment of cancer, particularly, cancers of the bladder, brain, breast and utérus, chronic lymphoid leukemia, cancer of the colon, esophagus and liver, lymphoblastic leukemia, acute myeloid leukemia, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-smallcell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

The combination of a compound of formula (I) with an anticancer agent may be administered simultaneously or sequentially. The administration route is preferably the oral route, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingrédients. The compounds of the combination may moreover be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingrédients, or in the form of a single pharmaceutical composition, in which the active ingrédients are in admixture.

The compounds of formula (I) may also be used in combination with radiotherapy in the treatment of cancer.

The following Préparations and Examples illustrate the invention but do not limit it in any way.

General Procedures

-33 Ail reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.

Flash chromatography was performed on ISCO CombiFlash Rf 200i with pre-packed silicagel cartridges (RediSe/?®/?? Gold High Performance).

Thin layer chromatography was conducted with 5x10 cm plates coated with Merck Type 60 F254 silica-gel.

Microwave heating was performed in an Anton Parr MonoWave or CEM Discover® instrument.

Préparative HPLC purifications were performed on an HANBON NP7000 Liquid Chromatography System with a Gemini-NX® 5 μΜ Cl8, 250 mm x 50 mm i.d. column running at a flow rate of 99.9 mL min'¹ with UV diode array détection (210 - 400 nm) using 5 mM aqueous NH4HCO3 solution and MeCN as eluents unless specified otherwise.

Analytical LC-MS: The compounds of the présent invention were characterized by high performance liquid chromatography-mass spectroscopy (HPLC-MS) on Agilent HP 1200 with Agilent 6140 quadrupole LC/MS, operating in positive or négative ion electrospray ionization mode. Molecular weight scan range is 100 to 1350. Parallel UV détection was done at 210 nm and 254 nm. Samples were supplied as a 1 mM solution in MeCN, or in THF/H2O (1:1) with 5 pL loop injection. LCMS analyses were performed on two instruments, one of which was operated with basic, and the other with acidic eluents.

Basic LCMS: Gemini-NX, 3 pm, C18, 50 mm x 3.00 mm i.d. column at 23 °C, at a flow rate of 1 mL.min'¹ using 5 mM ammonium bicarbonate (Solvent A) and acetonitrile (Solvent B) with a gradient starting from 100 % Solvent A and finishing at 100 % Solvent B over various/certain duration of time.

Acidic LCMS: ZORBAX Eclipse XDB-C18, 1.8 pm, 50 mm x 4.6 mm i.d. column at 40 °C, at a flow rate of 1 mL.min'¹ using 0.02 % v/v aqueous formic acid (Solvent A) and 0.02 % v/v formic acid in acetonitrile (Solvent B) with a gradient starting from 100 % Solvent A and finishing at 100 % Solvent B over various/certain duration of time.

H-NMR measurements were performed on Bruker Avance III 500 MHz spectrometer and Bruker Avance III 400 MHz spectrometer, using DMSO-dô or CDCI3 as solvent. 'H NMR data is in the form of delta values, given in part per million (ppm), using the residual peak

-34of the solvent (2.50 ppm for DMSO-dô and 7.26 ppm for CDC1₃) as internai standard. Splitting patterns are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet), br. (broad signal), brs (broad singlet), brd (broad doublet), brt (broad triplet), brq (broad quartet), brm (broad multiplet), vbrs (very broad singlet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), dq (doublet of quartet), ddd (doublet of doublet of doublets), dm (doublet of multiplets), tm (triplet of multiplets), qm (quartet of multiplets).

Combination gas chromatography and low resolution mass spectrometry were performed on Agilent 6850 gas chromatograph and Agilent 5975C mass spectrometer using 15 m x 0.25 mm column with 0.25 pm HP-5MS coating and hélium as carrier gas. Ion source: EI⁺, 70 eV, 230 °C, quadrupole: 150 °C, interface: 300 °C.

High resolution mass spectrometry was performed on JEOL AccuTOF MS instrument connected to Agilent 7693A gas chromatograph on Rxi-5Sil MS column 15 m x 0.25 mm column and hélium was used as carrier gas. Ion source: EI+, 70 eV, 200 °C, interface: 250 °C.

HRMS were determined on a Shimadzu IT-TOF, ion source température 200 °C, ESI +/-, ionization voltage: (+-)4.5 kV. Mass resolution min. 10000.

Elementary analyses were performed on a Thermo Flash EA 1112 Elemental Analyzer.

IUPAC Chemical names were generated using ACD/Name 2015 Pack 2 (File Version N20E41, Build 75170, 19 Dec 2014) or using ‘Structure to Name’ functionality within Accelrys Draw 4.2.

List of abbreviations

Abbreviation	Name
abs.	absolute
aq. AtaPhos*PdC12	aqueous bis(di-/eri-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II)
B oc	tert-butoxycarbonyl

CC. DCM DEE disp.	concentrated dichloromethane diethyl ether dispersion
5 DMF	dimethylformamide
EDC.HCI	7V-(3-dimethylaminopropyl)-7V-ethylcarbodiimide
	hydrochloride
eq.	équivalent
LC	liquid chromatography
10 MeCN	acetonitrile
Me-THF	2-methyltetrahydrofuran
MSM	methylsulfinylmethane
MTBE	teri-butyl methylether
r.t.	room température
15 sat.	saturated
THF	tetrahydroftiran
TMP.MgCl.LiCl	2,2,6,6-tetramethylpiperidine-magnesium chloride-lithium
	chloride (1:1) complex

General Procedure 1

4-chloro-6-methoxy-5-nitro-pyrimidine (1.0 eq.), the appropriate phénol (1.2 eq.), and potassium carbonate (1.2 eq.) were dissolved in MeCN. It was stirred at 80 °C till completion, then water was added to the reaction mixture. MeCN was evaporated. The residue extracted with DCM. The combined organic phase was dried over MgSO₄ and evaporated under reduced pressure to give Préparation R2a-R2n.

General Procedure 2

Autoclave was charged with Préparation R2a-R2h and R2k-R2n (1.0 eq.), Raney-nickel catalyst (10 w/w%) and 1,4-dioxane and then placed under a nitrogen atmosphère. After that it was filled with 10 bar 15 H₂ gas. The reaction mixture was stirred in autoclave at r.t. for 20 hours. The reaction mixture was removed from the autoclave and filtered. The filtrate 30 was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous

-36NFLHCCh-MeCN, gradient). Solvent was evaporated under reduced pressure to give

Préparation R3a-R3h and R3k-R3n.

General Procedure 3

Préparation R3a-R3n (1.0 eq.) was dissolved in 1,4-dioxane, then IN hydrochloric acid (3.0-5.0 eq.) was added. It was stirred at 95 °C till completion, then the reaction mixture concentrated under reduced pressure to give Préparation R4a-R4n.

General Procedure 4

Préparation R4a-R4n (1.0 eq.), the appropriate epoxide dérivative (1.0 eq.) and potassium carbonate (3.0 eq.) were dissolved in DMF. It was stirred at 70 °C till completion. The reaction mixture was directly injected through syringe filter to préparative HPLC (on C-18 Gemini-NX 5 pm column, 5 mM NH4HCO3 aqueous solution - MeCN, gradient 5-90 %). Fractions were collected and concentrated under reduced pressure, then dried in vacuum at 50 °C for overnight.

General Procedure 5: Boc deprotection

The appropriate Boc protected amine (1.0 eq.) was dissolved in 1,4-dioxane and IN hydrochloric acid solution (5.0 eq.) was added. It was stirred at 70 °C till completion, then the solvents were evaporated under reduced pressure to give the appropriate amine dérivative.

General Procedure 6: Acylation

The appropriate amine (1.0 eq.), EDC.HC1 (3.0 eq.) and corresponding carboxylic acid (1.0 eq.) were stirred in pyridine at r.t. for 2-24 hours.

Work-up 1:

The reaction mixture was evaporated, the residue was taken in DMF and injected to préparative LC (on C-18 Gemini-NX 5pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). The solvents were evaporated under reduced pressure.

Work-up 2:

The reaction mixture was evaporated. The residue was triturated with water and the resulted solid was filtered off.

General Procedure 7: Urea préparation from isocyanate

The appropriate amine (1.0 eq.) and isocyanato dérivative (1.3 eq.) were dissolved in DCM and stirred at r.t. till completion. Then the solvent was evaporated under reduced pressure, dissolved in DMF and injected to préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). The solvent was evaporated under reduced pressure to give the appropriate urea dérivative.

General Procedure 8: Urea préparation from amine

Bis(trichloromethyl) carbonate (0.5 eq.) was dissolved in MeCN, then the appropriate alkyl/aryl amine (1.5 eq.) was added and stirred for 10 minutes, after then N,N-diethylethanamine (5.0 eq.) was added and the mixture was stirred for 1 h. Then aminopyrimidone dérivative (150 mg, 0.2876 mmol, LO eq.) was added in 2 ml MeCN to the mixture and stirred at r.t. till completion. Then 6N NH3 solution in methanol was added and the mixture was evaporated under reduced pressure, dissolved in DMF/methanol then it was injected to préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3MeCN, gradient). The solvent was evaporated under reduced pressure to give the appropriate urea dérivative.

General Procedure 9: Alkylation/sulfonylation

The appropriate amine (1.0 eq.), corresponding sulfonyl chloride/alkyl halide (1.3 eq.) and K₂CO₃ (3.0 eq.) were stirred in DMF at r.t. till completion. The mixture was evaporated under reduced pressure, dissolved in DMF/methanol then it was injected to préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO₃-MeCN, gradient). Solvent was evaporated under reduced pressure.

General Procedure 10: Reductive amination

The appropriate amine (100 mg, 0.1797 mmol), aldéhyde dérivative (1.3 eq.), sodium triacetoxyborohydride (5.0 eq.), acetic acid (5.0 eq.) were dissolved in THF and stirred at r.t. till completion. The reaction mixture was purified by préparative LC (on C-18 Gemini-NX pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure.

General Procedure 11

The corresponding halogenated component (1.0 eq.), corresponding boronic acid (2.5 eq.), ATAphos*PdCb (0.1 eq.), CS2CO3 (3.5 eq.) was diluted with THF and water (1:1). The mixture was flushed with nitrogen and microwaved at 80 °C for 100-150 minutes. The reaction mixture was injected through syringe filter to préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure.

Préparation R2a: 4-(4-chlorophenoxy)-6-methoxy-5-nitro-pyrimidine

Using General Procedure 1 and 4-chlorophenol as reagent, Préparation R2a was obtained. HRMS calculated for C11H8CIN3O4: 281.0203; found 281.0198 (M⁺ form).

’H-NMR (400 MHz, dmso-d6) δ ppm 8.6 (s, 1H), 7.54 (m, 2H), 7.34 (m, 2H), 4.1 (s, 3H). ¹³C-NMR (100 MHz, dmso-d6) δ ppm 162.5, 161, 158.7, 150.7, 131, 130.3, 124.1, 56.7.

Préparation R2b: 4-(3-chIoro-5-methoxy-phenoxy)-6-methoxy-5-nitro-pyrimidine

Using General Procedure 1 and 3-chloro-5-methoxy-phenol as reagent, Préparation R2b was obtained. HRMS calculated for C12H10CIN3O5: 311.0309; found 312.0377 ((M+H)⁺form).

‘H-NMR (500 MHz, dmso-d6) δ ppm 8.63 (s, 1H), 7.05 (t, 1H), 7.01 (t, 1H), 6.93 (t, 1H), 4.11 (s, 3H), 3.78 (s, 3H).

¹³C-NMR(125 MHz, dmso-d6)ôppm 162.5, 161.4, 160.9,158.7,153.3, 134.6, 114.7, 112.9, 107.6, 56.7, 56.5.

Préparation R2c: 4-(4-chloro-3-fluoro-phenoxy)-6-methoxy-5-nitro-pyrimidine

Using General Procedure 1 and 4-chloro-3-fluoro-phenol as reagent, Préparation R2c was obtained. HRMS calculated for C11H7CIFN3O4: 299.0109; found 300.0179 ((M+H)⁺ form). ’H-NMR (500 MHz, dmso-d6) δ ppm 7.72 (t, 1H), 7.6 (dd, 1H), 7.24 (dm, 1H), 6.83 (s, 1H), 4.11 (s, 3H) ’³C-NMR(125 MHz, dmso-d6)ôppm 162.5, 160.7, 158.7,157.7,151.3, 131.6, 120.9,119.9,

17.8, 112.1, 56.8

Préparation R2d: 4-(4-fluoro-3-methoxy-phenoxy)-6-methoxy-5-nitro-pyrimidine

Using General Procedure 1 and 4-fluoro-3-methoxy-phenol as reagent, Préparation R2d was obtained. HRMS calculated for C12H10FN3O5: 295.0605; found 296.0675 ((M+H)⁺form).

’H-NMR (500 MHz, dmso-d6) δ ppm 8.84 (s, 1H), 7.33 (dd, 1H), 7.26 (dd, 1H), 6.91 (ddd, 1H), 3.81 (s, 3H), 3.81 (s, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 159.1, 116.8, 113.8, 108.5, 56.9, 56.9.

Préparation R2e: 4-methoxy-5-nitro-6-[3-(trifluoromethyl)phenoxy]pyrimidine

Using General Procedure 1 and 3-(trifluoromethyl)phenol as reagent, Préparation R2e was obtained. HRMS calculated for C12H8F3N3O4: 315.0467; found 316.0545 ((M+H)⁺form).

‘H-NMR (500 MHz, dmso-d6) δ ppm 8.62 (s, 1H), 7.79 (m, 1H), 7.72 (m, 1H), 7.72 (m, 1H), 7.65 (m, 1H), 4.12 (s, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 162.5, 160.9, 158.7, 152.2, 131.7, 131, 126.6, 124, 123.7, 119.5, 56.7.

Préparation R2f: 4-methoxy-5-nitro-6-[3-(trifluoromethoxy)phenoxy] pyrimidine

Using General Procedure 1 and 3-(trifluoromethoxy)phenol as reagent, Préparation R2f was obtained. HRMS calculated for C12H8F3N3O5: 331.0416; found 332.0488 ((M+H)⁺form).

'H-NMR (500 MHz, dmso-d6) δ ppm 8.62 (s, 1H), 7.62 (t, 1H), 7.47 (s, 1H), 7.37 (m, 1H), 7.36 (m, 1H), 4.11 (s, 3H).

¹³C-NMR(125 MHz, dmso-d6)ôppm 162.5, 160.8, 158.7, 152.6, 149.2, 131.8, 121.5, 121.4, 120.1, 119.4, 115.8, 56.7.

Préparation R2g: 4-methoxy-5-nitro-6-phenoxy-pyrimidine

Using General Procedure 1 and phénol as reagent, Préparation R2g was obtained. HRMS calculated for C11H9N3O4: 247.0593; found 248.0672 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 8.59 (s, 1H), 7.48 (m, 2H), 7.33 (tm, 1H), 7.27 (dm,

-402H), 4.1 (s, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 162.4, 161.1, 158.7, 152, 130.4, 126.8, 122.1, 56.6.

Préparation R2h: 4-(4-fluorophenoxy)-6-methoxy-5-nitro-pyrimidine

Using General Procedure 1 and 4-fluorophenol as reagent, Préparation R2h was obtained. HRMS calculated for CnH₈FN₃O₄: 265.0499; found 265.0496 (M⁺ form).

Ή-NMR (400 MHz, dmso-d6) δ ppm 8.59 (s, 1H), 7.33 (m, 2H), 7.33 (m, 2H), 4.1 (s, 3H). ¹³C-NMR(100MHz, dmso-d6) δ ppm 162.4, 161.6, 158.6, 124.1, 117, 56.7.

Préparation R2j; 4-(6-methoxy-5-nitro-pyrimidin-4-yl)oxybenzonitrile

Using General Procedure 1 starting from 4-hydroxybenzonitrile as reagent, Préparation R2j was obtained. HRMS calculated for C12H8N4O4: 272.0546; found 273.0621 ((M+H)⁺ form).

’H-NMR (400 MHz, dmso-d6) δ ppm 8.63 (s, 1H), 7.99 (d, 2H), 7.55 (d, 2H), 4.12 (s, 3H) ¹³C-NMR(100MHz, dmso-d6) δ ppm 162.6,160.6,158.7,155.4,134.9, 123.5, 118.8, 109.9, 56.8

Préparation R2k: 4-methoxy-5-nitro-6-(3-pyridyloxy)pyrimidine

Using General Procedure 1 and pyridin-3-ol as reagent, Préparation R2k was obtained. HRMS calculated for C10H8N4O4: 248.0546; found 249.0615 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 8.61 (s, 1H), 8.58 (d, 1H), 8.54 (dd, 1H), 7.82 (ddd, 1H), 7.55 (dd, 1H), 4.12 (s, 3H) ¹³C-NMR(125 MHz, dmso-d6) ôppm 162.5,160.9, 158.7, 148.8,147.9, 143.8, 130.2, 125.1, 120.9, 56.7

Préparation R21: 4-(6-methoxy-5-nitro-pyrimidin-4-yl)oxybenzaldehyde

Using General Procedure 1 and 4-hydroxybenzaldehyde as reagent, Préparation R21 was obtained. HRMS calculated for CMUNsOj: 275.0542; found 276.0612 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 10.03 (s, 1H), 8.63 (s, 1H), 8.03 (dm, 2H), 7.53 (dm, 2H), 4.12 (s, 3H) ^l3C-NMR(125 MHz, dmso-d6)ôppm 192.4, 162.6, 160.7, 158.7,156.4,134.7,131.9, 122.9, 121.2, 56.7

-41 Préparation R2m: 4-(4-chloro-3-methoxy-phenoxy)-6-methoxy-5-nitro-pyrimidine

Using General Procedure 1 and 4-chloro-3-methoxy-phenol as reagent, Préparation R2m was obtained. HRMS calculated for C12H10CIN3O5: 311.0309; found 312.0385 ((M+H)⁺form) ’H-NMR (400 MHz, dmso-d6) δ ppm 8.61 (s, 1H), 7.51 (d, 1H), 7.17 (d, 1H), 6.9 (dd, 1H), 4.11 (s, 3H), 3.83 (s, 3H) ¹³C-NMR (100 MHz, dmso-d6) δ ppm 162.4, 161, 158.7, 155.8, 151.6, 130.7, 119, 114.9, 107.7, 57, 56.7

Préparation R2n: 4-(4-cyclopropyl-3-methoxy-phenoxy)-6-methoxy-5-nitropyrimidine

Using General Procedure 1 and 4-cyclopropyl-3-methoxy-phenol as reagent, Préparation R2n was obtained. HRMS calculated for C15H15N3O5: 317.1012; found 318.10810 ((M+H)⁺form) ’H-NMR (500 MHz, dmso-d6) δ ppm 8.58 (s, 1H), 6.88 (d, 1H), 6.88 (d, 1H), 6.72 (dd, 1H), 4.1 (s, 3H), 3.78 (s, 3H), 2.07 (m, 1H), 0.88/0.62 (m+m, 4H) ¹³C-NMR (125 MHz, dmso-d6) δ ppm 158.7, 125.5, 113.4, 105, 56.6, 56.2, 9.5, 8.2

Préparation R3a: 4-(4-chlorophenoxy)-6-methoxy-pyrimidin-5-amine

Using General Procedure 2 starting from Préparation R2a as reagent, Préparation R3a was obtained. HRMS calculated for C11H10CIN3O2: 251.0462; found 252.0523 ((M+H)⁺form).

’H-NMR (400 MHz, dmso-d6) δ ppm 7.76 (s, 1H), 7.45 (m, 2H), 7.18 (m, 2H), 4.9 (s, 2H), 3.95 (s, 3H).

’³C-NMR(100 MHz, dmso-d6) δ ppm 158.1, 154.3, 153, 142.8, 129.8, 128.8, 123.3, 117.4, 54.4.

Préparation R3b: 4-(3-chloro-5-methoxy-phenoxy)-6-methoxy-pyrimidin-5-amine Using General Procedure 2 starting from Préparation R2b as reagent, Préparation R3b was obtained. HRMS calculated for C12H12CIN3O3: 281.0567; found 282.0645 ((M+H)⁺

-42form).

Ή-NMR (500 MHz, dmso-d6) δ ppm 7.79 (s, 1H), 6.87 (t, 1H), 6.81 (t, 1H), 6.73 (t, 1H), 4.91 (s, 2H), 3.96 (s, 3H), 3.77 (s, 3H).

¹³C-NMR(125 MHz, dmso-d6)Ôppm 161.2,158.3, 155.8, 153.8,142.8, 134.3, 117.8, 113.6, 110.7, 106.5, 56.3, 54.5.

Préparation R3c: 4-(4-chloro-3-fluoro-phenoxy)-6-methoxy-pyrimidin-5-amine

Using General Procedure 2 starting from Préparation R2c as reagent, Préparation R3c was obtained. HRMS calculated for C11H9CIFN3O2: 269.0367; found 270.044 ((M+H)⁺form).

’H-NMR (400 MHz, dmso-d6) δ ppm 7.79 (s, 1H), 7.61 (t, 1H), 7.36 (dd, 1H), 7.06 (dm, 1H), 4.97 (br., 2H), 3.96 (s, 3H).

¹³C-NMR(100MHz, dmso-d6) δ ppm 158.3, 157.7, 153.9, 153.7, 142.7, 131.2, 118.7, 117.7, 115.4, 110.7, 54.5.

Préparation R3d; 4-(4-fluoro-3-methoxy-phenoxy)-6-methoxy-pyrimidin-5-amine Using General Procedure 2 starting from Préparation R2d as reagent, Préparation R3d was obtained. HRMS calculated for C12H12FN3O3: 265.0863; found 266.0931 ((M+H)⁺form).

'H-NMR (500 MHz, dmso-d6) δ ppm 7.76 (s, 1H), 7.21 (dd, 1H), 7 (dd, 1H), 6.69 (dm, 1H), 4.85 (s, 2H), 3.95 (s, 3H), 3.8 (s, 3H).

¹³C-NMR(125 MHz, dmso-d6) δ ppm 142.9, 116.2, 113.3, 108.1.

Préparation R3e: 4-methoxy-6-[3-(trifluoromethyl)phenoxy]pyrimidin-5-amine

Using General Procedure 2 starting from Préparation R2e as reagent, Préparation R3e was obtained. HRMS calculated for C12H10F3N3O2: 285.0725; found 286.0796 ((M+H)+ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 7.79 (s, 1H), 7.64 (brt, 1H), 7.57 (dm, 1H), 7.52 (m, 1H), 7.48 (dm, 1H), 4.97 (br., 2H), 3.97 (s, 3H).

¹³C-NMR(125 MHz, dmso-d6)δppm 158.3, 154.5, 153.9, 142.8, 131.3, 130.7, 125.5, 124.3, 121.5, 118.1, 54.5.

-43 Préparation R3f: 4-methoxy-6-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-amine Using General Procedure 2 starting from Préparation R2f as reagent, Préparation R3f was obtained. HRMS calculated for C12H10F3N3O3: 301.0674; found 302.0742 ((M+H)⁺form).

Ή-NMR (500 MHz, dmso-d6) δ ppm (m, 3H), 7.79 (s, 1H), 7.53 (m, 1H), 4.96 (br., 2H), 3.96 (s, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 158.3, 153.8, 152.2, 149.2, 142.8, 131.3, 120.5, 120.4/117.2/114.4, 117.8, 54.5.

Préparation R3g: 4-methoxy-6-phenoxy-pyrimidin-5-amine

Using General Procedure 2 starting from Préparation R2g as reagent, Préparation R3g was obtained. HRMS calculated for C11H11N3O2: 217.0851; found 218.092 ((M+H)⁺ form). Ή-NMR (500 MHz, dmso-d6) δ ppm 7.75 (s, 1H), 7.4 (m, 2H), 7.19 (m, 1H), 7.12 (m, 2H), 4.85 (brs, 2H), 3.95 (s, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 158, 154.7, 154.1, 142.9, 129.9, 124.9, 121.4, 117.3, 54.4.

Préparation R3h: 4-(4-fluorophenoxy)-6-methoxy-pyrimidin-5-amine

Using General Procedure 2 starting from Préparation R2h as reagent, Préparation R3h was obtained. HRMS calculated for C11H10FN3O2: 235.0757; found 235.07503 (M⁺ form). Ή-NMR (500 MHz, dmso-d6) δ ppm 7.74 (s, 1H), 7.23 (m, 2H), 7.18 (m, 2H), 4.86 (s, 2H), 3.95 (s, 3H).

¹³C-NMR(125 MHz, dmso-d6) δ ppm 159.2, 157.9, 154.9, 150.1, 142.9, 123.4, 116.4, 54.4.

Préparation R3j: 4-(5-amino-6-methoxy-pyrimidin-4-yl)oxybenzonitrile

Préparation R2j (1.0 eq.), and tin(II) chloride dihydrate (3.5 eq.) were dissolved in 1,4-dioxane. The reaction mixture was stirred till completion at r.t. Then sat. NaHCO₃solution and EtOAc were added. The suspension was filtered through Celite, washed with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc and Celite was washed again with DCM-MeOH. Ail organic phases were collected and concentrated under reduced pressure. The residue was purified by préparative HPLC (on ΟΙ 8 Gemini-NX 5 pm column, 5 mM NH4HCO3 aqueous solution - MeCN, gradient

-445-90 %). Fractions were collected and concentrated under reduced pressure to give Préparation R3j. HRMS calculated for C12H10N4O2: 242.0804; found 243.088 ((M+H)⁺form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.88 (dm, 2H), 7.81 (s, 1H), 7.32 (dm, 2H), 5.04 (br., 5 2H), 3.97 (s, 3H).

’³C-NMR(125 MHz, dmso-d6)ôppm 158.6,158.1,152.9, 142.8,134.5, 121.6, 119.1, 118.5, 107, 54.6.

Préparation R3k: 4-methoxy-6-(3-pyridyloxy)pyrimidin-5-amine

Using General Procedure 2 starting from Préparation R2k as reagent, Préparation R3k 10 was obtained. HRMS calculated for C10H8N4O4: 248.0546; found 249.0615 ((M+H)⁺ form). ’H-NMR (500 MHz, dmso-d6) δ ppm 8.61 (s, 1H), 8.58 (d, 1H), 8.54 (dd, 1H), 7.82 (ddd, 1H), 7.55 (dd, 1H), 4.12 (s, 3H) ¹³C-NMR(125 MHz, dmso-d6)ôppm 162.5, 160.9,158.7, 148.8, 147.9, 143.8, 130.2, 125.1, 120.9, 56.7

Préparation R31: 4-(5-amino-6-methoxy-pyrimidin-4-yl)oxybenzaldehyde

Using General Procedure 2 starting from Préparation R21 as reagent, Préparation R31 was obtained. HRMS calculated for C12H11N3O3: 245.08; found 246.0873 ((M+H)⁺ form). ’H-NMR (500 MHz, dmso-d6) δ ppm 9.97 (s, 1H), 7.95 (m, 2H), 7.81 (s, 1H), 7.32 (m, 2H), 5.02 (s, 2H), 3.97 (s, 3H) ^l3C-NMR (125 MHz, dmso-d6) δ ppm 192.3, 159.4, 158.6, 153.1, 142.8, 132.8, 131.8, 121, 118.5, 54.6

Préparation R3m: 4-(4-chloro-3-methoxy-phenoxy)-6-methoxy-pyrimidin-5-amine Using General Procedure 2 starting from Préparation R2m as reagent, Préparation R3m was obtained. HRMS calculated for C12H12CIN3O3: 281.0567; found 282.0637 ((M+H)⁺25 form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.77 (s, 1H), 7.42 (d, 1H), 6.99 (d, 1H), 6.73 (dd, 1H), 4.89 (s, 2H), 3.95 (s, 3H), 3.82 (s, 3H) ’³C-NMR (125 MHz, dmso-d6) δ ppm 158.1, 155.6, 154.3, 154, 142.8, 130.3, 117.4, 117, 114.1, 106.9

-45 Préparation R3n: 4-(4-cyclopropyl-3-methoxy-phenoxy)-6-methoxy-pyrimidin-5amine

Using General Procedure 2 starting from Préparation R2n as reagent, Préparation R3n was obtained. HRMS calculated for C15H17N3O3:287.127; found 288.13500 ((M+H)⁺ form). ’H-NMR (500 MHz, dmso-d6) δ ppm 7.74 (s, 1H), 6.82 (d, 1H), 6.74 (d, 1H), 6.58 (dd, 1H), 4.8 (s, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 2.05 (m, 1H), 0.86/0.59 (m+m, 2H) ’³C-NMR (125 MHz, dmso-d6) δ ppm 142.9, 125.3, 113, 104.7, 56.1, 54.4, 9.5, 8

Préparation R4a: 5-amino-4-(4-chlorophenoxy)-lH-pyrimidin-6-one hydrochloride Using General Procedure 3 starting from Préparation R3a as reagent, Préparation R4a was obtained. HRMS calculated for C10H8CIN3O2: 237.0305; found 238.0379 ((M+H)⁺form).

’H-NMR (500 MHz, dmso-d6) δ ppm 12.92 (brs, 1H), 7.8 (s, 1H), 7.44 (m, 2H), 7.14 (m, 2H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 159.4, 153, 152.9, 141.8, 129.8, 128.8, 122.5.

Préparation R4b: 5-amino-4-(3-chloro-5-methoxy-phenoxy)-lH-pyrimidin-6-one hydrochloride

Using General Procedure 3 starting from Préparation R3b as reagent, Préparation R4b was obtained. HRMS calculated for C11H10CIN3O3: 267.0411; found 268.0482 ((M+H)⁺form).

’H-NMR (400 MHz, dmso-d6) δ ppm 13.18 (brs, 1H), 7.94 (s, 1H), 7.64 (brs, 3H), 6.9 (dd, 1H), 6.84 (dd, 1H), 6.75 (dd, 1H).

¹³C-NMR(100MHz, dmso-d6) δ ppm 161.3, 159.5, 155.3, 155.3, 144.2, 134.4, 113.5, 111, 106.5.

Préparation R4c: 5-amino-4-(4-chloro-3-fluoro-phenoxy)-lH-pyrimidin-6-one hydrochloride

Using General Procedure 3 starting from Préparation R3c as reagent, Préparation R4c was obtained. HRMS calculated for C10H7CIFN3O2: 255.0211; found 256.0283 ((M+H)⁺

-46form).

‘H-NMR (400 MHz, dmso-d6) δ ppm 12.97 (brs, 1H), 7.82 (s, 1H), 7.61 (t, 1H), 7.31 (dd, 1H), 7.03 (ddd, 1H), 6.74 (brs, 3H).

¹³C-NMR (100 MHz, dmso-d6) δ ppm 159.5, 157.7, 154, 152.1, 141.7, 131.2, 117.9, 115.2, 5 109.9.

Préparation R4d: 5-amino-4-(4-fluoro-3-methoxy-phenoxy)-lH-pyrimidin-6-one hydrochloride

Using General Procedure 3 starting from Préparation R3d as reagent, Préparation R4d was obtained. HRMS calculated for C11H10FN3O3: 251.0706; found 252.0777 ((M+H)⁺10 form).

‘H-NMR (500 MHz, dmso-d6) δ ppm 12.79 (br., 1H), 7.75 (s, 1H), 7.2 (dd, 1H), 6.97 (dd, 1H), 6.64 (ddd, 1H), 5.91 (br., 2H), 3.8 (s, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 159.4, 152.3, 150.6, 148.9, 148, 140.5, 116.2, 112.3, 107.3, 56.7.

Préparation R4e: 5-amino-4-[3-(trifluoromethyl)phenoxy1-lH-pyrimidin-6-one hydrochloride

Using General Procedure 3 starting from Préparation R3e as reagent, Préparation R4e was obtained. HRMS calculated for C11H8F3N3O2: 271.0569; found 272.0634 ((M+H)⁺form).

‘H-NMR (500 MHz, dmso-d6) δ ppm 12.73 (brs, 1H), 7.67 (s, 1H), 7.61 (t, 1H), 7.51 (dm, 1H), 7.42 (m, 1H), 7.39 (dm, 1H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 159.4, 155.1,148.9, 138.3, 131.3,130.6, 124.1,120.8, 116.7.

Préparation R4f; 5-amino-4-[3-(trifluoromethoxy)phenoxy]-lH-pyrimidin-6-one

Using General Procedure 3 starting from Préparation R3f as reagent, Préparation R4f was obtained. HRMS calculated for C11H8F3N3O3: 287.0518; found 288.0592 ((M+H)⁺form).

‘H-NMR (500 MHz, dmso-d6) δ ppm 12.81 (brs, 1H), 7.73 (s, 1H), 7.51 (t, 1H), 7.17 (dm, 1H), 7.14 (dm, 1H), 7.14 (m, 1H).

-47¹³C-NMR(125 MHz,dmso-d6)ôppm 159.5, 155.5, 150.5, 149.2,139.9,121.5, 121.3, 119.3, 116.8, 113.3.

Préparation R4g: 5-amino-4-phenoxy-lH-pyrimidin-6-one

Using General Procedure 3 starting from Préparation R3g as reagent, Préparation R4g was obtained. HRMS calculated for C10H9N3O2: 203.0695; found 204.077 ((M+H)⁺ form). 'H-NMR (500 MHz, dmso-d6) δ ppm 12.45 (brs, 1H), 7.5 (s, 1H), 7.35 (m, 2H), 7.11 (m, 1H), 7.02 (m, 2H), 4.6 (s, 2H).

^I3C-NMR (125 MHz, dmso-d6) δ ppm 159.3, 147.3, 135.7, 129.8, 123.8, 121.7, 119.7. ¹⁵N-NMR (50 MHz, dmso-d6) δ ppm 233, 171, 39.

Préparation R4h: 5-amino-4-(4-fluorophenoxy)-lH-pyrimidin-6-one hydrochloride Using General Procedure 3 starting from Préparation R3h as reagent, Préparation R4h was obtained. HRMS calculated for C10H8FN3O2: 221.0601; found 222.0669 ((M+H)⁺form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.87 (s, 1H), 7.2 (m, 2H), 7.2 (m, 2H).

’³C-NMR (125 MHz, dmso-d6) δ ppm 160.7, 159.5, 158.2, 149.8, 143.4, 122.9, 116.6.

Préparation R4j: 4-[(5-amino-6-oxo-lH-pyrimidin-4-yl)oxy]benzonitrile

Using General Procedure 3 starting from Préparation R3j as reagent, Préparation R4j was obtained. HRMS calculated for C11H8N4O2: 228.0647; found 229.0718 ((M+H)⁺ form). ’H-NMR (500 MHz, dmso-d6) δ ppm 12.54 (s, 1H), 7.82 (dm, 2H), 7.55 (s, 1H), 7.18 (dm, 20 2H), 4.93 (s, 2H).

¹³C-NMR (125 MHz, dmso-d6)ôppm 159.5,159.1, 145.1,135.6,134.5,123.3, 119.7,119.3, 105.8.

Préparation R4k: 5-amino-4-(3-pyridyloxy)-lH-pyrimidin-6-one

Using General Procedure 3 starting from Préparation R3k as reagent, Préparation R4k was obtained. HRMS calculated for C9H8N4O2: 204.0647; found 205.0722 ((M+H)⁺ form). ’H-NMR (400 MHz, dmso-d6) δ ppm 12.5 (brs, 1H), 8.38 (dd, 1H), 8.34 (dm, 1H), 7.52 (s, 1H), 7.49 (dm, 1H), 7.4 (dd, 1H), 4.73 (s, 2H)

-48Preparation R41: 4-[(5-amino-6-oxo-lH-pyrimidin-4-yl)oxy]benzaldehyde

Using General Procedure 3 starting from Préparation R31 as reagent, Préparation R41 was obtained. HRMS calculated for C11H9N3O3: 231.0644; found 232.0714 ((M+H)⁺ form). 'H-NMR(400 MHz, dmso-d6) δ ppm 12.55 (brs, 1H), 9.94 (s, 1H), 7.92 (d, 2H), 7.57 (s, 1H), 7.21 (d, 2H), 4.82 (brs, 2H) ¹³C-NMR(100 MHz, dmso-d6) δ ppm 192.1, 159.6, 131.9, 119.2

Préparation R4m: 5-amino-4-(4-chloro-3-methoxy-phenoxy)-lH-pyrimidin-6-one hydrochloride

Using General Procedure 3 starting from Préparation R3m as reagent, Préparation R4m was obtained. HRMS calculated for C11H10CIN3O3: 267.0411; found 268.0481 ((M+H)⁺form).

'H-NMR(500 MHz, dmso-d6) δ ppm 12.87 (brs, 1H), 7.78 (s, 1H), 7.4 (d, 1H), 6.86 (d, 1H), 6.68 (dd, 1H), 3.82 (s, 3H) ¹³C-NMR (125 MHz, dmso-d6) δ ppm 141.1, 130.3, 113.2, 106.2, 56.8

Préparation R4n; 5-amino-4-(4-cyclopropyl-3-methoxy-phenoxy)-lH-pyrimidin-6-one Using General Procedure 3 starting from Préparation R3n as reagent. Préparation R4n was obtained. HRMS calculated for C14H15N3O3:273.1113; found 274.1183 ((M+H)⁺ form). 'H-NMR (500 MHz, dmso-d6) δ ppm 12.42 (s, 1H), 7.49 (s, 1H), 6.77 (d, 1H), 6.66 (d, 1H), 6.47 (dd, 1H), 4.54 (s, 2H), 3.76 (s, 3H), 2.01 (m, 1H), 0.84/0.56 (m+m, 4H) ¹³C-NMR (125 MHz, dmso-d6) δ ppm 135.7, 125.3, 111.3, 103.4,56, 9.5, 7.9

Préparation R5a: tert-butyl (3R,4R)-4-(l-oxa-6-azaspiro[2.5]octane-6-carbonyl)-3phenyl-piperidine-l-carboxylate

Step 1: tert-butyl (3R,4R)-4-[(4-oxopiperidm-l-yl)carbonyl]-3-phenylpiperidine-lcarboxylate

4-piperidone hydrochloride hydrate (0.969 g, 6.3 mmol), EDC.HC1 (3.623 g, 18.9 mmol) and (3R,4R)-l-terZ-butoxycarbonyl-3-phenyl-piperidine-4-carboxylic acid (1.928 g, 6.3 mmol) were dissolved in pyridine (10 mL) and stirred at r.t. for 16 hours. The reaction

-49mixture was evaporated to Celite and purified by flash chromatography (DCM:MeOH, gradient) to give the product ofthe title. HRMS calculated for C22H30N2O4: 386.2206; found 409.2093 [(M+Na)⁺ form], ’H-NMR (500 MHz, DMSO-d6): δ 1.42 (s, 9H), 4.14-1.50 (m, 16H), 7.32-7.15 (m, 5H).

Step 2: Préparation R5a tert-butyl (3R,4R)-4-[(4-oxopiperidin-l-yl)carbonyl]-3-phenylpiperidine-l-carboxylate (5 g, 155 mmol, 1.0 eq.) and trimethylsulfoxonium-iodide (85.41 g, 388 mmol, 2.5 eq.) was charged into a round bottom flask and dissolved/suspended in MeCN (150 ml) and MTBE (150 ml). NaOH (15.5 g, 388 mmol, 2.5 eq.) was dissolved in water (21.6 ml) (-40% solution). The aq. NaOH solution was added to the mixture and stirred at 60 °C for 2 hours. After the reaction completed, the mixture was cooled to r.t., filtered through a Celite bed, the filter cake was washed with MTBE (2 x 60 ml). Water (150 ml) was added to the organic layer and after extraction the layers were separated. The aq. layer was extracted with further MTBE (2 x 60 ml). The combined organic layers were dried over MgSÜ4 and after filtration evaporated to give Préparation R5a as beige solid foam. HRMS calculated for C23H32N2O4: 400.2362; found 423.2247 [(M+Na)⁺ form].

’H-NMR (500 MHz, DMSO-d6): δ = 1.41 (s, 9H), 1.79-0.86 (m, 6H), 2.61-2.51 (m, 2H), 4.16-2.73 (m, 10H), 7.33-7.18 (m, 5H).

Préparation R5b: tert-butyl (3R,4R)-4-(4,4-difluoro-l-oxa-6-azaspiro[2.5]octane-6carbonyl)-3-phenyl-piperidine-l-carboxylate

Step 1: tert-butyl (3R,4R)-4-(3,3-difluoro-4,4-dihydroxy-piperidine-l-carbonyl)-3-phenylpiperidine-1 -carboxylate

3,3-Difluoropiperidin-4-one hydrochloride hydrate (3.61 g, 19.041 mmol), EDC.HC1 (10.951g, 57.123 mmol) and (3R,4R)-l-ter/-butoxycarbonyl-3-phenyl-piperidine-4carboxylic acid (6.397 g, 20.945 mmol) were dissolved in pyridine (80 mL) and stirred at r.t. for 17 hours. The reaction mixture was evaporated under reduced pressure. It was dissolved in DMF and then it was purified by préparative LC (on C-18 Luna 10 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure to give the product of the title. HRMS calculated for C22H30F2N2O5: 440.2123; found

-50463.2008 [(M+Na)⁺ form].

Step 2: Préparation R5b tert-butyl (3R,4R)-4-(3,3-difluoro-4,4-dihydroxy-piperidine-l-carbonyl)-3-phenylpiperidine-l-carboxylate (1.048 g, 2.379 mmol, 1.0 eq.) and trimethylsulfoxonium-iodide (1.309 g, 5.948 mmol, 2.5 eq.) was charged into a round bottom flask and dissolved/suspended in MeCN (30 ml) and MTBE (30 ml). NaOH (238 mg 5.948 mmol, 2.5 eq.) was dissolved in water (7 ml). The aq. NaOH solution was added to the mixture and stirred at 60 °C for 2 hours. After the reaction completed, the mixture was cooled to r.t, 15 g MgSO₄ and 30 ml MTBE were added the mixture was filtered after 10 minutes, the inorganic solid was washed with 2 x 30 ml MTBE, the mother liquor was evaporated under reduced pressure. Then 10 g MgSO₄ and DCM were added, then it was filtered and washed with 20 mL DCM. The organic solvent was evaporated under reduced pressure to give Préparation R5b. HRMS calculated for C23H3qF2N2O₄: 436.2174; found 459.20595 [(M+Na)⁺ form].

Préparation R6a: 3-fluoro-5-iodo-thiophene-2-carboxylic acid

Step 1: 3-fluoro-5-iodo-thiophene-2-carboxylate and methyl 3-fluoro-4,5-diiodothiophene-2-carboxylate

To the solution of methyl 3-fluorothiophene-2-carboxylate (2.42 g, 15.1 mmol) in THF (10 ml), TMP.MgCLLiCl (IN in THF/toluene, 25 ml, 25 mmol) was added dropwise at -45 °C in 5 minutes. After 30 minutes of stirring, iodine (4.04 mg, 15.9 mmol) was added in THF (10 ml) at -45 °C to the mixture. After warming up (1 hour), sat. NH₄C1 solution (50 ml, aq.) was added to the mixture while stirring. The mixture was extracted with DEE (5 x 10 ml). The combined organic layer was evaporated. The residue was purified by préparative LC (on C-18 Gemini-NX 5pm column, 5 mM aqueous NH₄HCO3-MeCN, gradient) to give 3-fluoro-5-iodo-thiophene-2-carboxyIate and methyl 3-fluoro-4,5-diiodo-thiophene-2carboxylate, separately.

Methyl 3-fluoro-5-iodo-thiophene-2-carboxylate

- 51 GC-MS calculated for C₆H₄FIO₂S: 285.8961; found 285.9 [(M, El) form], 'H-NMR (500 MHz, DMSO-d6): δ ppm 7.52 (s, 1H), 3.78 (s, 3H).

¹³C-NMR(125 MHz, DMSO-d6): δ ppm 159.4, 158.8, 128.5, 117.2, 86.4, 52.8.

Methyl 3-fluoro-4,5-diiodo-thiophene-2-carboxylate

GC-MS calculated for C₆H₄FIO₂S: 411.7927; found 411.9 [(M, El) form], 'H-NMR (500 MHz, DMSO-d6): δ ppm 3.8 (s, 3H).

¹³C-NMR(125 MHz, DMSO-d6): δ ppm 159, 158.2, 117.4, 96.1,90.6, 53.1.

Step 2: Préparation R6a

Methyl 3-fluoro-5-iodo-thiophene-2-carboxylate (1.188 g, 4.135 mmol), lithium-hydroxide 10 monohydrate (867 mg, 20.7 mmol) were stirred in méthanol (10 ml) and water (10 ml) at 70 °C for 1 hour. The mixture was partially evaporated and the aqueous residue was acîdified with IN HCl (25 ml, aq.). The resulted precipitate was filtered off, washed with water and dried to give Préparation R6a. GC-MS calculated for CsH₂FIO₂S: 271.8804; found 271.9 [(M, El) form], 15 'H-NMR (500 MHz, DMSO-d6): δ ppm 13.48 (brs, 1H), 7.74 (s, 1H).

¹³C-NMR (125 MHz, DMSO-d6): δ ppm 160.4, 158.3, 128.5, 119, 85.1.

Préparation R6b: 4-bromo-5-chloro-3-fluoro-thiophene-2-carboxyIic acid

Step 1 : methyl 5-bromo-3-fluoro-thiophene-2-carboxylate

To the solution of methyl 3-fluorothiophene-2-carboxylate (320 mg, 2 mmol) in THF (2 ml), 20 TMP.MgCl.LiCl (IN in THF/toluene, 4 ml, 4 mmol) was added dropwise at

-45 °C in 5 minutes. After 25 minutes of stirring l,2-dibromo-l,l,2,2-tetrachloro-ethane (716 mg, 2.2 mmol) was added in THF (2 ml) at -45 °C to the mixture. After warming up (30 minutes), sat. NH₄C1 solution (5 ml, aq.) was added to the mixture while stirring. The mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic layer was 25 evaporated. The residue was purified by préparative LC (on C-l 8 Gemini-NX 5 gm column, 5 mM aqueous NH₄HCO3-MeCN, gradient) to give the product of the title. GC-MS calculated for C₆H₄BrFO₂S: 237.9099; found 237.8 [(M, El) form], 'H-NMR (500 MHz, DMSO-d6): δ ppm 7.52 (s, 1H), 3.80 (s, 3H).

¹³C-NMR(125 MHz, DMSO-d6): δ ppm 159.5, 158.2, 123.2, 119.6, 113.8,53.0.

-52Step 2: methyl 4-bromo-5-chloro-3-fluoro-thiophene-2-carboxylate

To the solution of methyl 5-bromo-3-fluoro-thiophene-2-carboxylate (210 mg, 0.878 mmol) in THF (2 ml) at TMP.MgCl.LiCl (IN in THF/toluene, 2 ml, 2 mmol) was added dropwise at -45 °C in 5 minutes. After 20 minutes of stirring, 1,1,1,2,2,25 hexachloroethane (236 mg, 1 mmol) was added in THF (2 ml) at -45 °C to the mixture. After warming up (30 minutes), sat. NH4CI solution (5 ml, aq.) was added to the mixture while stirring. The mixture was extracted with ethyl acetate (3x10 ml). The combined organic layer was evaporated. The residue was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient) to give the product of the title. ’H10 NMR (500 MHz, dmso-d6) δ ppm 3.84 (s, 3H) ^,3C-NMR(125 MHz, dmso-d6) δ ppm 159, 154.4, 132.2, 111.3, 104.2,53.4 ¹⁹F-NMR (376.5 MHz, dmso-d6) δ ppm -107.25

Step 3: Préparation R6b

Methyl 4-bromo-5-chloro-3-fluoro-thiophene-2-carboxylate (116 mg, 0.424 mmol), 15 lithium-hydroxide monohydrate (53.3 mg, 1.27 mmol, 3.0 eq.) were stirred in methanol (1.5 ml) and water (1.5 ml) at 50 °C for 20 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate was filtered off, washed with water and dried to give Préparation R6b.

’H-NMR (500 MHz, MSM-d6): δ (ppm) 14.07 (brs, 1H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 160.0, 153.8, 131.2, 113.4, 103.9.

’⁹F-NMR (376.48 MHz, MSM-d6): δ (ppm) -108.9

Préparation R7a: ethyl (3R,4R)-3-phenylpiperidine-4-carboxylate

Step 1: ethyl (3R,4R)-3-phenylpiperidine-4-carboxylate hydrochloride

In a three-necked 100 ml flask under N2 atmosphère, (3À,47?)-l-(tert-butoxycarbonyl)-325 phenylpiperidine-4-carboxylic acid (953 mg; 3,12 mmol; 1.0 eq.) was suspended in abs.

EtOH (18.2 ml; 312 mmol; 100 eq.). After cooling to 0 °C with ice bath, thionyl-chloride was added via syringe at such rate that the température is kept under 50 °C. Then, the

-53 suspension was stirred for 60 hours at 50 °C. The solution was cooled to r.t., when white crystals formed in the flask. The precipitate was collected by filtration; the filtrate was stored at -18 °C for 2 hours when most of the product precipitated and it was filtered again. The combined white crystals were washed with ice-cold EtOH (5 ml) and DEE (2x10 ml), then dried in vacuum to give the product of the title.

Step 2: Préparation R7a

In a one-necked 50 ml flask, hydrochloride sait of (37?,4J?)-ethyl 3-phenylpiperidine-4carboxylate (270 mg; 1.0 mmol; 1.0 eq.) was dissolved in H₂O (5 ml). DCM (10 ml) was added to the solution. Then, NaHCOj dissolved in water (0.6M; 252 mg; 3.0 mmol; 3.0 eq.) was added to the biphasic System. The mixture was stirred vigorously for 40 minutes. Organic layer was separated; inorganic phase was extracted with DCM (3x10 ml). The combined organic phase was washed with brine (5 ml), dried over Na₂SO₄, filtered and evaporated to dryness to give Préparation R7a. HRMS calculated for C14H19NO2: 233.1416; found 234.1487 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.29-7.14 (m, 5H), 3.8 (q, 2H), 2.98/2.57 (dm+m, 2H), 2.87/2.53 (dm+m, 2H), 2.74 (m, 1H), 2.74 (m, 1H), 2.31 (vbrs, 1H), 1.8/1.54 (dm+m, 2H), 0.87 (t, 3H) ’³C-NMR (125 MHz, dmso-d6) δ ppm 59.8, 53.3, 48.1, 46.6, 45.4, 30.4, 14.3

Préparation R7b: (37?,4/î)-ethyl l-(3-(lH-benzo[d][l,2,3]triazol-l-yl)oxetan-3-yl)-3phenylpiperidine-4-carboxylate

In a one-necked 50 ml flask, to a stirred solution of oxetan-3-one (288 mg; 4.0 mmol; 2.0 eq.) and Préparation R7a (467 mg; 2.0 mmol; 1.0 eq.) in amylene stabilized DCM (0.2M; 10 ml), was added D7-benzo[iZ][l,2,3]triazole (262 mg; 2.2 mmol; 1.1 eq.) at r.t. The mixture was stirred at r.t. for 90 minutes and evaporated to dryness at 50 °C. The crude product was used in the foilowing step without any purification.

Préparation R8a: (3R,4R)-3-phenyl-l-(3-phenyloxetan-3-yl)piperidine-4-carboxylic acid

-54Step 1: ethyl (3R,4R)-3-phenyl-l-(3-phenyloxetan-3-yl)piperidine-4-carboxylate

Phenylmagnesium bromide (0.3M; 6 mL; 1.8 mmol; 2.0 eq.) was added via syringe into a flame-dried, 3-necked 100 mL flask equipped with thermometer, nitrogen inlet and septum. ZnCl₂ (2.0M Me-THF solution; 0.540 mL; 1.08 mmol; 1.2 eq.) was added dropwise to the 5 Grignard solution keeping the température between 25-30 °C. The formed organozinc reagent was stirred at r.t. for 15 minutes, followed by the addition of Préparation R7b (0.2M abs. THF; 4.5ml; 0.9 mmol; 1.0 eq.) in a rate that the température was kept between 2530 °C with water bath. The solution was stirred for 30 minutes at r.t. then quenched with water (3 mL). DEE (20 mL) and saturated Na₂CO₃ (3 mL) was added to the suspension and 10 stirred for further 5 minutes. The white suspension was filtered through a short pad of Celite which was washed with 3x15 mL DEE. The filtrate was washed with saturated Na₂CO₃ (5 mL), dried on Na₂SÜ4 and concentrated on a rotary evaporator under reduced pressure to dryness. The crude product was purified by flash chromatography (hexanes/ethyl acetate 3/1). Fractions were evaporated to give ethyl (3R,4R)-3-phenyl-l-(3-phenyloxetan-315 yl)piperidine-4-carboxylate. HRMS calculated for C₂₃H₂₇NO₃: 365.1991; found 366.2062 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.42-7.09 (m, 10H), 4.79-4.69 (m, 4H), 3.8 (m, 2H), 3.44 (td, 1H), 3.01 (td, 1H), 2.93/1.62 (d+td, 2H), 2.81/1.54 (dm+t, 2H), 1.89/1.75 (dm+qd, 2H), 0.85 (t, 3H) ”C-NMR (125 MHz, dmso-d6) δ ppm 174.1, 80.1/79.9, 66.6, 59.9, 53.1, 47.2, 45.8, 45.6, 29.4, 14.3

Step 2: Préparation R8a

Ethyl (3R,4R)-3-phenyl-l-(3-phenyloxetan-3-yl)piperidine-4-carboxylate (375 mg, 1.026 mmol), lithium hydroxide monohydrate (172 mg, 4.104 mmol, 4.0 eq.) were stirred in éthanol (5 ml) and water (5 ml) at r.t. for 28 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN aqueous HCl solution. The resulted precipitate was filtered off, washed with water and dried to give Préparation R8a. HRMS calculated for C₂iH₂₃NO₃: 337.1678; found 338.1743 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 11.89 (s, 1H), 3 (m, 1H), 7.41-7.08 (m, 10H), 4.8130 4.68 (m, 4H), 2.93/1.59 (m+m, 2H), 2.79/1.48 (m+m, 2H), 2.36 (m, 1H), 1.93/1.73 (m+m,

2H) ¹³C-NMR (125 MHz, dmso-d6) δ ppm 66.6, 53.4, 47, 45.8, 45.4, 29.7

Préparation R8b: (3R,4R)-l-[3-(2-fluorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4carboxylic acid

Step 1: Préparation of (2-fluorophenyl)magnesium bromide

In a three-necked 100ml flask under N2 atmosphère, 1-bromo-2-fluorobenzene (0.984 ml; 9.0 mmol; 6.0 eq.) was dissolved in 18 ml abs. THF. The solution was cooled to -10 °C. Then, isopropylmagnesium chloride solution (0.5M in abs. THF; 18 ml; 9.0 mmol; 6.0 eq.) was added via syringe, while keeping the température under -5 °C. The Grignard reagent was kept between -10 °C and -5 °C at this température and used up immédiately to the next step.

Step 2: Ethyl (3R,4R)-l-(3-(2-fluorophenyl)oxetan-3-yl)-3-phenylpiperidine-4-carboxylate In a three-necked 100 ml flask under N2 atmosphère, a (2-fluorophenyI)magnesium bromide solution (0.25M in abs. THF; 36 ml; 9.0 mmol; 6.0 eq.) was prepared according to .Step 1 above. To the freshly prepared Grignard reagent, ZnCh solution (2.0M in abs. Me-THF; 2.5 ml; 4.9 mmol; 3.3 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minutes the clear solution, Préparation R7b (0.2M abs. THF; 7.5 ml; 1.5 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture was allowed to warm to r.t. in 20 minutes then quenched with 3 ml cc. Na2CO3 solution while keeping the température under 30 °C. To the resulting suspension, 40 ml DCM was added, then stirred vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with 60 ml DCM then washed with 10 ml cc. Na2CCh solution. Organic phase was dried over anhydrous Na2SÛ4 then evaporated to dryness. Purification by flash chromatography (85/15 hexanes/ethyl acetate) afforded ethyl (3R,4R)-1 -(3-(2fluorophenyl)oxetan-3-yl)-3-phenylpiperidine-4-carboxylate as a colourless oil.

Step 3: Préparation R8b

Ethyl (3R,4R)-l-(3-(2-fluorophenyl)oxetan-3-yl)-3-phenylpiperidine-4-carboxylate (300 mg, 0.782 mmol), lithium hydroxide monohydrate (65.6 mg, 1.565 mmol, 2.0 eq.) were

-56stirred in éthanol (3 ml) and water (3 ml) at r.t. for 56 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate was filtered off, washed with water and dried to give Préparation R8b. HRMS calculated for C21H22FNO3: 355.1584; found 356.1653 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 11.93 (brs, 1H), 7.37 (dd, 1H), 7.25 (t, 2H), 7.21 (t, 1H), 7.2 (t, 1H), 7.19 (d, 2H), 7.18 (t, 1H), 7.12 (t, 1H), 4.81/4.76/4.74 (d+d+s, 4H), 3.03/1.64 (d+t, 2H), 3.02 (t, 1H), 2.89/1.53 (d+t, 2H), 2.42 (t, 1H), 1.95/1.75 (ddd+ddd, 2H). C-NMR (125 MHz, dmso-d6) δ ppm 175.8, 160.6, 142.7, 130.6, 130.2, 128.7, 128.2, 127, 124.4, 123.7, 116.2, 79.2/79, 64.8, 53.3, 47, 45.8, 45.3, 29.7

Préparation R8c: (3R,4R)-l-[3-(4-fluorophenyI)oxetan-3-yl]-3-phenyl-piperidine-4carboxylic acid

Step 1: ethyl (3R_!4R)-l-[3-(4-fluorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4-carboxylate To a three-necked 100 ml flask under N2 atmosphère, (4-fluorophenyl)magnesium bromide solution (0.5M in abs. THF; 24 ml; 12.0 mmol; 6.0 eq.) was added via syringe. The Grignard solution was cooled to -10 °C with ice-NaCl cooling bath and ZnCh solution (2.0M in abs. Me-THF; 3.3 ml; 6.6 mmol; 3.3 eq.) was added via syringe at such rate that the température was kept between -10 °C and -5 °C. After stirring 5 minutes the clear solution, Préparation R7b (0.2M abs. THF; 10 ml; 2.0 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml cc. Na2CO3 solution while keeping the température under 30 °C. To the resulting suspension, 40 ml DCM was added, then stirred vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with 60 ml DCM then washed with 10 ml cc. Na₇CO3 solution. Organic phase was dried over anhydrous Na2SÜ4 then evaporated to dryness. Purification by flash chromatography (4/1 hexanes/ethyl acetate) afforded ethyl (3R,4R)-l-[3-(4-fluorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4-carboxylate. HRMS calculated for C23H26FNO3: 383.1897; found 384.196 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 7.24 (t, 2H), 7.21 (dd, 2H), 7.2 (t, 2H), 7.19 (t, 1H), 7.16 (d, 2H), 4.74/4.69 (d+d, 2H), 4.73 (s, 2H), 3.8 (q, 2H), 3 (t, 1H), 2.92/1.59 (dd+t, 2H), 2.8/1.53 (dd+d, 2H), 2.46 (t, 1H), 1.89/1.74 (ddd+ddd, 2H), 0.85 (t, 3H).

-57 ¹³C-NMR(125 MHz, dmso-d6)Ôppm 174.1, 161.6,142.1,133.5,129.9, 128.7, 128.2, 127.1, 114.9, 80.1, 79.9, 66.2, 59.9, 53, 47.2, 45.8, 45.5, 29.4, 14.3

Step 2: Préparation R8c

Ethyl (3R,4R)-l-[3-(4-fluorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4-carboxylate (130 mg, 0.339 mmol), lithium hydroxide monohydrate (28.4 mg, 0.678 mmol, 2.0 eq.) were stirred in éthanol (3 ml) and water (3 ml) at 80 °C for 41 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate was filtered off, washed with water and dried to give Préparation R8c. HRMS calculated for C21H22FNO3: 355.1584; found 356.1659 ((M+H)⁺ form).

'H-NMR(400 MHz, dmso-d6) δ ppm 7.40-7.10 (br., 9H), 3.01 (br., 1H), 4.90-4.60 (br., 4H), 2.92/1.58 (br.+br., 2H), 2.79/1.48 (br.+br., 2H), 2.39 (br., 1H), 1.94/1.73 (br.+br„ 2H) ^l3C-NMR (100 MHz, dmso-d6) δ ppm 80, 53.3, 47.1, 45.8, 45.4, 29.7

Préparation R8d: (3R,4R)-l-(3-methyloxetan-3-yl)-3-phenyl-piperidine-4-carboxylic acid

Step 1: ethyl (3R,4R)-l-(3-methyloxetan-3-yl)-3-phenyl-piperidine-4-carboxylate

To a three-necked 100 ml flask under N₂ atmosphère, a méthylmagnésium chloride solution (0.5M in THF; 24 ml; 12.0 mmol; 6.0 eq.) was added via syringe. The Grignard solution was cooled to -10°C with ice-NaCl cooling bath and ZnCh solution (2.0M in abs. Me-THF; 3.3 ml; 6.6 mmol; 3.3 eq.) was added via syringe at such rate that the température is kept between -10 °C and 5 °C. After stirring 5 minutes, Préparation R7b (0.2M abs. THF; 10 ml; 2.0 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml cc. Na2CÜ3 solution while keeping the température under 30 °C. To the resulting suspension, 40 ml DCM was added, then stirred vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with 60 ml DCM then washed with 10 ml cc. Na2CÜ3 solution. Organic phase was dried over anhydrous Na₂SO4 then evaporated to dryness. Purification by flash chromatography (3/1 hexanes/ethyl acetate) afforded ethyl (3R,4R)-l-(3-methyloxetan-3-yl)-3-phenyl-piperidine-4-carboxylate. HRMS calculated for Ci8H₂₅NO₃: 303.1834; found 304.1909 ((M+H)⁺ form).

-58’H-NMR (500 MHz, dmso-d6) δ ppm 7.25 (m, 2H), 7.25 (m, 2H), 7.19 (t, 1H), 4.4/4.06 (d+d, 2H), 4.4/4.11 (d+d, 2H), 3.82 (q, 2H), 2.93 (t, 1H), 2.63 (t, 1H), 2.58/2.18 (dd+td, 2H), 2.46/2.14 (dd+td, 2H), 1.92/1.69 (ddd+ddd, 2H), 1.25 (s, 3H), 0.89 (t, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 174.2, 142.2, 128.6, 128.2, 127.1, 81.2, 81.1, 60.1, 5 59.9, 52.4, 47.6, 45.7, 44.7, 29.6, 14.8, 14.3

Step 2: Préparation R8d

Ethyl (3R,4R)-l-(3-methyloxetan-3-yl)-3-phenyl-piperidine-4-carboxylate (69 mg, 0.227 mmol), lithium hydroxide monohydrate (19.0 mg, 0.454 mmol, 2.0 eq.) were stirred in éthanol (2 ml) and water (2 ml) at 80 °C for 41 hours. The mixture was partially evaporated 10 and the aqueous residue was acidified with IN HCl (aq.) and it was extracted with 2 x 5 ml DCM. The combined organic layers were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to give Préparation R8c. HRMS calculated for C16H21NO3: 275.1521; found 276.1592 ((M+H)⁺ form).

'H-NMR (400/500 MHz, dmso-d6) δ ppm 12.52-11.62 (br., 1H), 7.50-7.00 (br., 5H), 5.2015 3.95 (br., 4H), 3.62-2.01 (br., 6H), 2.32-1.57 (br„ 2H), 1.64/1.23 (br.+br., 3H)

Préparation R8e: (3R,4R)-l-(3-isopropyloxetan-3-yl)-3-phenyl-piperidine-4carboxylic acid

Step 1: ethyl (3R,4R)-l-(3-isopropyloxetan-3-yl)-3-phenyl-piperidine-4-carboxylate

To a three-necked 100 ml flask under N2 atmosphère, an isopropylmagnesium çhloride 20 solution (0.5M in abs. THF; 31 ml; 15.6 mmol; 6.0 eq.) was added via syringe. The Grignard solution was cooled to -10 °C with ice-NaCl cooling bath, and ZnCh solution (2.0M in abs. Me-THF; 4.3 ml; 6.6 mmol; 3.3 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minutes the clear solution, Préparation R7b (0.2M abs. THF; 13 ml; 2.6 mmol; 1.0 eq.) was added dropwise to the organozinc 25 reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml cc. Na2COs solution while keeping the température under 30 °C. To the resulting suspension 40 ml DCM was added, then stirred vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with 60 ml DCM then washed with 10 ml cc. Na₂CO3 solution.

-59Organic phase was dried over anhydrous Na₂SO₄ then evaporated to dryness. Purification by flash chromatography (83/17 hexanes/ethyl acetate) afforded ethyl (3R,4R)-l-(3isopropyloxetan-3-yl)-3-phenyl-piperidine-4-carboxylate as a colourless oil. HRMS calculated for C₂₀H₂₉NO₃: 331.2148; found 332.22154 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 7.25 (m, 2H), 7.25 (m, 2H), 7.19 (t, 1H), 4.52/4.23 (d+d, 2H), 4.47/4.23 (d+d, 2H), 3.82 (q, 2H), 2.89/2.5 (d+t, 2H), 2.86 (t, 1H), 2.75/2.49 (d+t, 2H), 2.69 (t, 1H), 2.08 (m, 1H), 1.91/1.63 (d+dd, 2H), 0.97 (d, 6H), 0.88 (t, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 174.3, 142.3, 128.6, 128.2, 127.1, 74.7, 74.5, 66.2, 59.9, 53.9, 47.8, 46.6, 46.3, 31.3, 30.3, 18.4, 14.3

Step 2: Préparation R8e

Ethyl (3R,4R)-l-(3-isopropyloxetan-3-yl)-3-phenyl-piperidine-4-carboxylate (280 mg, 0.844 mmol), lithium hydroxide monohydrate (106 mg, 2.534 mmol, 3.0 eq.) were stirred in éthanol (3 ml) and water (3 ml) at r.t. for 44 hours. The mixture was partially evaporated and the aqueous residue was acîdified with IN HCl (aq.) and it was evaporated to Celite. Then it was purified via flash chromatography using DCM and MeOH as eluents. Solvents were evaporated under reduced pressure to give Préparation R8e. HRMS calculated for Ci₈H₂₅NO₃: 303.1834; found 304.1902 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm (m, 5H), 4.52/4.47/4.24 (br./br.+br., 4H), 2.91/2.5 (br.+br., 2H), 2.87 (br„ 1H), 2.75/2.45 (br.+br., 2H), 2.63 (br., IH), 2.08 (br., 1H), 1.95/1.63 (d+br., 2H), 0.96 (d, 6H) ¹³C-NMR (125 MHz, dmso-d6) δ ppm 74.5, 54.1, 47.4, 46.4, 46, 31, 30.4, 18.4

Préparation R8f: (3R,4R)-l-[3-(2-methoxyphenyI)oxetan-3-yl]-3-phenyl-piperidine-4carboxylic acid

Step 1: (3R,4R)-ethyl 3-phenyl-1 -(3-(o-tolyl)oxetan-3-yl)piperidine-4-carboxylate

To a three-necked 100 ml flask under N₂ atmosphère, ort/io-methyl-phenyl-MgBr solution (0.41M in abs. THF; 21 ml; 8.6 mmol; 6.0 eq.) was added via syringe. The Grignard-solution was cooled to -10 °C with ice-NaCl cooling bath, and ZnCl₂-solution (2.0M in abs. 2methyltetrahydrofuran; 2.3 ml; 4.6 mmol; 3.2 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minutes, Préparation R7b

-60(0.2M abs. THF; 7.1 ml; 1.43 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml sat. Na2CO3 solution while keeping the température under 30 °C. To the resulting suspension, 40 ml DCM was added, then stirred 5 vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with ml DCM then washed with 10 ml sat. Na2CO3 solution. Organic phase was dried over anhydrous Na₂SO₄ then evaporated to dryness. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded (3R,4R)-ethyl l-(3-(2-methoxyphenyl)oxetan-3-yl)-3phenylpiperidine-4-carboxylate. HRMS calculated for C2₄H29NO3: 379.2148; found 10 380.2222 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 7.29-6.93 (m, 9H), 4.95-4.81 (m, 4H), 3.82/3.79 (m+m, 2H), 3.08/2.22 (m+m, 2H), 2.97/2.23 (m+m, 2H), 2.86 (m, 1H), 2.61 (m, 1H), 2.16 (s, 3H), 1.93/1.64 (m+m, 2H), 0.86 (t, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 59.9, 53.2, 47.8, 46.1, 45.8, 29.8, 20, 14.3

Step 2: Préparation R8f (3R,4R)-ethyl 3-phenyl-l-(3-(o-tolyl)oxetan-3-yl)piperidine-4-carboxylate (369 mg, 0.972 mmol), lithium hydroxide monohydrate (122 mg, 2.917 mmol, 3.0 eq.) were stirred in éthanol (4 ml) and water (4 ml) at 50 °C for 80 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate was 20 filtered off, washed with water and dried to give Préparation R8f. HRMS calculated for C22H25NO3: 351.1834; found 352.1907 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 12.3 (brs, 1H), 7.25 (t, 2H), 7.2 (d, 2H), 7.18 (m, 1H), 7.17 (m, 1H), 7.16 (d, 1H), 7.12 (m, 1H), 6.96 (d, 1H), 4.92/4.9/4.85 (d+d+d, 4H), 3.07/2.2 (d+t, 2H), 2.96/2.17 (d+t, 2H), 2.86 (td, 1H), 2.53 (td, 1H), 2.16 (s, 3H), 1.96/1.61 (ddd+ddd, 25 2H).

¹³C-NMR(125 MHz, dmso-d6)ôppm 175.9,142.7, 139.1, 136.6, 131.8, 128.8, 128.7, 128.2, 127.7, 127, 125.5, 77.1/77, 68.8, 53.4, 47.6, 46, 45.7, 30.1, 20

Préparation R8g: (3R,4R)-l-[3-(2-methoxyphenyI)oxetan-3-yl]-3-phenyl-piperidine-4carboxylic acid

Step 1: (3R,4R)-ethyl l-(3-(2-methoxyphenyl)oxetan-3-yl)-3-phenylpiperidine-4carboxylate

To a three-necked 100 ml flask under N₂ atmosphère, οΗΛο-methoxy-phenyl-MgBr solution (0.35M in abs. THF; 17 ml; 6.0 mmol; 6.0 eq.) was added via syringe. The Grignard solution was cooled to -10 °C with ice-NaCl cooling bath, and ZnCl₂ solution (2.0M in abs. 2methyltetrahydrofuran; 1.6 ml; 3.2 mmol; 3.2 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minute,s Préparation R7b (0.2M abs. THF; 5 ml; 1.00 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml sat. Na₂CO₃ solution while keeping the température under 30 °C. To the resulting suspension, 40 ml DCM was added, then stirred vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with 60 ml DCM then washed with 10 ml sat. Na₂CO₃ solution. Organic phase was dried over anhydrous Na₂SO₄ then evaporated to dryness. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded (3R,4R)-ethyl l-(3-(2-methoxyphenyl)oxetan-3-yl)-3phenylpiperidine-4-carboxylate. FÏRMS calculated for C₂₄H₂9NO₄: 395.2097; found 396.2171 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 7.27 (m, 1H), 7.27-7.12 (7, 5H), 7.02 (dm, 1H), 6.92 (m, 1H), 6.88 (dm, 1H), 4.82-4.6 (m, 4H), 3.82/3.78 (m+m, 2H), 3.63 (s, 3H), 3.1/1.65 (m+m, 2H), 2.99 (m, 1H), 2.96/1.62 (m+m, 2H), 2.45 (m, 1H), 1.89/1.75 (m+m, 2H), 0.86 (t, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 129.7, 129.3, 120.3, 112.3, 59.8, 55.7, 53.3, 47.5, 45.9, 45.9, 29.7, 14.3

Step 2: Préparation R8g (3R,4R)-ethyl l-(3-(2-methoxyphenyl)oxetan-3-yl)-3-phenylpiperidine-4-carboxylate (274 mg, 0.692 mmol), lithium hydroxide monohydrate (87 mg, 2.078 mmol, 3.0 eq.) were stirred in éthanol (4 ml) and water (4 ml) at 45 °C for 20 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate was filtered off, washed with water and dried to give Préparation R8g. HRMS calculated for C₂₂H₂₅NO₄: 367.1783; found 368.1855 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 12.33 (brs, 1H), 7.27 (t, 1H), 7.24 (t, 2H), 7.17 (d,

-622H), 7.16 (t, 1H), 7.02 (d, 1H), 6.91 (t, 1H), 6.86 (d, 1H), 4.78/4.71/4.64 (d+d+d, 4H), 3.62 (s, 3H), 3.1/1.63 (d+t, 2H), 2.99 (td, 1H), 2.93/1.56 (d+t, 2H), 2.36 (td, 1H), 1.92/1.72 (ddd+ddd, 2H).

¹³C-NMR (500 MHz, dmso-d6) δ ppm 176, 157.8, 143, 129.7, 129.3, 128.7, 128.2, 127, 125, 5 120.4, 112.3, 79.2/79.1, 65.8, 55.7, 53.6, 47.4, 46.1, 45.5, 30

Préparation R8h: (3R,4R)-3-phenyl-l-[3-[3-(trifluoromethyI)phenyl]oxetan-3yl]piperidine-4-carboxylic acid

Step 1: (3R,4R)-ethyl 3-phenyl-l-(3-(3-(trifluoromethyl)phenyl)oxetan-3-yl)piperidme-4carboxylate

To a three-necked 100 ml flask under N₂ atmosphère, meta-trifluoromethyl-phenyl-MgBr solution (0.35M in abs. THF; 12 ml; 4.2 mmol; 6.0 eq.) was added via syringe. The Grignard solution was cooled to -10 °C with ice-NaCl cooling bath, and ZnCl₂ solution (2.0M in abs. 2-methyltetrahydrofuran; 1.1 ml; 2.24 mmol; 3.2 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minutes, Préparation R7b 15 (0.2M abs. THF; 3.5 ml; 0.70 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml sat. Na₂CO₃ solution while keeping the température under 30 °C. To the resulting suspension, 40ml DCM was added, then stirred vigorously for 5 minutes. The slurry was fdtered through a short pad of Celite, diluted with

60 ml DCM then washed with 10 ml sat. Na₂CO₃ solution. Organic phase was dried over anhydrous Na₂SÛ4 then evaporated to dryness. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded (3R,4R)-ethyl 3-phenyl-l-(3-(3-(trifluoromethyl)phenyl)oxetan3-yl)piperidine-4-carboxylate. HRMS calculated for C₂₄H₂6F₃NO₃: 433.1865; found 434.1934 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.69 (dm, 1H), 7.62 (t, 1H), 7.52 (brs, 1H), 7.48 (dm, 1H), 7.27-7.13 (m, 5H), 4.81-4.71 (m, 4H), 3.81/3.77 (m+m, 2H), 3 (m, 1H), 2.99/1.58 (m+m, 2H), 2.88/1.52 (m+m, 2H), 2.48 (m, 1H), 1.89/1.75 (m+m, 2H), 0.85 (t, 3H). ¹³C-NMR (125 MHz, dmso-d6) δ ppm 132, 129.3, 124.5, 124.2, 59.9, 52.9, 47.1, 45.8, 45.5, 29.4, 14.2

Step 2: Préparation R8h (3R,4R)-ethyl 3-phenyl-l-(3-(3-(trifluoromethyl)phenyl)oxetan-3-yl)piperidine-4carboxylate (235 mg, 0.542 mmol), lithium hydroxide monohydrate (68 mg, 1.626 mmol, 3.0 eq.) were stirred in éthanol (3 ml) and water (3 ml) at 45 °C for 18 hours. The mixture 5 was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate was filtered off, washed with water and dried to give Préparation R8h. HRMS calculated for C22H22F3NO3: 405.1552; found 406.1624 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 11.94 (brs, 1H), 7.79-7.4 (m, 4H), 7.25 (t, 2H), 7.18 (d, 2H), 7.17 (t, 1H), 4.78 (brd, 4H), 3.01/1.56 (br.+br„ 2H), 3 (br., 1H), 2.87/1.45 (br.+br., 10 2H), 2.41 (br., 1H), 1.94/1.75 (br.+br., 2H).

^I3C-NMR (125 MHz, dmso-d6) δ ppm 128.7, 128.3, 128.2, 79.7, 53, 47, 45.8, 45.4, 29.6

Préparation R8i: (3R,4R)-l-[3-(3-fluorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4carboxylic acid

Step 1: (3R,4R)-ethyl l-(3-(3-fluorophenyl)oxetan-3-yl)-3-phenylpiperidine-4-carboxylate

To a three-necked 100 ml flask under N₂ atmosphère, meta-fluoro-phenyl-MgBr solution (0.35M in abs. THF; 13.7 ml; 4.8 mmol; 6.0 eq.) was added via syringe. The Grignard solution was cooled to -10 °C with ice-NaCl cooling bath, and ZnCh solution (2.0M in abs. 2-methyltetrahydrofuran; 1.3 ml; 2.6 mmol; 3.2 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minutes, Préparation R7b (0.2M abs. THF; 4.0 ml; 0.80 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml sat. Na2CO3-solution while keeping the température under 30 °C. To the resulting suspension, 40ml DCM was added, then stirred vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with

60 ml DCM then washed with 10 ml sat. Na2CCb solution. Organic phase was dried over anhydrous Na2SO₄ then evaporated to dryness. Purification by flash chromatography (7:3 hexanes/EtOAc) afforded (3R,4R)-ethyI l-(3-(3-fluorophenyl)oxetan-3-yl)-3phenylpiperidine-4-carboxylate. HRMS calculated for C23H26FNO3: 383.1897; found 384.198 ((M+H)⁺form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.41 (m, 1H), 7.28-7.13 (m, 5H), 7.14 (m, 1H), 7.07

-64(dm, 1H), 6.99 (dm, 1H), 4.79-4.66 (m, 4H), 3.81/3.78 (m+m, 2H), 3 (m, 1H), 2.94/1.63 (m+m, 2H), 2.83/1.55 (m+m, 2H), 2.48 (m, 1H), 1.89/1.74 (m+m, 2H), 0.85 (t, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 130.1, 124, 114.8, 114.5, 59.9, 53, 47.2, 45.8, 45.6, 29.4, 14.3

Step 2: Préparation R8i (3R,4R)-ethyl l-(3-(3-fluorophenyl)oxetan-3-yl)-3-phenylpiperidine-4-carboxylate (245 mg, 0.638 mmol), lithium hydroxide monohydrate (80 mg, 1.916 mmol, 3.0 eq.) were stirred in éthanol (3 ml) and water (3 ml) at 45 °C for 42 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate 10 was filtered off, washed with water and dried to give Préparation R8i. HRMS calculated for C21H22FNO3: 355.1584; found 356.1654 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 11.91 (brs, 1H), 7.41 (dd, 1H), 7.25 (t, 2H), 7.18 (d, 2H), 7.16 (t, 1H), 7.15 (t, 1H), 7.07 (d, 1H), 6.99 (d, 1H), 4.77-4.68 (m, 4H), 3 (t, 1H), 2.93/1.61 (d+d, 2H), 2.8/1.49 (d+d, 2H), 2.39 (t, 1H), 1.93/1.73 (dd+dd, 2H).

’³C-NMR (125 MHz, dmso-d6) δ ppm 130, 128.7, 128.3, 127, 124, 114.8, 114.5, 80/79.7, 53.3, 47, 45.8, 45.4, 29.7

Préparation R8j: (3R,4R)-l-[3-(3-bromophenyl)oxetan-3-yl]-3-phenyl-piperidine-4carboxylic acid

Step 1: (3R,4R)-ethyl l-(3-(3-bromophenyl)oxetan-3-yl)-3-phenylpiperidine-4-carboxylate

In a three-necked 100ml flask under N2 atmosphère, 1,3-dibromobenzene (0.93 ml; 7.7 mmol; 7 eq.) was dissolved in 8 ml abs. THF. The solution was cooled to -10 °C. Then, z-PrMgCl-solution (1.3M in abs. THF; 5.1 ml; 6.6 mmol; 6.0 eq.) was added via syringe, while keeping the température under -5 °C, The reaction mixture was stirred for 1 hour at -10 °C to give the solution of zwe/iz-bromo-phenyl-MgBr.

In a three-necked 100 ml flask under N2 atmosphère, a solution of meta-bromo-pheny 1-MgBr (0.46M in abs. THF; 14 ml; 6.6 mmol; 6.0 eq.) was prepared. To the freshly prepared Grignard reagent, ZnCh solution (2.0M in abs. 2-methyltetrahydrofuran; 1.76 ml; 3.52 mmol; 3.2 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minutes, Préparation R7b (0.2M abs. THF; 5.5 ml; 1.1 mmol;

.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml sat. NazCOs solution while keeping the température under 30 °C. To the resulting suspension, 40ml DCM was added, then stirred vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with 60 ml DCM then washed with 10 ml sat. Na2COs solution. Organic phase was dried over anhydrous Na2SO₄ then evaporated to dryness. Purification by flash chromatography (75:25 hexanes/EtOAc) afforded (3R,4R)ethyl 1 -(3 -(3-bromopheny l)oxetan-3 -y l)-3 -phenylpiperidine-4-carboxy late. HRMS calculated for C23H26BrNO₃: 443.1096; found 444.1167 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.51 (dm, 1H), 7.4 (t, 1H), 7.34 (t, 1H), 7.28-7.14 (m, 5H), 7.17 (dm, 1H), 4.78-4.66 (m, 4H), 3.81/3.78 (m+m, 2H), 3 (m, 1H), 2.94/1.62 (m+m, 2H), 2.83/1.54 (m+m, 2H), 2.5 (m, 1H), 1.9/1.74 (m+m, 2H), 0.85 (t, 3H).

ⁱ³C-NMR (125 MHz, dmso-d6) δ ppm 130.6, 130.4, 130.4, 127, 59.9, 53, 47.1, 45.8, 45.5, 29.4, 14.3

Step 2: Préparation R8j (3R,4R)-ethyl l-(3-(3-bromophenyl)oxetan-3-yl)-3-phenylpiperidine-4-carboxylate (303 mg, 0.681 mmol), lithium hydroxide monohydrate (85 mg, 2.045 mmol, 3.0 eq.) were stirred in éthanol (3 ml) and water (3 ml) at 45 °C for 42 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate was filtered off, washed with water and dried to give Préparation R8j. HRMS calculated for C2iH₂2BrNO₃: 415.0783; found 416.0847 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 11.9 (brs, 1H), 7.51 (d, 1H), 7.39 (s, 1H), 7.33 (t, 1H), 7.25 (t, 2H), 7.19 (d, 2H), 7.16 (t, 1H), 7.15 (d, 1H), 4.76-4.68 (m, 4H), 3 (t, 1H), 2.94/1.61 (d+t, 2H), 2.81/1.48 (d+t, 2H), 2.42 (t, 1H), 1.94/1.73 (d+dd, 2H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 130.6, 130.4, 130.3, 128.7, 128.3, 127, 127, 79.9/79.7, 53.2, 46.9, 45.8, 45.4, 29.7

Préparation R8k: (3R,4R)-l-[3-(3-chlorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4carboxylic acid

Step 1: (3R,4R)-ethyl l-(3-(3-chlorophenyl)oxetan-3-yl)-3-phenylpiperidine-4-carboxylate

-66To a three-necked 100 ml flask under N2 atmosphère, meta-chloro-phenyl-MgBr solution (0.42M in abs. THF; 15.7 ml; 6.6 mmol; 6.0 eq.) was added via syringe. The Grignard solution was cooled to -10 °C with ice-NaCl cooling bath, and ZnCb solution (2.0M in abs. 2-methyltetrahydrofuran; 1.8 ml; 3.5 mmol; 3.2 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minutes, Préparation R7b (0.2M abs. THF; 5 ml; 1.1 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml sat. Na2CÛ3 solution while keeping the température under 30 °C. To the resulting suspension, 40 ml DCM was added, then stirred vigorously for 5 minutes. The slurry was fdtered through a short pad of Celite, diluted with 60 ml DCM then washed with 10 ml sat. Na2CÛ3 solution. Organic phase was dried over anhydrous NVSCfi then evaporated to dryness. Purification by flash chromatography (7:3 hexanes/EtOAc) afforded (3R,4R)-ethyl l-(3-(3-chlorophenyl)oxetan-3-yl)-3phenylpiperidine-4-carboxylate. HRMS calculated for C23H26CINO3: 399.1601; found 400.1672 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 7.43-7.09 (m, 9H), 4.79-4.65 (m, 4H), 3.81/3.78 (m+m, 2H), 3 (m, 1H), 2.94/1.62 (m+m, 2H), 2.84/1.54 (m+m, 2H), 2.5 (m, 1H), 1.9/1.74 (m+m, 2H), 0.85 (t, 3H).

C-NMR (125 MHz, dmso-d6) δ ppm 59.9, 53, 47.1, 45.8, 45.5, 29.4, 14.3

Step 2: Préparation R8k (3R,4R)-ethyl l-(3-(3-chlorophenyl)oxetan-3-yl)-3-phenylpiperidine-4-carboxylate (353 mg, 0.882 mmol), lithium hydroxide monohydrate (111 mg, 2.648 mmol, 3.0 eq.) were stirred in éthanol (3 ml) and water (3 ml) at 45 °C for 42 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate was filtered off, washed with water and dried to give Préparation R8k. HRMS calculated for C21H22CINO3: 371.1288; found 372.1355 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 11.91 (brs, 1H), 7.39 (t, 1H), 7.38 (s, 1H), 7.26 (d, 1H), 7.25 (t, 2H), 7.19 (d, 2H), 7.17 (t, 1H), 7.12 (d, 1H), 4.8-4.67 (m, 4H), 3 (t, 1H), 2.94/1.6 (d+t, 2H), 2.81/1.48 (d+t, 2H), 2.41 (t, 1H), 1.94/1.73 (d+dd, 2H).

C-NMR (125 MHz, dmso-d6) δ ppm 130.1, 128.7, 128.3, 127.8, 127.7, 127.1, 126.6, 79.9/79.7, 53.2, 46.9, 45.8, 45.4, 29.7

-67 Préparation R81: (3R,4R)-3-phenyl-l-[3-(p-tolyl)oxetan-3-yl]piperidine-4-carboxylic acid

Step 1: (3R,4R)-ethyl 3-phenyl-l-(3-(p-tolyl)oxetan-3-yl)piperidine-4-carboxylate

To a three-necked 100 ml flask under N2 atmosphère, /?cra-methyl-phenyl-MgBr solution (0.50M in abs. THF; 15 ml; 7.5 mmol; 6.0 eq.) was added via syringe. The Grignard solution was cooled to -10 °C with ice-NaCl cooling bath, and ZnCl₂ solution (2.0M in abs. 2methyltetrahydrofuran; 2.0 ml; 4.0 mmol; 3.2 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minutes, Préparation R7b (0.2M abs. THF; 6.3 ml; 1.25 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température stili between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml sat. Na₂COs solution while keeping the température under 30 °C. To the resulting suspension, 40 ml DCM was added, then stirred vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with 60 ml DCM then washed with 10 ml sat. Na₂COs solution. Organic phase was dried over anhydrous Na₂SO4 then evaporated to dryness. Purification by flash chromatography (7:3 hexanes/EtOAc) afforded (3R,4R)-ethyl 3-phenyl-l-(3-(p-tolyl)oxetan-3-yl)piperidine-4carboxylate. HRMS calculated for C₂4H₂9NO3: 379.2148; found 380.2219 ((M+H)⁺ form). ’H-NMR (500 MHz, dmso-d6) δ ppm 7.27-7.13 (m, 5H), 7.17 (m, 2H), 7.02 (m, 2H), 4.784.65 (m, 4H), 3.82/3.78 (m+m, 2H), 3 (m, 1H), 2.91/1.61 (m+m, 2H), 2.78/1.54 (m+m, 2H), 2.44 (m, 1H), 2.31 (s, 3H), 1.88/1.74 (m+m, 2H), 0.85 (t, 3H).

”C-NMR (125 MHz, dmso-d6) δ ppm 128.7, 127.7, 59.9, 53.1, 47.2, 45.8, 45.6, 29.4, 21.2, 14.3

Step 2: Préparation R81 (3R,4R)-Ethyl 3-phenyl-l-(3-(p-tolyl)oxetan-3-yl)piperidine-4-carboxylate (295 mg, 0.777 mmol), lithium hydroxide monohydrate (98 mg, 2.332 mmol, 3.0 eq.) were stirred in éthanol (4 ml) and water (4 ml) at 50 °C for 20 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate was filtered off, washed with water and dried to give Préparation R8L HRMS calculated for C₂₂H₂₅NO₃: 351.1834; found 352.19090 ((M+H)⁺ form).

-68’H-NMR (500 MHz, dmso-d6) δ ppm 12.41 (brs, 1H), 7.24 (t, 2H), 7.17 (t, 1H), 7.16 (d, 2H), 7.16 (d, 2H), 7.01 (d, 2H), 4.74/4.69 (d+d, 2H), 4.73 (s, 2H), 2.99 (td, 1H), 2.9/1.59 (d+t, 2H), 2.76/1.5 (d+t, 2H), 2.36 (td, 1H), 2.3 (s, 3H), 1.91/1.72 (ddd+ddd, 2H).

¹³C-NMR(125 MHz, dmso-d6) δ ppm 175.8,142.7,136.6, 134.3, 128.7,128.7, 128.2, 127.8, 127, 80.2, 80, 66.3, 53.4, 47, 45.8, 45.3, 29.7, 21.2

Préparation R8m: (3R,4R)-l-[3-(4-methoxyphenyl)oxetan-3-yl]-3-phenyl-piperidine4-carboxylic acid

Step 1: (3R,4R)-ethyl l-(3-(4-methoxyphenyl)oxetan-3-yl)-3-phenylpiperidine-4carboxylate

To a three-necked 100 ml flask under N₂ atmosphère, para-methoxy-phenyl-MgBr solution (0.50M in abs. THF; 15 ml; 7.5 mmol; 6.0 eq.) was added via syringe. The Grignard solution was cooled to -10 °C with ice-NaCl cooling bath, and ZnCl₂ solution (2.0M in abs. 2methyltetrahydrofuran; 2.0 ml; 4.0 mmol; 3.2 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minutes, Préparation R7b (0.2M abs. THF; 6.3 ml; 1.25 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 5 ml sat. Na₂CO₃ solution while keeping the température under 30 °C. To the resulting suspension, 40 ml DCM was added, then stirred vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with 60 ml DCM then washed with 10 ml sat. Na₂CO₃ solution. Organic phase was dried over anhydrous Na₂SO₄ then evaporated to dryness. Purification by flash chromatography (7:3 hexanes/EtOAc) afforded (3R,4R)-ethyl l-(3-(4-methoxyphenyl)oxetan-3-yl)-3phenylpiperidine-4-carboxylate. HRMS calculated for C₂₄H₂9NO₄: 395.2097; found 396.2173 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 7.27-7.13 (m, 5H), 7.07 (m, 2H), 6.91 (m, 2H), 4.774.65 (m, 4H), 3.82/3.77 (m+m, 2H), 3.75 (s, 3H), 3 (m, 1H), 2.89/1.61 (m+m, 2H), 2.77/1.55 (m+m, 2H), 2.45 (m, 1H), 1.88/1.73 (m+m, 2H), 0.86 (t, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 129.1, 113.4, 59.9, 55.5, 53.1, 47.2, 45.8, 45.6, 29.4, 14.3

Step 2: Préparation R8m (3R,4R)-ethyl 3-phenyl-l-(3-(p-tolyI)oxetan-3-yl)piperidine-4-carboxyIate (295 mg, 0.777 mmol), lithium hydroxide monohydrate (98 mg, 2.332 mmol, 3.0 eq.) were stirred in éthanol (4 ml) and water (4 ml) at 50 °C for 20 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The resulted precipitate was filtered off, washed with water and dried to give Préparation R8m. HRMS calculated for C22H25NO4: 367.1783; found 368.1856 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 12.3 (brs, 1H), 7.24 (t, 2H), 7.17 (t, 1H), 7.17 (d, 2H), 7.06 (d, 2H), 6.9 (d, 2H), 4.73/4.68 (d+d, 2H), 4.72 (s, 2H), 3.75 (s, 3H), 2.99 (td, 1H), 2.89/1.59 (d+t, 2H), 2.75/1.48 (d+t, 2H), 2.36 (td, 1H), 1.92/1.72 (ddd+ddd, 2H).

’³C-NMR (125 MHz, dmso-d6) δ ppm 175.8, 158.6, 142.7, 129.3, 129.1, 128.7, 128.2, 127, 113.5, 80.3, 80.1, 66.1, 55.5, 53.4, 47, 45.8, 45.4, 29.7

Préparation R8n: (3R,4R)-l-[3-(2-chlorophenyl)oxetan-3-yI]-3-phenyl-piperidine-4carboxylic acid

Step 1: ethyl (3R,4R)-l-[3-(2-chlorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4carboxylate

In a three-necked 100 ml flask under N2 atmosphère, 1 -bromo-2-chlorobenzene (1.5 g; 7.7 mmol; 7 eq.) was dissolved in 8 ml abs. THF. The solution was cooled to -10 °C. Then, z-PrMgCLLiCl-solution (1.3M in abs. THF; 5 ml; 6.6 mmol; 6.0 eq.) was added via syringe, while keeping the température under -5 °C. The Grignard-reagent was stirred between -10 °C and -5°C for 1 hour to give the solution of orZ/zo-chloro-phenyl-MgBr (0.5M in abs. THF; 13 ml; 6.6 mmol; 6.0 eq.). To the freshly prepared Grignard reagent, ZnCh solution (2.0M in abs. 2-methyltetrahydrofuran; 1.76 ml; 3.52 mmol; 3.2 eq.) was added via syringe at such rate that the température is kept between -10 °C and -5 °C. After stirring 5 minutes, Préparation R7b (0.2M abs. THF; 7.5ml; 1.5 mmol; 1.0 eq.) was added dropwise to the organozinc reagent, keeping the température still between -10 °C and -5 °C. The reaction mixture is allowed to warm to r.t. in 20 minutes then quenched with 3 ml sat. Na2CO3 solution while keeping the température under 30 °C. To the resulting suspension, 40 ml DCM was added, then stirred vigorously for 5 minutes. The slurry was filtered through a short pad of Celite, diluted with 60 ml DCM then washed with 10 ml sat. Na2CO3-solution.

Organic phase was dried over anhydrous Na₂SÛ4 then evaporated to dryness. Purification by flash chromatography (70:30 hexanes/EtOAc) afforded ethyl (3R,4R)-l-[3-(2chlorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4-carboxylate. HRMS calculated for C₂₃H₂₆C1NO₃: 399.1601; found 400.1678 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.46-7.05 (m, 4H), 7.28-7.15 (m, 5H), 4.93-4.69 (m, 4H), 3.82/3.78 (m+m, 2H), 3.25/1.88 (m+m, 2H), 3.11/1.85 (m+m, 2H), 2.98 (m, 1H), 2.54 (m, 1H), 1.92/1.74 (m+m, 2H), 0.86 (t, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 59.9, 53.4, 47.4, 46.1, 46, 29.6, 14.3

Step 2: Préparation R8n:

Ethyl (3R,4R)-l-[3-(2-chlorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4-carboxylate (203 mg, 0.507 mmol), lithium hydroxide monohydrate (64 mg, 1.522 mmol, 3.0 eq.) were stirred in éthanol (4 ml) and water (4 ml) at 50 °C for 20 hours. The mixture was partially evaporated and the aqueous residue was acidified with IN HCl (aq.). The solvent was evaporated, the resulted precipitate was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous 0.2 w% HCOOH-MeCN, gradient) and evaporated to give Préparation R8m. HRMS calculated for C₂iH₂₂C1NO₃: 371.1288; found 372.13610 ((M+H)+ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 11.94 (brs, 1H), 7.42 (m, 1H), 7.32 (m, 1H), 7.32 (m, 1H), 7.25 (t, 2H), 7.2 (d, 2H), 7.17 (t, 1H), 7.07 (m, 1H), 4.9/4.73 (d+d, 2H), 4.84/4.74 (d+d, 2H), 3.23/1.86 (d+t, 2H), 3.09/1.78 (d+t, 2H), 2.97 (td, 1H), 2.45 (td, 1H), 1.96/1.71 (ddd+ddd, 2H).

’³C-NMR(125 MHz, dmso-d6)ôppm 175.9,142.7, 135.1, 132.7, 131.2, 130.9, 129.8, 128.7, 128.2, 127.1, 127, 89, 77.9, 68.1, 53.7, 47.2, 46.3, 45.6, 30

Préparation R9b: l-[(3R,4R)-l-[3-(2-fluorophenyl)oxetan-3-yl]-3-phenyl-piperidine4-carbonyI] piperidin-4-one

Using General Procedure 6 starting from Préparation R8b and 4-piperidone hydrochloride hydrate as reagents, Préparation R9b was obtained. HRMS calculated for C₂6H₂₉FN₂O₃: 436.2162; found 437.22339 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.43-7.10 (m, 9H), 4.85-4.72 (m, 4H), 3.79-3.21 (m,

4H), 3.24-1.68 (m, 8H), 2.19-1.53 (m, 4H) ¹³C-NMR (125 MHz, dmso-d6) δ ppm 207.5, 172.8

Préparation R9c: l-[(3R,4R)-l-[3-(4-fluorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4carbonyl] piperidin-4-one

Using General Procedure 6 starting from Préparation R8c and 4-piperidone hydrochloride hydrate as reagents, Préparation R9c was obtained. HRMS calculated for C26H29FN2O3: 436.2162; found 437.2228 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.24-7.11 (m, 9H), 4.77-4.68 (m, 4H), 3.71/3.66/3.51/3.28 (m+m+m+m, 4H), 3.13 (t, 1H), 2.99 (dd, 1H), 2.88/1.67 (t+d, 2H), 2.81/1.67 (dd+t, 2H), 2.12/2.07/1.81/1.61 (m+m+m+m, 4H), 1.75/1.68 (m+m, 2H).

’³C-NMR (125 MHz, dmso-d6) δ ppm 80.3/80, 52.5, 45.8, 45.6, 43.3/40.4, 42.8, 41.3/40.8, 29.7

Préparation R9d: l-[(3R,4R)-l-(3-methyloxetan-3-yl)-3-phenyl-piperidine-4carbonyl] piperidin-4-one

Using General Procedure 6 starting from Préparation R8d and 4-piperidone hydrochloride hydrate as reagents, Préparation R9d was obtained. HRMS calculated for C21H28N2O3: 356.21; found 357.2159 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.25 (m, 2H), 7.25 (m, 2H), 7.15 (m, 1H), 4.42/4.41/4.12/4.07 (d+d+d+d, 4H), 3.75/3.72/3.59/3.3 (m+m+m+m, 4H), 3.14 (t, 1H), 3.05 (t, 1H), 2.56/2.25 (d+t, 2H), 2.47/2.29 (d+t, 2H), 2.16/2.14/1.85/1.63 (m+m+m+m, 4H), 1.78/1.73 (t+t, 2H), 1.28 (s, 3H).

¹³C-NMR (125 MHz, dmso-d6) δ ppm 207.5, 172.9, 143.1, 128.7, 128.3, 127, 81.3/81.2, 60.2, 51.8, 45.8, 44.8, 43.4/40.5, 43.2, 41.2/40.8, 29.9, 14.7

Préparation R9e: l-[(3R,4R)-l-(3-iisopropyloxetan-3-yl)-3-phenyl-piperidine-4carbonyl] piperidin-4-one

Using General Procedure 6 starting from Préparation R8e and 4-piperidone hydrochloride hydrate as reagents, Préparation R9e was obtained. HRMS calculated for C23H32N2O3: 384.2413; found 385.2485 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.25 (m, 2H), 7.25 (m, 2H), 7.16 (m, 1H),

4.52/4.49/4.25/4.24 (d+d+d+d, 4H), 3.79-1.60 (m, 14H), 3.19 (t, 1H), 2.98 (t, 1H), 2.11 (m, 1H), 0.99 (d, 6H) ¹³C-NMR (125 MHz, dmso-d6) δ ppm 207.6, 173, 143.2, 128.7, 128.3, 127, 74.7/74.6, 66.2, 46.6, 43.5, 31.2, 18.5/18.4

Préparation RlOb: [(3R,4R)-l-[3-(2-fluorophenyl)oxetan-3-yl]-3-phenyl-4-piperidylJ(l-oxa-6-azaspiro[2.5]octan-6-yI)methanone

Préparation R9b (180 mg, 0.412 mmol) and trimethylsulfoxonium-iodide (1.031 mmol, 2.5 eq.) was stirred in MeCN (8 ml) and MTBE (8 ml) at r.t. and solution of NaOH ( 1.031 mmol, 2.5 eq.) in water (1.1 ml) was added to the mixture. Then the reaction mixture was stirred at 60 °C for 21 hours. The reaction mixture was evaporated under reduced pressure. It was dissolved in 8 ml DCM and 5 ml water. The layers were separated and the aqueous phase was extracted with 2 x 8 ml DCM. The combined organic layer was dried over MgSO₄evaporated under reduced pressure to give Préparation RlOb. HRMS calculated for C27H31FN2O3: 450.2319; found 451.2384 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 7.38 (m, 1H), 7.23 (t, 2H), 7.22 (td, 1H), 7.2 (m, 1H), 7.17 (t, 1H), 7.16 (d, 2H), 7.14 (dd, 1H), 4.81/4.74 (d+d, 4H), 4.75 (s, 4H), 3.74-0.89 (m, 14H), 3.14 (t, 1H), 3 (m, 1H), 2.56/2.52 (t+dd, 2H) ¹³C-NMR (125 MHz, dmso-d6) δ ppm 130.7, 130.1, 128.6, 128.3, 126.9, 124.4, 116.2, 79.3, 79.1, 53.4/53.1, 45.7, 42.5/42.4

Préparation RIOc: [(3R,4R)-l-[3-(4-fluorophenyl)oxetan-3-yl]-3-phenyl-4-piperidyl](l-oxa-6-azaspiro[2.5]octan-6-yl)methanone

Préparation R9c (68 mg, 0.156 mmol) and trimethylsulfoxonium-iodide (0.389 mmol, 2.5 eq.) was stirred in MeCN (3 ml) and MTBE (3 ml) at r.t. and solution of NaOH (0.389 mmol, 2.5 eq.) in water (0.4 ml) was added to the mixture. Then the reaction mixture was stirred at 60 °C for 19 hours. The reaction mixture was evaporated under reduced pressure. It was dissolved in 3 ml DCM and 2 ml water. The layers were separated and the aqueous phase was extracted with 2 x 3 ml DCM. The combined organic layer was dried over MgSO₄ evaporated under reduced pressure to give Préparation RIOc. HRMS calculated for C27H31FN2O3: 450.2319; found 451.2396 ((M+H)⁺ form).

Ή-NMR (500 MHz, dmso-d6) δ ppm 7.28-7.10 (m, 9H), 4.79-4.66 (s, 4H), 3.77-2.88 (m, 6H), 3.18-1.57 (m, 6H), 2.60-2.48 (m, 2H), 1.37-0.87 (m, 4H),

Préparation RIOd: [(3R,4R)-l-(3-methyloxetan-3-yl)-3-phenyI-4-piperidyl]-(l-oxa-6azaspiro[2.5]octan-6-yI)methanone

Préparation R9d (14 mg, 0.039 mmol) and trimethylsulfoxonium-iodide (0.098 mmol, 2.5 eq.) was stirred in MeCN (2 ml) and MTBE (2 ml) at r.t. and solution of NaOH (0.098 mmol, 2.5 eq.) in water (0.2 ml) was added to the mixture. Then the reaction mixture was stirred at 60 °C for 19 hours. The reaction mixture was evaporated under reduced pressure. It was dissolved in 2 ml DCM and 2 ml water. The layers were separated and the aqueous phase 10 was extracted with 2 x 2 ml DCM. The combined organic layer was dried over MgSO₄evaporated under reduced pressure to give Préparation RIOd. HRMS calculated for C22H30N2O3: 370.2256; found 371.2340 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.30-7.12 (m, 5H), 4.44-4.04 (d+d, 4H), 3.81-2.97 (m, 6H), 2.64-2.50 (m, 2H), 2.62-2.18 (m, 4H), 1.80-1.62 (m, 2H), 1.44-0.89 (m, 4H), 1.27 (s, 15 3H)

Préparation RIOe: [(3R,4R)-l-(3-isopropyloxetan-3-yl)-3-phenyl-4-piperidyl]-(l-oxa6-azaspiro[2.5]octan-6-yI)methanone

Préparation R9e (30 mg, 0.078 mmol) and trimethylsulfoxonium-iodide (0.195 mmol, 2.5 eq.) was stirred in MeCN (2 ml) and MTBE (2 ml) at r.t. and solution of NaOH 20 (0.195 mmol, 2.5 eq.) in water (0.2 ml) was added to the mixture. Then the reaction mixture was stirred at 60 °C for 18 hours. The reaction mixture was evaporated under reduced pressure. It was dissolved in 3 ml DCM and 3 ml water. The layers were separated and the aqueous phase was extracted with 2 x 3 ml DCM. The combined organic layer was dried over MgSO₄ evaporated under reduced pressure to give Préparation RIOe. HRMS 25 calculated for C2₄H3₄N₂O₃: 398.257; found 399.2646 ((M+H)⁺ form).

’H-NMR (400 MHz, dmso-d6) δ ppm 7.40-7.05 (m, 5H), 4.55-4.18 (m, 4H), 3.90-2.50 (m, 12H), 2.1 (m, 1H), 1.80-0.90 (m, 6H), 0.99 (d, 6H)

-74Preparation RI la: 5-amino-3-[[(3S,4S)-3-fluoro-4-hydroxy-4-piperidyI] methyl] -6-(4fluorophenoxy)pyrimidin-4-one and 5-amino-3-[[(3R,4R)-3-fluoro-4-hydroxy-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one and

Préparation Rllb: 5-amino-3-[[(3R,4S)-3-fluoro-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one and 5-amino-3-[[(3S,4R)-3-fluoro-4-hydroxy-4piperidyl] methyl]-6-(4-fluorophenoxy)pyrimidin-4-one

The sodium hydroxide (216 mg, 2.5 eq., 5.4088 mmol) was dissolved in water (0.4 mL) and added to the stirred mixture of tert-butyl 3-fluoro-4-oxo-piperidine-l-carboxylate (470 mg, 2.1635 mmol), trimethyl sulfoxonium, iodide (1:1) (2.5 eq., 5.4088 mmol) dissolved in acetonitrile (3 mL) and 2-methoxy-2-methyl-propane (3 mL). Then the mixture was heated at 60 °C for 2 hours. Then potassium carbonate (598 mg, 2 eq., 4.327 mmol) and Préparation R4h (649 mg, 1 eq., 2.163 mmol) was added to this mixture and stirred at 70 °C for 17 hours. Then the reaction mixture was evaporated. The residue was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO₃-MeCN, gradient) and evaporated. Then the product was purified again by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO₃-MeCN, 48 % (ACN) isocratic method) and evaporated to give:

- the mixture of tert-butyl (3S,4S)-4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidinl-yl]methyl]-3-fluoro-4-hydroxy-piperidine-l-carboxylate and tert-butyl (3R,4R)-4[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-3-fluoro-4-hydroxypiperidine-l-carboxylate), and

- the mixture of tert-butyl (3S,4R)-4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidinl-yl]methyl]-3-fluoro-4-hydroxy-piperidine-l-carboxylate and tert-butyl (3R,4S)-4[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-3-fluoro-4-hydroxypiperidine-1 -carboxylate).

The mixture of tert-butyl (3S,4S)-4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-lyl]methyl]-3-fluoro-4-hydroxy-piperidine-l-carboxylate and tert-butyl (3R,4R)-4-[[5amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-3-fluoro-4-hydroxy-piperidine1-carboxylate) were reacted using General procedure 5 to give Préparation RI la. HRMS calculated for Ci6HisF2N₄O₃: 352.1347; found 353.1413 ((M+H)⁺ form).

-75Ή-NMR (500 MHz, dmso-d6) δ ppm 7.69 (s, 1H), 7.2 (t, 2H), 7.09 (dd, 2H), 5.12 (s, 1H), 4.67 (s, 2H), 4.41 (ddd, 1H), 4.2/3.98 (d+d, 2H), 2.87/2.78 (m+m, 2H), 2.55 (m, 2H), 1.42/1.33 (m+m, 2H).

¹³C-NMR(125 MHz, dmso-d6) δ ppm 159.2, 158.8, 151, 146.8, 139.2, 121.8, 120.1, 116.4, 5 92,71.7,51.6,45.5,40.8,35.

The mixture of tert-butyl (3S,4R)-4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-lyl]methyl]-3-fluoro-4-hydroxy-piperidine-l-carboxylate and tert-butyl (3R,4S)-4-[[5amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-3-fluoro-4-hydroxy-piperidine1-carboxylate) were reacted using General procedure 5 to give the mixture of Préparation 10 Rllb. HRMS calculated for C16H18F2N4O3: 352.1347; found 353.1418 ((M+H)⁺ form).

'H-NMR (500 MHz, dmso-d6) δ ppm 7.65 (s, 1H), 7.2 (t, 2H), 7.09 (dd, 2H), 5.33 (s, 1H), 4.69 (s, 2H), 4.38/3.75 (dd+d, 2H), 4.19 (dd, 1H), 2.94/2.85 (td+dd, 2H), 2.64 (m, 2H), 1.92 (br., 2H), 1.59/1.14 (td+dt, 2H).

¹³C-NMR(125 MHz, dmso-d6) δ ppm 159.3, 158.8, 151, 146.8, 139.3, 121.7, 120.2, 116.4, 15 90.6, 70.5, 51.4, 46, 40.8, 32.2.

-76EXAMPLES

The following Examples illustrate the invention but do not limit it in any way.

tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4-chlorophenoxy)-6-oxo-pyrimidin-lyl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 1)

Using General Procedure 4 starting from Préparation R4a and Préparation R5a as reagents, Example 1 was obtained. HRMS calculated for C33H40CIN5O6: 637.2667; found 638.2738 ((M+H)⁺ form).

tert-butyl (3R,4R)-4- [4- [ [5-amino-4-(3-chloro-5-methoxy-phenoxy)-6-oxo- pyrimidin-l-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 2)

Using General Procedure 4 starting from Préparation R4b and Préparation R5a as reagents, Example 2 was obtained. HRMS calculated for C34H42CIN5O7: 667.2773; found 668.286 (M+H)⁺ form).

tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4-chloro-3-fluoro-phenoxy)-6-oxo-pyrimidin-lyl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 3)

Using General Procedure 4 starting from Préparation R4c and Préparation R5a as reagents, Example 3 was obtained. HRMS calculated for C33H39CIFN5O6: 655.2573; found 20 678.2461 (M+Na)⁺form).

tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4-fluoro-3-methoxy-phenoxy)-6-oxo-pyrimidinl-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 4)

Using General Procedure 4 starting from Préparation R4d and Préparation R5a as 25 reagents, Example 4 was obtained. HRMS calculated for C34H₄2FN5O?: 651.3068; found 652.3146 ((M+H)⁺form).

tert-butyl (3R,4R)-4-[4-[[5-amino-6-oxo-4-[3-(trifluoromethyl)phenoxy]pyrimidin-l- yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 5)

Using General Procedure 4 starting from Préparation R4e and Préparation R5a as reagents, Example 5 was obtained. HRMS calculated for C34H40F3N5O6: 671.2931; found 5 672.2993 ((M+H)⁺ form).

tert-butyl (3R,4R)-4-[4-[[5-amino-6-oxo-4-[3-(trifluoromethoxy)phenoxy]pyrimidinl-yI]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxyIate (Example 6)

Using General Procedure 4 starting from Préparation R4f and Préparation R5a as 10 reagents, Example 6 was obtained. HRMS calculated for C34H40F3N5O7: 687.288; found 688.2958 ((M+H)⁺ form).

tert-butyl (3R,4R)-4-[4-[(5-amino-6-oxo-4-phenoxy-pyrimidin-l-yl)methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 7)

Using General Procedure 4 starting from Préparation R4g and Préparation R5a as 15 reagents, Example 7 was obtained. HRMS calculated for C33H41N5O6: 603.3057; found 604.314 ((M+H)⁺ form).

tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-lyl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 8)

Using General Procedure 4 starting from Préparation R4h and Préparation R5a as reagents, Example 8 was obtained. HRMS calculated for C33H40FN5O6: 621.2963; found 622.3033 ((M+H)⁺ form).

tert-butyl (3R,4R)-4-[(4S)-4-[(5-amino-6-oxo-4-phenoxy-pyrimidin-l-yl)methyl]-3,3difluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 9)

Using General Procedure 4 starting from Préparation R4g and Préparation R5b as reagents, the enantiomers were separated by chiral chromatography to give Example 9. HRMS calculated for C33H39F2N5O6: 639.2869; found 662.2762 ((M+Na)⁺ form).

tert-butyl (3R,4R)-4-[(4S)-4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-lyl]methyl]-3,3-difluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 10)

Using General Procedure 4 starting from Préparation R4h and Préparation R5b as reagents, the enantiomers were separated by chiral chromatography to give Example 10. HRMS calculated for C33H38F3N5O6: 657.2774; found 680.2659 ((M+Na)⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 11) Using General Procedure 5 starting from Example 10 as reagent, the crude product was purified by préparative LC (on C-18 Luna 10 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure to give Example 11. HRMS calculated for C28H30F3N5O4: 557.225; found 558.2314 ((M+H)⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyI]-6-phenoxy-pyrimidin-4-one (Example 12)

Using General Procedure 5 starting from Example 9 as reagent, the crude product was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3MeCN, gradient). Solvent was evaporated under reduced pressure to give Example 12. HRMS calculated for C28H31F2N5O4: 539.2344; found 540.2406 (M+H)⁺ form).

5-amino-3-{[(45)-3,3-difluoro-4-hydroxy-l-{(3R,4/?)-l-[(2-methylpyrimidin-4yI)methyl]-3-phenylpiperidine-4-carbonyl}piperidin-4-yl]methyl}-6-(4fluorophenoxy)pyrimidin-4(3Z0-one (Example 13)

Using General Procedure 9 starting from Example 11 and 4-(chloromethyl)-2-methylpyrimidine as reagents, Example 13 was obtained. HRMS calculated for C34H36F3N7O4: 663.2781; found 664.2849 ((M+H)⁺ form).

5-amino-6-(4-chlorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]pyrimidin-4-one hydrochloride (Example 14)

-79Using General Procedure 5 starting from Example 1 as reagent, the crude product was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3MeCN, gradient). Solvent was evaporated under reduced pressure to give Example 14. HRMS calculated for C28H32CIN5O4: 537.2143; found 538.2222 ((M+H)⁺ form).

5-amino-6-(3-chloro-5-methoxy-phenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 15)

Using General Procedure 5 starting from Example 2 as reagent, the crude product was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3MeCN, gradient). Solvent was evaporated under reduced pressure to give Example 15. HRMS calculated for C29H34CIN5O5: 567.2249; found 568.232 ((M+H)⁺ form).

5-amino-6-(4-chloro-3-fluoro-phenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] pyrimidin-4-one (Example 16)

Using General Procedure 5 starting from Example 3 as reagent, the crude product was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3MeCN, gradient). Solvent was evaporated under reduced pressure to give Example 16. HRMS calculated for C28H₃iClFN5O4: 555.2048; found 556.2118 ((M+H)⁺ form).

5-amino-6-(4-fluoro-3-methoxy-phenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one hydrochloride (Example 17)

Using General Procedure 5 starting from Example 4 as reagent, the crude product was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3MeCN, gradient). Solvent was evaporated under reduced pressure to give Example 17. HRMS calculated for C29H34FN5O5: 551.2544; found 552.2614 ((M+H)⁺ form).

5-amino-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl] methyl]-6-[3-(trifluoromethyl)phenoxy]pyrimidin-4-one hydrochloride (Example 18) Using General Procedure 5 starting from Example 5 as reagent, Example 18 was obtained. HRMS calculated for C29H32F3N5O4: 571.2407; found 572.2466 ((M+H)⁺ form).

5-amino-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]-6- [3-(trifluoromethoxy)phenoxy]pyrimidin-4-one hydrochloride (Example 19)

Using General Procedure 5 starting from Example 6 as reagent, Example 19 was obtained. HRMS calculated for C29H32F3N5O5: 587.2355; found 588.2414 ((M+H)⁺ form).

5-amino-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl] methyl]-6-phenoxy-pyrimidin-4-one (Example 20)

Using General Procedure 5 starting from Example 7 as reagent, the crude product was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3MeCN, gradient). Solvent was evaporated under reduced pressure to give Example 20. HRMS calculated for C28H33N5O4: 503.2533; found 504.2602 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 21)

Using General Procedure 5 starting from Example 8 as reagent, the crude product was purified by préparative LC (on C-18 Luna 10 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure to give Example 21 was obtained. HRMS calculated for C28H32FN5O4: 521.2438; found 522.2499 ((M+H)⁺ form).

5-amino-6-(4-chlorophenoxy)-3-[(4-hydroxy-l-{(32f,47?)-l-[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(31/)-one (Example 22)

Using General Procedure 6 starting from Example 14 and 4-methyl-2-(6-methyI-3pyridyl)thiazoIe-5-carboxylic acid as reagents, Example 22 was obtained. HRMS calculated for C39H40CIN7O5S: 753.25; found 754.2583 ((M+H)⁺ form).

5-amino-6-(3-chloro-5-methoxyphenoxy)-3-[(4-hydroxy-l-{(31?,47f)-l-[4-methyl-2(6-methylpyridin-3-yl)-l,3-thiazole-5-carbonyI]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3//)-one (Example 23)

Using General Procedure 6 starting from Example 15 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 23 was obtained. HRMS calculated for C40H42CIN7O6S: 783.2606; found 784.2664 ((M+H)⁺ form).

5-amino-6-(4-chloro-3-fluorophenoxy)-3-[(4-hydroxy-l-{(37?,4.ff)-l-[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazoie-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3Z/)-one (Example 24)

Using General Procedure 6 starting from Example 16 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 24 was obtained. HRMS calculated for C39H39CIFN7O5S: 771.2406; found 772.2473 ((M+H)⁺ form).

5-amino-6-(4-fluoro-3-methoxyphenoxy)-3-[(4-hydroxy-l-{(3.Æ,41f)-l-[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(327)-one (Example 25)

Using General Procedure 6 starting from Example 17 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxyIic acid as reagents, Example 25 was obtained. HRMS calculated for C40H42FN7O6S: 767.2902; found 768.2968 ((M+H)⁺ form).

5-amino-3-[(4-hydroxy-l-{(31î,41î)-l-[4-methyl-2-(6-methylpyridin-3-yl)-l,3thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}piperidin-4-yl)methyl]-6-[3(trifluoromethyl)phenoxy]pyrimidin-4(3Z/)-one (Example 26)

Using General Procedure 6 starting from Example 18 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 26 was obtained. HRMS calculated for C40H40F3N7O5S: 787.2764; found 788.284 ((M+H)⁺ form).

5-amino-3-[(4-hydroxy-l-{(3Æ,4.ff)-l-[4-methyl-2-(6-methylpyridin-3-yl)-l,3thiazoIe-5-carbonyI]-3-phenylpiperidine-4-carbonyl}piperidin-4-yl)methyl]-6-[3(trifluoromethoxy)phenoxy]pyrimidin-4(3Æ)-one(EXAMPLE 27)

Using General Procedure 6 starting from Example 19 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 27 was obtained. HRMS calculated for C40H40F3N7O6S: 803.2713; found 804.27833 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l-(thiazole-4carbonyl)piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 28)

-82Using General Procedure 6 starting from Example 21 and thiazole-4-carboxylic acid as reagents, Example 28 was obtained. HRMS calculated for C32H33FN6O5S: 632.2217; found 633.2285 ((M+H)⁺ form).

5-amino-3-({l-[(37f,4Æ)-l-(2-bromo-4-methyl-l,3-thiazole-5-carbonyI)-3- phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(3/Z)-one (Example 29)

Using General Procedure 6 starting from Example 21 and 2-bromo-4-methyl-thiazole-5carboxylic acid as reagents, Example 29 was obtained. HRMS calculated for C33H34BrFN₆O₅S: 724.1479; found 725.1548 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(benzenesulfonyl)-3-phenyl-piperidine-4-carbonyl]-4hydroxy-4-piperidyI]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 30) Using General Procedure 9 starting from Example 21 and benzenesulfonyl chloride as reagents, Example 30 was obtained. HRMS calculated for C34H36FN5O6S: 661.2371; found 662.2443 ((M+H)⁺ form).

5-amino-3-({l-[(3Jf,41î)-l-(3-bromobenzoyl)-3-phenylpiperidine-4-carbonyl]-4hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3Æ)-one (Example 31)

Using General Procedure 6 starting from Example 21 and 3-bromobenzoic acid as reagents, Example 31 was obtained. HRMS calculated for CssHssBrFNsOs: 703.1805; 20 found 704.1875 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-[3-(6-methyl-3-pyridyl) benzoyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 32)

Using General Procedure 11 starting from Example 31 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 32 was obtained. HRMS calculated for C41H41FN6O5: 716.3123; found 717.3189 ((M+H)⁺ form).

5-amino-3-({l-[(3«,4ff)-l-(5-bromopyridine-3-carbonyl)-3-phenylpiperidine-420308

-83carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3Æ)-one (Example 33)

Using General Procedure 6 starting from Example 21 and 5-bromopyridine-3-carboxylic acid as reagents, Example 33 was obtained. HRMS calculated for C34H34BrFN6Û5:

704.1758; found 705.1831 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(31f,4.Æ)-l-(6’-methyl[3,3'- bipyridine]-5-carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4yl}methyl)pyrimidin-4(3/0-one (Example 34)

Using General Procedure 11 starting from Example 33 and (6-methyl-3-pyridyl)boronic 10 acid as reagents, Example 34 was obtained. HRMS calculated for C40H40FN7O5: 717.3075;

found 718.3149 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(3.R,4Æ)-3-phenyl-l-(5- phenylpyridine-3-carbonyl)piperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin4(37/)-one (Example 35)

Using General Procedure 11 starting from Example 33 and phenylboronic acid as reagents, Example 35 was obtained. HRMS calculated for C40H39FN6O5: 702.2966; found 703.3035 ((M+H)⁺ form).

5-amino-3-({l-[(3/î,4/î)-l-benzoyl-3-phenylpiperidine-4-carbonyI]-4- hydroxypiperidin-4-yl}methyI)-6-(4-fluorophenoxy)pyrimidin-4(3Z/)-one (Example 36)

Using General Procedure 6 starting from Example 21 and benzoic acid as reagents, Example 36 was obtained. HRMS calculated for C35H36FN5O5: 625.27; found 626.2775 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(3Æ,4/î)-l-(l-methyl-lH-indole-225 carbonyI)-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin-4(37ï)-one (Example 37)

Using General Procedure 6 starting from Example 21 and l-methylindole-2-carboxylic acid as reagents, Example 37 was obtained. HRMS calculated for C38H39FN6O5: 678.2966;

-84found 679.3032 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-(l-methyl-5-phenylpyrrole-2-carbonyl)-3-phenyl-piperidine-4-carbonyl] -4-piperidyl] methyl] pyrimidin-4one (Example 38)

Using General Procedure 6 starting from Example 21 and l-methyl-5-phenyl-pyrrole-2carboxylic acid as reagents, Example 38 was obtained. HRMS calculated for C40H41FN6O5: 704.3123; found 705.3197 ((M+H)⁺ form).

5-amino-3-({l-[(37f,47î)-l-(3-fluoro-5-iodothiophene-2-carbonyl)-3- phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4-yi]methyl)-6-(4fluorophenoxy)pyrimidin-4(3/Z)-one (Example 39)

Using General Procedure 6 starting from Example 21 and Préparation R6a as reagents, Example 39 was obtained. HRMS calculated for C33H32F2IN5O5S: 775.1137; found 776.1198 ((M+H)⁺form).

5-amino-3-[(l-{(31î,4Æ)-l-[3-fluoro-5-(6-methylpyridin-3-yl)thiopIiene-2-carbonyl]3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-6-(4- fluorophenoxy)pyrimidin-4(3ET)-one (Example 40)

Using General Procedure 11 starting from Example 39 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 40 was obtained. HRMS calculated for C39H38F2N6O5S: 740.2592; found 741.2675 ((M+H)⁺ form).

5-amino-3-({(45)-l-[(32î,47î)-l-(2-bromo-4-methyl-l,3-thiazole-5-carbonyl)-3phenylpiperidine-4-carbonyI]-3,3-difluoro-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(3/Z)-one (Example 41)

Using General Procedure 6 starting from Example 11 and 2-bromo-4-methyl-thiazole-5carboxylic acid as reagents, Example 41 was obtained. HRMS calculated for C33H32BrF3N6OsS: 760.129; found 761.139 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(3Æ,4Æ)-l-{4-methyI-2-[6- (trifluoromethyl)pyridin-3-yi]-l,3-thiazoie-5-carbonyl}-3-phenylpiperidine-420308

carbonyl]piperidin-4-yl}methyl)pyrimidin-4(31Z)-one (Example 42)

Using General Procedure 11 starting from Example 29 and [6-(trifluoromethyl)-3pyridyl]boronic acid as reagents, Example 42 was obtained. HRMS calculated for C39H37F4N7O5S: 791.2513; found 792.258 ((M+H)⁺ form).

5-amino-3-({l-[(3R,41î)-l-{2-[6-(diniethylamino)pyridin-3-yl]-4-methyl-l,3-thiazole5-carbonyl}-3-phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(377)-one (Example 43)

Using General Procedure 11 starting from Example 29 and [6-(dimethylamino)-3pyridyl]boronic acid as reagents, Example 43 was obtained. HRMS calculated for 10 C40H43FN8O5S: 766.3061; found 767.3131 ((M+H)⁺ form).

5-amino-3-{[(4S)-3,3-difluoro-l-{(3R,4R)-l-[2-(4-fluorophenyl)-4-methyl-l,3thiazole-5-carbonyl]-3-phenyIpiperidine-4-carbonyl}-4-hydroxypiperidin-4yl]methyl}-6-(4-fluorophenoxy)pyrimidin-4(3//)-one (Example 44)

Using General Procedure 11 starting from Example 41 and (4-fluorophenyl)boronic acid 15 as reagents, Example 44 was obtained. HRMS calculated for C39H36F4N6O5S: 776.2404;

found 777.2481 ((M+H)⁺ form).

5-amino-3-{[(45)-3,3-difluoro-4-hydroxy-l-{(37î,47f)-l-[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyI]-3-phenylpiperidine-4-carbonyI} piperidin-4-yl]methyl}-6-(4-fluorophenoxy)pyrimidin-4(3H)-one (Example 45)

Using General Procedure 6 starting from Example 11 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 45 was obtained. HRMS calculated for C39H38F3N7O5S: 773.2607; found 774.2668 ((M+H)⁺ form).

5-amino-3-[(4-hydroxy-l-{(3R,41?)-l-[4-methyl-2-(6-niethylpyridin-3-yl)-l,3thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}piperidin-4-yl)methyl]-625 phenoxypyrimidin-4(3Æ)-one (Example 46)

Using General Procedure 6 starting from Example 20 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 46 was obtained. HRMS calculated for C39H41N7O5S: 719.289; found 720.2948 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3Æ,4Æ)-l-[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4- carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3//)-one (Example 47)

Using General Procedure 6 starting from Example 21 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 47 was obtained. HRMS calculated for C39H40FN7O5S: 737.2795; found 738.2863 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[(l-{(31î,4.R)-l-[2-(4-fluorophenyl)-4-methyl-l,3thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4yl)methyl]pyrimidin-4(3/7)-one (Example 48)

Using General Procedure 11 starting from Example 29 and (4-fluorophenyl)boronic acid as reagents, Example 48 was obtained. HRMS calculated for C39H38F2N6O5S: 740.2592; found 741.2661 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3- [ [4-hydroxy-1 - [(3R,4R)- l-(2-methylthiazole-5carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 49)

Using General Procedure 6 starting from Example 21 and 2-methylthiazole-5-carboxylic acid as reagents, Example 49 was obtained. HRMS calculated for C33H35FN₆O₅S: 646.2374; found 647.2452 ((M+H)⁺ form).

5-amino-3- [ [1 - [(3R,4R)-1- [(2-bromothiazol-5-yl)methyl] -3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 50)

Using General Procedure 9 starting from Example 21 and 2-bromo-5(bromomethyl)thiazole as reagents, Example 50 was obtained. HRMS calculated for C32H34BrFN6O4S: 696.153; found 697.1602 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(3Æ,4Æ)-l-{[2-(6-methylpyridin-3yl)-l,3-thiazol-5-yl]methyl}-3-phenylpiperidine-4-carbonyl]piperidin-4yl}methyI)pyrimidin-4(37Z)-one (EXAMPLE 51)

-87Using General Procedure 10 starting from Example 21 and 2-(6-methyl-3pyridyl)thiazole-5-carbaldehyde as reagents, Example 51 was obtained. HRMS calculated for C38H40FN7O4S: 709.2847; found 710.2918 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[(l-{(31î,4/f)-l-[(2-fIuorophenyl)methyl]-3phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]pyrimidin-4(3/T)-one (Example 52)

Using General Procedure 10 starting from Example 21 and 2-fluorobenzaldehyde as reagents, Example 52 was obtained. HRMS calculated for C3sH37F2N5O₄: 629.2814; found 630.2878 ((M+H)⁺ form).

5-amino-3-({(45)-3,3-difluoro-4-hydroxy-l-[(3J?,41î)-l-{[2-(6-methylpyridin-3-yl)l,3-thiazol-5-yl]methyl}-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(377)-one (Example 53)

Using General Procedure 10 starting from Example 11 and 2-(6-methyl-3pyridyl)thiazole-5-carbaldehyde as reagents, Example 53 was obtained. HRMS calculated for C38H38F3N7O4S: 745.2658; found 746.2726 ((M+H)⁺form).

5-amino-3-{[(4S)-3,3-difluoro-l-{(37î,4Æ)^_l-[(2-fluorophenyl)methyl]-3phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl]methyl}-6-(4fluorophenoxy)pyrimidin-4(3J7)-one (Example 54)

Using General Procedure 10 starting from Example 11 and 2-fluorobenzaldehyde as reagents, Example 54 was obtained. HRMS calculated for C35H35F4N5O4: 665.2625; found 666.2686 ((M+H)⁺ form).

5-amino-3-({l-[(32î,4Æ)-l-(3-ethoxybenzoyl)-3-phenyIpiperidine-4-carbonyl]-4hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(37Z)-one (Example 55)

Using General Procedure 6 starting from Example 21 and 3-ethoxybenzoic acid as reagents, Example 55 was obtained. HRMS calculated for C37H40FN5O6: 669.2963; found 670.3033 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-[3-(4-methylpiperazin-lyl)benzoyl] -3-phenyl-piperidine-4-carbonyl] -4-piperidyl] methyl] pyrimidin-4-one (Example 56)

Using General Procedure 6 starting from Example 21 and 3-(4-methylpiperazin-lyl)benzoic acid as reagents. Example 56 was obtained. HRMS calculated for C40H46FN7O5: 723.3544; found 724.3609 ((M+H)⁺ form).

6-[(31?,41f)-4-(4-{[5-amino-4-(4-fluorophenoxy)-6-oxopyrimidin-l(677)-yl]methyl}-4hydroxypiperidine-l-carbonyl)-3-phenylpiperidine-l-carbonyl]quinazolin-4(3/Z)-one (Example 57)

Using General Procedure 6 starting from EXAMPLE 21 and 4-oxo-3H-quinazoline-6carboxylic acid as reagents, Example 57 was obtained. HRMS calculated for C37H36FN7O6: 693.2711; found 694.2768 ((M+H)⁺ form).

5-[(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carbonyl]indoline-2,3-dione (Example 58)

Using General Procedure 6 starting from Example 21 and 2,3-dioxoindoline-5-carboxylic acid as reagents, Example 58 was obtained. HRMS calculated for C37H35FN6O7: 694.2551; found 695.2622 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-[(5-bromo-2-thienyl)sulfonyl]-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 59)

Using General Procedure 9 starting from Example 21 and 5-bromothiophene-2-sulfonyl çhloride as reagents, Example 59 was obtained. HRMS calculated for C32H33BrFNsO6S2: 745.1039; found 746.1123 ((M+H)⁺ form) (3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-N,3-diphenyl-piperidine-l-carbothioamide (Example 60)

Using General Procedure 7 starting from Example 21 and isothiocyanatobenzene as

-89reagents, Example 60 was obtained. HRMS calculated for C35H37FN6O4S: 656.2581; found 657.2656 ((M+H)⁺ form)

5-amino-3-({l-[(3R,41?)-l-(2-benzyl-4-methyl-l,3-thiazole-5-carbonyl)-3- phenyipiperidine-4-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(3Æ)-one (Example 61)

Using General Procedure 6 starting from Example 21 and 2-benzyl-4-methyl-thiazole5-carboxylic acid as reagents, Example 61 was obtained. HRMS calculated for C40H41FN6O5S: 736.2843; found 737.2903 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3R,4R)-3-phenyl-l-[(pyridin-3yl)methy 1] piperidine-4-carbonyl} piperidin-4-yl)methyI] py rimidin-4(3/f)-one (Example 62)

Using General Procedure 9 starting from Example 21 and 3-(chloromethyl)pyridine hydrochloride as reagents, Example 62 was obtained. HRMS calculated for C34H37FN6O4: 612.286; found 613.2922 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyrazin-2ylmethyl)piperidine-4-carbonyl] -4-piperidyl] methyl] pyrimidin-4-one (Example 63)

Using General Procedure 9 starting from Example 21 and 2-(chIoromethyl)pyrazine hydrochloride as reagents, Example 63 was obtained. HRMS calculated for C33H36FN7O4: 613.2813; found 614.2890 ((M+H)⁺ form)

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3R,41f)-l-[4-niethyl-2-(morpholin-4yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}piperidin-4- yl)methyl]pyrimidin-4(3/Z)-one (Example 64)

Using General Procedure 6 starting from Example 21 and 4-methyl-2-morpholinothiazole-5-carboxylic acid as reagents, Example 64 was obtained. HRMS calculated for C37H42FN7O6S: 731.2902; found 732.2964 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3R,4R)-l-[4-methyl-2-(pyrrolidin-lyl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}piperidin-4-

-90yl)methyl]pyrimidin-4(3/Z)-one (Example 65)

Using General Procedure 6 starting from EXAMPLE 21 and 4-methyl-2-pyrrolidin-l-ylthiazole-5-carboxylic acid as reagents, Example 65 was obtained. HRMS calculated for C37H42FN7O5S: 715.2952; found 716.3019 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(31î,4jR)-l-(4-methyl-2-phenyl-l,3thiazole-5-carbonyl)-3-phenyIpiperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin4(3/f)-one (Example 66)

Using General Procedure 6 starting from Example 21 and 4-methyl-2-phenyl-thiazole-5carboxylic acid as reagents, Example 66 was obtained. HRMS calculated for C39H39FN6O5S: 722.2687; found 723.2770 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(5-bromo-2,3-dihydrothieno[3,4-b][l,4]dioxine-7carbonyl)-3-phenyl-piperidine-4-carbonyl] -4-hydroxy-4-piperidyl] methyl] -6-(4fluorophenoxy)pyrimidin-4-one (Example 67)

Using General Procedure 6 starting from Example 21 and 5-bromo-2,3dihydrothieno[3,4-b][l,4]dioxine-7-carboxylic acid as reagents, Example 67 was obtained. HRMS calculated for CssHssBrFNsCbS: 767.1425; found 768.1486 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3jR,4jR’)-l-[7-(6-methylpyridin-3-yl)2,3-dihydrothieno[3,4-ô][l,4]dioxine-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyI]pyrimidin-4(3Z0-one (EXAMPLE 68)

Using General Procedure 11 starting from Example 67 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 68 was obtained. HRMS calculated for C41H41FN6O7S: 780.2742; found 781.2803 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(3-bromophenyl)sulfonyl-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyI]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 69)

Using General Procedure 9 starting from Example 21 and 3-bromobenzenesulfonyl chloride as reagents, Example 69 was obtained. HRMS calculated for C₃4H35BrFN5O6S: 739.1475; found 740.1540 ((M+H)⁺ form) ethyl 2-[(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]4-hydroxy-piperidine-l-carbonyl]-3-phenyI-l-piperidyl]-2-phenyl-acetate (Example 70)

Using General Procedure 9 starting from Example 21 and ethyl 2-bromo-2-phenyl-acetate as reagents, Example 70 was obtained. HRMS calculated for C38H42FN5O6: 683.3119; found 684.3224 and 684.3192 ((M+H)⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(3phenylcycIobutanecarbonyl)piperidine-4-carbonyl]-4-piperidyl] methyl]-6-(4fluorophenoxy)pyrimidin-4-one, diastereoisomer 1 (Example 71) and

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(3phenylcyclobutanecarbonyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one, diastereoisomer 2 (Example 72)

Using General Procedure 6 starting from Example 11 and 3-phenylcyclobutanecarboxylic acid as reagents, the enantiomers were separated by chiral chromatography to give Example 71 and Example 72.

Example 71: HRMS calculated for C39H40F3N5O5: 715.2982; found 716.3053 ((M+H)⁺form).

Example 72: HRMS calculated for C39H40F3N5O5: 715.2982; found 716.3044 ((M+H)⁺form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-(2-hydroxy-2-methylpropyl)-3-phenyl-piperidine-4-carbonyl] -4-piperidyl] methyl] pyrimidin-4-one (Example 73)

Using General Procedure 9 starting from Example 21 and 2,2-dimethyloxirane as reagents, Example 73 was obtained. HRMS calculated for C32H₄oFN₅0₅: 593.3013; found 594.3078 ((M+H)⁺ form).

2-[(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-l-piperidyl]-N-methyl-N-phenyl-acetamide

-92(Example 74)

Using General Procedure 9 starting from Example 21 and 2-bromo-N-methyl-N-phenylacetamide as reagents, Example 74 was obtained. HRMS calculated for C37H41FN6O5: 668.3123; found 669.3199 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(2,2-difluoro-2-phenyl-acetyl)-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyI]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 75)

Using General Procedure 6 starting from Example 21 and 2,2-difluoro-2-phenyl-acetic acid as reagents, Example 75 was obtained. HRMS calculated for C36H36F3N5O5: 675.2668; found 676.274 ((M+H)⁺ form).

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-N,3-diphenyl-piperidine-l-carboxamide (Example 76)

Using General Procedure 7 starting from Example 21 and isocyanatobenzene as reagents, Example 76 was obtained. HRMS calculated for C35H37FN6O5: 640.2809; found 641.2878 ((M+H)⁺ form).

(3R,4R)-4-[(4S)-4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-3,3difluoro-4-hydroxy-piperidine-l-carbonyl]-N,3-diphenyl-piperidine-l-carboxamide (Example 77)

Using General Procedure 7 starting from Example 11 and isocyanatobenzene as reagents, Example 77 was obtained. HRMS calculated for C35H35F3N6O5: 676.2621; found 677.269 ((M+H)⁺ form).

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-N-methyl-N,3-diphenyl-piperidine-l-carboxamide (Example 78)

Example 21 (150 mg, 0.2786 mmol), N-methyl-N-phenyl-carbamoyl chloride (1.3 eq., 0.373 mmol), N,N-diethylethanamine (2.0 eq., 0.5752 mmol) were dissolved in DCM (5 mL). The mixture was stirred at r.t. for 1 hour, then 5 ml isopropylalcohol was added,

-93then it was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure to give Example 78. HRMS calculated for C36H39FN6O5: 654.2966; found 655.3051 ((M+H)⁺form).

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyI]-N-benzyl-3-phenyl-piperidine-l-carboxamide (Example 79)

Using General Procedure 7 starting from Example 21 and isocyanatomethylbenzene as reagents, Example 79 was obtained. HRMS calculated for C36H39FN6O5: 654.2966; found 655.3025 ((M+H)⁺ form).

(31?,47?)-4-(4-{[5-amino-4-(4-fluorophenoxy)-6-oxopyrimidin-l(6/7)-yl]methyl}-4hydroxypiperidine-l-carbonyl)-7V-(4-methoxyphenyl)-3-phenylpiperidine-lcarboxamide (Example 80)

Using General Procedure 7 starting from Example 21 and l-isocyanato-4-methoxybenzene as reagents, Example 80 was obtained. HRMS calculated for C36H39FN6O6: 670.2915; found 671.299 ((M+H)⁺ form).

(31?,41?)-4-(4-{[5-amino-4-(4-fluorophenoxy)-6-oxopyrimidin-l(6H)-yl]methyl}-4hydroxypiperidine-l-carbonyl)-3-phenyl-/V-[3-(trifluoromethyl)phenyl]piperidine-lcarboxamide (Example 81)

Using General Procedure 7 starting from Example 21 and l-isocyanato-3(trifluoromethyl)benzene as reagents, Example 81 was obtained. HRMS calculated for C36H36F4N6O5: 708.2683; found 709.276 ((M+H)⁺ form).

(3R,4R)-4- [4- [ [5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l -yl] methyl] -4hydroxy-piperidine-l-carbonyl]-N-(2,4-dimethoxyphenyl)-3-phenyl-piperidine-lcarboxamide (Example 82)

Using General Procedure 7 starting from Example 21 and l-isocyanato-2,4-dimethoxybenzene as reagents, Example 82 was obtained. HRMS calculated for C37H41FN6O7: 700.3021; found 701.3091 ((M+H)⁺ form).

(3/?.4/?)-4-(4-; |5-amino-4-(4-fluorophenoxv)-6-oxopyrimidin-l(6/7)-yl]rnethyl}-4hydroxypiperidine-l-carbonyl)-2V-(3-bromophenyl)-3-phenylpiperidine-lcarboxamide (Example 83)

Using General Procedure 7 starting from Example 21 and l-bromo-3-isocyanato-benzene as reagents, Example 83 was obtained. HRMS calculated for CssHaeBrFNôOs: 718.1915; found 719.1973 ((M+H)⁺ form).

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-N-(4-fluorophenyl)-3-phenyl-piperidine-lcarboxamide (Example 84)

Using General Procedure 7 starting from Example 21 and l-fluoro-4-isocyanato-benzene as reagents, Example 84 was obtained. HRMS calculated for C35H36F2N6O5: 658.2715; found 659.2782 ((M+H)⁺ form).

(3R,4R)-4- [4- [ [5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-1 -y 1] methyl] -4hydroxy-piperidine-l-carbonyl]-N-[3-(6-methyl-3-pyridyl)phenyl]-3-phenylpiperidine-l-carboxamide (Example 85)

Using General Procedure 11 starting from Example 83 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 85 was obtained. HRMS calculated for C41H42FN7O5: 731.3231; found 732.3295 ((M+H)⁺ form).

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-N-thiazol-2-yI-piperidine-l-carboxamide (Example 86)

Using General Procedure 8 starting from Example 21 and thiazol-2-amine as reagents, Example 86 was obtained. HRMS calculated for C32H34FN7O5S: 647.2326; found 648.2396 ((M+H)⁺ form).

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-N-(l,3-benzothiazol-2-yl)-3-phenyl-piperidine-lcarboxamide (Example 87)

Using General Procedure 8 starting from Example 21 and l,3-benzothiazol-2-amine as reagents, Example 87 was obtained. HRMS calculated for C36H36FN7O5S: 697.2483; found 698.2558 ((M+H)⁺ form).

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-N-[4-(trifluoromethyI)thiazol-2yl]piperidine-l-carboxamide (EXAMPLE 88)

Using General Procedure 8 starting from Example 21 and 4-(trifluoromethyl)thiazol-2amine as reagents, Example 88 was obtained. HRMS calculated for C33H33F4N7O5S: 715.22; found 716.2273 ((M+H)⁺ form).

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-N-(2-fluorophenyI)-3-phenyl-piperidine-lcarboxamide (Example 89)

Using General Procedure 7 starting from Example 21 and l-fluoro-2-isocyanato-benzene as reagents, Example 89 was obtained. HRMS calculated for C35H36F2N6O5: 658.2715; found 659.2779 ((M+H)⁺ form).

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-N-(2,2,2-trifluoroethyl)piperidine-lcarboxamide (Example 90)

Using General Procedure 8 starting from Example 21 and 2,2,2-trifluoroethanamine as reagents, Example 90 was obtained. HRMS calculated for C31H34F4N6O5: 646.2527; found 647.2617 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-(2-methylpyridine-4carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-piperidyI]methyl]pyrimidin-4-one (Example 91)

Using General Procedure 6 starting from Example 21 and 2-methylpyridine-4-carboxylic acid as reagents, Example 91 was obtained. HRMS calculated for C₃5H3₇FN6O₅: 640.2809; found 641.28822 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(37î,4j^lî)-l-(5-methylpyridine-3carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin-4(377)-one (Example 92)

Using General Procedure 6 starting from Example 21 and 5-methylpyridine-3-carboxylic acid as reagents, Example 92 was obtained. HRMS calculated for C35H37FN6O5: 640.2809; found 641.28802 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-(6-methylpyridine-2carbonyl)-3-phenyl-piperidine-4-carbonyl] -4-piperidyl] methyl] pyrimidin-4-one (Example 93)

Using General Procedure 6 starting from Example 21 and 6-methylpyridine-2-carboxylic acid as reagents, Example 93 was obtained. HRMS calculated for C35H37FN6O5: 640.2809; found 641.2876 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-(4-methyIpyridine-2carbonyl)-3-phenyl-piperidine-4-carbonyl] -4-piperidyl] methyl] py rim idin-4-one (Example 94)

Using General Procedure 6 starting from Example 21 and 4-methylpyridine-2-carboxylic acid as reagents, Example 94 was obtained. HRMS calculated for C35H37FN6O5: 640.2809; found 641.2868 ((M+H)⁺ form).

5-amino-3-({l-[(3.R,4.ff)-l-(2-bromo-l-methyl-LH-imidazole-5-carbonyl)-3- phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4-yl]methyl)-6-(4fluorophenoxy)pyrimidin-4(317)-one (Example 95)

Using General Procedure 6 starting from Example 21 and 2-bromo-l-methyl-\Himidazole-5-carboxylic acid as reagents, Example 95 was obtained. HRMS calculated for C₃₃H3₅BrFN₇O5: 707.1867; found 708.1924 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(37î,4/f)-l-[l-methyl-2-(6- methylpyridin-3-yl)-lÆ-imidazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3//)-one (Example 96)

Using General Procedure 11 starting from Example 95 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 96 was obtained. HRMS calculated for C39H41FN8O5: 720.3184; found 721.3253 ((M+H)⁺ form)

5-amino-3-({l-[(37f,4Æ)-l-(2,6-dimethylpyridine-4-carbonyl)-3-phenylpiperidine-4carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3//)-one (Example 97)

Using General Procedure 6 starting from Example 21 and 2,6-dimethylpyridine-4carboxylic acid as reagents, Example 97 was obtained. HRMS calculated for C36H39FN6O5:

654.2966; found 654.2966 ((M+H)⁺ form).

5-amino-3-({l-[(3Jî,4.R)-l-(3-bromo-5-fluorobenzoyl)-3-phenylpiperidine-4- carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3_JE0-one (Example 98)

Using General Procedure 6 starting from Example 21 and 3-bromo-5-fluoro-benzoic acid as reagents, Example 98 was obtained. HRMS calculated for C35H34BrF2NsO5: 721.1711; found 722.1787 ((M+H)⁺ form).

5-amino-3- [ [1 - [(3R,4R)-1 -(3-fluoro-5-iodo-thiophene-2-carbonyl)-3-phenyl- piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-[3(trifluoromethyl)phenoxy]pyrimidin-4-one (EXAMPLE 99)

Using General Procedure 6 starting from Example 18 and Préparation R6a as reagents, Example 99 was obtained. HRMS calculated for C34H32F4IN5O5S: 825.1105; found 826.12 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(2-bromo-4-methyl-thiazoIe-5-carbonyl)-3-phenyl- piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-[3(trifluoromethyl)phenoxy]pyrimidin-4-one (Example 100)

Using General Procedure 6 starting from Example 18 and 2-bromo-4-methyl-thiazole-5carboxylic acid as reagents, Example 100 was obtained. HRMS calculated for C34H3₄BrF3N6OsS: 774.1447; found 775.1515 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-[3-fluoro-5-(6-methyl-3-pyridyl)thiophene-2-carbonyl]-3-

-98phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-[3(trifluoromethyl)phenoxy]pyrimidin-4-one (Example 101)

Using General Procedure 11 starting from Example 99 and (6-methyl-3-pyridyl)boronic acid as reagents, EXAMPLE 101 was obtained. HRMS calculated for C40H38F4N6O5S: 790.256; found 791.2615 ((M+H)⁺ form)

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(37î,41î)-l-(isoquinoline-5-carbonyl)3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin-4(3H)-one (Example 102)

Using General Procedure 6 starting from Example 21 and isoquinoline-5-carboxylic acid as reagents, Example 102 was obtained. HRMS calculated for C38H37FN6O5: 676.2809; found 677.28794 ((M+H)⁺ form).

5-amino-3-({(45)-3,3-difluoro-4-hydroxy-l-[(3JÎ,4/î)-l-{4-methyl-2-[6(trifluoromethyl)pyridin-3-yl]-l,3-thiazole-5-carbonyl}-3-phenylpiperidine-4carbonyl]piperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(37/)-one (Example 103)

Using General Procedure 11 starting from Example 41 and [6-(trifluoromethyl)-3pyridyl]boronic acid as reagents, Example 103 was obtained. HRMS calculated for C39H35F6N7O5S: 827.2325; found 828.2406 ((M+H)⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-l-[(3R,4R)-l-(3-fluoro-5-iodo-thiophene-2-carbonyl)3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4- fluorophenoxy)pyrimidin-4-one (Example 104)

Using General Procedure 6 starting from Example 11 and Préparation R6a as reagents, Example 104 was obtained. HRMS calculated for C33H₃oF4lN505S: 811.0948; found 812.1033 ((M+H)⁺form).

5-amino-3-{[(4>S)-3,3-difluoro-l-{(3/i’,4jR)-l-[3-fluoro-5-(6-methylpyridin-3yl)thiophene-2-carbonyl]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4yl]methyl}-6-(4-fluorophenoxy)pyrimidin-4(3Æ)-one (Example 105)

Using General Procedure 11 starting from Example 104 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 105 was obtained. HRMS calculated for C39H36F4N6O5S: 776.2404; found 777.2477 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(4-bromo-5-chloro-3-fluoro-thiophene-2-carbonyl)-3phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4- fluorophenoxy)pyrimidin-4-one (Example 106)

Using General Procedure 6 starting from Example 21 and Préparation R6b as reagents, Example 106 was obtained. HRMS calculated for C33H3iBrCIF₂N5O5S: 761.0886; found 762.09571 ((M+H)⁺form).

5-amino-3-[(l-{(3R,4R)^-l^_[5-chloro-3-fluoro-4-(6-methylpyridin-3-yl)thiophene-2carbonyl]-3-phenyIpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-6-(4fluorophenoxy)pyrimidin-4(3Æ)-one (Example 107)

Using General Procedure 11 starting from Example 106 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 107 was obtained. HRMS calculated for C39H37CIF2N6O5S: 774.2203; found 775.2268 ((M+H)⁺ form)

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l-(3phenyloxetan-3-yl)piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 108)

Step 1: tert-butyl 4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-1 -carboxylate

Using General Procedure 4 starting from Préparation R4h and tert-butyl l-oxa-6azaspiro[2.5]octane-6-carboxylate as reagents, tert-butyl 4-[[5-amino-4-(4-fluorophenoxy)6-oxo-pyrimidin-l-yl]methyl]-4-hydroxy-piperidine-l-carboxylate was obtained. HRMS calculated for C₂iH₂7FN₄O₅: 434.1965; found 435.2033 ((M+H)⁺ form).

’H-NMR (500 MHz, dmso-d6) δ ppm 7.66 (s, 1H), 7.2 (m, 2H), 7.09 (m, 2H), 4.91 (s, 1H), 4.67 (brs., 2H), 3.93 (s, 2H), 3.66/3.05 (brd+br, 4H), 1.44/1.33 (td+brd„ 4H), 1.39 (s, 9H). ’³C-NMR(125 MHz, dmso-d6) δ ppm 159.1, 158.8, 154.3, 151, 146.8, 139.2, 121.7, 120.2, 116.4, 79, 69.4, 54.4, 39.8, 34.8, 28.6

- 100 -

Step 2: 5-ammo-6-(4-fluorophenoxy)-3-[(4-hydroxy-4-piperidyl)methyl]pyrimidin-4-one hydrochloride

Using General Procedure 5 starting from tert-butyl 4-[[5-amino-4-(4-fluorophenoxy)-6oxo-pyrimidin-l-yl]methyl]-4-hydroxy-piperidine-l-carboxylate, 5-amino-6-(4fluorophenoxy)-3-[(4-hydroxy-4-piperidyl)methyl]pyrimidin-4-one hydrochloride was obtained. HRMS calculated for C16H19FN4O3: 334.1441; found 335.1508 ((M+H)⁺ form). ‘H-NMR (500 MHz, dmso-d6) δ ppm 9.1/8.88 (m+m, 2H), 8.04 (s, 1H), 7.24 (m, 2H), 7.18 (m, 2H), 4.02 (s, 2H), 3.12/2.98 (m+m, 4H), 1.79/1.56 (m+m, 4H) ¹³C-NMR(125 MHz, dmso-d6) δ ppm 159.2, 153, 145.3, 122.8, 116.6,53.9, 39.5,31.4

Step 3: Example 108

Using General Procedure 6 starting from 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-4piperidyl)methyl]pyrimidin-4-one hydrochloride and Préparation R8a as reagents, Example 108 was obtained. HRMS calculated for C37H40FN5O5: 653.3013; found 654.308 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3- [ [1 - [(3R,4R)-1 -[3-(2-fluorophenyl)oxetan-3-y 1] -3phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]pyrimidin-4-one (Ex AMPLE 109)

Using General Procedure 4 starting from Préparation R4h and Préparation RlOb as reagents, Example 109 was obtained. HRMS calculated for C37H39F2N5O5: 671.2919; found 672.2981 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[l-[(3R,4R)-l-[3-(4-fluorophenyl)oxetan-3-yl]-3phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyI]methyl]pyrimidin-4-one (Example 110)

Using General Procedure 4 starting from Préparation R4h and Préparation RIOc as reagents, Example 110 was obtained. HRMS calculated for C37H39F2N5O5: 671.2919: found 672.2996 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-(3-methyloxetan-3-yl)-3phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 111)

- 101 -

Using General Procedure 4 starting from Préparation R4h and Préparation RIOd as reagents, Example 111 was obtained. HRMS calculated for C32H38FN5O5: 591.2857; found 592.2925 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-(3-isopropyloxetan-3-yl)3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 112) Using General Procedure 4 starting from Préparation R4h and Préparation RIOe as reagents, Example 112 was obtained. HRMS calculated for C34H42FN5O5: 619.317; found 620.324 ((M+H)⁺ form).

5-amino-3-[[4-hydroxy-l-[(3R,4R)-l-(3-methyloxetan-3-yI)-3-phenyl-piperidine-4carbonyl] -4-piperidyl] methyl] -6-phenoxy-pyrimidin-4-one (Example 113)

Using General Procedure 4 starting from Préparation R4g and Préparation RIOd as reagents, Example 113 was obtained. HRMS calculated for C32H39N5O5: 573.2951; found 574.302 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-[3-(2-fluorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-phenoxy-pyrimidin-4-one (Example 114) Using General Procedure 4 starting from Préparation R4g and Préparation RIOe as reagents, Example 114 was obtained. HRMS calculated for C₃7H₄oFN₅05: 653.3013; found 654.3089 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-[3-(4-fluorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-phenoxy-pyrimidin-4-one (Example 115) Using General Procedure 4 starting from Préparation R4g and Préparation RIOe as reagents, Example 115 was obtained. HRMS calculated for C37H40FN5O5:653.3013; found 654.3086 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3Æ,4Æ)-3-phenyl-l-[3-(piperidin-3yl)benzoyI]piperidine-4-carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3Z0-one (Example 116)

-102Using General Procedure 6 starting from Example 21 and 3-(l-tert-butoxycarbonyl-3piperidyl)benzoic acid as reagents, tert-butyl 3-[3-[(3R,4R)-4-[4-[[5-amino-4-(4fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3phenyl-piperidine-l-carbonyl]phenyl]piperidine-l-carboxylate was obtained as a crude product and was directly reacted using General Procedure 5 to give Example 116. HRMS calculated for C40H45FN6O5: 708.3436; found 709.35076 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3- [ [4-hydroxy-1 -[(3R,4R)-1 - [ [5-(6-methyl-3-py ridyl)2-thienyl]sulfonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4one (Example 117)

Using General Procedure 11 starting from Example 59 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 117 was obtained. HRMS calculated for C38H39FN6O6S2: 758.2357; found 759.2423 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l-[[5-(2-thienyl)-2thienyl]sulfonyl]piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 118)

Using General Procedure 11 starting from Example 59 and 2-thienylboronic acid as reagents, Example 118 was obtained. HRMS calculated for C36H36FN5O6S3: 749.1812; found 750.1883 ((M+H)⁺ form).

5-amino-3- {[(45)-3,3-difluoro-4-hyd roxy-1 - [ (3Æ.4Æ )-1 - [4-methyI-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl]methyl}-6-phenoxypyrimidin-4(3/f)-one (Example 119)

Using General Procedure 6 starting from Example 12 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 119 was obtained. HRMS calculated for C39H39F₂N₇O₅S: 755.2701; found 756.27677 ((M+H)⁺ form).

5-amino-3-({(45)-3,3-difluoro-4-hydroxy-l-[(3Æ,4^)-l-(5-methyl-l-phenyl-17/pyrazoIe-3-carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(3/T)-one (Example 120)

Using General Procedure 6 starting from Example 11 and 5-methyl-l-phenyl-pyrazole20308

- 103 -

3-carboxylic acid as reagents, Example 120 was obtained. HRMS calculated for C39H38F3N7O5: 741.2886; found 742.2948 ((M+H)⁺ form).

5-amino-3-[(l-{(31î,41î)-l-[3-fluoro-5-(6-methylpyridin-3-yl)benzoyl]-3phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-6-(4- fluorophenoxy)pyrimidin-4(3Z0^-one (Example 121)

Using General Procedure 11 starting from Example 98 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 121 was obtained. HRMS calculated for C41H40F2N6O5: 734.3028; found 735.3104 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(37î,41î)-3-phenyl-l-[5- (trifluoromethyl)pyridine-3-carbonyl] piperidine-4-carbonyl] piperidin-4yl)methyl]pyrimidin-4(3.H)-one (Example 122)

Using General Procedure 6 starting from Example 21 and 5-(trifluoromethyl)pyridine-3carboxylic acid as reagents, Example 122 was obtained. HRMS calculated for C35H34F4N6O5: 694.2527; found 695.2593 ((M+H)⁺ form).

6-[(3.ff,4^)-4-(4-{[5-amino-4-(4-fluorophenoxy)-6-oxopyriniidin-l(6/7)-yl]niethyl}-4hydroxypiperidine-l-carbonyl)-3-phenylpiperidine-l-carbonyl]-3-methyIquinazolin4(3//)-one (Example 123)

Using General Procedure 6 starting from Example 21 and 3-methyl-4-oxo-quinazoline6-carboxylic acid as reagents, Example 123 was obtained. HRMS calculated for 20 C38H38FN7O6: 707.2867; found 708.2929 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-[3-fluoro-5-[6-(trifluoromethyI)-3-pyridyl]thiophene-2carbonyl] -3-phenyl-piperidine-4-carbonyl] -4-hydroxy-4-piperidyl] methyl] -6 - [3 (trifluoromethyl)phenoxy]pyrimidin-4-one (Example 124)

Using General Procedure 11 starting from Example 99 and [6-(trifluoromethyl)-3- pyridyl]boronic acid as reagents, Example 124 was obtained. HRMS calculated for C40H35F7N6O5S: 844.2278; found 845.2348 ((M+H)⁺ form).

5-amino-3- [ [4-hydroxy-l- [(3R,4R)-1 - [4-methyl-2- [6-(trifluoromethyl)-320308

- 104- py ridyl] thiazole-5-carbonyl] -3-phenyl-piperidine-4-carbonyl] -4-piperidy 1] methyl] -6[3-(trifluoromethyl)phenoxy]pyrimidin-4-one (Example 125)

Using General Procedure 11 starting from Example 100 and [6-(trifluoromethyl)-3pyridyl]boronic acid as reagents, Example 125 was obtained. HRMS calculated for C40H37F6N7O5S: 841.2481; found 842.255 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-[2-[6-(dimethylamino)-3-pyridyl]-4-methyl-thiazole-5carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-[3(trifluoromethyl)phenoxy]pyrimidin-4-one (Example 126)

Using General Procedure 11 starting from Example 100 and [6-(dimethylamino)-3pyridyl]boronic acid as reagents, Example 126 was obtained. HRMS calculated for C41H43F3N8O5S: 816.3029; found 817.3114 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(3-chloro-l-methyl-indole-2-carbonyl)-3-phenylpiperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin4-one (Example 127)

Using General Procedure 6 starting from Example 21 and 3-chloro-l-methyl-indole-2carboxylic acid as reagents, Example 127 was obtained. HRMS calculated for C38H38CIFN6O5: 712.2576; found 713.2653 ((M+H)⁺ form).

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-N-[2-(trifluoromethyI)phenyl]piperidine-lcarboxamide (Example 128)

Using General Procedure 8 starting from Example 21 and 2-(trifluoromethyl)aniline as reagents, Example 128 was obtained. HRMS calculated for C36H36F4N6O5: 708.2683; found 709.2756 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(3,5-difluorobenzoyl)-3-phenyl-piperidine-4-carbonyl]-4hydroxy-4-piperidyI]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 129) Using General Procedure 6 starting from Example 21 and 3,5-difluorobenzoic acid as reagents, Example 129 was obtained. HRMS calculated for C35H34F3N5O5: 661.2512; found 662.2579 ((M+H)⁺ form).

- 105 -

5-amino-3-[[l-[(3R,4R)-l-(3,5-dichlorobenzoyl)-3-phenyl-piperidine-4-carbonyl]-4hydroxy-4-piperidyI]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 130)

Using General Procedure 6 starting from Example 21 and 3,5-dichlorobenzoic acid as reagents, Example 130 was obtained. HRMS calculated for C35H34CI2FN5O5: 693.1921; found 694.1991 ((M+H)⁺ form).

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6methyl-3-pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one (Example 131)

Using General Procedure 4 starting from Préparation R4j and Préparation R5a as reagents, tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4-cyanophenoxy)-6-oxo-pyrimidin-lyl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate was obtained.

Using General Procedure 5 starting from tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4cyanophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenylpiperidine-l-carboxylate as reagent, the crude product was purified by préparative LC (on C-18 Luna 10 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure to give 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile.

Using General Procedure 6 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and 4-methyl-2-(6-methyl-3-pyridyl)thiazole-5-carboxylic acid as reagents, 4-[5-amino-l[[4-hydroxy-l-[(3R,4R)-l-[4-methyI-2-(6-methyl-3-pyridyl)thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile was obtained.

Using General Procedure 2 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l-[4methyI-2-(6-methyl-3-pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile as reagent, Example 131 was obtained. HRMS calculated for C40H44N8O5S: 748.3156; found 749.32279 ((M+H)⁺ form).

- 106-

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l-(l- phenyIcyclopropanecarbonyl)piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4one (Example 132)

Using General Procedure 6 starting from Example 21 and 5 1-phenylcyclopropanecarboxylic acid as reagents, Example 132 was obtained. HRMS calculated for C38H40FN5O5: 665.3013; found 666.3087 ((M+H)⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(5-chloropyridine-3-carbonyl)-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 133)

Using General Procedure 6 starting from Example 21 and 5-chloropyridine-3-carboxylic acid as reagents, Example 133 was obtained. HRMS calculated for C34H34CIFN6O5: 660.2263; found 661.23313 ((M+H)⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[l-[(3R,4R)-l-(5-fluoropyridine-3-carbonyl)-3phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]pyrimidin-4-one (Example 134)

Using General Procedure 6 starting from Example 21 and 5-fluoropyridine-3-carboxylic acid as reagents, Example 134 was obtained. HRMS calculated for C34H3₄F2N₆O5: 644.2559; found 645.26271 ([M+H]⁺ form).

tert-butyl (3R,4R)-4-[(4S)-4-[[5-amino-6-(4-fluoro-3-methoxy-phenoxy)pyrimidin-420 yl]oxymethyl]-3,3-difluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenyI-piperidine-lcarboxylate (Example 135)

Using General Procedure 4 starting from Préparation R4d and Préparation R5b as reagents, the enantiomers were separated by chiral chromatography to give Example 135. HRMS calculated for C34H40F3N5O7: 687.288; found 710.2764 ([M+Na]⁺ form).

[(4S)-4-[[5-amino-6-(4-fluoro-3-methoxy-phenoxy)pyrimidin-4-yl]oxymethyl]-3,3difluoro-4-hydroxy-l-piperidyl]-[(3R,4R)-3-phenyl-4-piperidyl]methanone hydrochloride (Example 136)

- 107Using General Procedure 5 starting from Example 135 as reagent, Example 136 was obtained. HRMS calculated for C29H32F3N5O5: 587.2355; found 588.2426 ([M+H]⁺ form).

tert-butyl (3R,4R)-4-[4-[[5-amino-6-oxo-4-(3-pyridyIoxy)pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 137) Using General Procedure 4 starting from Préparation R4k and Préparation R5a as reagents, Example 137 was obtained. HRMS calculated for C32H40N6O6: 604.3009; found 605.3079 ([M+H]⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-[3-(o-tolyl)oxetan-3-yl]-3phenyl-piperidine-4-carbonyl]-4-piperidyI]methyl]pyrimidin-4-one (Example 138) Using General Procedure 6 starting from 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-4piperidyl)methyl]pyrimidin-4-one hydrochloride and Préparation R8f as reagents, Example 138 was obtained. HRMS calculated for C38H42FN5O5: 667.317; found 668.3237 ([M+H]⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-[3-(2methoxyphenyl)oxetan-3-yl] -3-phenyl-piperidine-4-carbonyl] -4piperidyl]methyl]pyrimidin-4-one (Example 139)

Using General Procedure 6 starting from 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-4piperidyl)methyl]pyrimidin-4-one hydrochloride and Préparation R8g as reagents, Example 139 was obtained. HRMS calculated for C₃8H42FN₅O6: 683.3119; found 684.3175 ([M+H]⁺ form).

5-amino-3-[[l-[(3R,4R)-l-[3-(2-chlorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Ex ample 140)

Using General Procedure 6 starting from 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-4piperidyl)methyl]pyrimidin-4-one hydrochloride and Préparation R8n as reagents, Example 140 was obtained. HRMS calculated for C₃7H39C1FN₅O₅: 687.2624; found 688.2687 ([M+H]⁺ form).

- 108- tert-butyl (3R,4R)-4-[(4S)-4-[[5-amino-6-oxo-4-[3(trifluoromethyl)phenoxy]pyrimidin-l-yl] methyl] -3,3-difluoro-4-hydroxy-piperidinel-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 141)

Using General Procedure 4 starting from Préparation R4e and Préparation R5b as reagents, the enantiomers were separated by chiral chromatography to give Example 141. HRMS calculated for C34H38F5N5O6: 707.2742; found 730.2632 ([M+Na]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]-6-[3-(trifluoromethyl)phenoxy]pyrimidin-4-one, hydrochloride (Example 142)

Using General Procedure 5 starting from Example 141 as reagent, Example 142 was obtained. HRMS calculated for C29H30F5N5O4: 607.2218; found 608.2283 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(2-methylpyrimidin-4yl)methyl] -3-phenyI-piperidine-4-carbonyl] -4-piperidyl] methyl] -6- [3(trifluoromethyl)phenoxy]pyrimidin-4-one (Example 143)

Using General Procedure 9 starting from Example 142 and 4-(chloromethyl)-2-methylpyrimidine as reagents, Example 143 was obtained. HRMS calculated for C35H36F5N7O4: 713.2749; found 714.2814 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(5-methylpyrazin-2yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-[3(trifluoromethyl)phenoxy]pyrimidin-4-one (Example 144)

Using General Procedure 9 starting from Example 142 and 2-(chloromethyl)-5-methylpyrazine hydrochloride as reagents, Example 144 was obtained. HRMS calculated for C35H36F5N7O4: 713.2749; found 714.2813 ([M+H]⁺ form).

tert-butyl (3R,4R)-4-[(4S)-4-[[5-amino-4-(4-chloro-3-fluoro-phenoxy)-6-oxopyrimidin-l-yl]methyl]-3,3-difluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenylpiperidine-l-carboxylate (Example 145)

- 109-

Using General Procedure 4 starting from Préparation R4c and Préparation R5b as reagents, the enantiomers were separated by chiral chromatography to give Example 145. HRMS calculated for C33H37CIF3N5O6: 691.2385; found 714.2275 ([M+Na]⁺ form).

5-amino-6-(4-chloro-3-fluoro-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)5 3-phenylpiperidine-4-carbonyl]-4-piperidyI]methyl]pyrimidin-4-one, hydrochloride (Example 146)

Using General Procedure 5 starting from Example 145 as reagent, Example 146 was obtained. HRMS calculated for C28H29CIF3N5O4: 591.186; found 592.1923 ([M+H]⁺ form).

5-amino-6-(4-chloro-3-fluoro-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)10 l-[(2-methylpyrimidin-4-yI)methyI]-3-phenyl-piperidine-4-carbonyl]-4piperidyl] methyl] pyrimidin-4-one (Example 147)

Using General Procedure 9 starting from Example 146 and 4-(chloromethyl)-2-methylpyrimidine as reagents, Example 147 was obtained. HRMS calculated for C34H35CIF3N7O4: 697.2391; found 698.2453 ([M+H]⁺ form).

5-amino-6-(4-chloro-3-fluoro-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)1 - [(5-methylpyrazin-2-yI)methyl] -3-phenyl-piperidine-4-car bonyl] -4piperidyl]methyl]pyrimidin-4-one (Example 148)

Using General Procedure 9 starting from Example 146 and 2-(chloromethyl)-5-methylpyrazine hydrochloride as reagents, Example 148 was obtained. HRMS calculated for 20 C34H35CIF3N7O4: 697.2391; found 698.2447 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(2-methylpyrimidin-4yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluoro-3methoxy-phenoxy)pyrimidin-4-one (Example 149)

Using General Procedure 9 starting from Example 136 and 4-(chloromethyl)-2-methyl25 pyrimidine as reagents, Example 149 was obtained. HRMS calculated for C35H38F3N7O5: 693.2886; found 694.2959 ([M+H]⁺ form).

- 110-

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(2thienyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one (Example 150)

Using General Procedure 11 starting from Example 29 and 2-thienylboronic acid as reagents, Example 150 was obtained. HRMS calculated for C37H37FN6O5S2: 728.2251; found 729.2313 ([M+H]⁺ form).

5-amino-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl] methyl]-6-(3-pyridyloxy)pyrimidin-4-one, hydrochloride (Example 151)

Using General Procedure 5 starting from Example 137 as reagent, Example 151 was obtained. HRMS calculated for C27H32N6O4: 504.2485; found 505.2555 ([M+H]⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l-[3-[3(trifluoromethyl)phenyl]oxetan-3-yl]piperidine-4-carbonyl]-4- piperidyl] methyl] pyrimidin-4-one (Example 152)

Using General Procedure 6 starting from 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-4piperidyl)methyl]pyrimidin-4-one hydrochloride and Préparation R8h as reagents, Example 152 was obtained. HRMS calculated for C38H39F4N5O5: 721.2888; found 722.2945 ([M+H]⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[l-[(3R,4R)-l-[3-(3-fluorophenyl)oxetan-3-yl]-3phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]pyrimidin-4-one (Example 153)

Using General Procedure 6 starting from 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-4piperidyl)methyl]pyrimidin-4-one hydrochloride and Préparation R8i as reagents, Example 153 was obtained. HRMS calculated for C37H39F2N5O5: 671.2919; found 672.2976 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(5-methylpyrazin-2yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluoro-3methoxy-phenoxy)pyrimidin-4-one (Example 154)

- 111 Using General Procedure 9 starting from Example 136 and 2-(chloromethyl)-5-methylpyrazine hydrochloride as reagents, Example 154 was obtained. HRMS calculated for C35H38F3N7O5: 693.2886; found 694.2949 ([M+H]⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l-[3-(pto!yl)oxetan-3-yl] piperidine-4-carbonyl] -4-pi peridyl] methyl] pyrimidin-4-one (Ex AMPLE 155)

Using General Procedure 6 starting from 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-4piperidyl)methyl]pyrimidin-4-one hydrochloride and Préparation R81 as reagents, Example 155 was obtained. HRMS calculated for C38H42FN5O5: 667.317; found 668.3237 ([M+H]⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-[3-(4methoxyphenyl)oxetan-3-yl] -3-phenyl-piperidine-4-carbonyl] -4- piperidyl]methyl]pyrimidin-4-one (Example 156)

Using General Procedure 6 starting from 5-amino-6-(4-flùorophenoxy)-3-[(4-hydroxy-4piperidyl)methyl]pyrimidin-4-one hydrochloride and Préparation R8m as reagents, Example 156 was obtained. HRMS calculated for C₃8H4₂FN5O6: 683.3119; found 684.3186 ([M+H]⁺ form).

5-amino-3- [ [(4S)-3,3-difluoro-4-hydroxy-1- [(3R,4R)-l-(5-methylpyridine-3carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one (Example 157)

Using General Procedure 6 starting from Example 11 and 5-methylpyridine-3-carboxylic acid as reagents, Example 157 was obtained. HRMS calculated for C35H35F3N6O5: 676.2621; found 677.2682 ([M+H]⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(2-cyclohexyl-4-methyl-thiazole-5-carbonyl)-3-phenylpiperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin4-one (Example 158)

- 112-

Using General Procedure 6 starting from Example 21 and 2-cyclohexyl-4-methylthiazole-5-carboxylic acid as reagents, Example 158 was obtained. HRMS calculated for C39H45FN6O5S: 728.3156; found 729.3221 ([M+H]⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-[3-(6-methyI-3- pyridyI)phenyl]sulfonyl-3-phenyl-piperidine-4-carbonyl]-4piperidyl] methyl] pyrimidin-4-one (Example 159)

Using General Procedure 11 starting from Example 69 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 159 was obtained. HRMS calculated for C40H41FN6O6S: 752.2792; found 753.2871 ([M+H]⁺ form).

5-amino-3-[[(4S)-l-[(3R,4R)-l-[(2-chloropyrimidin-4-yl)methyl]-3-phenyIpiperidine-4-carbonyl] -3,3-difluoro-4-hydroxy-4-piperidyl] methyl] -6-(4fluorophenoxy)pyrimidin-4-one (Example 160)

Using General Procedure 9 starting from Example 11 and 2-chloro-4(chloromethyl)pyrimidine as reagents, Example 160 was obtained. HRMS calculated for 15 C33H33CIF3N7O4: 683.2234; found 684.2304 ([M+H]⁺ form).”

5-amino-3-[[l-[(3R,4R)-l-(2-cyclopentyl-4-methyl-thiazole-5-carbonyl)-3-phenylpiperidine-4-carbonyl]-4-hydroxy-4-piperidyI]methyI]-6-(4-fluorophenoxy)pyrimidin4-one (Example 161)

Using General Procedure 6 starting from Example 21 and 2-cyclopentyl-4-methyl20 thiazole-5-carboxylic acid as reagents, Example 161 was obtained. HRMS calculated for C38H43FN6O5S: 714.3; found 715.3061 ([M+H]⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(3-chIoro-5-methyl-benzoyl)-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyI]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 162)

Using General Procedure 6 starting from Example 21 and 3-chloro-5-methyl-benzoic acid as reagents, Example 162 was obtained. HRMS calculated for C36H37CIFN5O5: 673.2467; found 674.2543 ([M+H]⁺ form).

- 113 -

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l-(5-pyrrol-lylpy ridine-3-carbonyl)piperidine-4-carbonyl] -4-piperidyl] methyl] pyrimidin-4-one (Example 163)

Using General Procedure 6 starting from Example 21 and 5-pyrrol-l-ylpyridine-3carboxylic acid as reagents, Example 163 was obtained. HRMS calculated for C38H38FN7O5: 691.2919; found 692.3003 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[[6-(6-methyl-3pyridyl)pyrimidin-4-yl]methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]6-(4-fluorophenoxy)pyrimidin-4-one (Example 164)

Using General Procedure 9 starting from Example 11 and 4-chloro-6(chloromethyl)pyrimidine, 5-amino-3-[[(4S)-l-[(3R,4R)-l-[(6-chloropyrimidin-4yl)methyl]-3-phenyl-piperidine-4-carbonyl]-3,3-difluoro-4-hydroxy-4-piperidyl]methyl]-6(4-fluorophenoxy)pyrimidin-4-one was obtained as a crude product and was directly reacted with (6-methyl-3-pyridyl)boronic acid using General Procedure 11 to give Example 164. HRMS calculated for C₃9H39f3N₈O4: 740.3046; found 741.3119 ([M+H]⁺ form).

5-amino-3-[[l-[(3R,4R)-l-(2-cyclobutyl-4-methyl-thiazole-5-carbonyl)-3-phenylpiperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin4-one (Example 165)

Using General Procedure 6 starting from Example 21 and 2-cyclobutyl-4-methylthiazole-5-carboxylic acid as reagents, Example 165 was obtained. HRMS calculated for C37H41FN6O5S: 700.2843; found 701.2913 ([M+H]⁺ form).

tert-butyl (3R,4R)-4-[(4S)-4-[[5-amino-4-(4-chlorophenoxy)-6-oxo-pyrimidin-lyl]methyl]-3,3-difluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 166)

Using General Procedure 4 starting from Préparation R4a and Préparation R5b as reagents, the enantiomers were separated by chiral chromatography to give Example 166. HRMS calculated for C33H38CIF2N5O6: 673.2479; found 696.2384 ([M+Na]⁺ form).

- 114-

5-amino-6-(4-chlorophenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3phenyIpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 167) Using General Procedure 5 starting from Example 166 as reagent, the crude product was purified by préparative LC (on C-18 Gemini-NX 5 gm column, 5 mM aqueous NH4HCO3-

MeCN, gradient) and solvent was evaporated to give Example 167. HRMS calculated for C28H30CIF2N5O4: 573.1954; found 574.2028 ([M+H]⁺ form).

5-amino-6-(4-chlorophenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(2methylpyrimidin-4-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one (Example 168)

Using General Procedure 9 starting from Example 167 and 4-(chloromethyl)-2-methylpyrimidine as reagents, Example 168 was obtained. HRMS calculated for C34H36CIF2N7O4: 679.2485; found 680.2556 ([M+H]⁺ form).

5-amino-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3-pyridyl)thiazole-5carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(315 pyridyIoxy)pyrimidin-4-one (Example 169)

Using General Procedure 6 starting from Example 151 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 169 was obtained. HRMS calculated for C38H40N8O5S: 720.2842; found 721.2914 ([M+H]⁺ form).

5-amino-3-[[l-[(3R,4R)-l-[3-(3-bromophenyl)oxetan-3-yl]-3-phenyl-piperidine-4- carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 170)

Using General Procedure 6 starting from 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-4piperidyl)methyl]pyrimidin-4-one hydrochloride and Préparation R8j as reagents, Example 170 was obtained. HRMS calculated for C37H39BrFN₅O₅: 731.2119; found

732.2182 ([M+H]⁺ form).

• 5-amino-3-[[l-[(3R,4R)-l-[3-(3-chlorophenyl)oxetan-3-yl]-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 171)

- 115 Using General Procedure 6 starting from 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-4piperidyl)methyI]pyrimidin-4-one hydrochloride and Préparation R8k as reagents, Example 171 was obtained. HRMS calculated for C37H39CIFN5O5: 687.2624; found 688.2697 ([M+H]⁺ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(3piperidyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4- piperidyl] methyl] pyrimidin-4-one (Example 172)

Using General Procedure 6 starting from Example 21 and 2-(l-tert-butoxycarbonyl-3piperidyl)-4-methyl-thiazole-5-carboxylic acid, tert-butyl 3-[5-[(3R,4R)-4-[4-[[5-amino-4(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3phenyl-piperidine-l-carbonyl]-4-methyl-thiazol-2-yl]piperidine-l-carboxylate was obtained as a crude product and was directly reacted using General procedure 5 to give Example 172. HRMS calculated for C38H44FN7O5S: 729.3109; found 730.3178 ([M+H]⁺form).

tert-butyl (3R,4R)-4-[(4S)-4-[[5-amino-4-(3-chloro-5-methoxy-phenoxy)-6-oxopyrimidin-l-yl]methyl]-3,3-difluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenylpiperidine-l-carboxylate (Example 173)

Using General Procedure 4 starting from Préparation 4b and Préparation 5b as reagents, the enantiomers were separated by chiral chromatography to give Example 173. HRMS calculated for C34H40CIF2N5O7: 703.2584; found 604.2122 ([M+H-C₄H₈-CO2]⁺ form)

5-amino-6-(3-chloro-5-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyI]pyrimidin-4-one hydrochloride (Example 174)

Using General Procedure 5 starting from Example 173 as reagent, Example 174 was obtained. HRMS calculated for C29H32CIF2N5O5: 603.206; found 604.213 ([M+H]⁺ form).

5-amino-6-(3-chloro-5-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[(2-methylpyrimidin-4-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl] methyl] pyrimidin-4-one (Example 175)

- 116-

Using General Procedure 9 starting from Example 174 and 4-(chloromethyl)-2-methylpyrimidine as reagents, Example 175 was obtained. HRMS calculated for C35H38CIF2N7O5: 709.2591; found 710.2668 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[[2-(6-methyl-3- py ridyl)py rimidin-4-yl] methyl] -3-phenyl-piperidine-4-carbonyI] -4-piperidyl] methyl] 6-(4-fluorophenoxy)pyrimidin-4-one (Example 176)

Using General Procedure 11 starting from Example 160 and (6-methyl-3-pyridyl)boronic acid as reagents, Example 176 was obtained. HRMS calculated for C₃9H₃9F₃N8O4: 740.3046; found 741.3102 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-[(2phenylpyrimidin-4-yl)methyl]piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one (Example 177)

Using General Procedure 11 starting from Example 160 and phenylboronic acid as reagents, Example 177 was obtained. HRMS calculated for C₃9H₃8F₃N7O4: 725.2938; found 726.3025 ([M+H]⁺ form).

5-amino-6-(3-chloro-5-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[(5-methyIpyrazin-2-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one (Example 178)

Using General Procedure 9 starting from Example 174 and 2-(chloromethyl)-5-methylpyrazine hydrochloride as reagents, Example 178 was obtained. HRMS calculated for C₃₅H₃8C1F₂N7O₅: 709.2591; found 710.2653 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6(4-fluoro-3-methoxy-phenoxy)pyrimidin-4-one (Example 179)

Using General Procedure 6 starting from Example 136 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 179 was obtained. HRMS calculated for C4oH₄₀F₃N₇06S: 803.2713; found 804.2772 ([M+H]⁺ form).

- 117 - tert-butyl (3R,4R)-4- [(4S)-4- [ [5-amino-4-(4-chloro-3-methoxy-phenoxy)-6-oxopyrimidin-l-yl]methyl]-3,3-difluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenylpiperidine-l-carboxylate (Example 180)

Using General Procedure 4 starting from Préparation R4m and Préparation 5b as reagents, the enantiomers were separated by chiral chromatography to give Example 180. HRMS calculated for C34H40CIF2N5O7: 703.2584; found 726.2469 ([M+Na]⁺ form).

5-amino-6-(4-chloro-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] pyrimidin-4-one hydrochloride (Example 181)

Using General Procedure 5 starting from Example 180 as reagent, Example 181 was obtained. HRMS calculated for C29H32CIF2N5O5: 603.206; found 604.2127 ([M+H]⁺ form).

5-amino-6-(4-chloro-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[(2-methylpyrimidin-4-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one (Example 182)

Using General Procedure 9 starting from Example 181 and 4-(chloromethyl)-2-methylpyrimidine as reagents, Example 182 was obtained. HRMS calculated for C35H38CIF2N7O5: 709.2591; found 710.2659 ([M+H]⁺ form).

5-amino-6-(4-chloro-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[(5-methylpyrazin-2-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one (Example 183)

Using General Procedure 9 starting from Example 181 and 2-(chloromethyl)-5-methylpyrazine hydrochloride as reagents, Example 183 was obtained. HRMS calculated for C35H38CIF2N7O5: 709.2591; found 710.2656 ([M+H]⁺ form).

5-amino-6-(4-chloro-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l](3R,4R)-l-[4-methyl-2-(6-methyl-3-pyridyl)thiazoIe-5-carbonyl]-3-phenyl-piperidine4-carbonyl]-4-piperidyl] methyl] pyrimidin-4-one (Example 184)

- 118-

Using General Procedure 6 starting from Example 181 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 184 was obtained. HRMS calculated for C40H40CIF2N7O6S: 819.2418; found 820.2483 ([M+H]⁺ form).

5-amino-3- [ [(4S)-3,3-difluoro-4-hydroxy-l- [(3R,4R)-1- [4-methyl-2- [6-methyl-5(trifluoromethyl)-3-pyridyl]thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (EXAMPLE 185)

Using General Procedure 11 starting from Example 41 and 2-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine as reagents, Example 185 was obtained. HRMS calculated for C40H37F6N7O5S: 841.2481; found 842.2549 ([M+H]⁺ form).

tert-butyl (3R,4R)-4-[(4S)-4-[[5-amino-4-(4-cyclopropyl-3-methoxy-phenoxy)-6-oxopyrimidin-l-yl]methyl]-3,3-difluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenylpiperidine-l-carboxylate (Example 186)

Using General Procedure 4 starting from Préparation R4n and Préparation R5b as reagents, the enantiomers were separated by chiral chromatography to give Example 186. HRMS calculated for C37H45F2N5O7: 709.3287; found 732.3172 ([M+Na]⁺ form).

5-amino-6-(4-cyclopropyl-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] py rimidin-4-one hydrochloride (EXAMPLE 187)

Using General Procedure 5 starting from Example 186 as reagent, Example 187 was obtained. HRMS calculated for C32H37F2N5O5: 609.2763; found 610.2834 ([M+H]⁺ form).

5-amino-6-(4-cyclopropyl-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[(2-methylpyrimidin-4-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl] pyrimidin-4-one (EXAMPLE 188)

Using General Procedure 9 starting from Example 187 and 4-(chloromethyl)-2-methylpyrimidine as reagents, Example 188 was obtained. HRMS calculated for C38H43F2N7O5: 715.3293; found 716.3353 ([M+H]⁺ form).

- 119-

5-amino-3-[[l-[(3R,4R)-l-[2-(3,3-difluorocyclobutyl)-4-methyl-thiazole-5-carbonyl]3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one (Example 189)

Using General Procedure 6 starting from Example 21 and 2-(3,3-difluorocyclobutyl)-4methyl-thiazole-5-carboxylic acid as reagents, Example 189 was obtained. HRMS calculated for C37H39F3N6O5S: 736.2655; found 737.2724 ([M+H]⁺ form).

5-amino-3-[[(4S)-l-[(3R,4R)-l-[2-(3,3-difluorocyclobutyl)-4-methyl-thiazoIe-5carbonyl]-3-phenyl-piperidine-4-carbonyl]-3,3-difluoro-4-hydroxy-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 190)

Using General Procedure 6 starting from Example 11 and 2-(3,3-difluorocyclobutyl)-4methyl-thiazole-5-carboxylic acid as reagents, Example 190 was obtained. HRMS calculated for C37H37F5N6O5S: 772.2466; found 773.2533 ([M+H]+ form).

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-(4-methyl-2tetrahydropyran-4-yl-thiazole-5-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4piperidyl] methyl] pyrimidin-4-one (Example 191)

Using General Procedure 6 starting from Example 21 and 4-methyl-2-tetrahydropyran-4yl-thiazole-5-carboxylic acid as reagents, Example 191 was obtained. HRMS calculated for C38H43FN6O6S: 730.2949; found 731.3013 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-(4-methyl-2tetrahydropyran-4-yl-thiazole-5-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one (Example 192)

Using General Procedure 6 starting from Example 11 and 4-methyl-2-tetrahydropyran-4yI-thiazole-5-carboxylic acid as reagents, Example 192 was obtained. HRMS calculated for C38H41F3N6O6S: 766.2761; found 767.2827 ([M+H]⁺ form).

tert-butyl (3R,4R)-4-[(3SR,4RS)-4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidinl-yl]methyl]-3-fluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate and

- 120- tert-butyl (3R,4R)-4-[(3RS,4SR)-4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-lyl]methyl]-3-fluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 193)

Using General Procedure 6 starting from Préparation Rllb and (3R,4R)-l-(tertbutoxycarbonyl)-3-phenylpiperidine-4-carboxylic acid as reagents. Example 193 was obtained. HRMS calculated for C33H39F2N5O6: 639.2869; found 540.2411 and 540.2424 ([M+H-C4Hs-CO2]⁺ form).

tert-butyl (3R,4R)-4-[(3SR,4SR)-4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidinl-yl]methyl]-3-fluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate and tert-butyl (3R,4R)-4-[(3RS,4RS)-4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-lyl]methyl]-3-fluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 194)

Using General Procedure 6 starting from Préparation Rlla and (3R,4R)-l-(tertbutoxycarbonyl)-3-phenylpiperidine-4-carboxylic acid as reagents, Example 194 was obtained. HRMS calculated for C₃₃H39F2N5O6: 639.2869; found 540.2403 and 540.2401 ([M+H-C4H₈-CO₂]⁺ form).

5-amino-3-[[(3SR,4RS)-3-fluoro-4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one hydrochloride and

5-amino-3-[[(3RS,4SR)-3-fluoro-4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one hydrochloride (Example 195)

Using General Procedure 5 starting from Example 193 as reagent, Example 195 was obtained. HRMS calculated for C28H31F2N5O4: 539.2344; found 540.2407 and 540.2410 ([M+H]⁺ form).

5-amino-3-[[(3SR,4SR)-3-fluoro-4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one hydrochloride

- 121 - and

5-amino-3-[[(3RS,4RS)-3-fluoro-4-hydroxy-l-[(3R,4R)-3-phenyIpiperidine-4carbonyl]-4-piperidyI]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one hydrochloride (Example 196)

Using General Procedure 5 starting from Example 194 as reagent, Example 196 was obtained. HRMS calculated for C28H31F2N5O4: 539.2344; found 540.2399 and 540.2398 ([M+H]⁺ form).

5-amino-3-[[(3SR,4RS)-3-fluoro-4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6(4-fluorophenoxy)pyrimidin-4-one and

5-amino-3-[[(3RS,4SR)-3-fluoro-4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyI]-4-piperidyl]methyl]-6(4-fluorophenoxy)pyrimidin-4-one (Example 197)

Using General Procedure 6 starting from Example 195 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 197 was obtained. HRMS calculated for C39H39F2N7O5S: 755.2701; found 756.2764 and 756.2767 ([M+H]⁺ form).

5-amino-3-[[(3SR,4SR)-3-fluoro-4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyI-3pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyI]-6(4-fluorophenoxy)pyrimidin-4-one and

5-amino-3-[[(3RS,4RS)-3-fluoro-4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6(4-fluorophenoxy)pyrimidin-4-one (Example 198)

Using General Procedure 6 starting from Example 196 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, Example 198 was obtained. HRMS calculated for C39H39F2N7O5S: 755.2701; found 756.2769 and 756.2759 ([M+H]⁺ form).

- 122 -

5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(l-methyl-3piperidyl)thiazoIe-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4- piperidyl] methyl] pyrimidin-4-one (Example 199)

Using General Procedure 6 starting from Example 21 and 4-methyl-2-(l-methyl-3piperidyl)thiazole-5-carboxylic acid hydrochloride as reagents, Example 199 was obtained. HRMS calculated for C39H46FN7O5S: 743.3265; found 744.3326 ([M+H]⁺ form).

5-amino-6- [4-(hydroxymethyl)phenoxy] -3- [ [4-hyd roxy-1 - [(3R,4R)-1 - [(2methylpyrimidin-4-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4- piperidyl] methyl] pyrimidin-4-one (Example 200)

Using General Procedure 4 starting from Préparation R41 and Préparation R5a as reagents, tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4-formylphenoxy)-6-oxo-pyrimidin-lyl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate was obtained as a crude product.

Tert-butyl (3R,4R)-4-[4- [[5 -am ino-4-(4-formylphenoxy)-6-oxo-pyrimidin-1 -y 1] methyI]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate was reacted using General procedure 5 to give 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzaldehyde hydrochloride, which was reacted with 2-(chloromethyl)-4-methyl-pyrimidine using General procedure 9 to give 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l-[(2-methylpyrimidin-4-yl)methyl]-3phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4yl]oxybenzaldehyde.

4- [5 -amino-1 - [[4-hydroxy-1 - [(3R,4R)-1 - [(2-methylpyrimidin-4-y l)methy l]-3-pheny 1piperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzaldehyde (24 mg, 0.037 mmol) and sodium borohydride (1.4 mg, 1 eq.) were disolved in methanol (3 ml) at r.t. for 20 hours. The residue was directly injected to préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient) and evaporated to give Example 200. HRMS calculated for C35H41N7O5: 639.3169; found 640.3221 ([M+H]⁺form).

- 123 -

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(5-methylpyrazin-2yl)methy 1] -3-phenyl-piperidine-4-carbonyl] -4-piperidyl] methyl] -6-(4fluorophenoxy)pyrimidin-4-one (Example 201)

Using General Procedure 9 starting from Example 11 and 2-(chloromethyl)-5-methylpyrazine hydrochloride as reagents, Example 201 was obtained. HRMS calculated for C34H36F3N7O4: 663.2781; found 664.2846 ([M+H]⁺ form).

5-amino-3- [ [(4S)-3,3-difluoro-4-hydroxy-l - [(3R,4R)-3-phenyl-l -(py razin-2ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin4-one (Example 202)

Using General Procedure 9 starting from Example 11 and 2-(chloromethyl)pyrazine hydrochloride as reagents, Example 202 was obtained. HRMS calculated for C33H34F3N7O4: 649.2625; found 650.2687 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyridazin-3ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin4-one (Example 203)

Using General Procedure 9 starting from Example 11 and 3-(bromomethyl)pyridazine hydrobromide as reagents, Example 203 was obtained. HRMS calculated for C33H34F3N7O4: 649.2625; found 650.2687 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyrimidin-2ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin4-one (Example 204)

Using General Procedure 9 starting from Example 11 and 2-(chloromethyl)pyrimidine hydrochloride as reagents, Example 204 was obtained. HRMS calculated for C33H34F3N7O4: 649.2625; found 650.2706 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(4-methylpyrimidin-2yl)methy I] -3-phenyl-piperidine-4-carbonyl] -4-piperidyl] methyl] -6-(4fluorophenoxy)pyrimidin-4-one (Example 205)

- 124 -

Using General Procedure 9 starting from Example 11 and 2-(chloromethyl)-4-methylpyrimidine as reagents, Example 205 was obtained. HRMS calculated for C34H36F3N7O4: 663.2781; found 664.2844 ([M+H]⁺ form).

5-amino-3-[[(4S)-l-[(3R,4R)-l-[(4,6-dimethylpyrimidin-2-yl)methyl]-3-phenylpiperidine-4-carbonyl]-3,3-difluoro-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one (Example 206)

Using General Procedure 9 starting from Example 11 and 2-(chloromethyl)-4,6-dimethylpyrimidine as reagents, Example 206 was obtained. HRMS calculated for C35H38F3N7O4: 677.2938; found 678.302 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(6-methylpyrazin-2yl)methyl] -3-phenyl-piperidine-4-carbonyl] -4-piperidyI] methyl] -6-(4fluorophenoxy)pyrimidin-4-one (Example 207)

Using General Procedure 9 starting from Example 11 and 2-(chloromethyl)-6-methylpyrazine hydrochloride as reagents, Example 207 was obtained. HRMS calculated for C34H36F3N7O4: 663.2781; found 664.2874 ([M+H]⁺ form).

tert-butyl (3R,4R)-4-[(4S)-4-[[5-amino-4-(4-cyanophenoxy)-6-oxo-pyrimidin-lyl]methyl]-3,3-difluoro-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 208)

Using General Procedure 4 starting from Préparation R4j and Préparation R5b as reagents, the enantiomers were separated by chiral chromatography to give Example 208. HRMS calculated for C₃4H38F2N₆O₆: 664.2821; found 687.2704 ([M+Na]⁺ form).

4-[5-amino-l-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitriIe hydrochloride (Example 209)

Using General Procedure 5 starting from Example 208 as reagent, EXAMPLE 209 was obtained. HRMS calculated for C29H30F2N6O4: 564.2297; found 565.2355 ([M+H]⁺ form).

- 125 -

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l[4-methyI-2-(6-methyl-3-pyridyl)thiazole-5-carbonyI]-3-phenyl-piperidine-4carbonyl]-4-piperidyI]methyl]pyrimidin-4-one (Example 210)

Using General Procedure 6 starting from Example 209 and 4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carboxylic acid as reagents, 4-[5-amino-l-[[(4S)-3,3-difluoro-4hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3-pyridyl)thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile was obtained as a crude product and was directly reacted using General Procedure 2 to give Example 210. HRMS calculated for C40H42F2N8O5S: 784.2967; found 785.3033 ([M+H]⁺form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(3-methylpyrazin-2yl)methyl] -3-phenyl-piperidine-4-carbonyl] -4-piperidyl] methyl] -6-(4fluorophenoxy)pyrimidin-4-one (Example 211)

Using General Procedure 9 starting from Example 11 and 2-(chloromethyl)-3-methylpyrazine hydrochloride as reagents, EXAMPLE 211 was obtained. HRMS calculated for C3₄H36F3N₇O4: 663.2781; found 664.2847 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyrimidin-4ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin4-one (Example 212)

Using General Procedure 9 starting from Example 11 and 4-(chloromethyl)pyrimidine as reagents, Example 212 was obtained. HRMS calculated for C33H34F3N7O4: 649.2625; found 650.2672 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyI-l-(pyrazin-2ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluoro-3-methoxyphenoxy)pyrimidin-4-one (Example 213)

Using General Procedure 9 starting from Example 136 and 2-(chloromethyl)pyrazine hydrochloride as reagents, Example 213 was obtained. HRMS calculated for C34H36F3N7O5: 679.273; found 680.2784 ([M+H]⁺ form).

- 126-

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyridazin-3- ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluoro-3-methoxyphenoxy)pyrimidin-4-one (Example 214)

Using General Procedure 9 starting from Example 136 and 3-(bromomethyl)pyridazine hydrobromide as reagents, Example 214 was obtained. HRMS calculated for C34H36F3N7O5: 679.273; found 680.2781 ([M+H]⁺ form)

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyrimidin-2- ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluoro-3-methoxyphenoxy)pyrimidin-4-one (Example 215)

Using General Procedure 9 starting from Example 136 and 2-(chloromethyl)pyrimidine hydrochloride as reagents, Example 215 was obtained. HRMS calculated for C34H36F3N7O5: 679.273; found 680.2786 ([M+H]⁺ form).

5-amino-3- [ [(4S)-3,3-difluoro-4-hydroxy-1 - [(3R,4R)-1 - [(4-methyIpy rimidin-2- yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]niethyl]-6-(4-fluoro-3methoxy-phenoxy)pyrimidin-4-one (Example 216)

Using General Procedure 9 starting from Example 136 and 2-(chloromethyl)-4-methylpyrimidine as reagents, Example 216 was obtained. HRMS calculated for CssHssFsVOs: 693.2886; found 694.2953 ([M+H]⁺ form).

5-amino-3-[[(4S)-l-[(3R,4R)-l-[(4,6-dimethylpyrimidin-2-yl)methyl]-3-phenylpiperidine-4-carbonyl]-3,3-difluoro-4-hydroxy-4-piperidyl]methyl]-6-(4-fluoro-3methoxy-phenoxy)pyrimidin-4-one (Example 217)

Using General Procedure 9 starting from Example 136 and 2-(chloromethyl)-4,6dimethyl-pyrimidine as reagents, Example 217 was obtained. HRMS calculated for C36H40F3N7O5: 707.3043; found 708.3094 ([M+H]⁺ form)

5-amino-3-[[(4S)-3,3-difIuoro-4-hydroxy-l-[(3R,4R)-l-[(6-methyIpyrazin-2- yl)methyl]-3-phenyI-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluoro-3methoxy-phenoxy)pyrimidin-4-one (Example 218)

- 127-

Using General Procedure 9 starting from Example 136 and 2-(chloromethyl)-6-methylpyrazine hydrochloride as reagents, Example 218 was obtained. HRMS calculated for C35H38F3N7O5: 693.2886; found 694.2942 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(3-methylpyrazin-25 yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluoro-3methoxy-phenoxy)pyrimidin-4-one (Example 219)

Using General Procedure 9 starting from Example 136 and 2-(chloromethyl)-3-methylpyrazine;hydrochloride as reagents, Example 219 was obtained. HRMS calculated for C35H38F3N7O5: 693.2886; found 694.2938 ([M+H]⁺ form).

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyrimidin-4ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluoro-3-methoxyphenoxy)pyrimidin-4-one (Example 220)

Using General Procedure 9 starting from Example 136 and 4-(chloromethyl)pyrimidine as reagents, Example 220 was obtained. HRMS calculated for C34H36F3N7O5: 679.273;

found 680.2795 ([M+H]⁺ form)

5-amino-6-(4-chlorophenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(5methylpyrazin-2-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl] methyl] pyrimidin-4-one (Example 221)

Using General Procedure 9 starting from Example 167 and 2-(chloromethyl)-5-methyl- pyrazine hydrochloride as reagents, Example 221 was obtained. HRMS calculated for C34H36C1F₂N₇O₄: 679.2485; found 680.2539 ([M+H]⁺ form).

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[(4S)-l-[(3R,4R)-l-(3,5-dichlorobenzoyl)-3phenyl-piperidine-4-carbonyl]-3,3-difluoro-4-hydroxy-4-piperidyl]methyl]pyrimidin4-one (Example 222)

Using General Procedure 6 starting from Example 209 and 3,5-dichlorobenzoic acid as reagents, 4-[5-amino-l-[[(4S)-l-[(3R,4R)-l-(3,5-dichlorobenzoyl)-3-phenyl-piperidine-4carbonyl]-3,3-difluoro-4-hydroxy-4-piperidyl]methyl]-6-oxo-pyrimidin-4yl]oxybenzonitrile was obtained as a crude product and was directly reacted using General

-128Procedure 2 to give Example 222. HRMS calculated for C36H36CI2F2N6O5: 740.2092; found 741.2176 ([M+H]⁺ form).

tert-butyl N-[[4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3py ridyl)thiazole-5-carbony 1] -3-phenyI-piperidine-4-carbonyl] -4-piperidyl] methyl] -6oxo-pyrimidin-4-yI]oxyphenyl]methyl]carbamate (Example 223)

Example 210 (1.0 eq.), tert-butoxycarbonyl tert-butyl carbonate (3.8 eq.), and sodium hydrogen carbonate (5.0 eq.) were dissolved in THF and water (1:1). The reaction mixture was stirred at r.t. till completion. The reaction mixture was extracted with EtOAc. The combined organic phase dried on MgSO4 and the solvent was evaporated. The crude product was purified by préparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HCO₃-MeCN, gradient). Solvent was evaporated under reduced pressure to give Example 223. HRMS calculated for C45H52N8O7S: 848.368; found 849.3732 ([M+H]+ form).

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[4-hydroxy-l-[(3R,4R)-l-H2-(6-methyl-3pyridyI)thiazol-5-yl]methyl]-3-phenyl-piperidine-4-carbonyl]-4- piperidyl] methyl] pyrimidin-4-one (Example 224)

Using General Procedure 5 starting from tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4cyanophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenylpiperidine-l-carboxylate as reagent, the crude product was purified by préparative LC (on C-18 Luna 10 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure to give 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile. Using General Procedure 9 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and 5-[5-(chloromethyl)-l,3-thiazol-2-yl]-2-methylpyridine as reagents, 4-[5-amino-l-[[420308

- 129- hydroxy-l-[(3R,4R)-l-[[2-(6-methyl-3-pyridyl)thiazol-5-yl]methyl]-3-phenyl-piperidine4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile was obtained.

Using General Procedure 2 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l-[[2-(6methyl-3-pyridyl)thiazol-5-yl]methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile as reagent, Example 224 was obtained. HRMS calculated for C39H44N8O4S: 720.3206; found 721.3275 ((M+H)⁺ form).

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l(pyridine-3-carbonyl)piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 225) and

5-amino-6- [4-(aminomethyl)phenoxy] -3- [[1 - [(3R,4R)-1 -(5-chloropy ridine-3carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]pyrimidin4-one (Example 226)

Using General Procedure 5 starting from tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4cyanophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenylpiperidine-1-carboxylate as reagent, the crude product was purified by préparative LC (on C-18 Luna 10 pm column, 5 mM aqueous NH₄HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure to give 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile.

Using General Procedure 6 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and 5-chloropyridine-3-carboxylic acid as reagents, 4-[5-amino-l-[[l-[(3R,4R)-l-(5chloropyridine-3-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile was obtained.

Using General Procedure 2 starting from 4-[5-amino-l-[[l-[(3R,4R)-l-(5-chloropyridine3-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-oxopyrimidin-4-yl]oxybenzonitrile as reagent, Example 225 and Example 226 was obtained.

- 130-

Example 225: HRMS calculated for C35H39N7O5: 637.3013; found 638.3085 ((M+H)⁺form).

Example 226: HRMS calculated for C35H38CIN7O5: 671.2623; found 672.2701 ((M+H)⁺form).

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-[6(trifluoromethyl)-3-pyridyl]thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl] methyl] pyrimidin-4-one (Example 227)

Using General Procedure 6 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and 2-bromo-4-methyl-thiazole-5-carboxylic acid as reagents, 4-[5-amino-l-[[l-[(3R,4R)l-(2-bromo-4-methyl-thiazole-5-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile was obtained.

Using General Procedure 11 starting from 4-[5-amino-l-[[l-[(3R,4R)-l-(2-bromo-4methyl-thiazole-5-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and [6-(trifluoromethyl)-3pyridyl]boronic acid as reagent, 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-[6(trifluoromethyl)-3-pyridyl]thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile was obtained.

Using General Procedure 2 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l-[4methyl-2-[6-(trifluoromethyl)-3-pyridyl]thiazole-5-carbonyl]-3-phenyl-piperidine-4carbony 1] -4-piperidy l]methy 1] -6-oxo-pyrimidin-4-y 1] oxybenzonitrile as reagent,

- 131 Example 227 was obtained. HRMS calculated for C40H41F3N8O5S: 802.2873; found 803.2939 ((M+H)⁺ form).

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[l-[(3R,4R)-l-[2-[6-(dimethylamino)-3pyridyl]-4-methyl-thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4- piperidyl]methyl]pyrimidin-4-one (Example 228)

Using General Procedure 5 starting from tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4cyanophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenylpiperidine-1 -carboxylate as reagent, the crude product was purified by préparative LC (on C-18 Luna 10 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure to give 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-315 phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile.

Using General Procedure 6 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and 2-bromo-4-methyl-thiazole-5-carboxylic acid as reagents, 4-[5-amino-l-[[l-[(3R,4R)l-(2-bromo-4-methyl-thiazole-5-carbonyI)-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-420 piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile was obtained.

Using General Procedure 11 starting from 4-[5-amino-l-[[l-[(3R,4R)-l-(2-bromo-4methyl-thiazole-5-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and [6-(dimethylamino)-3pyridyl]boronic acid as reagent, 4-[5-amino-l-[[l-[(3R,4R)-l-[2-[6-(dimethylamino)-325 pyridyl]-4-methyl-thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4piperidyI]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile was obtained.

Using General Procedure 2 starting from 4-[5-amino-l-[[l-[(3R,4R)-l-[2-[6(dimethylamino)-3-pyridyl]-4-methyl-thiazole-5-carbonyl]-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile as reagent,

Example 228 was obtained. HRMS calculated for C41H47N9O5S: 777.3421; found 778.3506 ((M+H)⁺ form).

- 132-

5-amino-6- [4-(aminomethyl)phenoxy] -3- [[4-hydroxy-l - [(3R,4R)-1- [5-(6-methyl-3pyridyl)pyridine-3-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one (Example 229)

Using General Procedure 6 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and 5-chloropyridine-3-carboxylic acid as reagents, 4-[5-amino-l-[[l-[(3R,4R)-l-(5chloropyridine-3 -carbonyl)-3 -pheny 1-p iperidine-4-carbonyl] -4-hydroxy-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile was obtained.

Using General Procedure 11 starting from 4-[5-amino-l-[[l-[(3R,4R)-l-(5chloropyridine-3-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and (6-methyl-3-pyridyl)boronic acid as reagent, 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l-[5-(6-methyl-3-pyridyl)pyridine3-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4yl]oxybenzonitrile was obtained.

Using General Procedure 2 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l-[5-(6methyl-3-pyridyl)pyridine-3-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile as reagent, Example 229 was obtained. HRMS calculated for C41H44N8O5: 728.3434; found 729.3489 ((M+H)⁺ form).

- 133 -

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[4-hydroxy-l-[(3R,4R)-l-(isoquinoline-5carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one (Example 230)

Using General Procedure 4 starting from Préparation R4j and Préparation R5a as 5 reagents, tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4-cyanophenoxy)-6-oxo-pyrimidin-lyl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate was obtained.

Using General Procedure 5 starting from tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4cyanophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl10 piperidine-l-carboxylate as reagent, the crude product was purified by préparative LC (on C-18 Luna 10 gm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure to give 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidm-4-yl]oxybenzonitrile.

Using General Procedure 6 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-315 phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and isoquinoline-5-carboxylic acid as reagents, 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l(isoquinoline-5-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxopyrimidin-4-yl]oxybenzonitrile was obtained.

Using General Procedure 2 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l20 (isoquinoline-5-carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxopyrimidin-4-yl]oxybenzonitrile as reagent, Example 230 was obtained. HRMS calculated for C39H41N7O5: 687.3169; found 688.3237 ((M+H)⁺ form).

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[4-hydroxy-l-[(3R,4R)-l-[[2-(6-methyl-3pyridyl)pyrimidin-4-yl]methyl]-3-phenyl-piperidine-4-carbonyl]-4- piperidyl]methyl]pyrimidin-4-one (Example 231)

Step 1: 2-(6-methyl-3-pyridyl)pyrimidine-4-carbaldehyde

2-chloropyrimidine-4-carbaldehyde (17.7 g, 124 mmol), (6-methyl-3-pyridyl)boronic acid (34 g, 248 mmol, 2 eq.), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) (1.76 g, 0.02 eq., 2.48 mmol), and cesiumcarbonate (80.9 g, 2 eq., 248 30 mmol, 100 mass%) were dissolved in THF (85 mL) and water (85 mL). After stirring at

- 134-

100 °C for until completion, the phases were separated and the aqueous phase extracted with EtOAc. The aqueous phase was set to pH = 7 with IM HCl, then extracted with DCM. The organic phases were combined and evaporated. The crude product was dissolved in 500 mL DCM , then 105 g Celite was added and the volatiles were removed under reduced pressure. Then it was purified via flash chromatography using DCM and EtOAc as eluents, gradient method 0-50 % to give 2-(6-methyl-3-pyridyl)pyrimidine-4-carbaldehyde. HRMS calculated for CnHçNjO: 199.0746; found 200.0813 ((M+H)⁺ form).

’H-NMR (400 MHz, dmso-d6) δ ppm 10.03 (s, 1H), 9.46 (d, 1H), 9.23 (d, 1H), 8.63 (dd, 1H), 7.83 (d, 1H), 7.47 (d, 1H), 2.58 (s, 3H)

Step 2: EXAMPLE 231

Using General Procedure 5 starting from tert-butyl (3R,4R)-4-[4-[[5-amino-4-(4cyanophenoxy)-6-oxo-pyrimidin-1 -yl]methy l]-4-hydroxy-piperidine-1 -carbonyl]-3-pheny 1piperidine-l-carboxylate as reagent, the crude product was purified by préparative LC (on C-18 Luna 10 pm column, 5 mM aqueous NH4HCO3-MeCN, gradient). Solvent was evaporated under reduced pressure to give 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yI]oxybenzonitrile. Using General Procedure 10 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-3phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile and 2-(6-methyl-3-pyridyl)pyrimidine-4-carbaldehyde (as obtained in Step 1 above) as reagents, 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l-[[2-(6-methyl-3-pyridyl)pyrimidin-4yl]methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-oxo-pyrimidin-4yfloxybenzonitrile was obtained.

Using General Procedure 2 starting from 4-[5-amino-l-[[4-hydroxy-l-[(3R,4R)-l-[[2-(6methyl-3-pyridyl)pyrimidin-4-yl]methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-oxo-pyrimidin-4-yl]oxybenzonitrile as reagent, Example 231 was obtained. HRMS calculated for C40H45N9O4: 715.3594; found 716.3677 ((M+H)⁺ form)

- 135 -

PHARMACOLOGICAL STUDY

EXAMPLE A: Evaluation of the inhibition of USP7 by the Fluorescence Intensity (FEINT) readings

USP7 activity was measured using Rhodamine-110 c-terminal labelled Ubiquitin as a substrate (UbiQBio). Incubation with USP7 results in the release of Rhodamine-110 leading to an increase in fluorescence which can be used in the continuous measurement of USP7 activity.

The USP7 reactions were performed in a 50 pL volume, in 384 well black solid low binding plates (Corning #3575). The reaction buffer consisted of 100 mM Bicine pH 8.0, 0.01 % TritonXIOO, 1 mM TCEP, and 10 % DMSO.

0.25 nM His-His-USP7 (aa208-560, [C315A]) was incubated with compound (final concentration 10 % DMSO) for 60 minutes at 30 °C. The reaction was then initiated by the addition of 500 nM Ubiquitin-Rhodamine-110 substrate or 4 μΜ Ubiquitin-Rhodamine-110 substrate and the plate read every 3 minutes for 21 minutes to measure the release of Rhodamine-110. Fluorescence Intensity (FLINT) readings were measured using a Biomek Neo plate reader (Ex.485 nm, Em.535 nm).

The inhibition of increasing doses of compound was expressed as a percentage réduction in kinetic rate compared to the kinetic rates established between ‘DMSO only’ and ‘total inhibition’ Controls (no USP7). The inhibitory concentrations that gave a 50 % réduction in kinetic rate (IC50) were determined, from 11-point dose response curves, in XL-Fit using a 4-Parameter Logistic Model 205 (Sigmoidal Dose-Response Model). The Ki values were determined from the IC50 values according to Cer et al. Nucleic Acids Res. 2009, Jul 1; 37(WebServer issue): W441-W445.

The results presented in Table 1 below show that compounds of the invention inhibit interaction between USP7 protein and the fluorescent peptide described hereinbefore.

- 136EXAMPLE B; In vitro cytotoxicity

The cytotoxicity studies were evaluated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide] assay and carried out on Z138 mantle cell lymphoma tumour cell Unes. The cells are distributed onto microplates and exposed to the test compounds for 5 96 hours. MTT is then added for 4 hours and converted by NAD(P)H-dependent cellular oxidoreductase enzymes in formazan, which has a purple color. The viable cell number is proportional to the production of formazan salts and cell viability can be quantified by the absorbance of the solution at 540nm with a spectrophotometer (Carmichael et al.. Cancer Res. 1987, 47, 936-942). The results are expressed in IC50 (the concentration of compound 10 that inhibits cell viability by 50 % compared to DMSO treated cells only) and are presented in Table 1 below.

The results show that the compounds of the invention are cytotoxic.

Table 1: IC50 of USP7 inhibition and of cytotoxicity for Z138 cells

Example	Ki (M) USP7 FLINT	IC50 (M) MTT	Example	Ki (M) USP7 FLINT	IC50 (M) MTT
1	1.03E-07	NT	18	3.29E-07	NT
2	1.91E-07	NT	19	3.44E-07	NT
3	1.25E-07	NT	20	1.12E-07	NT
4	1.15E-07	NT	21	1.03E-07	NT
5	2.99E-07	NT	22	3.0E-09	4.0E-09
6	3.98E-07	NT	23	7.46E-09	2.77E-09
7	1.37E-07	NT	24	4.0E-09	9.9E-09
8	1.31E-07	NT	25	2.9E-09	2.3E-09
9	8.25E-08	NT	26	6.1E-09	2.0E-08
10	1.04E-07	NT	27	8.8E-09	1.7E-08
11	9.94E-08	3.9E-07	28	6.41E-08	1.38E-07
13	2.33E-08	1.06E-08	29	7.1E-09	1.8E-09
14	1.15E-07	NT	30	2.84E-08	9.1E-09
15	2.86E-07	NT	31	9.15E-09	5.45E-09
16	2.32E-07	NT	32	4.6E-09	NT
17	1.16E-07	NT	33	7.77E-09	2.55E-09

- 137-

Example	Ki (M) USP7 FLINT	IC₅o (M) MTT	Example	Ki (M) USP7 FLINT	IC₅₀ (M) MTT
34	3.58E-09	1.1E-08	66	6.5E-09	4.5E-09
35	1.13E-08	5.0E-09	67	1.4E-08	2.78E-08
36	1.51E-08	8.93E-09	68	4.0E-09	6.67E-09
37	1.36E-08	6.66E-09	69	1.81E-08	2.17E-08
38	1.4E-08	1.1E-08	70	6.3E-08	3.4E-08
39	8.2E-09	1.3E-08	71	1.12E-07	NT
40	4.19E-09	1.7E-09	72	2.35E-07	NT
41	6.7E-09	2.5E-09	73	3.26E-07	NT
42	4.1E-09	3.66E-09	74	7.8E-08	7.0E-08
43	6.42E-09	1.2E-09	75	3.9E-08	4.3E-08
44	1.81E-08	7.4E-09	76	1.7E-08	2.2E-08
45	3.6E-09	1.4E-09	77	3.7E-08	1.3E-08
46	2.9E-09	3.1E-09	78	5.8E-08	1.5E-08
47	2.2E-09	9.2E-10	79	1.21E-07	NT
48	5.2E-09	3.0E-09	80	1.9E-08	6.2E-09
49	2.49E-08	3.1E-08	81	4.4E-08	5.1E-09
50	7.89E-09	6.17E-09	82	1.6E-08	NT
51	2.6E-09	1.4E-09	83	4.2E-08	8.5E-09
52	1.3E-08	5.4E-09	84	2.1E-08	1.8E-08
53	6.6E-09	3.4E-09	85	9.9E-09	3.4E-08
54	1.3E-08	9.1E-09	86	5.8E-08	8.38E-07
55	1.5E-08	1.2E-08	87	8.8E-08	4.5E-08
56	1.6E-08	4.2E-08	88	1.87E-07	NT
57	5.1E-09	NT	89	2.0E-08	2.6E-08
58	6.51E-09	NT	90	3.45E-07	NT
59	3.58E-08	4.11E-08	91	1.3E-08	7.6E-08
60	7.59E-08	1.28E-07	92	4.9E-09	4.57E-08
61	7.9E-09	1.7E-08	93	5.1E-08	8.64E-08
62	1.4E-08	1.4E-08	94	3.0E-08	4.9E-08
63	1.24E-08	1.63E-08	95	2.1E-08	2.7E-08
64	6.4E-09	8.39E-09	96	7.21E-09	2.73E-08
65	4.2E-09	1 7.66E-09	97	9.8E-09	4.27E-08

- 138-

Example	Ki (M) USP7 FLINT	IC₅₀ (M) MTT	Example	Ki (M) USP7 FLINT	IC₅₀ (M) MTT
98	3.05E-09	7.0E-09	130	1.83E-09	7.5E-09
99	5.6E-08	1.2E-07	131	6.4E-11	5.3E-09
100	2.4E-08	4.76E-08	132	3.54E-08	4.78E-08
101	1.1E-08	2.53E-08	133	1.52E-09	9.8E-09
102	4.1E-09	9.31E-09	134	3.7E-09	1.7E-08
103	6.4E-09	6.63E-09	135	2.06E-07	NT
104	1.5E-08	3.72E-08	137	2.26E-07	NT
105	2.6E-09	5.08E-09	138	4.5E-08	2.4E-08
106	1.5E-08	1.86E-08	139	1.9E-08	2.46E-08
107	3.3E-09	7.64E-09	140	1.2E-08	2.0E-08
108	6.3E-08	5.0E-08	143	4.2E-08	2.17E-07
109	6.5E-08	1.1E-08	144	2.2E-08	8.02E-08
110	1.82E-07	NT	147	1.9E-08	4.87E-08
111	3.12E-07	NT	148	7.5E-09	3.99E-08
112	2.03E-07	NT	149	1.4E-08	2.41E-08
113	3.06E-08	NT	150	2.19E-08	NT
114	6.6E-08	2.2E-08	151	2.14E-07	NT
115	4.18E-07	NT	152	8.2E-08	2.02E-07
116	8.0E-09	NT	153	2.87E-08	6.2E-08
117	2.86E-08	2.76E-08	154	7.8E-09	1.14E-08
118	1.23E-07	NT	155	9.7E-08	5.88E-07
119	1.53E-09	4.3E-09	156	1.4E-07	NT
120	4.54E-08	4.13E-08	157	4.83E-09	5.18E-09
121	4.68E-09	6.4E-09	158	1.07E-08	5.24E-09
122	1.36E-08	2.3E-08	159	2.22E-08	8.18E-09
123	6.92E-09	4.32E-08	160	1.69E-08	6.47E-09
124	1.2E-08	3.15E-08	161	1.01E-08	3.63E-09
125	7.98E-09	2.66E-08	162	1.27E-08	3.72E-09
126	4.44E-09	2.95E-08	163	9.76E-09	1.41E-09
127	5.93E-09	2.04E-08	164	6.48E-09/5.16E-09	1.83E-09
128	3.86E-08	7.5E-08	165	9.33E-09	2.74E-09
129	2.87E-09	5.2E-09	168	3.85E-08	1.38E-08

- 139-

Example	Ki (M) USP7 FLINT	IC50 (M) MTT	Example	Ki (M) USP7 FLINT	IC50 (M) MTT
169	3.47E-09	1.66E-08	201	2.39E-08	7.51E-09
170	7.85E-08	NT	202	2.18E-08	1.17E-08
171	4.28E-08	3.14E-08	203	4.71E-08	3.3E-08
172	7.64E-09	3.85E-07	204	3.65E-08	2.69E-08
175	8.12E-08	2.65E-08	205	3.58E-08	2.35E-08
176	3.2E-09	1.52E-09	206	3.72E-08	2.05E-08
177	9.99E-09	2.32E-09	207	2.74E-08	1.18E-08
178	7.01E-08	3.18E-08	210	2.15E-10	1.85E-09
179	5.58E-09	1.34E-09	211	2.77E-08	2.49E-08
182	4.04E-08	9.95E-09	212	3.41E-08	2.14E-08
183	3.7E-08	9.5E-09	213	3.64E-08	1.56E-08
184	7.28E-09	3.96E-09	214	4.83E-08	3.13E-08
185	1.3E-08	7.65E-09	215	5.41E-08	2.46E-08
188	6.99E-08	6.9E-08	216	2.57E-08	1.91E-08
189	1.11E-08	6.34E-09	217	4.26E-08	2.31E-08
190	1.24E-08	6.82E-09	218	3.01E-08	1.15E-08
191	1.77E-08	2.01E-08	219	3.03E-08	2.34E-08
192	8.8E-09	8.48E-09	220	9.82E-08	NT
197	1.4E-08	9.7E-09	221	3.55E-08	1.02E-08
198	1.07E-08	3.14E-09	222	5.58E-10	7.42E-08
199	9.23E-09	3.41E-08	223	4.2E-09	7.32E-08
200	3.0E-08	1.06E-07

NT: not tested

- 140EXAMPLE C: Pharmaceutical composition: Tablets

1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 231 5 g

Wheat starch.....................................................................................................................20g

Maize starch......................................................................................................................20g

Lactose..............................................................................................................................30g

Magnésium stéarate............................................................................................................2g

Silica...................................................................................................................................1g

Hydroxypropylcellulose.....................................................................................................2g

Claims

1. Compound of formula (I):

wherein:

♦ Q represents an oxygen atom or a sulphur atom, ♦ Ri represents a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, ♦ R2 represents an aryl group or a heteroaryl group, ♦ R3 represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched halo(Ci-C6)alkyl, a linear or branched hydroxy(Ci-C6)alkyl group, a -C(O)-R8 group, a -C(O)-ORs group, a -C(O)-NH-Rs group, or a /Y Y ^P’ ♦ R4 represents a hydrogen atom or a halogen atom, ♦ R5 represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched halo(Ci-Cô)alkyl group, or an aryl(Ci-C6)alkyl group, ♦ n is an integer equal to 0, 1 or 2, ♦ J represents a -C(O)- group, a -CH(Re)- group, a -SO2- group, a -C(X)-N(R?)O group, a -CH₂-C(O)-N(R₇)- group, or a \ Y group, ♦ Rô represents a hydrogen atom, a linear or branched (Ci-C6)alkyl group, or a -C(O)-ORs group, ♦ R7 represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group,

- 142 - ♦ Rs represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, or a linear or branched halo(Ci-C6)alkyl group, ♦ K represents a bond or a -Cyi- group, ♦ L represents a linear or branched (Ci-Côjalkyl group, a -Cy2 group or a -C(R9)2-Cy2 group, ♦ X represents an oxygen atom or a sulphur atom, ♦ R9 represents a hydrogen atom or a halogen atom, ♦ Cyi represents a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, which is linked to the group J and to the group L, ♦ Cy2 represents a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, it being understood that:

- “aryl” means a phenyl, naphthyl, or indanyl group,

- “heteroaryl” means any mono- or fused bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,

- “heterocycloalkyl” means any non-aromatic mono- or fused bi-cyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined to be substituted by from 1 to 4 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched (C2-C6)alkenyl, linear or branched (C2-Cô)alkynyl, linear or branched halo(Ci-C6)alkyl, -Yi-OR’, -Yi-NR’R”, -Yi-S(O)_m-R’, oxo, V-oxide (where appropriate), pentafluorosulfide, nitro, -Υι-CN, -C(O)-R’, -C(O)-OR’, -O-C(O)-R’, -Yi-C(O)-NR’R”, -Yi-NR’-C(O)-R”, -Yi-NR’-C(O)-OR”, halogen, cyclopropyl and pyridinyl which can be substituted by a linear or branched (Ci-C6)alkyl group,

- 143 - it being understood that:

- R’ and R” independently of one another, represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C2-Cé)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-Cô)alkoxy group, a linear or branched halo(Ci-C6)alkyl, a linear or branched hydroxy(Ci-C6)alkyl group, a linear or branched (Ci-C6)alkoxy(Ci-C6)alkyl group, a formyl group, a phenyl group, a benzyl group, a cyclopropyl group, a cyclopropylmethyl group, a tetrahydropyranyl group, or the pair (R’, R”) together with the nitrogen atom to which they are attached forms a non-aromatic ring composed of from 4 to 7 ring members, which may contain in addition to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by from 1 to 2 groups representing a hydrogen atom, or a linear or branched (Ci-Côjalkyl group,

- m is an integer equal to 0, 1 and 2, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

2. Compound according to claim 1, wherein Q represents an oxygen atom.

3. Compound according to claim 1, wherein Ri represents an aryl group or a heteroaryl group.

4. Compound according to claim 3, wherein Ri represents a phenyl group or a pyridinyl group.

5 to yield the compound of formula (X):

wherein R₂, R3, R4 and n are as defined hereinbefore, compound of formula (XI) which is further subjected to coupling with compound of formula (VI):

(VI) wherein Ri, R5 and Q are as defined for formula (I),

- 159to yield the compound of formula (I), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharrnaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

5 séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of

5 compound of formula (IV) which is further converted to an epoxide compound of formula (V):

(V) wherein R₂, R4, n and PG are as defined hereinbefore, compound of formula (V) which is further subjected to coupling with compound of

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[(4S)-l-[(3R,4R)-l-(3,5dichlorobenzoyl)-3-phenyl-piperidine-4-carbonyl]-3,3-difluoro-4-hydroxy-4piperidyl]methyl]pyrimidin-4-one.

- 5-amino-6-(4-chlorophenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(5methylpyrazin-2-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

- 5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyrimidin-4ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[4-methyl-2-(6-methyl-3-pyridyl)thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(6-methyIpyrazin-2yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(420308

- 154- fluorophenoxy)pyrim id in-4-one ;

5-amino-3-[[(4S)-3,3-difluoiO-4-hydroxy-l-[(3R,4R)-3-phenyl-l-(pyrazin-2ylmethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

- 5-amino-3-[[(4S)-l-[(3R,4R)-l-[2-(3,3-difluorocyclobutyl)-4-methyl-thiazole-5carbonyl]-3-phenyl-piperidine-4-carbonyl]-3,3-difluoro-4-hydroxy-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

- 5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[4-rnethyl-2-[6-methyl-5(trifluoromethy l)-3-pyridy l]thiazole-5 -carbony 1] -3 -phenyl-piperidine-4-carbony 1] 4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

5-amino-6-(4-chloro-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[(5-methylpyrazin-2-yl)inethyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

5-amino-6-(4-chloro-3-methoxy-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[(2-methylpyrimidin-4-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-3-phenyl-l-[(2phenylpyrimidin-4-yl)methyl]piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

- 153 -

-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyI]-4-piperidyl]rnethyl]6-(4-fluoro-3-methoxy-phenoxy)pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[[2-(6-methyl-3pyridyl)pyrimidin-4-yl]methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6-methyl-3-pyridyl)thiazole-5carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(3pyridyloxy)pyrimidin-4-one;

5-amino-6-(4-chiorophenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(2methylpyrirnidin-4-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

5-amino-3-[[l-[(3R,4R)-l-(2-cyclobutyl-4-methyl-thiazole-5-carbonyl)-3-phenylpiperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[[6-(6-methyl-3pyridyl)pyrimidin-4-yl]methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[l-[(3R,4R)-l-(3-chloro-5-methyl-benzoyl)-3-phenyI-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one; 5-amino-6-(4-fluorophenoxy)-3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l-(5-pyrrol-lylpyridine-3-carbonyl)piperidine-4-carbonyl]-4-piperidyl]meÎhyl]pyrimidin-4-one;

5-amino-3-[[l-[(3R,4R)-l-(2-cyclopentyl-4-methyl-thiazole-5-carbonyl)-3-phenylpiperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[(4S)-l-[(3R,4R)-l-[(2-chloropyrimidin-4-yl)rnethyl]-3-phenylpiperidine-4-carbonyl]-3,3-difluoro-4-hydroxy-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[l-[(3R,4R)-l-(2-cyclohexyl-4-methyl-thiazole-5-carbonyl)-3-phenylpiperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(420308

- 152- fluorophenoxy)pyrim idin-4-one;

- 5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-(5-methylpyridine-3carbonyl)-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4fluorophenoxy)pyrimidin-4-one;

- 5-amino-3-[[(4S)-3,3-difluoro-4-hydroxy-l-[(3R,4R)-l-[(5-methylpyrazin-2yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-6-(4-fluoro-3methoxy-phenoxy)pyrimidin-4-one;

- 5 -amino-6-(4-fluorophenoxy)-3- [ [ 1 - [(3R,4R)-1 -(5-fluoropyridine-3 -carbonyl)-3 phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]pyrimidin-4-one; 5-amino-6-(4-chloro-3-fluoro-phenoxy)-3-[[(4S)-3,3-difluoro-4-hydroxy-l[(3R,4R)-l-[(5-methyIpyrazin-2-yl)methyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

- 5-amino-3-[[l-[(3R,4R)-l-(5-chloropyridine-3-carbonyl)-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

5-amino-6-[4-(aminomethyl)phenoxy]-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-(6methyl-3-pyridyl)thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]pyrimidin-4-one;

5-amino-3-[[l-[(3R,4R)-l-(3,5-dichlorobenzoyl)-3-phenyl-piperidine-4-carbonyl]4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[l-[(3R,4R)-l-(3,5-difluorobenzoyl)-3-phenyl-piperidine-4-carbonyl]4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

5-amino-3-[[l-[(3R,4R)-l-[2-[6-(dimethylamino)-3-pyridyl]-4-rnethyl-thiazole-5carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-[3(trifluoromethyl)phenoxy]pyrimidin-4-one;

5-amino-3-[[4-hydroxy-l-[(3R,4R)-l-[4-methyl-2-[6-(trifluoromethyl)-3pyridyI]thiazole-5-carbonyl]-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]6-[3-(trifluoromethyl)phenoxy]pyrimidin-4-one;

- 5-amino-3-[(l-{(3R,4R)-l-[3-fluoro-5-(6-methylpyridin-3-yl)benzoyl]-3phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-6-(4fl uorophenoxy)py rim i d i n -4(3 H)-one ;

5-amino-3-{[(45)-3,3-difluoro-4-hydroxy-l-{(37?,47?)-l-[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl]methyl}-6-phenoxypyrimidin-4(3//)-one;

5 -amino-3-[( 1 - {(3R, 4R)-1 - [5 -chloro-3-fluoro-4-(6-methy lpyridin-3 -yl)thiophene-2carbonyl]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-6-(4fluorophenoxyjpyrimidinAp/Tj-one;

5-amino-3-{ [(45)-3,3-difluoro-l-{(3R,47?)-l-[3-fluoro-5-(6-methylpyridin-3yl)thiophene-2-carbonyl]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4yl]methyl}-6-(4-fluorophenoxy)pyrimidin-4(3//)-one;

5-amino-3 -( {(45)-3,3 -difluoro-4-hydroxy-1 - [(3 RAR)-1 - {4-methy 1-2- [6(trifluoromethyl)pyridin-3-yl]-l,3-thiazole-5-carbonyl}-3-phenylpiperidine-4carbonyl]piperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3/7)-one;

- 5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(3À,4À)-l-(isoquinoline-5carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin-4(3/7)one;

5-amino-3-({l-[(3R,4À)-l-(3-bromo-5-fluorobenzoyl)-3-phenylpiperidine-4carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3/?)one;

- 5-amino-3-({l-[(37?,47?)-l-(2,6-dimethylpyridine-4-carbonyl)-3-phenylpiperidine4-carbonyl] -4-hydroxypiperidin-4-y 1} methy l)-6-(4-fluorophenoxy)pyrim id in4(377)-one;

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3R,4R)-l-[l-methyl-2-(6methy lpyridin-3 -y 1)-1 Æ-im idazole-5 -carbony 1] -3 -pheny Ipiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(327)-one;

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-l-[(37?,4À)-l-(5-methylpyridine-3carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin-4(3/7)one;

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3À,4R)-l-[7-(6-methylpyridin-3yl)-2,3-dihydrothieno[3,4-/>][l,4]dioxine-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3//)-one;

- (3R,47?)-4-(4-{[5-amino-4-(4-fluorophenoxy)-6-oxopyrimidin-l(677)-yl]methyl}-4hydroxypiperidine-l-carbonyl)-?/-(4-methoxyphenyl)-3-phenylpiperidine-lcarboxamide;

- (3R,4R)-4-(4-{[5 -am ino-4-(4-fluorophenoxy)-6-oxopyrimidin-1 (677)-y 1] methyl} -4hydroxypiperidine-l-carbonyl)-3-phenyl-7V-[3-(trifluoromethyl)phenyl]piperidine1-carboxamide;

(3R,4R)-4-(4- {[5 -amino-4-(4-fluorophenoxy)-6-oxopyrim idin-1 (6//)-yl] methyl} -4hydroxypiperidine-1 -carbony l)-A-(3-bromophenyl)-3-phenylpiperidine-1 carboxamide;

(3R,4R)-4-[4-[[5-amino-4-(4-fluorophenoxy)-6-oxo-pyrimidin-l-yl]methyl]-4hydroxy-piperidine-l-carbonyl]-N-[3-(6-methyl-3-pyridyl)phenyl]-3-phenylpiperidine-1 -carboxamide;

- 150-

5-amino-6-(4-fluorophenoxy)-3-({4-hydroxy-1 -[(37ζ4Λ)-1 -(4-methyl-2-phenyl-1,3thiazole-5-carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4yl} methy l)pyrimidin-4(3/f)-one;

- 5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-1 - {(3R,4R)-1 -[4-methyl-2-(pyrrolidin1 -y 1)-1,3 -thiazole-5 -carbony 1] -3-phenylpiperidine-4-carbonyl} piperid in-4yl)methyl]pyrimidin-4(327)-one;

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(3À,47?)-l-[4-methyl-2(morpholin-4-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3//)-one;

5-amino-6-(4-fluorophenoxy)-3 - [(4-hydroxy-1 - {(3R,4R)-3 -phenyl-1 - [(pyridin-3 yl)methyl]piperidine-4-carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3/7)-one;

5 -amino-3 -( {1 - [(3R,47?)-1 -(2-benzy 1-4-methy I-1,3 -thiazole-5 -carbony l)-3 phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(3/7)-one;

5-amino-3-( {1 - [(3À,4À)-1-(3-ethoxybenzoy 1)-3-pheny lpiperidine-4-carbonyl]-4hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3//)-one;

5-amino-3-{[(45)-3,3-difluoro-l-{(35,45)-l-[(2-fluorophenyl)methyl]-3phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl]methyl}-6-(420308

- 149- fluorophenoxy)pyrimidin-4(377)-one;

5-amino-3-({(45)-3,3-difluoro-4-hydroxy-l-[(35, 45)-1 -{[2-(6-methylpyridin-3-yl)l,3-thiazol-5-yl]methyl}-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)-6(4-fluorophenoxy)pyrimidin-4(3/7)-one;

5-amino-6-(4-fluorophenoxy)-3-[(l-{(35,45)-1-[(2-fluorophenyl)methyl]-3phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]pyrimidin-4(3//)one;

5-amino-6-(4-fluorophenoxy)-3-( {4-hydroxy-1 - [(35,45)-1 - {[2-(6-methy lpyridin-3yl)-l,3-thiazol-5-yl]methyl}-3-phenylpiperidine-4-carbonyl]piperidin-4yl}methyl)pyrimidin-4(377)-one;

5-amino-3-[[l-[(3R,4R)-l-[(2-bromothiazol-5-yl)methyl]-3-phenyl-piperidine-4carbonyl]-4-hydroxy-4-piperidyl]methyl]-6-(4-fluorophenoxy)pyrimidin-4-one;

5-amino-6-(4-fluorophenoxy)-3-[(l-{(35,45)-l-[2-(4-fluorophenyI)-4-methyl-l,3thiazole-5-carbonyl]-3-phenyIpiperidine-4-carbonyl}-4-hydroxypiperidin-4yl)methyl]pyrimidin-4(377)-one;

5-amino-6-(4-fluorophenoxy)-3-[(4-hydroxy-l-{(35,45)-1-[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl} piperidin-4-yl)methyl]pyrimidin-4(327)-one;

5-amino-3-[(4-hydroxy-1 -{(3R,4R)-1 -[4-methyl-2-(6-methylpyridin-3-yl)-1,3thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}piperidin-4-yl)methyl]-6phenoxypyrimidinMQÀQ-one;

5-amino-3-{ [(45)-3,3-difluoro-4-hydroxy- 1-{(35,45)-1 -[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyI]-3-phenylpiperidine-4carbonyl}piperidin-4-yl]methyl}-6-(4-fluorophenoxy)pyrimidin-4(3Z/)-one;

5-amino-3-{ [(45)-3,3-difluoro-l-{(3R,4R)-1 -[2-(4-fluorophenyl)-4-methyl-1,3thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4yl]methyl}-6-(4-fluorophenoxy)pyrimidin-4(3//)-one;

5-amino-3-({l-[(35,45)-l-{2-[6-(dirnethylamino)pyridin-3-yl]-4-rnethyl-l,3thiazole-5-carbonyl}-3-phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3//)-one;

5 -am ino-6-(4-fluorophenoxy)-3-( { 4-hydroxy-1 - [(3R,4R)-1 - {4-methy l-2-[6(trifluoromethyl)pyridin-3-yl]-l,3-thiazole-5-carbonyl}-3-phenyIpiperidine-420308

- 148 - carbonyl]piperidin-4-yl}methyl)pyrimidin-4(3/7)-one;

- 5-amino-3-({(4S)-l-[(3R,4À)-l-(2-bromo-4-methyl-l,3-thiazole-5-carbonyl)-3phenylpiperidine-4-carbonyl]-3,3-difluoro-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(3/7)-one;

- 5-amino-3-[(l-{(3À,4R)-l-[3-fluoro-5-(6-methylpyridin-3-yl)thiophene-2carbonyl]-3-phenylpiperidine-4-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-6-(4fluorophenoxy)pyrimidin-4(377)-one;

- 5-amino-3 -( {1 - [(3Λ,4Λ)-1 -(3 -fluoro-5 -iodothiophene-2-carbony l)-3 - phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(317)-one;

- 5-amino-3-({l-[(3R,4R)-l-benzoyl-3-phenylpiperidine-4-carbonyl]-4hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3/7)-one; 5-amino-6-(4-fluorophenoxy)-3-( { 4-hydroxy-1 - [(3À,47?)-1 -( 1 -methy 1-1 /Z-indole-2carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin-4(3//)one;

5-am ino-6-(4-fluorophenoxy)-3-( { 4-hydroxy-1 - [(3R,4À)-3 -phenyl-1 -(5phenylpyridine-3-carbonyl)piperidine-4-carbonyl]piperidin-4-yl}methyl)pyrimidin4(377)-one;

5-am ino-6-(4-fluorophenoxy)-3-( {4-hydroxy-1 - [(3R,4R)-1 -(6'-methy 1 [3,3 ' bipyridine]-5-carbonyl)-3-phenylpiperidine-4-carbonyl]piperidin-4yl}methyl)pyrimidin-4(3//)-one;

- 5-amino-3-({l-[(3À,4À)-l-(5-bromopyridine-3-carbonyl)-3-phenylpiperidine-4carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3/7)one;

- 5-amino-3-({l-[(3À,4Æ)-l-(3-bromobenzoyl)-3-phenylpiperidine-4-carbonyl]-4hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(377)-one;

- 5 -amino-3 -( {1 - [(3À,47?)-1 -(benzenesulfonyl)-3 -pheny lpiperidine-4-carbony 1] -4- hydroxypiperidin-4-yl}methyl)-6-(4-fluorophenoxy)pyrimidin-4(3/0-one;

- 5 -am ino-3 -( {1 -[(3 R,4R)-1 -(2-bromo-4-methy I-1,3 -thiazole-5-carbony l)-3 - phenylpiperidine-4-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-6-(4fluorophenoxy)pyrimidin-4(3/7)-one;

- 5 -amino-3 - [(4-hydroxy-1 - {(3R,4R)-1 -[4-methy l-2-(6-methy lpyridin-3-y 1)-1,3- thiazole-5-carbonyl]-3-phenylpiperidine-4-carbonyl}piperidin-4-yl)methyl]-6-[3(trifluoromethoxy)phenoxy]pyrimidin-4(3/?)-one;

- 147-

- 5-amino-3-[(4-hydroxy-l-{(3Æ,4Æ)-l-[4-methyl-2-(6-methylpyridin-3-yl)-l,3thiazole-5 -carbony 1] -3 -pheny lpiperidine-4-carbony 1} piperidin-4-y l)methy l]-6-[3 (trifluoromethyl)phenoxy]pyrimidin-4(3/7)-one;

5-amino-6-(4-fluoro-3-methoxyphenoxy)-3-[(4-hydroxy-l-{(37?,4.Æ)-l-[4-methyl-2(6-methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl} piperidin-4-y l)methyl]pyrimidin-4(377)-one;

5-amino-6-(4-chloro-3-fluorophenoxy)-3-[(4-hydroxy-l-{(3.Æ,42?)-l-[4-methyl-2(6-methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3H)-one;

5-amino-6-(3-chloro-5-methoxyphenoxy)-3-[(4-hydroxy-l-{(3À,47?)-l-[4-methyl2-(6-methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(3f7)-°^ne;

5-amino-6-(4-chlorophenoxy)-3-[(4-hydroxy-1 - {(3Λ,4Λ)-1 -[4-methyl-2-(6methylpyridin-3-yl)-l,3-thiazole-5-carbonyl]-3-phenylpiperidine-4carbonyl}piperidin-4-yl)methyl]pyrimidin-4(37y)-one;

- 5-amino-3-{ [(45)-3,3-difluoro-4-hydroxy-l-{(3Æ, 4À)-l-[(2-methylpyrimidin-4- yl)methyl]-3-phenylpiperidine-4-carbonyl}piperidin-4-yl]methyl}-6-(4fluorophenoxy)pyrimidin-4(37/)-one;

5. Compound according to claim 1, wherein R2 represents an aryl group.

6-[(3À,4R)-4-(4-{[5-amino-4-(4-fluorophenoxy)-6-oxopyrimidin-l(677)yl]methyl}-4-hydroxypiperidine-l-carbonyl)-3-phenylpiperidine-l-carbonyl]-320308

- 151 - methylquinazolin-4(377)-one;

6. Compound according to claim 5, wherein R2 represents a phenyl group.

7. Compounds according to claim 1, wherein R3 represents a hydrogen atom, a linear or

- 144branched hydroxy(Ci-C6)alkyl, a -C(O)-OR₈ group, a -C(O)-NH-R₈ group, or a

L Y group.

8.

9.

10 the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

10 formula (I-b):

wherein Ri, R₂, R4, R5, Q and n are as defined hereinbefore and R3’ represents a linear or branched (Ci-Ce)alkyl group, a linear or branched halo(Ci-C6)alkyI, a linear or

- 157 branched hydroxy(Ci-C6)alkyl group, a -C(O)-R₈ group, a -C(O)-OR₈ group, a a -C(0)-NH-R₈ group, or a

group, compound of formula (I-a) and compound of formula (I-b), which constitute the totality of compounds of formula (I), may then be purified according to a conventional

10 formula (VI):

- 156-

wherein Ri, R₂, R4, R5, Q, n and PG are as defined hereinbefore, (VII) compound of formula (VII) which is subjected to a reaction removing the protecting group PG, to yield compound of formula (I-a), a particular case of compound of formula 5 (I):

wherein Ri, R₂, R4, R5, Q and n are as defined hereinbefore, compound a formula (I-a), a particular case of compound of formula (I), which is further subjected to substitution reaction on piperidine’s nitrogen to yield the compound of

10.

11.

Compounds according to

L V group.

claim 7, wherein R₃ represents a

Compound according to claim 1, wherein R₄ represents a hydrogen atom or a fluorine atom.

Compound according to claim 1, wherein Rs represents a hydrogen atom.

Compound according to claim 1, wherein J represents a -C(O)- group, a -CH2- group, a -CH[C(O)-O-CH₂-CH₃]- group, a -SO₂- group, a -CH₂-C(O)-N(R₇)- group a -C(X)-N(R₇)- group, or a

group.

12.

13.

14.

Compound according to claim 11, wherein J represents a -C(O)- group, a -CH₂- group, a -SO2- group, or a -C(O)-NH- group.

Compound according to claim 1, wherein K represents a bond or a -Cyi- group selected from a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyrazolyl group, a pyridinyl group, a pyrimidinyl group, a dihydrothienodioxinyl group, a cyclopropyl group, or a cyclobutyl group.

Compound according to claim 1, wherein L represents a linear or branched (Ci-Cô)alkyl group, a -Cy₂ group, a -CH₂-Cy2 group, or a -CF2-Cy₂ group.

15 wherein Rz is as defined for formula (I), and PG represents a protecting group of the carboxylic acid function, which is subjected to substitution reaction on piperidine’s nitrogen to yield the compound of formula (IX):

(ix)

- 158 wherein R₂ and R3 are as defined for formula (I), and PG represents a protecting group of the carboxylic acid function, compound of formula (IX) which, after a reaction removing the protecting group PG, is further subjected to coupling with a compound of formula (II),

15. Compound according to claim 1, wherein Cy2 represents a cycloalkyl group, a

- 145 heterocycloalkyl group, an aryl group or a heteroaryl group which are substituted by 1, 2 or 3 groups selected from linear or branched (C i -Côjalkyl, linear or branched halo(Ci-C6)alkyl, -Yi-OR’, -Yi-NR’R”, oxo, halogen, in which R’ and R” independently of one another represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, or the pair (R’, R”) together with the nitrogen atom to which they are attached forms a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen a second heteroatom selected from oxygen and nitrogen, it being understood that the second nitrogen in question may be substituted by a linear or branched (Ci-Cô)alkyl group.

16. Compound according to claim 14 or claim 15, wherein Cy2 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a piperidinyl group, a tetrahydropyranyl group, a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, a dihydroindolyl group, a isoquinolinyl group, a dihydrothienodioxinyl group, a benzothiazolyl group, or a quinazolinonyl group.

17. Compound according to claim 1, wherein K represents a phenyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyrazolyl group, a pyridinyl group, a pyrimidinyl group, a dihydrothienodioxinyl group, a cyclopropyl group, or a cyclobutyl group and L represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a piperidinyl group, a tetrahydropyranyl group, a phenyl group, a benzyl group, a pyrrolyl group, a thienyl group, or a pyridinyl group.

18. Compound according to claim 1, wherein K represents a bond and L represents a phenyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, a dihydroindolyl group, a isoquinolinyl group, a dihydrothienodioxinyl group, a benzothiazolyl group, or a quinazolinonyl group.

19. Compounds according to claim 1, which is compound of formula (I-a):

- 146-

wherein Ri, R4, J, K, L and n are as defined for claim 1.

20. Compounds according to claim 1, which are:

21. Process for the préparation of a compound of formula (I) according to claim 1, characterized in that there is used as starting material the compound of formula (II):

wherein R4 and n are as defined for formula (I), which is subjected to coupling with a compound of formula (III):

(III) wherein R2 is as defined for formula (I), and PG represents a protecting group of the

- 155 amine function, to yield the compound of formula (IV):

wherein R₂, R4, n and PG are as defined hereinbefore,

22. Process for the préparation of a compound of formula (I) according to claim 1, characterized in that there is used as starting material the compound of formula (VIII):

(VIII)

23. Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20 or an addition sait thereof with a pharrnaceutically acceptable acid or base in combination with one or more pharrnaceutically acceptable excipients.

24. Pharmaceutical composition according to claim 23 for use as pro-apoptotic and/or antiproliférative agents.

25. Pharmaceutical composition according to claim 24 for use in the treatment of cancers and of auto-immune and immune System diseases.

26. Pharmaceutical composition according to claim 25 for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukemia, cancer of the colon, esophagus and liver, lymphoblastic leukemia, acute myeloid leukemia, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

27. Compound of formula (I) according to any one of claims 1 to 20, or an addition sait thereof with a pharrnaceutically acceptable acid or base, for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukemia, cancer of the colon, esophagus and liver, lymphoblastic leukemia, acute myeloid leukemia, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, nonsmall-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

f

- 160-

28. Combination of a compound of formula (I) according to any one of claims 1 to 20 with anti-cancer agents selected from genotoxic agents, mitotic poisons, anti-metabolites, protéasome inhibitors, kinase inhibitors, protein-protein interaction inhibitors, immunomodulators, E3 ligase inhibitors, chimeric antigen receptor T-cell therapy and 5 antibodies.

29. Pharmaceutical composition comprising a combination according to claim 28 in combination with one or more pharmaceutically acceptable excipients.

30. Combination according to claim 28 for use in the treatment of cancers.

31. Compound of formula (I) according to any one of claims 1 to 20 for use in the treatment 10 of cancers requiring radiotherapy.