OA19084A

OA19084A - New piperidinyl derivatives, a process for their preparation and pharmaceutical compositions containing them.

Info

Publication number: OA19084A
Application number: OA1201800514
Authority: OA
Inventors: Didier DEMARLES; Olivier Geneste; Maïa CHANRION; James Brooke MURRAY; Csaba WÉBER; András Kotschy; Attila Vasas; Alba Macias; Elodie LEWKOWICZ; Balázs MOLNÁR; Árpád KISS
Original assignee: Les Laboratoires Servier; Vernalis (R&D) Limited
Priority date: 2016-06-10
Filing date: 2017-06-09
Publication date: 2020-01-20

Abstract

Compounds of formula (I) wherein R1, R2, R3, n and W are as defined in the description. Medicaments.

Description

NEW PIPERIDINYL DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new piperidinyl dérivatives, to a process for their préparation and to pharmaceutical compositions containing them.

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

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

Dysrégulation of DUBs hâve been associated with several diseases such as 15 neurodegeneratîve 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, el5891; Rolen et al., Mol. Carcinog. 2006, 45, 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 (Nicholson et al., Cell Biochem. Biophys. 2011, 60, 61-68). In addition, USP7 25 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. Sel. USA 2013, 110, 618-623). 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., Biochem. Soc. Trans. 2004, 32, 731-732).

i ·²' j . ,, ï USP7 overexpression has been associated with late stages of cancers and poor prognosis in l lung, neuroblastoma, myeloma, prostate, colon and breast cancers. Although some i inhibitors hâve been published in the literature, most of them were not sélective and, to ! date, no USP7 inhibitors hâve entered the clinic (Kemp et al., Progress in Médicinal i

i 5 Chemistry 2016, 55, 149-192). There is, therefore, a therapeutic need for compounds that i inhibit the activity of the protein USP7.

i j

In addition to being new, the compounds of the present 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 10 auto-immune diseases.

The present invention relates more especially to compounds of formula (1):

O R!

wherein:

♦ Ri represents an aryl group or a heteroaryl group, ♦ R2 represents a hydrogen atom or a halogen atom, ♦ R₃ represents a hydrogen atom, a lïnear or brànched (Ci-Ce)alkyl group, a linear or branched halo(Ci-Cé)alkyl, a -C(O)-Rs group, a -C(O)-ORg group, ♦ n is an integer equal to 0, 1 or 2,

W represents the group

R/

O

A

, wherein:

A represents a heteroaryl ring,

X represents a carbon atom or a nitrogen atom,

R₄ represents a hydrogen atom, a halogen atom, a linear or branched (Ci-Cg)alkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-Câ)alkynyl group, a -Yi-NRôR? group, a -Yi-ORô group, a linear or branched halo(Ci-C6)alkyl group, an oxo group, a -Yi-Cyi group, a -Cyi-R? group, a -Cyi-OR? group, or a -Yi-NR₆-C(O)-R7 group,

R₅ represents a hydrogen atom, a halogen atom, a linear or branched (Ci-Cô)alkyl group, a cyano group, or a -hydroxy(Ci-C6)alkyl group,

Râ represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, or a-Y2-Si[(Ci-C4)alkyl]3 group,

R? represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, or a -Y2-Cy₂ group,

Yi and Y₂ independently of one another represent a bond or a linear or branched (Ci-C4)alkylene group, ♦ Rs represents a hydrogen atom or a linear or branched (Ci-Cô)alkyl group, ♦ Cyi and Cy₂ independently of one another, represent 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,

- “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-C₆)alkenyl, linear or branched (C₂-Cô)alkynyl, linear or branched halo(Ci-C₆)alkyl, -Yi-OR’, -Yj-NR’R”, -Yi-S(O)_m-R’, oxo (or A-oxide where

-4appropriate), nitro, cyano, -C(O)-R’, -C(0)-0R’, -0-C(0)-R’, -C(O)-NR’R”, -Yi-NR’-C(O)-R”, -Yi-NR’-C(0)-0R”, halogen, cyclopropyl, and pyridinyl which can be substituted by a linear or branched (Ci-C6)alkyl group, it being understood that R’ and R” independently of one another represent a hydrogen atom, a linear or branched (Ci-Cé)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (Ci-Cô)alkoxy group, a linear or branched halo(Cî-C6)alkyl, a linear or branched hydroxy(Ci-Cé)alkyl group, a linear or branched (Ci-Câ)alkoxy(Ci-C6)alkyl group, a phenyl group, a cyclopropylmethyl group, a tetrahydropyranyl group, or the substituents of the pair (R’, R”) form together with the nitrogen atom carrying them 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 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, and it being understood that m is an integer equal to 0, 1 and 2, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochlorîc acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succînic acid, 20 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 hydroxîde, trîethylamine, tert-butylamine etc.

Among the heteroaryl groups there may be mentioned, without implying any limitation, 25 pyrrolyl, furyl, thîenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrldinonyl, indolyl, dihydroindolyl,

-5 dihydroisoindolyl, indazolyl, dihydrocyclopentathienyl, benzothienyl, tetrahydrobenzothienyl, benzofuranyl, imidazopyridinyl, benzotriazolyl, benzodioxolyl, dihydrobenzodioxinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, dihydroquinoxalinyl, dihydrothienodioxinyl, 5 quinazolinonyl, pyrrolopyridazinyl, 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.

In another embodiment of the invention, W advantageously represents the group

O

wherein R₄, R₅ and A are as defined for formula (I).

In another embodiment of the invention, W advantageously represents the group

Ri advantageously represents a phenyl group.

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

or

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

Preferabiy, R₂ represents a hydrogen atom.

In some preferred embodiment of the invention, R3 represents a hydrogen atom, a methyl group, a -CH₂-CH(CH3)₂ group, a -CH2-CF3 group, a -C(O)-CH3 group, a -C(O)-CH(CH3)2 group, a -C(O)-CH₂-C(CH₃)3 group, or a -C(O)-OC(CH₃)3 group.

In the preferred compounds of the invention, R4 represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C₂-Cé)alkenyl group, a linear or 10 branched (C₂-C6)alkynyl group, a -Yj-NRôR? group, a -Yi-ORô group, a linear or branched halo(Ci-C6)alkyl group, a -Yi-Cyt group, a -Cyi-R? group, or a -Cyi-OR? group.

Advantageously, Cyi represents a phenyl group, a naphthyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, a pyridinyl group, a pyrimidinyl group, a pyridinonyl group, a benzodioxolyl group, a dihydrobenzodioxinyl group, 15 a cyclopropyl group, a cyclobutyl group, or a piperidinyl group.

Advantageously, R5 represents a hydrogen atom, an iodine atom, a chlorine atom, a methyl group or a -CH2-OH group.

i 19084 !

i

-9In the preferred compounds of the invention, Rô represents a hydrogen atom, a methyl group, or a -(CH2)2-Si(CH3)3 group.

R? preferably represents a hydrogen atom, a methyl group, or a -CH2~Cy2 group. Preferably, Cy2 represents a phenyl group.

Among the preferred compounds of the invention there may be mentioned:

- ieri-buty! (3S,45)-4-({4-hydroxy-4-[(4-oxothieno[2,3-<7[pyrirnidin-3(42f)yl)methyl]piperidin-l-yl}carbonyl)-3-phenylpiperidine-l-carboxylate;

- tert-butyl (37?,4R)-4-[(4-hydroxy-4-{[4-oxo-7-(pyridin-2-yl)-4,7-dihydro-3/7pyrrolo[2,3-iZ]pyrimidin-3-yl]methyl}piperidin-l-yl)carbonyl]-3-phenylpiperidine-l-

IO carboxylate;

- teri-butyl (3À,4R)-4-[(4-hydroxy-4-{[7-(4-methoxyphenyl)-4-oxo-4,7-dihydro-377pyrrolo[2,3-7]pyrimidin-3-yl]methyI}piperidin-l-yl)carbonyl]-3-phenylpiperidine-lcarboxylate;

- Zeri-butyl (3R,47ï)-4-[(4-hydroxy-4-{[l-(4-methoxyphenyl)-4-oxo-l,4-dihydro-5ZZ- pyrazolo[3,4-t(|pyrimidin-5-yl]methyl}piperidin-l-yl)carbonyl]-3-phenylpiperidine-lcarboxylate;

- fôrt-butyl (3R,4IÏ)-4-[(4-{[7-(4-fluoro-3-methoxyphenyl)-4-oxo-4,7-dihydro-377pyrrolo[2,3-7]pyrimidin-3-yl]methyl}-4-hydroxypiperidin-l-yl)carbonyl]-3phenylpiperidine-1 -carboxylate;

- re/7-butyl (3R,4R)-4-[(4-{[l-(2,3-dihydro-l,4-benzodioxin-6-yl)-4-oxo-l,4-dihydro57/-pyrazolo[3,4-<7]pyrimid i n-5-y l]methyl}-4-hydroxypiperid in-1 -yl)carbony l]-3 phenylpiperidine-1-carboxylate;

- 3-[(4-hydroxy-l-{[(37?,4À)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]7-phenyl-3,7-dihydro-4/7-pyrrolo[2,3-7]pyrimidin-4-one;

- 5-[(4-hydroxy-l-{[(3Â,4J?)-3phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]1-phenyl-1,5-dihydro-4ff-pyrazolo[3,4-7]pyrimidin-4-one;

- 3-[(4-hydroxy-l-{[(3R,47î)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]7-(pyridin-2-yl)-3,7-dihydro-4/7-pyrrolo[2,3-<7]pyrimidin-4-one;

- 3-[(4-hydroxy-l-{[(3R,4Â)-3-phenyl-1-(2,2,2-trifluoroethyl)piperidin-4- yl]carbonyl}piperidin-4-yl)rnethyl]-3,7-dihydro-4//-pyrrolo[2,3-7]pyrimidin-4-one;

- 10. 3-[(4-hydroxy-l-{[(37?,47?)-l -methyl-3-phenylpiperidin-4-yl]carbonyl}piperidin-4yl)methyl]-7-phenyl-3,7-dîhydro-4Æ-pyrrolo[2,3-i7]pyrimidÎn-4-one;

- 7-(4-fluorophenyl)-3-[(4-hydroxy-l-{[(3À,47?)-3-phenylpiperidin-4yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4//-pyrrolo[2,3-(7|pyrimidin-4-one;

.3-[(4-hydroxy-l-{[(3À,47î)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]7-(4-methoxyphenyl)-3,7-dihydro-4//-pyrrolo[2,3-i/]pyrimidin-4-one;

. 3-[(4-hydroxy-l-{[(37?,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]7-(3-methoxyphenyl)-3,7-dihydro-4//-pyrrolo[2,3-i/]pyrimidin-4-one;

- 7-(4-fluorophenyl)-3-[(4-hydroxy-l-{[(3Æ,47î)-l-methyl-3-phenylpiperidin-4- yl]carbonyl}piperidin-4-yl)methyl]-3_}7-dihydro-477-pyrrolo[2,3-i(|pyriniidin-4-one;

- 7-(3-chlorophenyl)-3-[(4-hydroxy-l-{[(37ï,4_Jff)-3-phenylpiperidin-4yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4/f-pyrrolo[2,3-<7]pyrimidin-4-one;

. 7-(4-chlorophenyl)-3-[(4-hydroxy-l-{[(3/Ü,4R)-3-phenylpiperidin-4yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydiO-4.H-pyrrolo[2,3-<7]pyrimidin-4-one;

- 3-[(l-{[(3À,4À)-l-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4yl)methyl]-7-phenyl-3_s7-diliydro-4H-pyrrolo[2,3-<7|pyrimidin-4-one;

_ 3-[(4-hydroxy-l-{[(37ï,4/ï)-l-meÎhyl-3-phenylpiperidÎn-4-yl]carbonyl}piperidin-4yl)methyl]-7-(4-methoxyphenyl)-3,7-dihydro-4/Z-pyrrolo[2,3-<7|pyrimidin-4-one;

- 7<3-chlorophenyl)-3-[(4-hydroxy-l-{[(3Æ,4R)-l-methyl-3-phenylpiperidin-4- yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4/7-pyrrolo[2,3-ùQpyriniidin-4-one;

_ 7-(4-chlorophenyl)-3-[(4-hydroxy-l-{[(37ï,47î)-l-methyl-3-phenylpiperidin-4yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-427-pyrrolo[2,3-tZ]pyrimidin-4-one;

- 7-(4-fluoro-3-methoxyphenyl)-3-[(4-hydroxy-l-{[(37?,4À)-3-phenylpiperidin-4yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-477-pyrrolo[2,3-rf]pyrimidin-4-one;

- 3-[(4-hydroxy-l-{[(3À,47?)-l-(2-methylpropyl)-3-phenylpiperidin-4yl]carbonyl}piperidîn-4-yl)methyl]-7-phenyl-3,7-dihydro-47/-pyrrolo[2,3-i/]pyrimidin4-one; .

- l-(2,3-dihydro-l,4-benzodioxin-6-yl)-5-[(4-hydroxy-l-{[(3R,4Æ)-3-phenylpiperidin4-yl]carbonyl}piperidin-4-yl)methyl]-l,5-dihydro-4/7-pyrazolo[3_J4-<7]pyriniidin-4-one;

- 3-[(l-{[(3À,47î)-l-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypÎperidin-4yl)methyl]-7-(4-fluorophenyl)-3,7-dihydro-47ï-pyrrolo[2,3-i/]pyrimidin-4-one;

- (37î,47î)-4-[(4-hydroxy-4- {[ 1 -(4-methoxyphenyl)-4-oxo-1,4-d ihydro-5//pyrazolo[3,4-(/]pyrimidin-5-yl]methyl}piperidin-l-yl)carbonyl]-l,l-dimethyl-3phenylpiperidinium;

- 3-[(4-hydroxy-1 -{[(32?,47?)-1 -(2-methylpropanoyl)-3-pheny lpiperidin-4- yl]carbonyl}piperidin-4-yl)methyl]-7-phenyl-3.7-dihydro-4H-pyrrolo[2,3-i/]pyrimidin4-one;

3-[(l-{[(37?,4Â)-l-acetyI-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypîperidin-4yl)methyl]-7-(4-methoxyphenyl)-3,7-dihydro-4Æ-pyrrolo[2,3-ri]pyrimidin-4-one;

- 3-[( 1 - {[(3R,4R)-1 -acetyl-3-phenylpiperidin-4-yl]carbonyl} -4-hydroxypiperidin-4- yl)methyl]-7-(3-methoxyphenyl)“3,7-dihydro-42Z-pyrrolo[2,3-c(]pyrimidin-4-one;

- 3-[(l-{[(37Î,4À)-l-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4yl)methyl]-7-(3-chlorophenyl)-3,7-dihydro-4/7-pyrrolo[2,3-i/]pyrimidin-4-one;

- 3-[(l-{[(3À,4À)-l-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4yl)methyI]-7-(4-chlorophenyl)-3,7-dihydro-47ï-pyrrolo[2,3-<7]pyrimidin-4-one;

- 3-[( 1 -{[(3À,4À)-1 -(2,2-dimethy lpropanoyl)-3-phenylpiperidin-4-yl]carbony I }-4hydroxypiperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-4/f-pyrrolo[2,3-<7]pyrimidin-4one;

3-[(l-{[(3Æ_}4k)-l-(3,3-dimethylbutanoyl)-3-phenylpiperidin-4-yl]carbonyl}-4hydroxypiperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-477-pyrrolo[2,3-i(]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 R2 and n are as defined for formula (I), which is subjected to coupling with a compound of formula (III):

(ΙΠ) wherein Ri is as defined for formula (I), and Rj’ represents a -C(O)-ORs group wherein Rg is as defined for formula (I), to yield the compound of formula (IV):

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

O Ri wherein Rj, R2, R3’ and n are as defined hereinbefore, compound of formula (V) which is further subjected to coupling with compound of formula (VI):

(Vl) wherein W is as defined for formula (I), to yield the compound of formula (I-a), a particular case of the compounds of formula (I):

wherein Ri, R2, R₃’, n and W are as defined hereînbefore, which compound of formula (I/a) may then, if required, be subjected to a reaction removing the R3’ group, to yield the compound of formula (I-b), a particular case of the compounds of formula (I):

wherein Rj, R2, n and W are as defined hereînbefore, which compound of formula (I/b) may then, if required, be subjected to a coupling reaction with compound of formula R₃”-CI wherein R3” represents a linear or branched (Ci-Ce)alkyl group, a linear or branched halo(Ci-C6)alkyl, or a -C(O)-Rg group wherein Rs is as defined for formula (I), to yield the compound of formula (I-c), a particular case of the compounds of formula (I):

O Ri wherein Ri, R2, R3”, n and W are as defined hereinbefore, which compounds of formuiae (I/a) to (I/c), which constitute the totality ofthe compounds of formula (I), may then be purified according to a conventional séparation technique, 5 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 10 synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

The compounds of formuiae (II), (III), (VI) and R₃”-C1 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 diseases.

Among the cancer treatments envisaged there may be mentioned, without implying any 20 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.

I ο

- 15More especially, the compounds according to the invention will be useful în the treatment of chemo-, targeted therapy- or radio-resistant cancers.

The present invention relates also to pharmaceutical compositions comprising at least one compound of formula (I) in combination with one or more pharmaceutically acceptable 5 excipients.

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, 10 suppositories, créants, oîntments, 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 polyvînylpyrrolidone, ♦ as disintegrants: agar, alginic acid and its sodium sait, effervescent mixtures.

The 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 în one or more administrations.

Furthermore, the present invention relates also to the combination of a compound of 25 formula (I) with anti-cancer agents selected from genotoxic agents, mitotic poisons, antimetabolites, protéasome inhibitors, kinase inhibitors, protein-protein interaction inhibitors,

- 16immunomodulators, E3 ligase inhibitors, chimeric antigen receptor T-cell therapy and antibodies, and also to pharmaceutîcal compositions comprising that type of combination and their use in the manufacture of médicaments for use in the treatment of cancer.

The combination of a compound of formula (I) with an anticancer agent may be admînistered simultaneously or sequentially. The administration route is preferably the oral route, and the corresponding pharmaceutîcal compositions may allow the instantaneous or delayed release of the active ingrédients. The compounds of the combination may moreover be admînistered in the form of two separate pharmaceutîcal compositions, each containing one of the active ingrédients, or in the form of a single pharmaceutîcal 10 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

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 20 silica-gel cartridges (RediSep®Rf Gold High Performance).

Thin layer chromatography was conducted with 5 x 10 cm plates coated with Merck Type 60 F254 silica-gel.

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

- 17Preparative HPLC purifications were performed on an HANBON NP7000 Liquid Chromatography System with a Gemini-NX® 5μΜ 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 present 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 ionisation 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 ACN, or in 10 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, Cl8, 50 mm x 3.00 mm i.d. column at 23 °C, at a flow rate of 1 mL min¹ using 5 mM ammonium bicarbonate (Solvent A) and acetonitrile (Solvent B) with a gradient starting from 100 % Solvent A and finishing at 100 % 15 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 CDCh as solvent. ’H NMR data is in the form of delta values, given in part per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-dé and 7.26 ppm for CDCh) as internai standard. Splitting patterns are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet), 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).

- 18Combination gas chromatography and low resolution mass spectrometry were performed on Agilent 6850 gas chromatograph and Agilent 5975C mass spectrometer using 15 m χ 0.25 mm column with 0.25 μηι HP-5MS coating and hélium as carrier gas. Ion source: ΕΓ, 70 eV, 230 °C. quadrupole: 150 °C, interface: 300 °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.

List of abbreviations
	Abbreviation	Naine
10	abs.	absolute
	aq.	aqueous
	Ar	argon
	AtaPhos*PdC12	bis(di-ZerZ-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II)
15	Boc	ZerZ-butoxycarbonyl
	cc.	concentrated
	DCM	dichloromethane
	DEE	diethyl ether
	DIPO	diisopropyl oxide
20	disp.	dispersion
	DMEDA	;V..V-dÎmethylethylencdiaminc
	DMF	dimethylformamide
	EDC.HCI	A-(3-dimethylaminopropyl)-M-ethylcarbodiimide hydrochloride
25	EEO	ethyl ethanoate
	eq.	équivalent

iPr₂NH	isopropylamine
LC	liquid chromatography
LDA	lithium diisopropylamide
MeCN	acetonitrile
5 MSM	methy Isu 1 fi ny 1 methane
MTBE	Zert-butyl methylether
PDO	p-dioxane
Pd2(dba)3	tris(dibenzylideneacetone)dipalladium
r.t.	room température
10 sat.	saturated
TFA	trifluoroacetic acid
THF	tetrahydrofuran

General Procedure 1

Step 1:

To a stirred solution of 4-chloro-7H-pyrrolo[2,3-<7]pyrimidine (Préparation Rla; 1.84 g, mmol, 1 eq.) in abs. DMF (15 ml) sodium-hydride (720 mg, 60 % disp, in minerai oil, 18 mmol, 1.5 eq.) was added, and stirred for 10 minutes at r.t. under Ar. Alkylating agent (13.18 mmol) was added to the reaction mixture and stirred for 1-6 hours at r.t. The mixture was poured into water (150 ml), then it was extracted with EEO (3 x 150 ml). The combined organic layer was washed with water, brine, dried over MgSCU, and evaporated.

Step 2:

A part of this residue (1.36 mmol) and lithium-hydroxide monohydrate (571 mg, 13.62 mmol, 10 eq.) were stirred in PDO-water (40 ml, 1:1 v/v) mixture at 110 °C for 7-36 hours. The reaction mixture was neutralized with 1 N aq. HCl solution. The resulted 25 precipitate was filtered off, washed with water and dried.

General Procedure 2

-20Step 1 :

Préparation Rla (460 mg, 3 mmol, 1 eq.), heteroaryl/aryl-boronic acid (7.5 mmol) and copper(II)-acetate (817 mg, 4.5 mmol) were stirred in pyridine (10 ml) at 50-60 °C for

16-72 hours.

Work-up 1:

The mixture was evaporated to Celite, purified by flash chromatography (heptane-EEO, gradient).

Work-up 2:

The mixture was filtered, the resulted filtrate was purified by préparative LC (on C-18 10 Gemini-NX 5pm column, 5 mM aqueous NfLHCOa-MeCN, gradient).

Step 2:

The resulted compound (1.36 mmol) and lithium-hydroxide monohydrate (571 mg, 13.62 mmol, 10 eq.) were stirred in PDO-water (40 ml, El v/v) mixture at 110 °C for 7-24 hours. The reaction mixture was neutralized with 1 N aq. HCl solution. The resulted 15 precipitate was filtered off, washed with water and dried.

General Procedure 3

Step I:

Préparation Rlb (746 mg, 5 mmol, 1 eq.), heteroaryl/aryl-iodide (10 mmol), Cul ( 286 mg, 1.5 mmol, 0.3 eq.), l?,Æ-diaminocyclohexane (171 mg, 1.5 mmol, 0.3 eq.), 20 anhydrous K3PO4 (4.24 g, 20 mmol, 4 eq.) was stirred in diglyme (15 ml) for 6-16 hours at

120 °C under N2 atmosphère.

Work-up 1:

After the reaction completed, the mixture was diluted with water (200 ml) (or. 25 % aq.

NH3) and cooled to r.t. The mixture was filtered, and washed with water (3x30 ml), aq. 25 NH3 solution (40 ml, 25 %), water (3 x 50 ml), heptane (50 then 30 ml), dried in vacuum.

-21 Work-up2:

The reaction mixture was evaporated to Celite, then purified by flash chromatography (heptane:1+0, gradient).

Step 2:

The corresponding 4-methoxy-7-aryl-pyrrolo[2,3-rf]pyrimidine (61.3 mmol, 1 eq.), cc. HCl aqueous solution (10 ml, -12.2 M, 122.5 mmol, 2 eq.) and PDO (70 ml) was stirred at 100 °C for 0.5-2 hours. After the reaction completed, the mixture was partially evaporated. The formed suspension was fïltered and the solid on the filter was washed with water and dried.

General procedure 4

Step 1:

Préparation Rla (154 mg, 1 mmol, 1 eq.), di-teH-butyl-diazodicarboxylate (690 mg, mmol, 3 eq.), triphenylphosphine (786 mg, 3 mmol, 3 eq.) and corresponding alcohol (3 mmol, 3 eq.) were stirred in abs. toluene (10 ml) under Ar atmosphère at 50 °C for 15 2 hours. The reaction mixture was evaporated, taken in THF and purified by préparative

LC (on C-l 8 Gemini-NX 5pm column, 5 mM aqueous NH^HCCh-MeCN, gradient).

Step 2:

A part of this residue (4-chloro-7-aryl/alkyl-pyrrolo[2,3-iZ]pyrimidine) (1.36 mmol) and lithium-hydroxide monohydrate (571 mg, 13.62 mmol) were stirred in PDO-water (40 ml, 20 1:1 v/v) mixture at 110 °C for 7-24 hours. The reaction mixture was neutralized with 1 N aq. HCl solution. The resulted precipitate was fïltered off, washed with water and dried.

General procedure 5

Pyrimidine-4-one dérivative (1 mmol), epoxide compound Préparation Rlc (400.5 mg, 1 mmol, 1 eq.) and K2CO3 (276.4 mg, 2 mmol, 2 eq.) were stirred in DMF (5 ml) at 75 °C 25 for 2-8 hours.

Work-up 1 :

-22The mixture was poured into ice-water mixture. The resuited precipitate was filtered off, washed with water, and dried.

Work-up 2:

The reaction mixture was filtered, the solid was washed with DMF. The resuited filtrate 5 was purified by préparative LC (on C-18 Gemini-NX 5pm column, 5 mM aqueous NH₄HCO₃-MeCN, gradient).

General procedure 6

Compound obtained in General Procedure 5 (~ 1 mmol) was stirred in aq. HCl solution (1 N, 10 ml, 10 mmol, 10 eq.) and PDO (5 ml) for 1-3 hours at 75 °C.

Work-up 1:

The mixture was cooled to about 0-5 °C with ice bath and the white precipitate was filtered off, dried in vacuum (resuited HCl sait).

Work-up2:

The mixture was totally evaporated, and was used to the further step (resuited HCl sait).

Work-up3:

The mixture was purified by préparative LC (on C-18 Gemini-NX 5pm column, 5 mM aqueous NH4HCO₃-MeCN, gradient, resuited as free base).

General procedure 7

Compound obtained in General Procedure 6 (1 mmol, 1 eq.), alkyl-X (1 mmol, 1 eq.) and 20 K₂CO₃ (483 mg, 3.5 mmol, 3.5 eq.) were stirred in DMF (10 ml) at r.t. for 4-16 hours.

Work-upl:

The mixture was poured into ice-water mixture. The resuited precipitate was filtered off, washed with water, and dried.

Work-up2:

-23The mixture was fïltered and the filtrate was injected to préparative LC (on C-18 GeminiNX 5μηι column, 5 mM aqueous NLUHCCh-MeCN, gradient).

General procedure 8

Compound obtained in General Procedure 6 (2.7 mmol), EDC.HC1 (1.183 g, 5 6.172 mmol) and corresponding carboxylic acid (2.7 mmol) were stirred in pyridine (25 ml) at r.t. for 16 hours.

Work-upl:

The reaction mixture was evaporated, the residue was taken in DMF and injected to préparative LC (on C-18 Gemini-NX 5μηι column, 5 mM aqueous NEUHCCh-MeCN, 10 gradient).

Work-up2:

The reaction mixture was evaporated and the residue was trituated with water. The resulted solid was fïltered off.

Préparation Rlb: 4-methoxy-7Z?-pyrrolo[2,3-r/|pyrimidine

Préparation Rla (100 g, 0,651 mol, 1 eq.), NaOH (31,26 g, 0,781 mol, 1.2 eq.) and

MeOH (400 ml) was stirred at 90 °C for 24 hours. The mixture was quenched with water (1200 ml) and cooled to r.t. with ice bath. The mixture was stirred for 30 minutes, and fïltered through a glass fïlter. The precipitate was washed with water (3 x 100 ml) then dried and Préparation Rlb is obtained as white solid. HRMS calculated for C7H7N3O: 20 149.0589; found 150.0667 [(M+H)⁺ form], ‘H-NMR (400 MHz, MSM-d₆): δ = 12.02 (vbrs, 1 H), 8.37 (s, 1 H), 7.35 (d, 1 H), 6.47 (d, 1 H), 4.02 (s, 3 H).

^!3C-NMR (100 MHz, MSM-dô): δ ppm 162.6, 152.9, 150.8, 124.6, 104.8, 98.3, 53.7.

Préparation Rlc: to/7-butyl (3/î,4jR)-4-(2-oxa-6-azaspÎro[2.5]octane-6-carbonyl)-325 phenyl-piperidine-1 -carboxy late

-24Step 1: tert-butyl (3R,4R)-4-(4-oxopiperidine-l-carbonyl)-3-phenyl-piperidine-lcarhoxylate

4-piperidone hydrochloride hydrate (0.969 g, 6.3 mmol), EDC.HCI (3.623 g, 18.9 mmol) and (3R,47?)-l-/eH-butoxycarbonyl-3-phenyl-piperidine-4-carboxylic acid (1.928 g, 5 6.3 mmol) were dissolved in pyridine (10 mL) and stirred at r.t. for 16 hours. The reaction mixture was evaporated to Celite, purified by flash chromatography (DCM;MeOH, gradient) to give the product of the title. HRMS calculated for C22H30N2O4: 386.2206; found 409.2093 [(M+Na)⁺ form].

'H-NMR (500 MHz, MSM-d₆): δ = 1.42 (s, 9 H), 4.14-1.50 (m, 16 H), 7.32-7.15 (m, 5 H).

Step 2: Préparation RIc

Ze/7-Butyl (3R,4R)-4-(4-oxopiperidÎne-l -carbonyl)-3-phenylpiperidine- 1-carboxylate) (60 g, 155 mmol 1 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% 15 solution). The aq. NaOH solution was added to the mixture and stirred at 60 °C for hours. After the réaction completed, the mixture was cooled to r.t., fïltered 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 20 MgSÛ4, and after filtration evaporated to give Préparation Rlc as beige solid foam.

HRMS calculated for C23H32N2O4: 400.2362; found 423.2247 [(M+Na)⁺ form].

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

Préparation R2b: 7-(pyridin-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and 2-iodopyridine as reagents, Préparation R2b was obtained. HRMS calculated for C11H8N4O: 212.0698; found 213.0774 [(M+H)⁺ form].

'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.29 (s, 1 H), 8.55 (dd, 1 H), 8.47 (dd, 1 H), 8.06 (brs, 1 H), 8.03 (t, 1 H), 7.9 (d, 1 H), 7.4 (t, 1 H), 6.7 (d, 1 H).

-25^,3C-NMR(125 MHz, MSM-d6): δ (ppm) 149.1, 145, 139.4, 122.5, 122, 116.9, 104.

^I5N-NMR (50.6 MHz, MSM-d6): δ (ppm) 171.2.

Préparation R2c: 7-(4-methoxyphenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and 4-lodoanisole as reagents, Préparation R2c was obtained. HRMS calculated for C13H11N3O2: 241.0851; found 242.0929 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.04 (brs, 1 H), 7.92 (d, 1 H), 7.58 (dd, 1 H), 7.4 (d, 1 H), 7.08 (d, 1 H), 6.65 (d, 1 H), 3.81 (s, 3 H).

^,3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.8, 158.8, 147.3, 144.4, 130.9, 126.1, 124.4, 10 114.8,109.4,103.1,55.9.

Préparation R2e: 7-(4-fluoro-3-methoxyphenyI)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin 4-one

Using General Procedure 3 starting from Préparation Rlb and l-fluoro-4-iodo-2methoxybenzene as reagents, Préparation R2e was obtained. HRMS calculated for 15 C13H10N3O2F: 259.0757; found 260.0818 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.1 (s, 1 H), 7.95 (s, 1 H), 7.51 (d, 1 H), 7.48 (dd, 1 H), 7.38 (dd, 1 H), 7.27 (ddd, 1 H), 6.68 (d, 1 H), 3.9 (s, 3 H).

^I3C-NMR(125 MHz, MSM-d6): δ (ppm) 144.7, 124.5, 117, 116.5, 111, 103.4,56.8.

Préparation R2g: 7-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and iodomethane as alkylating agent, Préparation R2g was obtained. HRMS calculated for C7H7N3O: 149.0589; found 150,0668 [(M+H)⁺ form], ’H-NMR (500 MHz, MSM-d6): δ (ppm) 11.85 (brs, 1 H), 7.88 (brs, 1 H), 7.09 (d, 1 H), 6.44 (d, 1 H), 3.70 (m, 1 H).

^I3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.7, 147.7, 143.8, 125.1, 108.1, 101.7,31.8.

Préparation R2h: 7-ethyl-3H,4H,7H-pyrrolo[2,3-d]pyritnidin-4-onc

Ο

-26Usîng General Procedure 1 starting from Préparation Rla and iodoethane as reagents, Préparation R2h was obtained. HRMS calculated for C8H9N3O: 163.0746; found 164.0823 [(M+H)⁺ form], ’H-NMR (500 MHz, MSM-d6): δ (ppm) 11.38 (brs., 1 H), 7.87 (d, J=2.0 Hz, 1 H), 7.16 (d, 5 J=3.4 Hz, 1 H), 6.45 (d, J=3.4 Hz, 1 H), 4.14 (q, J=7.1 Hz, 2 H), 1.34 (t, J=7.1 Hz, 3 H).

Préparation R2i: 7-(prop-2-yn-l-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rlb (instead of Préparation Rla) and 3-bromoprop-l-yne as reagents (without the hydrolysis step), the crude methoxypyrimidine product (400 mg, 2.3 mmol) was dissolved in PDO (4 ml) and aqueous HCl solution (37 %, 0.18 ml) was added. The mixture was heated for 100 °C for minutes in a Schlenk tube. After cooling, DIPO (4 ml) was added to the reaction mixture and the resulted precipitate was filtered off and dried to give Préparation R2i. HRMS calculated for C9H7N3O: 173.0589; found 174.0665 [(M+H)⁺ form], ^lH-NMR (500 MHz, MSM-d6): δ (ppm) 11.98 (brs, 1 H), 7.93 (s, 1 H), 7.19 (d, 1 H), 6.5 15 (d, 1 H), 4.98 (d, 2 H), 3.42 (t, 1 H).

^I3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.6, 147.3, 144.3, 123.6, 102.5, 79.4, 76, 34.1.

Préparation R2i: 7-cyclopropyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 2 starting from Préparation Rla and cyclopropylboronic acid as reagents, Préparation R2j was obtained. HRMS calculated for C9H9N3O: 175.0746;

found 176.0819 [(M+H)⁺ form].

^lH-NMR (500 MHz, MSM-d6): δ (ppm) 11.88 (brs., 1 H), 7.89 (brs., 1 H), 7.05 (d, 1 H), 6.4 (d, 1 H), 3.53 (m, 1 H), 1.06-0.92 (m, 4 H).

^I3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.7, 148.9, 143.8, 123.4, 108.8, 101.6, 27.5, 6.6.

Préparation R2k: 7-(buta-2,3-dien-l-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rlb (instead of Préparation Rla) and 4-bromobuta-l,2-diene as reagents (without the hydrolysis step), the crude methoxypyrimidine product (300 mg, 1.65 mmol) was dissolved in PDO (4 ml) and aq. HCl solution (37 %, 0.18 ml) was added. The mixture was heated for 100 °C for

-27 30 minutes in a Schlenk tube. After cooling, the réaction mixture was evaporated to give Préparation R2k. HRMS calculated for C10H9N3O: 187.0745; found 188.0821 [(M+H)⁺form].

^lH-NMR (500 MHz, MSM-d6): δ (ppm) 11.91 (brs, 1 H), 7.89 (s, 1 H), 7.12 (d, 1 H), 6.46 5 (d, 1 H), 5.48 (m, 1 H), 4.87 (m, 2 H), 4.73 (m, 2 H).

^!3C-NMR (125 MHz, MSM-d6): δ (ppm) 208.3, 158.7, 147.4, 143.9, 123.9, 108.2, 102.1, 88.3, 78.1,43.

Préparation R21: 7-(cyclopropylmethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and cyclopropylmethyl bromide as reagents, Préparation R2I was obtained. HRMS calculated for C10H11N3O: 189.0902; found 190.0980 [(M+H)⁺ form], *H-NMR(500 MHz, MSM-d6): δ (ppm) 11.84 (s, 1 H), 7.87 (s, 1 H), 7.2 (d, 1 H), 6.45 (d, 1 H), 3.97 (d, 2 H), 1.21 (m, 1 H), 0.52-0.35 (m, 4 H).

ⁱ³C-NMR(125 MHz, MSM-d6): δ (ppm) 158.7, 147.3, 143.7, 124, 108.1, 101.7, 49, 12.3, 15 4.07.

Préparation R2m: 7-(2-methylpropyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and l-bromo-2methylpropane as reagents, Préparation R2m was obtained. HRMS calculated for C10H13N30:191.1059; found 192.1132 [(M+H)⁺ form], ^lH-NMR (500 MHz, MSM-d6): δ (ppm) 11.84 (brs, 1 H), 7.86 (s, 1 H), 7.12 (d, 1 H), 6.45 (d, 1 H), 3.92 (d, 2 H), 2.1 (sept., 1 H), 0.82 (d, 6 H).

¹³C-NMR(125 MHz, MSM-d6): δ (ppm) 158.8, 147.7, 143.7, 124.5, 108, 101.6, 52, 29.6,

20.2.

Préparation R2n: 9-methyl-3H-pyrimido[4,5-b]indol-4-one

Préparation Rlb (500 mg, 3.06 mmol) and 2,5-dimethoxytetrahydrofurane (810 mg, 6.13 mmol, d= 1.02, 795 μΐ) in 5 ml 1,4-dioxane were heated up to 100 °C for 102 hours, then 5ml IN HCl was added. It was dissolved in DMF and purified by préparative LC (on C-18 Gemini-NX 5gm column, 5 mM aqueous NFLHCCh-MeCN, gradient) to give

-28Preparation R2n. HRMS calculated for C11H9N3O: 199.0746; found 200.0827 [(M+H)⁺form].

'H-NMR(500 MHz, dmso-d6) δ ppm 12.33 (brs, 1 H), 8.21 (s, 1 H), 7.63 (dm, 1 H), 7.41 (ddd, 1 H), 7.29 (td, 1 H), 3.86 (s, 3 H) ^l3C-NMR(500 MHz, dmso-d6) δ ppm 158.5, 153.5, 148.1, 137, 124.6, 122, 121.8, 121,

110.7, 100.1,28.5

Préparation R2o: 7-(cyclobutylmethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and (bromomethyl)cyclobutane as reagents, Préparation R2o was obtained. HRMS calculated for Ci 1H13N3O: 203.1059; found 204.1134 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 11.83 (brs, 1 H), 7.87 (d, 1 H), 7.12 (d, 1 H), 6.43 (d, 1 H), 4.13 (d, 2 H), 2.72 (m, 1 H), 1.92/1.74 (m+m, 4 H), 1.82 (m, 2 H).

^I3C-NMR (125 MHz, MSM-d6): δ (ppm) 143.7, 124.2, 101.7, 49.6, 36, 25.6, 18.

Préparation R2p: 7-[2-(dimethylamino)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4 15 one

Using General Procedure 1 starting from Préparation Rla and 2-brotno-V.Vdimethylethylamîne hydrobromide as reagents, Préparation R2p was obtained. HRMS calculated for C10H14N4O: 206.1168; found 207.1242 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 11.84 (brs, 1 H), 7.88 (brd, 1 H), 7.16 (d, 1 H), 20 6.44 (d, 1 H), 4.19 (t, 2 H), 2.6 (t, 2 H), 2.16 (s, 6 H).

^,3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.7, 147.5, 143.7, 124.4, 108.1, 101.7, 59.2, 45.5, 42.6.

Préparation R2q: 7-phenyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and iodobenzene as reagents, 25 Préparation R2q was obtained. HRMS calculated for C12H9N3O: 211.0746; found 212.083 [(M+H)⁺ form], ’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.1 (brs, 1 H), 7.95 (d, 1 H), 7.71 (m, 2 H), 7.54 (m, 2 H), 7.5 (d, 1 H), 7.4 (m, 1 H), 6.69 (d, 1 H).

Ο

-29^l3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.8, 147.3, 144.6, 137.8, 129.7, 127.4, 124.6,

124.1, 109.8, 103.6.

Préparation R2s: 7-(pyrimidin-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Préparation Rlb (300 mg, 2.011 mmol, 1 eq.), 2-chloropyrimidine (2.413 mmol, 1.2 eq.) and anhydrous K2CO3 (417 mg, 3.017 mmol, 1.5 eq.) was heated in DMF (10 ml) at 150 °C for 2 hours. The reaction mixture was filtered and purified by préparative LC (on C-18 Gemini-NX 5pm column, 5 mM aqueous NH4HCO3-MCN, gradient) to give 4-methoxy-7-pyrimidin-2-yl-pyrrolo[2,3-<7]pyrimidine.

Then the obtained product (0.633 mmol, 1 eq.), IM HCl aqueous solution (3 ml) and PDO 10 (60 ml) were stirred at 100 °C for 1 hour. After the reaction completed, the mixture was evaporated and purified by préparative LC (on C-18 Gemini-NX 5pm column, 5 mM aqueous NH4HCO3-MCN, gradient) to give Préparation R2cj. HRMS calculated for C10H7N5O: 213.0651; found 214,0735 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.19 (brs, 1 H), 8.94 (d, 1 H), 8.01 (s, 1 H), 7.78 15 (d, 1 H), 7.54 (t, 1 H), 6.71 (d, 1 H).

^,3C-NMR (125 MHz, MSM-d6): δ (ppm) 159.7, 158.7, 156, 148.1, 145.2, 123.3, 120.1, 111.4, 104.5.

Préparation R2t: 6,8-dimethylpyrimido[5,4-ô]indolizin-4(3Æ)-one

Préparation Rlb (1.74 g, 11.67 mmol) was dissolved in DMF (80 ml) and cooled to 0 °C.

Sodium hydride (60 % disp., 1.87 g, 46.67 mmol) was slowly added and the solution was stirred for 30 minutes at 0 °C. Hydroxylamine-O-sulfonic acid (2.11 g, 18.67 mmol) was added to the reaction mixture and allowed to warm up to r.t. and stirred for 20 hours. Water (100 ml) was added to the reaction mixture and extracted with DCM (4 x 50 ml). The combined organic layers were washed with water, dried over MgSCU and evaporated.

A part of the resulted ;V-amino compound (300 mg, 1.83 mmol) and acetylacetone (206 μΐ, 201 mg 2.01 mmol) were dissolved in 5 ml acetic acid and heated up to 120 °C for 2 hours and 30 minutes, then TFA (5 ml) was added. It was heated at 120 °C for more 18 hours. Then 1 ml water and 10 ml methanol were added, then it was evaporated. The residue was purified by préparative LC (on C-18 Gemini-NX 5pm column, 5 mM aqueous NH4HCO319084

Π

-30MeCN, gradient) to give Préparation R2t. HRMS calculated for C11H10N4O: 214.0855; found 215.0935 [(M+H)⁺ form], ’H-NMR(500 MHz, dmso-d6) δ ppm 12,16 (s, 1 H), 8 (s, 1 H), 6.89 (s, 1 H), 6.68 (d, 1 H), 2.45 (d, 3 H), 2.44 (s, 3 H) ^l3C-NMR(500 MHz, dmso-d6) δ ppm 159.7, 152.5, 143.4, 141.2, 138.9, 127.7, 115.5,

109.8,91.2, 21.9, 17.4

Préparation R2u: 7-(l-methyl-lH-imidazol-4-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin4-one

Using General Procedure 3 starting from Préparation Rlb and 4-iodo-1 -methyl-\/t10 imidazole as reagents, Préparation R2u was obtained. HRMS calculated for CioHgNsO: 215.0807; found 216.0879 [(M+H)⁺ form].

¹ H-NMR (500 MHz, MSM-d6): δ (ppm) 9.24-7.3 (vbrs, 3 H), 7.51 (d, 1 H), 6.72 (brs, 1 H), 3.77 (s, 3 H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 121.7, 103.5, 35.

¹⁵N-NMR (50.6 MHz, MSM-d6): δ (ppm) 153.

Préparation R2v: 7-(thiophen-3-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 2 starting from Préparation Rla and thiophene-3-boronic acid pinacol ester as reagents, Préparation R2v was obtained. HRMS calculated for C10H7N3OS: 217.0310; found 218.0390 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.14 (s, 1 H), 7.99 (d, 1 H), 7.92 (dd, 1 H), 7.71 (dd, 1 H), 7.68 (dd, 1 H), 7.57 (d, 1 H), 6.66 (d, 1 H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 158.6, 147, 144.8, 136.3, 127, 123.8, 123.3, 1 15.1, 109.5, 103.5.

Préparation R2w: 7-(thiophen-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and 2-iodothiophene as reagents, Préparation R2w was obtained. HRMS calculated for C10H7N3OS: 217.0310; found 218.0384 [(M+H)⁺ form].

‘H-NMR (500 MHz, MSM-d6): δ (ppm) 12.2 (brs, 1 H), 8.03 (s, 1 H), 7.58 (d, 1 H), 7.43 (dd, 1 H), 7.39 (dd, 1 H), 7.07 (dd, I H), 6.69 (d, 1 H).

-31 ¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 158.5, 147.2, 145.3, 138.7, 126, 124.3, 122.8,

119.2, 109.4, 104.2.

Préparation R2x: 7-(2,2,2-trifluoroethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and 2,2,2-trifluoroethyl 5 trifluoromethanesulfonate as reagents, Préparation R2x was obtained. HRMS calculated for C8H6N3OF3: 217.0463; found 218.0543 [(M+H)⁺ form].

'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.08 (brs, 1 H), 7.97 (s, 1 H), 7.19 (d, 1 H), 6.57 (d, 1 H), 5.06 (q, 2 H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 158.5, 148.4, 144.9, 124.7, 124.4, 108.8, 103.2, 10 45.1.

^l9F-NMR (376.5 MHz, MSM-d6): δ (ppm) -70.3.

Préparation R2y: 7-(l,3-thiazol-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and 2-iodothiazole as reagents, Préparation R2ck was obtained. HRMS calculated for C9H6N4OS: 218.0262;

found 219.0335 [(M+H)⁺ form].

'H-NMR (500 MHz, MeCN-d3) δ ppm 8.5 (s, 1 H), 7.62 (d, 1 H), 7.52 (d, 1 H), 7.22 (d, 1 H), 6.51 (d, 1 H).

^,3C-NMR (125 MHz, MeCN-d3) δ ppm 154.5, 137.9, 116.8, 114.8, 104.2.

Préparation R2z; 7-[3-(dimethylamino)propyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-420 one

Using General Procedure 1 starting from Préparation Rla and 3-dimethylaminopropyl chloride hydrochloride as reagents, Préparation R2z was obtained. HRMS calculated for C11H16N4O: 220.1324; found 221.1401 [(M+H)⁺ form].

'H-NMR (500 MHz, MSM-d6): δ (ppm) 11.84 (brs, 1 H), 7.88 (s, 1 H), 7.13 (d, 1 H), 6.44 25 (d, 1 H), 4.12 (t, 2 H), 2.15 (t, 2 H), 2.1 (s, 6 H), 1.85 (p, 2 H).

^,3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.8, 147.4, 143.8, 124.2, 108.2, 101.7, 56.4, 45.6,43,28.6.

Préparation R2aa: 7-(3-methyIphenyI)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Ο

-32Usïng General Procedure 3 starting from Préparation RI b and 3-iodotoluene as reagents, Préparation R2aa was obtained. HRMS calculated for C13H11N3O: 225.0902; found 226.098 [(M+H)⁺ form].

'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.08 (brs, 1 H), 7.95 (d, 1 H), 7.52 (brs, 1 H),

7.49 (dm, 1 H), 7.46 (d, 1 H), 7.41 (t, 1 H), 7.22 (brd., 1 H), 6.67 (d, 1 H), 2.39 (s, 3 H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 158.8, 147.3, 144.6, 139.2, 137.8, 129.5, 128.1,

125.2, 124.2, 121.8, 109.7, 103.5, 21.4.

Préparation R2ab: 7-(4-methylphenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and 4-iodotoluene as 10 reagents, Préparation R2ab was obtained. HRMS calculated for C13HHN3O: 225,0902;

found 226.0987 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.06 (brs, 1 H), 7.93 (s, 1 H), 7.58 (dm, 1 H), 7.44 (d, 1 H), 7.33 (dm, 1 H), 6.66 (d, 1 H), 2.37 (s, 3 H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 158.8, 147.3, 144.5, 136.8, 135.4, 130.1, 124.5, 15 124.1,109.6,103.4,21.

Préparation R2ac: 7-benzyl-3H,4H,7H-pyrroIo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and benzyl bromide as reagents, Préparation R2ac was obtained. HRMS calculated for CbHuNjO: 225.0902; found 226.0986 [(M+H)⁺ form], 'H-NMR (400 MHz, MSM-d6): δ (ppm) 11.91 (brs, 1 H), 7.91 (s, 1 H), 7.36-7.17 (m, 5 H), 7.2 (d, 1 H), 6.49 (d, 1 H), 5.34 (s, 2 H).

^I3C-NMR (100 MHz, MSM-d6): δ (ppm) 144.1, 124.3, 102.2, 48.1.

Préparation R2ad: 6-methyl-7-phenyl-3H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and iodobenzene as reagents, 25 4-methoxy-7-phenyl-pyrrolo[2,3-d]pyrimidine was obtained (without hydrolysis).

This crude product (450 mg, 2 mmol) was dissolved in THF (18 ml) stirred at -78 °C, then LDA solution (1.8 M, 1.7 ml, 3 mmol) was added. After one hour of stirring at -78 °C, îodomethane (190 μΐ, 3 mmol) solution in THF (5 ml) was added, and continued stirring

Ο

-33 for 90 minutes. Then the reaction mixture was diluted with brine (10 ml), evaporated to Celite and purified by flash chromatography (Hexane-EEO=7-1).

The resuited crude product (400 mg, 1.6 mmol) was dissolved in cc. HCl aqueous solution (330 μΐ, -12.2 M, 4 mmol) and PDO (5 ml) was stirred at 100 °C for 2 hours. After the reaction completed, the mixture was partially evaporated and the formed suspension was filtered. The solid on the filter was washed with water and dried to give Préparation R2de. HRMS calculated for C13H11N3O: 225.0902; found 226.0985 [(M+H)⁺form].

'H-NMR(500 MHz, MSM-d6) δ ppm 11.94 (s, 1 H), 7.76 (d, 1 H), 7.55 (tm, 2 H), 7.49 10 (tm, 1 H), 7.4 (dm, 2 H), 6.41 (d, 1 H), 2.17 (d, 3 H).

^I3C-NMR(125 MHz, MSM-d6) δ ppm 158.4, 143.6, 136.2, 132.6, 129.6, 128.7, 128.5, 100.9, 13.3.

Préparation R2ae: 7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2_>3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and 4-fluoroiodobenzene as reagents, Préparation R2ae was obtained. HRMS calculated for C^HgFNsO: 229.0651; found 230.0714 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.12 (brs, 1 H), 7.95 (d, 1 H), 7.74 (m, 2 H), 7.48 (d, 1 H), 7.39 (m, 2 H), 6.68 (d, 1 H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 144.7, 126.8, 124.2, 116.4, 103.5.

Préparation R2ai: 6-chloro-7-phenyl-3H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and iodobenzene as reagents, 4-methoxy-7-phenyl-pyrrolo[2,3-iZ]pyrimidine was obtained (without hydrolysis).

The crude product (394 mg, 1.75 mmol) was dissolved in THF (14 ml) stirred at -78 °C, then LDA solution (1.8 M, 1.2 ml, 2.16 mmol) was added. After one hour of stirring at

-78 °C, hexachloroethane (632 mg, 2.63 mmol) solution in THF (5 ml) was added, and continued stirring for 90 minutes. Then the reaction mixture was diluted with brine (10 ml), evaporated to Celite and purified by flash chromatography (Hexane-EEO=9-1). The resuited crude product (110 mg, 0.42 mmol) was dissolved in cc. HCl aqueous solution (82 μΐ, -12.2 Μ, 1 mmol) and PDO (5 ml) was stirred at 100 °C for 2 hours. After the reaction completed, the mixture was partially evaporated and the formed suspension ( )

- 34was filtered. The solid on the filter was washed with water and dried to give Préparation R2dh. HRMS calculated for C12H8N3OCI: 245.0356; found 246.043 [(M+H)⁺form].

'H-NMR(500 MHz, MSM-d6) δ ppm 12.16 (s, 1 H), 7.88 (s, 1 H), 7.6-7.52 (m, 5 H), 6.78 5 (s, 1 H).

^I3C-NMR(125 MHz, MSM-d6)ôppm 157.6, 148.2, 145.3, 101.6.

Préparation R2aj: 6-iodo-7-methyl-3H-pyrrolo[2,3-d]pyrimidin-4-one

To a stirred solution of Préparation Rla (8 g, 52.1 mmol) in abs. DMF (50 ml) was cooled down to 0 °C, then sodium-hydride (3.13 g, 60 % disp, in minerai oil, 78.2 mmol,

1.5 eq.) was added, and stirred for 20 minutes at r.t. under Ar. Methyl iodide (8.2 g,

57.2 mmol, d=2.28, 3.6 ml) was added to the reaction mixture and stirred for 1.5 hours at r.t. The mixture was poured into water (50 ml). Solid compound was formed, which was filtered off.

A part of the resulted /V-methylated compound (500 mg, 2.98 mmol) was dîssolved in 5 ml abs. THF and cooled down to -78 °C. Then 2M LDA (1.7 ml, 3.4 mmol) was added dropwise. The mixture was stirred at -78°C for 1 hour, then iodide (757 mg, 2.98 mmol) was added. The solution was allowed to warm to r.t. and stirred for 22 hours, then 5 ml water was added. Solid compound was formed and filtered off to give Préparation R2aj. HRMS calculated for C7H6IN3O: 274.9556; found 275.9634 [(M+H)+ form].

’H-NMR(500 MHz, dmso-d6) δ ppm 11.97 (s, 1 H), 7.85 (s, 1 H), 6.79 (s, 1 H), 3.64 (s, 3

H) ^l3C-NMR(5OO MHz, dmso-d6) δ ppm 157.3, 149.1, 144.2, 111.4, 110.3, 80.4,33.2

Préparation R2al: 6-iodo-7-(2-trimethylsilylethoxymethyl)-3H-pyrrolo[2,3-d] pyrimidin-4-one

233 mg (0.82mmol) 2-[(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethylsilane was dîssolved in 4 ml dry THF and cooled down to -78 °C and 500 pL (1.8 M stock solution, 0.9 mmol, 1.1 eq.) LDA was added. The mixture was stirred under nitrogen for 40 minutes at -78 °C then 208 mg iodîne (0.82 mmol, 1 eq.) was added and allowed to warm to r.t. It was stirred for 40 minutes, then water was added. The solution was extracted with EEO (2 x 15 ml), combined organic phase was dried (magnésium sulfate) and

Ο

-35evaporated. The residue was purified by flash chromatography (Eluent: heptane-EEO gradient).

Resulted crude 2-[(4-chloro-6-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethylsilane was solved in 3 ml PDO and 3 ml water and 166 mg (3.98 mmol) lithium hydroxide hydrate was added. The mixture was heated and stirred at 110 °c for 5 hours. The solution was cooled to r.t., then 1 N HCl was added till pH 3-4. Solid compound was formed, which was filted off, and washed with water, Préparation R2al was obtained.

HRMS calculated for C12H18IN3O2S1: 391.0213; found 392.0298 [(M+H)+ form], ’H-NMR(500 MHz, DMSO-d6) δ ppm 12.1 (brs, 1 H), 7.91 (d, 1 H), 6.84 (s, 1 H), 5.45 (s,

2H), 3.51 (m, 2H), 0.82 (m, 2H), -0.08 (s, 9H).

¹³C-NMR(500 MHz, DMSO-d6) δ ppm 157.3, 149.9, 144.8, 112.9, 110.5, 79.3, 73.7, 66.0, 17.5.

Préparation R2am: 7-(3,4,5-trimethoxyphenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidm-4one

Using General Procedure 3 starting from Préparation Rlb and 5-îodo-1,2,3trimethoxybenzene as reagents, Préparation R2am was obtained. HRMS calculated for C15H15N3O4: 301.1063; found 302.1138 [(M+H)⁺ form], ’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.07 (brs, 1 H), 7.95 (d, 1 H), 7.49 (d, 1 H), 6.99 (s, 2 H), 6.66 (d, 1 H), 3.82 (s, 6 H), 3.7 (s, 3 H).

^,3C-NMR (125 MHz, MSM-d6): δ (ppm) 144.5, 124.6, 103.2, 103, 60.6, 56.6.

Préparation R2an: 7-(3,5-dichlorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one Using General Procedure 2 starting from Préparation Rla and 3,5-dichlorophenylboronic acid as reagents, Préparation R2an was obtained. HRMS calculated for C12H7CI2N3O: 278.9966; found 280.0040 [(M+H)⁺ form],

Ή-NMR (500 MHz, MSM-d6): δ (ppm) 12.03 (vbrs, 1 H), 8.03 (s, 1 H), 7.95 (d, 2 H), 7.64 (t, 1 H), 7.63 (d, 1 H), 6.71 (d, 1 H).

¹³C-NMR(125 MHz, MSM-d6): δ (ppm) 145.3, 126.7, 123.8, 122.7, 104.4

Préparation R2ao: 7-(3-chloro-5-methoxyphenyl)-3H,4H,7H-pyrrolo[2,3-

d]pyrimidin-4-one j 19084

-36Using General Procedure 2 starting from Préparation Rla and 3-chloro-5methoxyphenyiboronic acid as reagents, Préparation R2ao was obtained. HRMS calculated for Ci₃H_i0CIN₃O2: 275.0461; found 276.0541 [(M+H)⁺ form].

^lH-NMR (400 MHz, MSM-d6): δ (ppm) 12.18 (s, 1 H), 8 (d, 1 H), 7.6 (d, 1 H), 7.51 (t, 1

H), 7.33 (t, 1 H), 7.08 (t, 1 H), 6.69 (d, 1 H), 3.85 (s, 3 H).

¹³C-NMR(100 MHz, MSM-d6): δ (ppm) 161, 158.7, 147.5, 145, 139.7, 134.5, 124, 116.3, 112.7, 110.2, 109.4, 104, 56.4

Préparation R2ap: 7-(3,5-dimethoxyphenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4one

Using General Procedure 2 starting from Préparation Rla and 2-(3,5-dimethoxy)phenyl-4,4,5,5-tetramethyl-(l,3,2)-dioxaborolane as reagents, Préparation R2ap was obtained. HRMS calculated for €ηΗι₃Ν₃Ο₃: 271.0957; found 272.1030 [(M+H)⁺ form], ’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.11 (s, 1 H), 7.95 (d, 1 H), 7.52 (d, 1 H), 6.91 (d, 2 H), 6.66 (d, 1 H), 6.54 (t, 1 H), 3.8 (s, 6 H).

¹³C-NMR (125 MHz, MSM-d6): Ô (ppm) 144.5, 124.2, 103.5, 103.1, 98.9.

Préparation R2aq: 7-(3,4-dichlorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one Using General Procedure 2 starting from Préparation Rlb and

3,4-dichlorophenylboronic acid as reagents, Préparation R2aq was obtained. HRMS calculated for CnHyChW: 278.9966; found 280.003 [(M+H)⁺ form].

'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.21 (brs, 1 H), 8.15 (t, 1 H), 8.02 (brs, 1 H), 7.82 (d, 1 H), 7.82 (d, 1 H), 7.61 (d, 1 H), 6.72 (d, 1 H).

^l3C-NMR (125 MHz, MSM-d6): δ (ppm) 145.1, 131.5, 125.9, 124.3, 123.8, 104.2.

Préparation R2ar: 7-(4-chloro-3-fluoroplienyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4one

Using General Procedure 3 starting from Préparation Rlb and 4-chloro-3fluoroiodobenzene as reagents, Préparation R2ar was obtained. HRMS calculated for Ci2H7ClFN₃O: 263.0262; found 264.0339 [(M+H)⁺ form].

¹ H-NMR (500 MHz, MSM-d6): δ (ppm) 12.21 (s, 1 H), 8.02 (d, 1 H), 7.97 (dd, 1 H), 7.77 (dd, 1 H), 7.72 (dd, 1 H), 7.6 (d, 1 H), 6.72 (d, 1 H).

Ο

-37^l3C-NMR(125 MHz, MSM-d6): δ (ppm) 145.1, 131.5, 123.7, 121.5, 112.8, 104.2.

Préparation R2as: 7-(4-chloro-3-methoxyphenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin4-one

Using General Procedure 3 starting from Préparation Rlb and 2-chloro-5-iodoanisole as reagents, Préparation R2as was obtained. HRMS calculated for C13H10CIN3O2: 275.0461; found 276.0537 [(M+H)⁺ form].

^lH-NMR (500 MHz, MSM-d6): δ (ppm) 12.15 (brs, 1 H), 7.98 (brs, 1 H), 7.58 (d, 1 H), 7.57 (d, 1 H), 7.49 (d, 1 H), 7.36 (dd, 1 H), 6.7 (d, 1 H), 3.93 (s, 3 H).

^I3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.7, 155.3, 147.4, 144.8, 137.7, 130.5, 124.2, 10 119.8, 117.3, 110, 109.4, 103.7, 56.9.

Préparation R2at: 7-(3,4-dimethoxyphenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one Using General Procedure 2 starting from Préparation Rlb and

3,4-dimethoxyphenylboronîc acid pinacol ester as reagents, Préparation R2at was obtained. HRMS calculated for C14H13N3O3: 271.0957; found 272.103 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 7.92 (d, 1 H), 7.43 (d, 1 H), 7.25 (d, 1 H), 7.19 (dd, 1 H), 7.08 (d, 1 H), 6.65 (d, 1 H), 3.8 (s, 6 H).

¹³C-NMR(125 MHz, MSM-d6): δ (ppm) 144.5, 124.6, 116.9, 112.2, 109.3, 103.1,56.3.

Préparation R2au: 4-{4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-7-yl}benzonitrile Using General Procedure 3 starting from Préparation Rlb and 4-îodobenzonitrile as reagents, Préparation R2au was obtained. HRMS calculated for C13H8N4O: 236,0698; found 237.0775 [(M+H)⁺ form].

'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.25 (brs, 1 H), 8.05 (m, 2 H), 8.03 (m, 2 H), 8.02 (brs, 1 H), 7.66 (d, 1 H), 6.75 (d, 1 H).

^I3C-NMR (125 MHz, MSM-d6): δ (ppm) 147.6, 145.2, 141.5, 134, 124.6, 123.6, 119, 25 110.6,109.4,104.7.

Préparation R2av: 7-[4-(trifluoromethyl)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin4-one

-38Using General Procedure 3 starting from Préparation Rlb and 4-iodobenzotrifluoride as reagents, Préparation R2av was obtained. HRMS calculated for C13H8F3N3O: 279,0619; found 280.0691 [(M+H)⁺ form].

'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.23 (brs, 1 H), 8.02 (m, 2 H), 8.01 (d, 1 H), 5 7.92 (m, 2 H), 7.63 (d, 1 H), 6.74 (d, 1 H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 158.7, 147.6, 145.1, 126.9, 124.7, 123.8, 110.4, 104.5 ^l5N-NMR (50.6 MHz, MSM-d6): δ (ppm) 170.9.

Préparation R2aw: 7-[4-(difluoromethyl)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin4-one

Using General Procedure 3 starting from Préparation Rlb and l-(difluoromethyl)-4iodobenzene as reagents, Préparation R2aw was obtained. HRMS calculated for C13H9F2N3O: 261.0714; found 262.0784 [(M+H)⁺ form].

¹ H-NMR (500 MHz, MSM-d6): δ (ppm) 12.17 (brs, 1 H), 7.99 (d, 1 H), 7.91 (m, 2 H), 7.75 (m, 2 H), 7.58 (d, 1 H), 7.12 (t, 1 H), 6.72 (d, 1 H).

^l3C-NMR (125 MHz, MSM-d6): δ (ppm) 144.9, 127.2, 124.7, 123.9, 115.1, 104.1.

Préparation R2ax: 7-[4-(hydroxymethyl)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin4-one

Using General Procedure 3 starting from Préparation Rlb and 4-iodobenzyl alcohol as reagents, Préparation R2ax was obtained. HRMS calculated for C13H11N3O2: 241.0851;

found 242.0925 [(M+H)⁺ form], ¹ H-NMR (500 MHz, MSM-d6): δ (ppm) 12.07 (brs, 1 H), 7.94 (s, 1 H), 7.66 (m, 2 H), 7.47 (m, 2 H), 7.45 (d, 1 H), 6.67 (d, 1 H), 5.31 (t, 1 H), 4.56 (d, 2 H).

^,3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.9, 147.4, 144.6, 142.2, 136.6, 127.6, 124.3,

124.2, 109.9, 103.5,62.8.

Préparation R2ay: 7-(4-chIorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and l-chloro-4-iodobenzene as reagents, Préparation R2ay was obtained. HRMS calculated for C12H8CIN3O: 245.0356; found 246.0427 [(M+H)⁺ form].

η

-39¹ H-NMR (500 MHz, MSM-d6): δ (ppm) 12.15 (brs, 1 H), 7.97 (d, 1 H), 7.78 (dm, 1 H),

7.61 (dm, 1 H), 7.53 (d, 1 H), 6.7 (d, 1 H).

^I3C-NMR(125 MHz, MSM-d6): δ (ppm) 158.7, 147.3, 144.8, 136.7, 131.7, 129.6, 126.1, 123.9, 109.9, 103.9.

Préparation R2az: 7-[4-(dimethylamino)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin 4-one

Using General Procedure 2 starting from Préparation Rla and 4-(dimethylamino)phenylboronic acid as reagents, Préparation R2az was obtained. HRMS calculated for C14H14N4O: 254.1168; found 255.1243 [(M+H)⁺ form].

'H-NMR (400 MHz, MSM-d6): δ (ppm) 11.98 (brs, 1 H), 7.89 (d, 1 H), 7.43 (m, 2 H), 7.33 (d, 1 H), 6.82 (m, 2 H), 6.61 (d, 1 H), 2.94 (s, 6 H).

¹³C-NMR(100 MHz, MSM-d6): δ (ppm) 144.1, 125.6, 124.3, 112.7, 102.7, 40.6.

Préparation R2ba: 7-[4-(trifluoromethoxy)phenyl]-3H,4H,7H-pyrrolo[2,3 d] pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and l-iodo-4(trifluoromethoxy)benzene as reagents, Préparation R2ba was obtained. HRMS calculated for C13H8F3N3O2: 295.0569; found 296.0648 [(M+H)⁺ form].

'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.15 (s, 1 H), 7.97 (d, 1 H), 7.86 (m, 2 H), 7.56 (m, 2 H), 7.54 (m, 1 H), 6.71 (d, 1 H).

^,3C-NMR(125 MHz, MSM-d6): δ (ppm) 144.8, 126.4, 124.1, 122.5, 103.9.

Préparation R2bb: 7- [4-(benzy loxy)pheny I] -3H,4H,7H-py r rolo [2,3-d] py r i midin-4-one Using General Procedure 3 starting from Préparation Rlb and 4-benzyloxyiodobenzene as reagents, Préparation R2bb was obtained. HRMS calculated for C19H15N3O2: 317.1164; found 318.1243 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.05 (brs, 1 H), 7.92 (d, 1 H), 7.59 (dm, 2 H),

7.48 (dm, 2 H), 7.41 (d, 1 H), 7.41 (tm, 2 H), 7.35 (tm, 1 H), 7.16 (dm, 2 H), 6.65 (d, 1 H), 5.18 (s, 2 H).

^bC-NMR (125 MHz, MSM-d6): δ (ppm) 158.8, 157.6, 147.3, 144.4, 137.4, 131, 129,

128.4, 128.2, 126.1, 124.3, 115.7, 109.4, 103.1,69.9.

Ο

-40Preparation R2bc: 7-(5-methylthiophen-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4one

Using General Procedure 3 starting from Préparation Rlb and 2-iodo-5methylthiophene as reagents, Préparation R2bc was obtained. HRMS calculated for

Ci 1H9N3OS: 231.0466; found 232.0541 [(M+H)⁺ form].

Ή-NMR (400 MHz, MSM-d6): δ (ppm) 12.17 (brs, 1 H), 7.99 (d, 1 H), 7.49 (d, 1 H), 7.14 (d, 1 H), 6.76 (dq, 1 H), 6.67 (d, 1 H), 2.46 (d, 3 H).

¹³C-NMR (100 MHz, MSM-d6): δ (ppm) 145, 124.2, 123.9, 119.4, 103.9, 15.4.

Préparation R2bd: 7-(5-chlorothiophen-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4 10 one

Using General Procedure 3 starting from Préparation Rlb and 2-chloro-5iodothiophene as reagents, Préparation R2bd was obtained. HRMS calculated for CioHôNaOSCl: 250.9920; found 252.0005 ((M+H)⁺ form],

H-NMR (500 MHz, dmso-d6) δ ppm 12.28 (brs, 1 H), 8.07 (d, 1 H), 7.67 (d, 1 H), 7.3 (d, 15 1 H), 7.13 (d, 1 H), 6.72 (d, 1 H).

13C-NMR (500 MHz, dmso-d6) δ ppm 158.4, 146.8, 145.6, 136.4, 125.5, 124.6, 123.3,

117.5, 109.3, 104.6 .

Préparation R2be: 7-(2,3-dihydro-l,4-benzodioxin-6-yl)-3H,4H,7H-pyrrolo[2,3 d] pyrimidin-4-one

Using General Procedure 2 starting from Préparation Rla and l,4-benzodioxane-6boronic acid as reagents, Préparation R2be was obtained. HRMS calculated for C14HHN3O3: 269,0800; found 270.0881 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.05 (brs, 1 H), 7.92 (d, 1 H), 7.4 (d, 1 H), 7.22 (d, 1 H), 7.13 (dd, 1 H), 6.99 (d, 1 H), 6.63 (d, 1 H), 4.33-4.25 (m, 4 H).

^l3C-NMR (125 MHz, MSM-d6): δ (ppm) 144.4, 124.3, 117.7, 117.6, 113.8, 103.2.

Préparation R2bf: 7-(2H-l,3-benzodioxol-5-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4 one i

I i

-41 Using General Procedure 2 starting from Préparation Rla and

3,4-methylenedioxyphenylboronic acid as reagents, Préparation R2bf was obtained.

HRMS calculated for C13H9N3O3: 255,0644; found 256.0719 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.05 (brs, 1 H), 7.92 (d, 1 H), 7.4 (d, 1 H), 7.29 5 (d, 1 H), 7.12 (dd, 1 H), 7.05 (d, 1 H), 6.63 (d, 1 H), 6.11 (s, 2 H).

’³C-NMR(125 MHz, MSM-d6): δ (ppm) 144.5, 124.5, 118.2, 108.7, 106.5, 103.1, 102.2.

Préparation R2bg: 7-(naphthalen-2-yl)-3H,4H,7H-pyrroIo[2,3-d]pyrimidin-4-one

Using General Procedure 2 starting from Préparation Rla and 2-naphthaleneboronic acid as reagents, Préparation R2bg was obtained. HRMS calculated for CiôHuNjO: 10 261,0902; found 262.0982 [(M+H)⁺ form], ’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.14 (s, 1 H), 8.25 (d, 1 H), 8.09 (d, 1 H), 8.01 (m, 1 H), 8.01 (m, 1 H), 8 (s, 1 H), 7.91 (dd, 1 H), 7.63 (d, 1 H), 7.6 (tm, 1 H), 7.57 (tm, 1 H), 6.74 (d, 1 H).

’³C-NMR (125 MHz, MSM-d6): δ (ppm) 158.8, 147.6, 144.8, 135.4, 133.4, 132, 129.4, 15 128.4, 128.2, 127.4, 126.9, 124.4, 123.5, 122.3, 109.9, 103.8.

Préparation R2bh: 7-[3-(trifluoromethyl)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin4-one

Using General Procedure 3 starting from Préparation Rlb and 3-iodobenzotrifluoride as reagents, Préparation R2bh was obtained. HRMS calculated for C13H8F3N3O: 279.0620;

found 280.0699 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.19 (brs, 1 H), 8.18 (brs, 1 H), 8.07 (dm, 1 H), 8.02 (d, 1 H), 7.79 (t, 1 H), 7.77 (dm, l H), 7.65 (d, 1 H), 6.73 (d, 1 H).

’³C-NMR(125 MHz, MSM-d6): δ (ppm) 145.1, 131.1, 128.3,124, 123.9, 121, 104.1.

Préparation R2bi: 7-{3-[(4-methylpiperazin-l-yl)methyl]phenyl}-3H,4H,7H 25 pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 2 starting from Préparation Rlb and 3-(4-methyl-lpiperazinylmethyl)benzeneboronic acid pinacol ester as reagents, Préparation R2bi was . obtained. HRMS calculated for C18H21N5O: 323.1746; found 324.1828 [(M+H)⁺ form].

-42¹ H-NMR (500 MHz, MSM-d6): δ (ppm) 12.37/12.2/11.95 (brs, 3 H), 8.04 (brs, 1 H), 7.98 (s, 1 H), 7.91 (dm, 1 H), 7.67 (dm, 1 H), 7.63 (d, 1 H), 7.62 (t, 1 H), 6.72 (d, 1 H), 4.49 (brs, 2 H), 3.8-3.3 (brm, 8 H), 2.8 (brs, 3 H).

^,3C-NMR (125 MHz, MSM-d6): δ (ppm) 144.8, 130.3, 130, 127.3, 125.7, 124, 103.9, 58.7, 5 42.7.

Préparation R2bi: 7-[3-(hydroxymethyl)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin4-one

Using General Procedure 3 starting from Préparation Rlb and 3-iodobenzyl alcohol as reagents, Préparation R2bj was obtained. HRMS calculated for C13HUN3O2: 241.0851;

found 242.0935 [(M+H)⁺ form], ‘H-NMR (500 MHz, MSM-d6): δ (ppm) 12.11 (brs, 1 H), 7.95 (d, 1 H), 7.64 (brt, 1 H), 7.55 (dm, 1 H), 7.48 (t, 1 H), 7.46 (d, 1 H), 7.35 (dm, 1 H), 6.68 (d, 1 H), 4.58 (s, 2 H).

^I3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.8, 147.4, 144.6, 144.4, 137.7, 129.4, 125.4,

124.2, 123, 122.5, 109.7, 103.5, 62.9.

Préparation R2bk: 7-(3-chlorophenyl)-3H,4H,7H-pyrrolo[2,3-d] pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and l-chloro-3-iodobenzene as reagents, Préparation R2bk was obtained. HRMS calculated for C12H8CIN3O: 245.0356; found 246.0437 [(M+H)⁺ form], 'H-NMR (400 MHz, MSM-d6): δ (ppm) 12.17 (brs, 1 H), 8 (d, 1 H), 7.92 (m, 1 H), 7.74 20 (dm, 1 H), 7.58 (d, 1 H), 7.57 (t, 1 H), 7.47 (dm, 1 H), 6.7 (d, 1 H).

^l3C-NMR(100MHz, MSM-d6): δ (ppm) 145, 131.3, 127.2, 124.1, 123.9, 122.9, 104.

Préparation R2bl: 7-(3-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and l-fluoro-3-iodobenzene as reagents, Préparation R2bl was obtained. HRMS calculated for C12H8N3OF: 229.0651;

found 230.0729 [(M+H)⁺ form].

'H-NMR (400 MHz, MSM-d6): δ (ppm) 12.17 (brs, 1 H), 7.99 (d, 1 H), 7.72 (dm, 1 H), 7.64 (m, 1 H), 7.58 (d, 1 H), 7.58 (m, 1 H), 7.25 (m, 1 H), 6.71 (d, 1 H).

¹³C-NMR(100 MHz, MSM-d6): δ (ppm) 144.9, 131.4, 130.9, 123.9, 120.2, 114, 111.6. ¹⁹F-NMR (376.5 MHz, MSM-d6): δ (ppm) -111.7.

Ο

V i

-43Preparation R2bm: 7-[3-(dimethylamino)phenyl]-3H,4H,7H-pyrrolo]2,3-d]pyrimidin4-one

Using General Procedure 2 starting from Préparation Rla and 3-(N,Ndimethylamino)phenylboronic acid as reagents, Préparation R2bm was obtained. HRMS calculated for C14H14N4O: 254.1168; found 255.1229 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.04 (brs, 1 H), 7.92 (d, 1 H), 7.45 (d, 1 H), 7.3 (t, 1 H), 6.94 (m, 1 H), 6.93 (dm, l H), 6.74 (dm, 1 H), 6.65 (d, l H), 2.95 (s, 6 H).

^I3C-NMR (125 MHz, MSM-d6): δ (ppm) 144.3, 129.9, 124.4, 112.4, 111.4, 108.6, 103.1,

40.5.

Préparation R2bn: 7-[3-(morpholin-4-yl)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin 4-one

Using General Procedure 2 starting from Préparation Rla and 3-(morpholino)phenylboronic acid as reagents, Préparation R2bn was obtained. ’H-NMR (400 MHz, MSM-d6): δ (ppm) 12.05 (brs, 1 H), 7.93 (s, 1 H), 7.47 (d, J=3.53 Hz, 1 H), 15 7.36 (t, J=8.13 Hz, 1 H), 7.19 (t, J=2.20 Hz, 1 H), 7.11 (dd, J=1.27, 7.93 Hz, 1 H), 6.98 (dd, >1.96, 8.49 Hz, 1 H), 6.65 (d, >3.5 Hz, 1 H), 3.75 (t, >4.61 Hz, 4 H), 3.18 (t, >4.61 Hz, 4 H).

Préparation R2bo: 7-[3-(trifluoromethoxy)phenyl]-3H,4H,7H-pyrrolo[2,3 d] py rimidin-4-one 20 Using General Procedure 3 starting from Préparation Rlb and

3-(trifluoromethoxy)iodobenzene as reagents, Préparation R2bo was obtained. HRMS calculated for C13H8F3N3O2: 295.0569; found 296.0651 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.91 (s, 1 H), 8 (s, 1 H), 7.87 (t, 1 H), 7.82 (ddd, 1 H), 7.68 (t, 1 H), 7.6 (d, 1 H), 7.41 (ddd, 1 H), 6.71 (d, 1 H).

’³C-NMR (125 MHz, MSM-d6): δ (ppm) 145.1, 131.5, 123.9, 123.2, 119.5, 117.1, 104.1.

Préparation R2bp: 7-(3-methoxyphenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one ( J

-44Using General Procedure 3 starting from Préparation Rlb and 3-iodoanisole as reagents, Préparation R2bp was obtained. HRMS calculated for C13H11N3O2: 241.0851; found 242.0928 [(M+H)⁺ form].

'H-NMR (400 MHz, MSM-d6): δ (ppm) 12.1 (brs, 1 H), 7.95 (d, 1 H), 7.51 (d, 1 H), 7.44 5 (t, 1 H), 7.31 (m, 1 H), 7.3 (m, 1 H), 6.98 (dm, 1 H), 6.67 (d, 1 H), 3.82 (s, 3 H).

^l3C-NMR(100 MHz, MSM-d6): δ (ppm) 144.6, 130.4, 124.2, 116.7, 112.9, 110.5, 103.5.

Préparation R2bq: 7-[3-(benzyloxy)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and l-benzyloxy-3iodobenzene as reagents, Préparation R2bq was obtained. HRMS calculated for

C19H15N3O2: 317.1164; found 318.1235 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.1 (brs, 1 H), 7.95 (d, 1 H), 7.51 (d, 1 H), 7.517.31 (m, 5 H), 7.44 (t, 1 H), 7.41 (m, 1 H), 7.32 (dm, 1 H), 7.05 (dm, 1 H), 6.68 (d, 1 H), 5.18 (s, 2 H).

^,3C-NMR (125 MHz, MSM-d6): δ (ppm) 144.6, 130.5, 124.1, 116.8, 113.6, 111.4, 103.6, 15 70.

Préparation R2br: 7-(6-methylpyridin-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one Using General Procedure 3 starting from Préparation Rlb and 2-iodo-6-methylpyridine as reagents, Préparation R2br was obtained. HRMS calculated for C12H10N4O: 226.0855; found 227.0933 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 12 (brs, 1 H), 8.25 (dm, 1 H), 8.05 (s, 1 H), 7.9 (t, 1 H), 7.88 (d, 1 H), 7.25 (dm, 1 H), 6.68 (d, 1 H), 2.52 (s, 3 H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 144.9, 139.5, 122, 121.8, 113.8, 103.7, 24.4.

Préparation R2bs: 7-(6-methoxypyridin-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4one

The mixture of Préparation Rla (1.0 g, 6.51 mmol) ), 2-iodo-6-methoxy-pyridine (2.35 g, 9.77 mmol, 1.5 eq.), copper(I)-iodide (125 mg, 0.65 mmol, 0.1 eq.), potassium-phosphate tribasic (2.76 g, 13 mmol, 2 eq.), (U?,2^)-(-)-1,2-diaminocyclohexane (74 mg, 0.65 mmol, 0.1 eq.) in PDO (50 ml) was stirred under înert atmosphère for 4 hours at 100 °C. The

-45inorganics was filtered off and the filtrate was evaporated. The resulted residue was purified by flash chromatography (DCM).

The arylated product (920 mg, 3.5 mmol) and lithium-hydroxide monohydrate (1.48 g, mmol) were stirred in the mixture of PDO (15 ml) and water (15 ml) at 110 °C for 5 24 hours. The residue was acidified by aq. HCl solution (1 N, 50 ml) and the resulted precipitate was filtered off and dried to give Préparation R2bs. HRMS calculated for C12H10N4O2: 242.0804; found 243.0884 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 12.21 (brs, 1 H), 8.08 (dd, 1 H), 8.03 (s, 1 H), 7.94 (d, 1 H), 7.9 (t, 1 H), 6.78 (dd, 1 H), 6.7 (d, 1 H), 3.94 (s, 3 H).

^l3C-NMR (125 MHz, MSM-d6): δ (ppm) 163.2, 158.5, 147.6, 147.4, 144.9, 141.9, 121.9,

111.2, 108.4, 108.4, 103.8, 53.9.

Préparation R2bt: 7-(naphthaIen-l-yI)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 2 starting from Préparation Rla and 1-naphthaleneboronic acid as reagents, Préparation R2bt was obtained. HRMS calculated for C16H11N3O: 15 261.0902; found 262.0984 [(M+H)⁺ form], ’ll-NMR (500 MHz, MSM-d6): δ (ppm) 12.04 (s, 1 H), 8.12 (d, 1 H), 8.09 (d, 1 H), 7.78 (d, 1 H), 7.67 (t, 1 H), 7.61 (dm, 1 H), 7.6 (t, 1 H), 7.51 (tm, 1 H), 7.39 (d, 1 H), 7.21 (t, 1 H), 6.77 (d, 1 H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 158.9, 149.2, 144.6, 134.2, 134.1, 130.4, 129.5, 20 128.7, 127.8, 127.2, 126.4, 126.3, 126, 123, 108.7, 103.1

Préparation R2bu: 7-(pyridin-3-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 2 starting from Préparation Rla and pyridîne-3-boronic acid as reagents, Préparation R2bu was obtained. HRMS calculated for CnHgNiO: 212.0698; found 213.0774 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 12.29 (s, 1 H), 8.55 (dd, 1 H), 8.47 (dd, 1 H), 8.06 (brs, 1 H), 8.03 (t, 1 H), 7.9 (d, 1 H), 7.4 (t, 1 H), 6.7 (d, 1 H).

¹³C-NMR (125 MHz, MSM-d6): δ (ppm) 149.1, 145, 139.4, 122.5, 122, 116.9, 104.

^,SN-NMR (50.6 MHz, MSM-d6): δ (ppm) 171.2.

Préparation R2bv: 7-(pyridin-4-yl)-3H,4H,7H-pyrroIo[2,3-d]pyrimidin-4-one

Q

-46Using General Procedure 2 starting from Préparation Rla and pyridine-4-boronic acid pinacol ester as reagents, Préparation R2bv was obtained. HRMS calculated for CiiH₈N₄O: 212.0698; found213.0773 [(M+H)⁺ form].

'H-NMR (500 MHz, MSM-d6): δ ppm 12.31 (brs, 1 H), 8.69 (m, 2 H), 8.05 (s, 1 H), 7.99 5 (m, 2 H), 7.73 (d, 1 H), 6.76 (d, 1 H).

¹³C-NMR(125 MHz, MSM-d6): δ (ppm) 151.3, 145.6, 122.8, 117.3, 105.

Préparation R2bw: 7-[l-(dîfluoromethyl)-lH-pyrazol-4-yl]-3H,4H,7H-pyrrolo[2,3 d] pyrimidin-4-one

Using General Procedure 3 starting from Préparation Rlb and l-(difluoromethyl)-410 iodo-l/f-pyrazole as reagents, Préparation R2bw was obtained. HRMS calculated for C10H7F2N5O: 251.0619; found 252.0682 [(M+H)⁺ form].

'H-NMR (500 MHz, MSM-d6): δ (ppm) 11.88 (brs, 1 H), 8.83 (d, 1 H), 8.4 (d, 1 H), 8.03 (s, 1 H), 7.91 (t, 1 H), 7.58 (d, 1 H), 6.69 (d, 1 H).

^,3C-NMR(125 MHz, MSM-d6): δ (ppm) 145.2, 136.2, 123.2, 121.3, 111, 104.

Préparation R2bx: 7-(l-methyl-lH-pyrazol-4-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin4-one

Using General Procedure 3 starting from Préparation Rlb and 4-iodo-1 -methyl-\Hpyrazole as reagents, Préparation R2bx was obtained. HRMS calculated for C10H9N5O: 215.0807; found 216.0889 [(M+H)⁺ form], ‘H-NMR (500 MHz, MSM-d6): δ (ppm) 12.12 (brs, 1 H), 8.27 (s, 1 H), 7.96 (s, 1 H), 7.91 (d, 1 H), 7.42 (d, 1 H), 6.63 (d, 1 H), 3.89 (s, 3 H).

^!3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.6, 146.9, 144.7, 132.1, 124.3, 123.4, 121.4, 109, 103.4, 38.5.

Préparation R2by: 7-(propan-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and 2-iodopropane as reagents, Préparation R2by was obtained. HRMS calculated for C9H11N3O: 177.0902; found 178.0979 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 11.83 (brs, 1 H), 7.87 (s, 1 H), 7.24 (d, 1 H), 6.47 (d, 1 H), 4.85 (sept., 1 H), 1.42 (d, 6 H).

η

-47 ^,3C-NMR(125 MHz, MSM-d6): δ (ppm) 158.8, 146.8, 143.5, 120.7, 108.2, 102, 46.5, 23.

^!5N-NMR (50.6 MHz, MSM-d6): δ (ppm) 168.

Préparation R2ca: 7-cyclobutyI-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and cyclobutyl bromide as reagents, Préparation Rica was obtained. HRMS calculated for CioHhNsO: 189.0902; found 190.0974 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 11.85 (brs, 1 H), 7.88 (brs, 1 H), 7.09 (d, 1 H), 6.44 (d, 1 H), 3.70 (m, 1 H) ^l3C-NMR (125 MHz, MSM-d6): δ (ppm) 158.7, 147.7, 143.8, 125.1, 108.1, 101.7, 31.8.

Préparation R2cb: 7-(l-methylpiperidin-4-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4 one

Using General Procedure 4 starting from Préparation Rla and 4-hydroxy-lmethylpiperîdine as reagents, Préparation R2cb was obtained. HRMS calculated for Ci2H₁₆N4O: 232.1324; found 233.1405 [(M+H)⁺ form].

’H-NMR (500 MHz, MSM-d6): δ (ppm) 11.82 (brs, l H), 7.86 (d, 1 H), 7.29 (d, 1 H), 6.46 (d, 1 H), 4.44 (m, 1 H), 2.89/2.05 (m, 4 H), 2.22 (s, 3 H), 2.02/1.82 (m, 4 H).

ⁱ³C-NMR(125 MHz, MSM-d6): δ (ppm) 143.9, 121.2, 102.1,55.1,52.1,46.1,32.3.

Préparation R2cc: 7-(2,2-difluoroethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and 2-iodo-l,l20 difluoroethane as reagents, Préparation R2cc was obtained. HRMS calculated for C8H7N3OF2: 199.0557; found 200.0634 ((M+H)⁺ form].

’H-NMR (400 MHz, DMSO-d6) δ ppm 11.99 (brs, 1 H), 7.93 (s, 1 H), 7.16 (d, 1 H), 6.53 (d, 1 H), 6.37 (tt, 1 H), 4.6 (td, 2 H).

^I3C-NMR (400 MHz, DMSO-d6) δ ppm 144.4, 124.8, 114.3, 102.5, 46.2 .

Préparation R2cd: 7-(2-fluoroethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and l-fluoro-2-iodoethane as reagents, Préparation R2cd was obtained. HRMS calculated for CsHgNOF: 181.0651; found 182.0728 ((M+H)⁺ form].

I

-48¹ H-NMR (400 MHz, dmso-d6) δ ppm 11.91 (brs, 1 H), 7.9 (s, 1 H), 7.17 (d, 1 H), 6.49 (d,

I H), 4.74 (dt, 2 H), 4.43 (dt, 2 H).

¹³C-NMR(400 MHz, dmso-d6) δ ppm 144, 124.3, 102, 83.1, 45.1.

Préparation R2ce: 7-(2-hydroxyethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

Using General Procedure 1 starting from Préparation Rla and 2-chloroethanôl as reagents, Préparation R2ce was obtained. 'H-NMR (400 MHz, MSM-d6): δ (ppm) 11.83 (brs, 1 H), 7.86 (d, J=2.4 Hz, 1 H), 7.12 (d, J=3.92 Hz, 1 H), 6.43 (d, J=3.14 Hz, 1 H), 4.92 (t, J=5.49 Hz, 1 H), 4.15 (t, J=6.28 Hz, 2 H), 3.68 (q, J=5.49 Hz, 2 H).

Préparation R2cg: 7-[(4-chlorophenyI)methyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-410 one

Using General Procedure 1 starting from Préparation Rla and 4-chlorobenzyl bromide as reagents, Préparation R2cg was obtained. HRMS calculated for C13H10CIN3O: 259.0512; found 260.0583 [(M+H)⁺ form], 'H-NMR (400 MHz, MSM-d6): δ (ppm) 11.93 (s, 7.9 (s, 1 H), 7.39 (m, 2 H), 7.23 (m, 2 15 H), 7.22 (d, 1 H), 6.51 (d, 1 H), 5.34 (s, 2 H).

^,3C-NMR (100 MHz, MSM-d6): δ (ppm) 158.7, 147.4, 144.2, 137.5, 132.5, 129.5, 129,

124.2, 108.3, 102.4, 47.5.

Préparation R2ch: 7-[(3-chlorophenyl)methy 1]-3H,4H,7H-pyrrolo[2,3-d] py rimidi n-4one

Using General Procedure 1 starting from Préparation Rla and 3-chlorobenzyl bromide as reagents, Préparation R2ch was obtained. HRMS calculated for C13H10CIN3O: 259.0512; found 260.0580 [(M+H)⁺ form], 'H-NMR (500 MHz, MSM-d6): δ (ppm) 11.94 (brs, 1 H), 7.92 (d, 1 H), 7.35 (m, 1 H), 7.35 (m, 1 H), 7.28 (t, 1 H), 7.25 (d, 1 H), 7.16 (dm, 1 H), 6.51 (d, 1 H), 5.35 (s, 2 H).

¹³C-NMR (125 MHz, MSM-d6): 5 (ppm) 158.7, 147.6, 144.3, 140.9, 133.6, 131.1, 128, 127.5, 126.4, 124.3, 108.4, 102.4,47.5.

Préparation R2ci: 7-[(2-chlorophenyl)methyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4 one

(. )

-49Using General Procedure 1 starting from Préparation Rla and 2-chlorobenzyl bromide as reagents, Préparation R2ci was obtained. HRMS calculated for C13H10CIN3O: 259.0512; found 260.0587 [(M+H)⁺ form], 'H-NMR (400 MHz, MSM-d6): δ (ppm) 11.95 (brs, 1 H), 7.89 (d, 1 H), 7.5 (dm, 1 H), 5 7.32 (m, 1 H), 7.26 (m, 1 H), 7.17 (d, 1 H), 6.72 (dm, 1 H), 6.55 (d, 1 H), 5.44 (s, 2 H).

^,3C-NMR (100 MHz, MSM-d6): δ (ppm) 144.3, 129.8, 129.8, 128.8, 128.1, 124.5, 102.5, 46.

EXAMPLES

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

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(7-methyl-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 1)

Using General Procedure 5 starting from Préparation R2g and Préparation Rlc as reagents, Example 1 was obtained. HRMS calculated for C30H39N5O5: 549.2951; found 550.3021 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxothieno[2,3-d]pyrimidin-3yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 2)

Using General Procedure 5 starting from 3//-thieno[2,3-i/]pyrimidin-4-one and Préparation Rlc as reagents, Example 2 was obtained. HRMS calculated for C29H36N4O5S: 552.2406; found 553.2479 [(M+H) form], tert-butyl (3R,4R)-4-[4-[(7-ethyl-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylàte (Example 3)

Using General Procedure 5 starting from Préparation R2h and Préparation Rlc as reagents, Example 3 was obtained. HRMS calculated for C31H41N5O5: 563.3108; found 564.319 [(M+H) form].

“ tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-7-prop-2-ynyl-pyrrolo[2,3-d]pyrimidin-3yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 4)

Using General Procedure 5 starting from Préparation R2i and Préparation Rlc as reagents, Example 4 was obtained. HRMS calculated for C32H39N5O5: 573.2951; found 574.3024 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[(7-cyclopropyl-4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl)methyi]4-hydroxy-piperidine-l-carbonyl]-3-phenyI-piperidine-l-carboxylate (Example 5)

Using General Procedure 5 starting from Préparation R2j and Préparation Rlc as reagents, Example 5 was obtained. HRMS calculated for C32H41N5O5: 575.3108; found 576.3189 [(M+H) form].

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

Using General Procedure 5 starting from 7-chloro-377-thieno[3,4-t/]pyrimidin-4-one and Préparation Rlc as reagents, Example 6 was obtained. HRMS calculated for

C29H35CIN4O5S: 586.2017; found 609.1912 [(M+Na) form].

tert-butyl (3R,4R)-4- [4- [(7-buta-2,3-dieny 1-4-oxo-py rrolo [2,3-d] py rimidi n-3yl)methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 7)

Using General Procedure 5 starting from Préparation R2k and Préparation Rlc as reagents, Example 7 was obtained. HRMS calculated for C33H41N5O5: 587.3108; found 588.318 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(cyclopropylmethyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 8)

Using General Procedure 5 starting from Préparation R21 and Préparation Rlc as reagents, Example 8 was obtained. HRMS calculated for C33H43N5O5: 589.3264; found 590.3342 [(M+H) form], tert-butyl (3R,4R)-4- [4-hydroxy-4- [(7-iso buty 1-4-oxo-pyr rolo [2,3 -d] py rimidin -3yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 9)

Using General Procedure 5 starting from Préparation R2m and Préparation Rlc as reagents, Example 9 was obtained. HRMS calculated for C33H45N5O5: 591.342; found 592.3501 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(9-methy 1-4-oxo-py rimido [4,5-b] indol-3yl)methyI]piperidine-l-carbonyl]-3-plienyl-piperidine-l-carboxylate (Example 10)

Using General Procedure 5 starting from Préparation R2n and Préparation Rlc as reagents, Example 10 was obtained. HRMS calculated for C34H41N5O5: 599.3108; found 600.3181 [(M+H) form].

ί ! ο

I -52- tert-butyl (3R,4R)-4- [4-[ [7-(cyclobutylmethyl)-4-oxo-pyrrolo [2,3-d] pyrimidin-3- yl] methyl]-4-hyd roxy-pi pe ridine-1-carbonyl]-3-phenyl-pipe ridine-1-car boxylate (Example 11)

Using General Procedure 5 starting from Préparation R2o and Préparation Rlc as reagents, Example 11 was obtained. HRMS calculated for C34H45N5O5: 603.342; found 604.3502 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(2-dimethylaminoethyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-

3-yi] methyl] -4-hyd roxy-piperidine- 1-carbonyl] -3-phenyl-piperidine-l-carboxylate (Example 12)

Using General Procedure 5 starting from Préparation R2p and Préparation Rlc as reagents, Example 12 was obtained. HRMS calculated for C33H46N6O5: 606.353; found 607.36 [(M+H) form].

tert-b uty 1 (3R,4R)-4- [4-hydroxy-4- [(4-oxo-7-pheny 1-py r rolo [2,3-d ] py rimid in-3yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 13)

Using General Procedure 5 starting from Préparation R2q and Préparation Rlc as reagents, Example 13 was obtained. HRMS calculated for C35H41N5O5: 611.3108; found 612.3192 [(M+H) form], tert-b uty 1 (3R,4R)-4- [4-hyd roxy-4- [(4-oxo-7-pheny l-5H-py r rolo [3,2-d] py r im idi n-3yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 14)

Using General Procedure 5 starting from 7-phenyl-3,5-dihydropyrrolo[3,2-i7]pyrimidin-4one and Préparation Rlc as reagents, Example 14 was obtained. HRMS calculated for C35H41N5O5: 611.3108; found 612.3182 [(M+H) form].

tert-butyl (3R,4R)-4- [4-hyd roxy-4- [[4-oxo-7-(2-pyridyl)pyrrolo [2,3-d] pyrimidin-3yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 15)

Using General Procedure 5 starting from Préparation R2b and Préparation Rlc as reagents, Example 15 was obtained. HRMS calculated for C34H40N6O5: 612.306; found 613.3132 [(M+H) form].

tert-b utyl (3R,4R)-4- [4-hyd roxy-4- [(4-oxo-1 -ph eny 1-py razolo [3,4-d] py rimidin-5yl)metliyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 16)

Using General Procedure 5 starting from l-phenyl-577-pyrazolo[3,4-<7|pyrimidin-4-one and Préparation Rlc as reagents, Example 16 was obtained. HRMS calculated for

C34H40N6O5: 612.306; found 613.312 [(M+H) form], tert-butyl (3R,4R)-4- [4-hyd roxy-4- [(6-oxo-9-pheny l-p u r in-1 -y l)methy 1] pi peridine-1carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 17)

Using General Procedure 5 starting from 9-phenyl-177-purin-6-one and Préparation Rlc as reagents, Example 17 was obtained. HRMS calculated for C34H40N6O5: 612.306; found 10 613.3142 [(M+H) form], tert-butyl (3R,4R)-4-[4-[(7-bromo-4-oxo-pyrrolo[2,l-f| [l,2,4]triazin-3-yI)methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 18)

Using General Procedure 5 starting from 7-bromo-3//-pyrrolo[2,l-y][l,2,4]triazÎn-4-one and Préparation Rlc as reagents, EXAMPLE 18 was obtained. HRMS calculated for 15 C29H₃6BrN₅O5: 613.19; found 612.1851 [(M-H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(7-oxo-3-phenyl-isoxazolo[4,5-d]pyrimidin-6yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 19)

Using General Procedure 5 starting from 3-phenyl-6/7-isoxazolo[4,5-i/]pyrimidin-7-one and Préparation Rlc as reagents, Example 19 was obtained. HRMS calculated for 20 C34H39N5O6: 613.29; found 636.2782 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-7-pyrimidin-2-yl-pyrrolo[2,3-d] pyrimidin-3-yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 20)

Using General Procedure 5 starting from Préparation R2s and Préparation Rlc as reagents, Example 20 was obtained. HRMS calculated for C33H39N7O5: 613.3013; found

614.3102 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(7-oxo-3-phenyl-triazolo[4,5-d]pyrimidin-6yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 21)

Using General Procedure 5 starting from 3-phenyl-6//-triazolo[4,5-rf]pyrimidin-7-one and Préparation Rlc as reagents, Example 21 was obtained. HRMS calculated for

C33H39N7O5: 613.3013; found 614.3095 [(M+H) form], tert-butyl (32î,4_JR)-4-({4-[(6,8-diniethyl-4-oxopyriinido[5,4-i']indolizin-3(4£?)yl)methyl]-4-hydroxypiperidin-l-yl}carbonyl)-3-phenylpiperidine-l-carboxyIate (Example 22)

Using General Procedure 5 starting from Préparation R2t and Préparation Rlc as reagents, Example 22 was obtained. HRMS calculated for C34H42N6O5: 614.3217; found 615.3301 [(M+H) form], tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(l-methylimidazol-4-yl)-4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 23)

Using General Procedure 5 starting from Préparation R2u and Préparation Rlc as reagents, Example 23 was obtained. HRMS calculated for C33H41N7O5: 615.3169; found 616.324 [(M+H) form].

tert-butyl (3R,4R)-4- [4-hyd roxy-4- [ [4-oxo-7-(3-thieny 1) py r rolo [2,3-d] py r imi d in-3yl] methyl] piperidine-1-carbonyl] -3-phenyl-piperidine-l -carboxylate (Example 24)

Using General Procedure 5 starting from Préparation R2v and Préparation Rlc as reagents, Example 24 was obtained. HRMS calculated for C33H39N5O5S: 617.2672; found 618.2736 [(M+H) form], tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-(2-thienyl)pyrrolo[2,3-d]pyrimidin-3yI]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 25)

Using General Procedure 5 starting from Préparation R2w and Préparation Rlc as reagents, Example 25 was obtained. HRMS calculated for C33H39N5O5S: 617.2672; found 618.2744 [(M+H) form].

ter t-buty 1 (3 R,4R)-4- [4-hydroxy-4- [[4-oxo-7-(2,2,2-tr iflu oroethyl)py r rolo [2,3-d] pyrimidîn-3-yl]methyl]piperidine-l-carbonyI]-3-phenyl-piperidine-l-carboxylate (Example 26)

Using General Procedure 5 starting from Préparation R2x and Préparation Rlc as reagents, EXAMPLE 26 was obtained. HRMS calculated for C31H38F3N5O5: 617.2825; found 618.2912 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-7-thiazol-2-yl-pyrrolo[2,3-d]pyrimidin-3yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 27)

Using General Procedure 5 starting from Préparation R2y and Préparation Rlc as reagents, Example 27 was obtained. HRMS calculated for C32H3.8N6O5S: 618.2625; found 641.251 [(M+Na) form].

tert-b uty 1 (3R,4R)-4- [4- [ [7- [3-(dimethylamino)p ropyl] -4-oxo-pyr rolo [2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 28)

Using General Procedure 5 starting from Préparation R2z and Préparation Rlc as reagents, Example 28 was obtained. HRMS calculated for C34H48N6O5: 620.3686; found 621.3731 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(m-tolyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yI]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 29)

Using General Procedure 5 starting from Préparation R2aa and Préparation Rlc as reagents, Example 29 was obtained. HRMS calculated for C36H43N5O5: 625.3264; found

626.3357 [(M+H) form], tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-(p-tolyl)pyrrolo[2,3-d]pyrimidin-3- yl] methyl] piperid in e- 1-ca rbonyl] -3-phenyl-piperid ine- 1-carboxylate (Example 30)

Using General Procedure 5 starting from Préparation R2ab and Préparation Rlc as reagents, Example 30 was obtained. HRMS calculated for C36H43N5O5: 625.3264; found

626.3358 [(M+H) form].

tert-butyl (3R,4R)-4- [4- [(7-benzyI-4-oxo-pyrrolo [2,3-d] pyrimidin-3-yl)methyl] -4hydroxy-piperidine-1 -carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 31)

Using General Procedure 5 starting from Préparation R2ac and Préparation Rie as reagents, Example 31 was obtained. HRMS calculated for C36H43N5O5: 625.3264; found

626.3343 [(M+H) form], tert-butyl (3R,4R)-4-[4-hydroxy-4-[(6-methyl-4-oxo-7-phenyl-pyrrolo[2,3-d] pyrimidin-3-yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 32)

Using General Procedure 5 starting from Préparation R2ad and Préparation Rlc as reagents, Example 32 was obtained. HRMS calculated for C36H43N5O5: 625.3264; found 626.3335 [(M+H) form], tert-butyl (3R,4R)-4-[4-hydroxy-4-[(7-oxo-3-phenyl-isothiazolo[4,5-d]pyrimidin-6yl)methyl]piperïdine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 33)

Using General Procedure 5 starting from 3-phenyl-6/7-isothiazolo[4,5-(/]pyrimidin-7-one 15 and Préparation Rlc as reagents, Example 33 was obtained. HRMS calculated for C34H39N5O5S: 629.2672; found 652.2559 [(M+Na) form], tert-butyl (3R,4R)-4-[4-[[7-(4-fluorophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 34)

Using General Procedure 5 starting from Préparation R2ae and Préparation Rlc as reagents, Example 34 was obtained. HRMS calculated for C35H40FN5O5: 629.3013; found 530.2568 [(M+H-Boc) form].

tert-butyl (3R,4R)-4-[4-[[7-(3-fluorophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 35)

Using General Procedure 5 starting from Préparation R2bl and Préparation Rlc as reagents, Example 35 was obtained. HRMS calculated for C35H40FN5O5: 629.3013; found 652.2909 [(M+Na) form].

Ο tert-butyl (3R,4R)-4-[4-[(7-bromo-4“Oxo-thieno[3,2-d]pyrimÎdin-3-yl)methyl]-4hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 36)

Using General Procedure 5 starting from 7“bromo-3H-thieno[3,2-iZ]pyrimidin-4-one and

Préparation Rlc as reagents, Example 36 was obtained, HRMS calculated for 5 C2₉H35BrN4O₅S: 630.1511; found 653.1419 [(M+Na) form].

tert-butyl (3R,4R)-4- [4-hydroxy-4- [ [7-(5-metliyl-2-thienyl)-4-oxo~pyrrolo [2,3-d] pyrimidin-3-yl]methyI]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 37)

Using General Procedure 5 starting from Préparation R2bc and Préparation Rlc as reagents, Example 37 was obtained. HRMS calculated for C34H41N5O5S: 631.2828; found 654.2719 [(M+Na) form], tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(l-methyl-4-piperidyl)-4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 38)

Using General Procedure 5 starting from Préparation R2cb and Préparation Rlc as reagents, Example 38 was obtained. HRMS calculated for C35H48N6O5: 632,3686; found 633.3766 [(M+H) form], tert-butyl (3R,4R)-4-[4-[[7-(4-cyanophenyl)-4-oxo-py rrolo[2,3 -d ] py rimid in-3- yl] methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 39)

Using General Procedure 5 starting from Préparation R2au and Préparation Rlc as reagents, Example 39 was obtained. HRMS calculated for C36H40N6O5: 636.306; found 637.3127 [(M+H) form].

tert-butyl (3R,4R)-4- [4-hyd roxy-4- [ [7-(4-methoxyphenyl)-4-oxo-pyrrolo [2,3-d] pyrimidin-3-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 40)

Ο

-58Using General Procedure 5 starting from Préparation R2c and Préparation Rlc as reagents, Example 40 was obtained. HRMS calculated for C36H43N5O6: 641.3214; found 642.3297 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(3-methoxyphenyI)-4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl] methyl] piperidine-l-carbonyl]-3-phenyi-piperidine-l-carboxylate (Example 41)

Using General Procedure 5 starting from Préparation R2bp and Préparation Rlc as reagents, Example 41 was obtained. HRMS calculated for C36H43N5O6: 641.3214; found 642.3313 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-[4-(hydroxymethyl)phenyl]-4-oxopyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 42)

Using General Procedure 5 starting from Préparation R2ax and Préparation Rlc as reagents, Example 42 was obtained. HRMS calculated for C36H43N5O6: 641.3214; found 15 642.3288 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[6-(hydroxymethyI)-4-oxo-7-phenyI-pyrrolo [2,3-d]pyrimidin-3-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 43)

Préparation Rlb (10 g, 67.05 mmol, 1 eq.), iodobenzene (87.2 mmol, 1.3 eq.), Cul 20 (1.28 g, 190.45, 6,705 mmol, 0.1 eq.), DMEDA (1.45 ml, 13,4 mmol, 1,18 g, 0.2 eq.), anhydrous K2CO3 (12.05 g, 87.16 mmol, 1.3 eq.) was suspended in dry acetonitrile (50 ml), flushed with N2 and stirred at 80 °C for 1.5 h. After the reaction completed, the mixture was diluted with water (200 ml) and cooled to r.t. The mixture was fîltered, and washed with water (3 x 30 ml), aq. NH3 solution (40 ml, 25%), water (3 x 50 ml), heptane 25 (50 then 30 ml) and dried in vacuum.

A flame dried 3-necked round flask was charged with 5 ml dry THF under N₂ atmosphère.

420 μΐ (1.5 eq.) iP^NH was added via a syringe and the round flask was cooled to -78°C.

1.25 ml (1.5 eq.) h-BuLï was added via a syringe and stirred for 30 minutes. Then 4-methoxy-7-phenyl-pyrrolo[2,3-<7]pyrimidine obtained in previous step (450 mg, 2 mmol,

- 591 eq.) dîssolved in 20 ml dry THF was added dropwise and stirred for 1 hour. Then methyl formate (360 mg, 3 eq.) was added dîssolved in 10 ml dry THF. After the reaction was completed 40 ml sat. NH4CI was added and extracted with 3 x 40 ml EEO, dried, filtered and evaporated. Flash chromatography with Hexane:EEO gave (4-methoxy-7-phenyl5 pyrrolo[2,3-(7]pyrimidin-6-yl)methanol.

A part of the crude product (127 mg, 0.5 mmol) was dîssolved in 2.5 ml PDO and cc. HCl (82 pL, 1 mmol, 2 eq.) was added. The solution was heated, stirred at 100 °C for 2 hours, and it was evaporated to give 6-(hydroxymethyl)-7-phenyl-3Zf-pyrrolo[2,3-tf]pyrimidin-4one which was reacted according to General Procedure 5 with Préparation Rlc as 10 reagents to give Example 43. HRMS calculated for C36H43N5O6: 641.3214; found 642.3295 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[l-(4-methoxyphenyI)-4-oxo-pyrazolo[3,4-d] pyrimidin-5-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 44)

Using General Procedure 5 starting from l-(4-mcthoxyphenyl)-5H-pyrazolo[3,4-<7] pyrimidin-4-one and Préparation Rlc as reagents, Example 44 was obtained. HRMS calculated for C35H42N6O6: 642.3166; found 665.3057 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(6-methoxy-2-pyridyl)-4-oxo-pyrrolo[2,3-d] py ri midin-3-y 1] methy 1] piperidi n e-1-car bony 1]-3-ph eny 1-pi peridine-1-car boxy late (Example 45)

Using General Procedure 5 starting from Préparation R2bs and Préparation Rlc as reagents, Example 45 was obtained. HRMS calculated for C35H42N6O6: 642.3166; found 643.3231 [(M+H) form], ter t-b uty 1 (3R,4R)-4- [4- [ [7-(4-ch lor ophenyl)-4-oxo-py r rolo [2,3-d] py rimidin-3 25 yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 46)

Using General Procedure 5 starting from Préparation R2ay and Préparation Rlc as reagents, Example 46 was obtained. HRMS calculated for C35H40CIN5O5: 645.2718; found 646.2787 [(M+H) form].

tert-butyl (3R,4R)-4- [4- [ [7-(3-chlorophenyl)-4-oxo-py rrolo [2,3-d] pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 47)

Using General Procedure 5 starting from Préparation R2bk and Préparation Rlc as reagents, Example 47 was obtained. HRMS calculated for C35H40CIN5O5: 645.2718; found 646.2821 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[(6-chloro-4-oxo-7-phenyl-pyrrolo[2,3-d]pyrimidin-3yl)methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 48)

Using General Procedure 5 starting from Préparation R2ai and Préparation Rlc as reagents, Example 48 was obtained. HRMS calculated for C35H40CIN5O5: 645.2718; found 646.2782 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(5-chIoro-2-thienyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 49)

Using General Procedure 5 starting from Préparation R2bd and Préparation Rlc as reagents, Example 49 was obtained. HRMS calculated for C33H38CIN5O5S: 651.2282; found 652.2348 [(M+H) form].

’ tert-butyl (3R,4R)-4- [4- [ [7- [l-(difluoromethyl)pyrazol-4-yl] -4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 50)

Using General Procedure 5 starting from Préparation R2bw and Préparation Rlc as reagents, Example 50 was obtained. HRMS calculated for C33H39F2N7O5: 651.2981; found 674.2867 [(M+Na) form], tert-butyl (3R,4R)-4-[4-[[7-(4-dimethylaminophenyl)-4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidme-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 51)

-61 Using General Procedure 5 starting from Préparation R2az and Préparation Rlc as reagents, Example 51 was obtained. HRMS calculated for C37H46N6O5: 654.353; found

655.3589 [(M+H) form], tert-butyl (3R,4R)-4- [4- [ [7- [3 - (d imethy lamino) phcny 1] -4-oxo-py rrolo [2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 52)

Using General Procedure 5 starting from Préparation R2bm and Préparation Rlc as reagents, Example 52 was obtained. HRMS calculated for C37H46N6O5: 654.353; found 655.3602 [(M+H) form], tert-butyl (3R,4R)4-[4-[[7-(l,3-benzodioxol-5-yl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 53)

Using General Procedure 5 starting from Préparation R2bf and Préparation Rlc as reagents, Example 53 was obtained. HRMS calculated for C36H41N5O7: 655.3006; found 15 655.3006 [(M+H) form], ’ tert-b utyl (3R,4R)-4- [4- [ [7- [(2-ch loro phenyl)methy 1] -4-oxo-pyrrolo [2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 54)

Using General Procedure 5 starting from Préparation R2ci and Préparation Rlc as 20 reagents, Example 54 was obtained. HRMS calculated for C36H42N5O5CI: 659.2875;

found 660.2949 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-[(3-chlorophenyl)methyl]-4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 55)

Using General Procedure 5 starting from Préparation R2ch and Préparation Rlc as reagents, Example 55 was obtained. HRMS calculated for C36H42CIN5O5: 659.2875; found 660.2933 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-[(4-chlorophenyl)methyl]-4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 56)

Using General Procedure 5 starting from Préparation R2cg and Préparation Rlc as reagents, Example 56 was obtained. HRMS calculated for C36H42CIN5O5: 659.2875; found 660.2949 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(4-fluoro-3-methoxy-phenyl)-4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 57)

Using General Procedure 5 starting from Préparation R2e and Préparation Rlc as reagents, Example 57 was obtained. HRMS calculated for C36H42FN5O6: 659.3119; found 660.3194 [(M+H) form], tert-butyl (3R,4R)-4- [4- [ [7- [4-(difluoromethy 1)phenyI] -4-oxo-pyrrolo [2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l- carboxylate (Example 58)

Using General Procedure 5 starting from Préparation R2aw and Préparation Rlc as reagents, Example 58 was obtained. HRMS calculated for C36H41F2N5O5: 661.3076; found 662.3141 [(M+H) form].

tert-butyl (3R,4R)-4- [4-hydroxy-4- [ [7-(l -naphthyl)-4-oxo-pyrrolo [2,3-d] pyrimidin-

3-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 59)

Using General Procedure 5 starting from Préparation R2bt and Préparation Rlc as reagents, Example 59 was obtained. HRMS calculated for C39H43N5O5: 661.3264; found 662.3345 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(2-naphthyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-

3-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 60)

Using General Procedure 5 starting from Préparation R2bg and Préparation Rlc as reagents, Example 60 was obtained. HRMS calculated for C35H35N5O5: 661.3264; found 606.2715 [(M+H-C(CH3)3) form].

tert-butyl (3R,4R)-4-[4-[[7-(4-chloro-3-fluoro-phenyl)-4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 61)

Using General Procedure 5 starting from Préparation R2ar and Préparation Rlc as reagents, Example 61 was obtained. HRMS calculated for C35H39CIFN5O5: 663.2624; found 564.218 [(M+H-Boc) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-(2trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-lcarbonyl]-3-phenyl-piperidine-l-carboxylate (Example 62)

Using General Procedure 5 starting from 7-(2-trimethylsilylethoxymethyl)-377pynOlo[2,3-iflpyrimidin-4-one and Préparation Rlc as reagents, Example 62 was obtained. HRMS calculated for C35H51N5O6S1: 665.3609; found 666.3696 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(2,3-dihydro-l,4-benzodioxin-6-yl)-4-oxo-pyrrolo[2,3-d] pyrimÎdin-3-yl]methyl]-4-hydroxy-piperidÎne-l-carbonyl]-3-phenyl-piperidine-l- carboxylate (Example 63)

Using General Procedure 5 starting from Préparation R2be and Préparation Rlc as reagents, Example 63 was obtained. HRMS calculated for C37H43N5O7: 669.3162; found 670.3238 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[l-(2,3-dihydro-l,4-benzodioxin-6-yl)-4-oxo-pyrazolo[3,4-d] pyrimidin-5-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 64)

Using General Procedure 5 starting from l-(2,3-dihydro-l,4-benzodioxin-6-yl)-577pyrazolo[3,4-iZ|pyrimidin-4-one and Préparation Rlc as reagents, Example 64 was obtained. HRMS calculated for C36H42N6O7: 670.3115; found 693.3019 [(M+Na) form], tert-butyl (3R,4R)-4-[4-[[7-(3,4-dimethoxyphenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 65)

-64Using General Procedure 5 starting from Préparation R2at and Préparation Rlc as reagents, Example 65 was obtained. HRMS calculated for C37H45N5O7: 671.3319; found 672.3396 [(M+H) form], tert-butyl (3R,4R)-4-[4-[[7-(3,5-dimethoxyphenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3- yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 66)

Using General Procedure 5 starting from Préparation R2ap and Préparation Rlc as reagents, Example 66 was obtained. HRMS calculated for C37H45N5O7: 671.3319; found 672.3401 [(M+H) form], tert-butyl (3R,4R)-4-[4-hydroxy-4-[(6-iodo-7-methyl-4-oxo-pyrrolo[2,3-d]pyrimidin3-yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 67)

Using General Procedure 5 starting from Préparation R2aj and Préparation Rlc as reagents, Example 67 was obtained. HRMS calculated for C30H38IN5O5: 675.1918; found 676.1994 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(3-chloro-5-methoxy-phenyl)-4-oxo-pyrrolo[2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-lcarboxylate (Example 68)

Using General Procedure 5 starting from Préparation R2ao and Préparation Rlc as reagents, Example 68 was obtained. HRMS calculated for C36H42CIN5O6: 675.2823;

found 676.2891 [(M+H) form], tert-butyl (3R,4R)-4- [4- [ [7-(4-chloro-3- methoxy-ph enyl)-4-oxo-pyrrolo [2,3-d] pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-l-carbonyI]-3-phenyl-piperidine-lcarboxylate (Example 69)

Using General Procedure 5 starting from Préparation R2as and Préparation Rlc as reagents, Example 69 was obtained. HRMS calculated for C36H42CIN5O6: 675.2823; found 676.2885 [(M+H) form].

) tert-butyl (3R,4R)-4-[4-[[7-(3,4-dichlorophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 70)

Using General Procedure 5 starting from Préparation R2aq and Préparation Rlc as 5 reagents, Example 70 was obtained. HRMS calculated for C35H39CI2N5O5: 679.2328;

found 680.2399 [(M+H) form], tert-butyl (3R,4R)-4-[4-[[7-(3,5-dichlorophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 71)

Using General Procedure 5 starting from Préparation R2an and Préparation Rlc as reagents, Example 71 was obtained. HRMS calculated for C35H39CI2N5O5: 679.2328; found 680.2399 [(M+H) form].

tert-butyl (3R,4R)-4- [4-hydroxy-4- [[4-oxo-7- [4-(trifluoromethyl)phenyl] pyrrolo [2,3-d]pyrimidin-3-yl]methyI]piperidine-l-carbonyl]-3-phenyl-piperidine-l- carboxylate (Example 72)

Using General Procedure 5 starting from Préparation R2av and Préparation Rlc as reagents, Example 72 was obtained. HRMS calculated for C36H40F3N5O5: 679.2982; found 680.3068 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-[3-(trifluoromethyl)phenyl]pyrrolo

[2,3-d]pyrimidin-3-yl]methyl]piperidine-l-carbonyl]-3-plienyl-piperidine-lcarboxylate (Example 73)

Using General Procedure 5 starting from Préparation R2bh and Préparation Rlc as reagents, Example 73 was obtained. HRMS calculated for C36H40F3N5O5: 679.2982; found 702.2875 [(M+Na) form], tert-butyl (3R,4R)-4-[4-hydroxy-4-[[6-iodo-4-oxo-7-(2tri methy Isilylethoxy methy l)py rrolo [2,3-d] py rimidin-3-y I] methyl] piperid in e-1 carbonyI]-3-phenyl-piperidine-l-carboxylate (Example 74)

-66Using General Procedure 5 starting from Préparation R2al and Préparation Rlc as reagents, Example 74 was obtained. HRMS calculated for CssHsolNsOôSi: 791.2575; found 792.265 [(M+H) form], tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-[3- (triflu oromethoxy)pheny 1] py r rolo [2,3-d] py rimidin-3-y 1] methyl] piperid in e-1carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 75)

Using General Procedure 5 starting from Préparation R2bo and Préparation Rlc as reagents, Example 75 was obtained. HRMS calculated for C36H40F3N5O6: 695.2931; found 696.2997 [(M+H) form].

· tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-[4(trifluoromethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-lcarbonyl]-3-phenyl-piperidine-l-carboxylate (Example 76)

Using General Procedure 5 starting from Préparation R2ba and Préparation Rlc as reagents, Example 76 was obtained. HRMS calculated for C36H40F3N5O6: 695.2931;

found 696.3006 [(M+H) form].

tert-butyl (3R,4R)-4- [4-hyd roxy-4-[ [7-(3-morpholinoph enyl)-4-oxo-pyrrolo [2,3 -d] pyrimidin-3-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 77)

Using General Procedure 5 starting from Préparation R2bn and Préparation Rlc as reagents, Example 77 was obtained. HRMS calculated for C39H48N6O6: 696.3635; found 697.3708 [(M+H) form], tert-butyl (3R,4R)-4- [4-hy droxy-4- [ [4-oxo-7-(3,4,5-tr imethoxy ph eny i)py r rolo [2,3-d] pyrimidin-3-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 78)

Using General Procedure 5 starting from Préparation R2am and Préparation Rlc as reagents, Example 78 was obtained. HRMS calculated for C38H47N5O8: 701.3425; found 702.3487 [(M+H) form].

Ο tert-butyl (3R,4R)-4-[4-[[7-(4-benzyloxyphenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 79)

Using General Procedure 5 starting from Préparation R2bb and Préparation Rie as reagents, Example 79 was obtained. HRMS calculated for C42H47N5O6: 717.3527; found 718.3603 [(M+H)form].

tert-butyl (3R,4R)-4-[4-[[7-(3-benzyloxyphenyI)-4-oxo-pyrrolo[2,3-d]pyrimidin-3yl]methyl]-4-hydroxy-piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 80)

Using General Procedure 5 starting from Préparation R2bq and Préparation Rlc as reagents, Example 80 was obtained. HRMS calculated for C42H47N5O6: 717.3527; found 740.3423 [(M+Na) form].

tert-butyl (3R,4R)-4- [4-hydroxy-4- [ [7- [3- [(4-methylpiperazin- 1-yl)methy 1] phenyl] -4oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-

1-carboxylate (Example 81)

Using General Procedure 5 starting from Préparation R2bi and Préparation Rlc as reagents, Example 81 was obtained. HRMS calculated for C41H53N7O5: 723.4108; found 724.4175 [(M+H)form].

tert-butyl (3R,4R)-4-[4-[[6-cyano-4-oxo-7-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxypiperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 82)

Example 74 was dissolved in PDO and copper cyanide (4.2 eq), tetraethylammonium cyanide (1.05 eq.), Pd2(dba)3 (0.1 eq.), and l,r-bis(diphenylphosphino)ferrocene (0.4 eq.) were added. The mixture was heated and stirred at 110 °C till the reaction was completed.

The residue was purified by flash chromatography in DCM-MeOH gradient to give

Example 82. HRMS calculated for CaôHsoNeOèSi: 690.3561; found 691.3637 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7Hpyirolo[2,3-d]pyrimidin-4-one (Example 83)

Using General Procedure 5 starting from 77ï-pyrrolo[2,3-i7jpyrimidin-4-one and

Préparation Rlc as reagents, the resulted Boc-protected crude product was reacted using 5 General Procedure 6, to give Example 83 as HCl sait. HRMS calculated for

C24H29N5O3: 435.2271; found 436.2345 [(M+H) form],

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7methyl-pyrroIo[2,3-d]pyrimidin-4-one (Example 84)

Using General Procedure 6 starting from Example 1 as reagent, Example 84 was 10 obtained as HCl sait. HRMS calculated for C25H31N5O3: 449.2427; found 450.2517

[(M+H) form].

- [ [4-hyd roxy-1- [(3R,4R)-3 -phenylpiper id i ne-4-car bonyl] -4piperidyl]methyl]thieno[2,3-d]pyrimidin-4-one (Example 85)

Using General Procedure 6 starting from Example 2 as reagent, Example 85 was 15 obtained as HCl sait. HRMS calculated for C24H28N4O3S: 452.1882; found 453.1933

[(M+H) form].

7-ethyl-3- [[4-hydroxy-l - [(3R,4R)-3-pheny Ipiper idine-4-ca r bonyl] -4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 86)

Using General Procedure 6 starting from Example 3 as reagent, Example 86 was 20 obtained as HCl sait. HRMS calculated for C26H33N5O3: 463.2583; found 464.2654

[(M+H) form].

3- [[4-hydroxy-1 - [(3R,4R)-3-pheny Ipiperidine-4-carbonyl] -4-piperidy 1] methy 1] -7prop-2-ynyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 87)

Using General Procedure 6 starting from Example 4 as reagent, Example 87 was obtained as HCl sait. HRMS calculated for C27H₃iN5O₃: 473.2427; found 474.2502

[(M+H) form].

7-cyclopropyl-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl] methy l]pyr rolo [2,3-d]pyrimidin-4-one (Example 88)

Using General Procedure 6 starting from Example 5 as reagent, Example 88 was obtained as HCl sait. HRMS calculated for C27H33N5O3: 475.2583; found 476.2668

[(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7isopropyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 89)

Using General Procedure 5 starting from Préparation R2by and Préparation Rlc as reagents, the resulted Boc-protected crude product was reacted using General 10 Procedure 6, to give Example 89 as HCl sait. HRMS calculated for C27H35N5O3: 477.274; found 478.2819 [(M+H) form].

7-(2-hydroxyethyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrrok»[2,3-d]pyrimidin-4-one (Example 90)

Using General Procedure 5 starting from Préparation R2ce and Préparation Rlc as 15 reagents, the resulted Boc-protected crude product was reacted using General

Procedure 6, to give Example 90 as HCl sait. HRMS calculated for C26H33N5O4: 479.2533; found (NMR available form].

7-(2-fluoroethyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 91)

Using General Procedure 5 starting from Préparation R2cd and Préparation Rlc as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give Example 91 as HCl sait. HRMS calculated for C26H32N5O3F: 481.2489; found 482.2555 [(M+H) form],

7-chloro-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyI]-4- piperidyl] methyl] thieno [3,4-d] pyrimidin-4-one (Example 92)

Using General Procedure 6 starting from Example 6 as reagent, Example 92 was obtained as HCl sait. HRMS calculated for C24H27CIN4O3S: 486.1492; found 487.1544 [(M+H) form].

7-buta-2,3-dienyl-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 93)

Using General Procedure 6 starting from Example 7 as reagents, Example 93 was obtained as HCl sait. HRMS calculated for C28H33N5O3: 487.2583; found 488.2657

[(M+H) form],

7-cyclobutyl-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 94)

Using General Procedure 5 starting from Préparation R2ca and Préparation Rie as reagents, the resulted Boc-protected crude product was reacted using General 10 Procedure 6, to give Example 94 as HCl sait. HRMS calculated for C28H35N5O3: 489.274; found 490.2796 [(M+H) form].

7-(cyclopropylmethyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-earbonyl]-4piperidyl]methyl]pyrrolo[2,3-d]pyrimîdîn-4-one (EXAMPLE 95)

Using General Procedure 6 starting from Example 8 as reagent, Example 95 was 15 obtained as HCl sait. HRMS calculated for C28H35N5O3: 489.274; found 490.2817 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyI]-4-piperidyl]methyI]-7isobutyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 96)

Using General Procedure 6 starting from Example 9 as reagent, Example 96 was 20 obtained as HCl sait. HRMS calculated for C28H37N5O3: 491.2896; found 492.2963

[(M+H) form],

-(2,2-difluoroethyl)-3- [ [4-hydroxy-l - [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 97)

Using General Procedure 5 starting from Préparation R2cc and Préparation Rlc as 25 reagents, the resulted Boc-protected crude product was reacted using General

Procedure 6, to give Example 97 as HCl sait. HRMS calculated for C26H31N5O3F2: 499.2395; found 500.2485 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-9methyl-pyrimido[4,5-b]indol-4-one (Example 98)

Using General Procedure 6 starting from Example 10 as reagent, Example 98 was obtained as HCl sait. HRMS calculated for C29H33N5O3: 499.2583; found 500.2677 5 [(M+H) form],

7-(cyclobuty Imethy l)-3- [ [4-hy d roxy-1 - [(3R,4R)-3-pheny Ipipe ridine-4-carbonyl] -4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 99)

Using General Procedure 6 starting from Example 11 as reagent, Example 99 was obtained as HCl sait. HRMS calculated for C29H37N5O3: 503.2896; found 504.2957 10 [(M+H) form].

7-{2-dimethylaminoethyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl] -4-piperidyl] methy 1] pyrrolo[2,3-d] pyrimidin-4-one (Example 100)

Using General Procedure 6 starting from Example 12 as reagent, Example 100 was obtained as HCl sait. HRMS calculated for C28H38N6O3: 506.3005; found 254.1581 15 [(M+2H)2+form].

- [ [4- hydroxy-1 - [(3R,4R)-3-phenylpi peridine-4-car bonyl] -4-pipe ridy 1] methy 1]-7 phenyl-pyrrolo[2,3-d]pyrÎmidÎn-4-one (Example 101)

Using General Procedure 6 starting from Example 13 as reagent, Example 101 was obtained as HCl sait. HRMS calculated for C30H33N5O3: 511.2583; found 512.2648 20 [(M+H) form],

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-one (Example 102)

Using General Procedure 6 starting from Example 14 as reagents, Example 102 was obtained as HCl sait. HRMS calculated for C30H33N5O3: 511.2583; found 512.2647 25 [(M+H) form].

π

5-[[4-hyd roxy-1- [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] -1phenyI-pyrazolo[3,4-d]pyrimidin-4-one (Example 103)

Using General Procedure 6 starting from Example 16 as reagent, Example 103 was obtained as HCl sait. HRMS calculated for C29H32N6O3: 512.2536; found 513.2623

[(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(2pyridyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 104)

Using General Procedure 6 starting from Example 15 as reagent, Example 104 was obtained as HCl sait. HRMS calculated for C29H32N6O3: 512.2536; found 257.134 10 [(M+2H)2+ form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(3pyridyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 105)

Using General Procedure 5 starting from Préparation R2bu and Préparation Rlc as reagents, the resulted Boc-protected crude product was reacted using General 15 Procedure 6, to give Example 105 as HCl sait. HRMS calculated for C29H32N6O3:

512.2536; found 513.261 [(M+H) form],

3- [ [4-hyd roxy-1 - [(3R,4R)-3-pheny 1 pi pcrid i nc-4-car bonyl | -4-piperidyl] methyl] -7-(4pyridyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 106)

Using General Procedure 5 starting from Préparation R2bv and Préparation Rlc as reagents, the resulted Boc-protected crude product was reacted using General

Procedure 6, to give Example 106 as HCl sait. HRMS calculated for C29H32N6O3: 512.2536; found 513.2609 [(M+H) form].

- [ [4-hydroxy-l - [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] -9phenyl-purin-6-one (Example 107)

Using General Procedure 6 starting from Example 17 as reagent, Example 107 was obtained as HCl sait. HRMS calculated for C29H32N6O3: 512.2536; found 513.2616 [(M+H) form].

7-bromo-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrrolo[2,l-f] [l,2,4]triazin-4-one (Example 108)

Using General Procedure 6 starting from Example 18 as reagent, Example 108 was obtained as HCl sait. HRMS calculated for C₂4H₂8BrN₅O3: 513.1376; found 514.1462

[(M+H) form],

6-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-3phenyl-isoxazolo[4,5-d]pyrimidin-7-one (Example 109)

Using General Procedure 6 starting from Example 19 as reagent, Example 109 was obtained as HCl sait. HRMS calculated for C29H31N5O4: 513.2376; found 514.2451 10 [(M+H) form],

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7pyrimidin-2“yl-pyrrolo[2,3-d]pyriimdin-4-one (Example 110)

Using General Procedure 6 starting from Example 20 as reagent, Example 110 was obtained as HCl sait. HRMS calculated for C28H31N7O3: 513.2488; found 257.6326 15 [(M+2H)2+form],

6- [[4-hyd roxy-1 - [(3R,4R)-3-pheny lpiperidine-4-car bony 1] -4-pipe r idy 1] methyl] -3 phenyl-triazolo[4,5-d]pyrimidin-7-one (Example 111)

Using General Procedure 6 starting from Example 21 as reagent, Example 111 was obtained as HCl sait. HRMS calculated for C28H31N7O3: 513.2488; found 514.2576 20 [(M+H) form],

3-[(4-hydroxy-l-{[(3JÎ,4JÎ)-3-phenylpiperidin-4-yl]carbonyl}piperidin“4“yl)methyI]6,8-dimethylpyrimido[5,4-ô]indolizin-4(3H)-one (Example 112)

Using General Procedure 6 starting from Example 22 as reagent, Example 112 was obtained as HCl sait. HRMS calculated for C29H34N6O3: 514.2692; found 515.2757 25 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(lmethylimidazol-4-yl)pyrrolo[2,3-d]pyrimidin-4-one (Example 113)

C j

-74Using General Procedure 6 starting from Example 23 as reagent, Example 113 was obtained as HCl sait. HRMS calculated for C28H33N7O3: 515.2645; found 516.2728 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(l 5 methylpyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-4-one (Example 114)

Using General Procedure 5 starting from Préparation R2bx and Préparation Rlc as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give Example 114 as HCl sait. HRMS calculated for C28H33N7O3: 515.2645; found 516.2716 [(M+H) form],

3-[[4-hydroxy-l-[(3R,4R)-3-phenyIpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(2 thienyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 115)

Using General Procedure 6 starting from Example 25 as reagent, Example 115 was obtained as HCl sait. HRMS calculated for C28H31N5O3S: 517.2148; found 518.2231 [(M+H) form],

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(3 thienyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 116)

Using General Procedure 6 starting from Example 24 as reagent, Example 116 was obtained as HCl sait. HRMS calculated for C28H31N5O3S: 517.2148; found 518.2233 [(M+H) form].

“ 3-[[4-hydroxy-l-[(3R,4R)-3-phenyl-l-(2,2,2-trifluoroethyI)piperidine-4-carbonyl]-4 piperidyl]methyl]-7H-pyrrolo[2,3-d] pyrimidin-4-one (Example 117)

Example 62 (610 mg, 0.92 mmol) was dîssolved in 12 ml DCM, then TFA (211 μΐ, 2.73 mmol, 3 eq.) and formic acid (399 μΐ, 10.6 mmol, 11.5 eq.) were added. The mixture was stirred at r.t. for 118 hours, then potassium carbonate (2.22g 16.1 mmol) was added.

The solution was extrated with DCM (2x70 ml) and organic phase was dried (MgSCL) and evaporated.

112 mg (0.2 mmol) of crude 3-[[4-hydroxy-l-[(3R,4JÏ)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-i/]pyrimidin-4-one product

Ο

-75 was solved in 2 ml dry THF, then triethyl amine (42 μΐ, 0.3 mmol, 1.5 eq.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (32 μΙ, 0.22 mol, 1.2 eq.) were added. The mixture was stirred at r.t. for 141 hours, then 5 ml water was added. The solution was extracted with DCM (2x10 ml) and organic phase was dried (MgSCu) and evaporated

The obtained 3-[[4-hydroxy-l-[(37i,4J?)-3-phenyl-l-(2,2,2-trifluoroethyl)piperidÎne-4carbonyl]-4-piperidyl]methyl]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-<7]pyrimidin-4one was solved in 270 μΙ dry THF, and tetrabutylammonîum fluoride (270 μΐ, IM in THF, 0.27 mmol) and molecular sieves were added and stirred at 75 °C for 20 hours, then the molecular sieves was filtered off and the residue was purified by préparative HPLC in

25mM NH4HCO3-acetonitrile gradient method, to give Example 117. HRMS calculated for C26H30F3N5O3: 517.2301; found 518.2361 [(M+H) form].

3- [[4-hydroxy-l- [(3R,4R)-3-phenylpiperidine-4-car bonyl] -4-piperidyl] methyl] -7(2,2,2-trifluoroethyI)pyrrolo [2,3-d] pyrimidin-4-one (Example 118)

Using General Procedure 6 starting from Example 26 as reagent, Example 118 was 15 obtained as HCl sait. HRMS calculated for C26H30F3N5O3: 517.2301; found 518.2386

[(M+H) form],

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7thiazol-2-yl-pyrrolo[2,3-d]pyrimidin-4-one (Example 119)

Using General Procedure 6 starting from Example 27 as reagent, Example 119 was 20 obtained as HCl sait. HRMS calculated for C27H30N6O3S: 518.21; found 519.2181 [(M+H) form].

7-[3-(dimethylamino)propyl]-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 120)

Using General Procedure 6 starting from Example 28 as reagent, Example 120 was obtained as HCl sait. HRMS calculated for C29H40N6O3: 520.3162; found 261.1666 [(M+2H)2+ form].

“ 3-[[4-hydroxy-l-[(3R,4R)-l-methyl-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 121)

-76Using General Procedure 7 starting from Example 101 and methyl iodide as reagents,

Example 121 was obtained as HCl sait. HRMS calculated for C31H35N5O3: 525.274;

found 526.2802 [(M+H) form].

7-benzyl-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4- piperidyI]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 122)

Using General Procedure 6 starting from Example 31 as reagent, Example 122 was obtained as HCl sait. HRMS calculated for C31H35N5O3: 525.274; found 526.2822 [(M+H) form].

3- [ [4-hy d roxy-1- [(3 R,4R)-3 -pheny Ipiperid ine-4-carbony 1] -4-piperidy 1] methyl] -7-(p10 tolyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 123)

Using General Procedure 6 starting from Example 30 as reagent, Example 123 was obtained as HCl sait. HRMS calculated for C31H35N5O3: 525.274; found 526.2816 [(M+H) form].

3- [ [4-hydroxy-l- [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyI] methyl] -7-(m15 tolyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 124)

Using General Procedure 6 starting from Example 29 as reagent, Example 124 was obtained as HCl sait. HRMS calculated for C31H35N5O3: 525.274; found 526.2825 [(M+H) form].

3- [[4-hydroxy-l- [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] -6- methyl-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 125)

Using General Procedure 6 starting from Example 32 as reagent, Example 125 was obtained as HCl sait. HRMS calculated for C31H35N5O3: 525.274; found 526.2827 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(625 methyl-2-pyridyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 126)

Using General Procedure 5 starting from Préparation R2br and Préparation Rlc as reagents, the resulted Boc-protected crude product was reacted using General

-77 Procedure 6, to give Example 126 as HCl sait. HRMS calculated for C30H34N6O3:

526.2692; found 527.2764 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-7-phenyl-thieno[3,4-d]pyrimidin-3yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxylate (Example 127)

Example 6 (370 mg, 0.63 mmol) was dissolved in 2 ml THF and 2 ml water, then phenyl boronic acid (308 mg, 2.52 mmol, 4 eq.), AtaPhos*PdCl₂ (8.6 mg, 0.012 mmol, 0.2 eq.), césium carbonate (617 mg, 1.89 mmol, 3 eq.) were added. The mixture was heated and stirred in Anton Paar microwave reactor for 1 hour at 100 °C. The residue was purified by préparative HPLC in 5mM NH4HCCh-MeCN gradient method, to give Example 127.

HRMS calculated for C35H40N4O5S: 628.2719; found 629.2788 [(M+H) form].

3- [ [4-hydroxy-1- [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl]-7-(6oxo-lH-pyridin-2-yl)pyrrolo[2,3-d]pyrimidin-4-one (Example 128)

Using General Procedure 6 starting from Example 45 as reagents, Example 128 was obtained. HRMS calculated for C29H32N6O4: 528.2485; found 529.2567 [(M+H) form].

6-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]“4-piperidyl]methyl]-3phenyl-isothiazolo[4,5-d]pyrimidin-7-one (Example 129)

Using General Procedure 6 starting from Example 33 as reagent, Example 129 was obtained. HRMS calculated for C29H31N5O3S: 529.2148; found 530.2223 [(M+H) form].

7-(4-fluorophenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4- piperidyl]methyI]pyrrolo[2,3-d]pyrimidin-4-one (Example 130)

Using General Procedure 6 starting from Example 34 as reagent, Example 130 was obtained. HRMS calculated for C30H30FN5O3: 529.2489; found 530.2584 [(M+H) form],

7-(3-fluorophenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 131)

Using General Procedure 6 starting from Example 35 as reagents, Example 131 was obtained. HRMS calculated for C30H32FN5O3: 529.2489; found 530.2571 [(M+H) form].

3- [[4-hydroxy-l- [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] -7-(5methyl-2-thienyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 132)

Using General Procedure 6 starting from Example 37 as reagent, Example 132 was obtained. HRMS calculated for C29H33N5O3S: 531.2304; found 532.2361 [(M+H) form].

3- [[4-hydroxy-l- [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] -7-(1methyl-4-piperidyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 133)

Using General Procedure 6 starting from Example 38 as reagent, Example 133 was obtained. HRMS calculated for C30H40N6O3: 532.3162; found 267.1658 [(M+2H)2+ form].

4-[3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-4oxo-pyrrolo[2,3-d]pyrimidin-7-yl]benzonitrile (Example 134)

Using General Procedure 6 starting from Example 39 as reagent, Example 134 was obtained. HRMS calculated for C31H32N6O3: 536.2536; found 537.2599 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(4methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 135)

Using General Procedure 6 starting from Example 40 as reagents, Example 135 was obtained. HRMS calculated for C31H35N5O4: 541.2689; found 542.2784 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyI]methyl]-7-(3methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 136)

Using General Procedure 6 starting from Example 41 as reagents, Example 136 was obtained. HRMS calculated for C31H35N5O4: 541.2689; found 542.2777 [(M+H) form].

7-[4-(hydroxymethyl)phenyl]-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 137)

Using General Procedure 6 starting from Example 42 as reagents, Example 137 was obtained. HRMS calculated for C31H35N5O4: 541.2689; found 542.2787 [(M+H) form].

7-[3-(hydroxymethyl)phenyl]-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 138)

-79Using General Procedure 5 starting from Préparation R2bj and Préparation Rlc as reagents, the resulted Boc-protected crude product was reacted using General

Procedure 6, to give Example 138. HRMS calculated for C31H35N5O4: 541.2689; found

542.2769 [(M+H) form],

6-(hydroxymethyl)-3- [ [4-hydroxy-l -[(3R,4R)-3-phenylpiperidine-4-carbonyl] -4piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 139)

Using General Procedure 6 starting from Example 43 as reagent, Example 139 was obtained. HRMS calculated for C31H35N5O4: 541.2689; found 542.2763 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(610 methoxy-2-pyridyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 140)

Using General Procedure 6 starting from Example 45 as reagent, Example 140 was obtained. HRMS calculated for C30H34N6O4: 542.2642; found 543.2698 [(M+H) form].

7-(4-fluorophenyI)-3-[[4-hydroxy-l-[(3R,4R)-l-methyl-3-phenyl-piperidine-4carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyriinidin-4-one (Example 141)

Using General Procedure 7 starting from Example 130 and methyl iodide as reagents, Example 141 was obtained. HRMS calculated for C31H34N5O3F: 543.2646; found 544.2721 [(M+H) form].

7-(3-chlorophenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl] methyl] pyrrolo [2,3-d]pyrimidin-4-one (Example 142)

Using General Procedure 6 starting from Example 47 as reagent, Example 142 was obtained. HRMS calculated for C30H32CIN5O3: 545.2194; found 546.2248 [(M+H) form].

7-(4-chlorophenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 143)

Using General Procedure 6 starting from Example 46 as reagent, Example 143 was 25 obtained. HRMS calculated for CaoHaiCINsCh: 545.2194; found 546.2262 [(M+H) form],.

-80’ 6-chloro-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 144)

Using General Procedure 6 starting from Example 48 as reagent, Example 144 was obtained. HRMS calculated for C30H32CIN5O3: 545.2194; found 546.2277 [(M+H) form].

7-(5-chloro-2-thienyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 145)

Using General Procedure 6 starting from Example 49 as reagent, Example 145 was obtained. HRMS calculated for C28H30CIN5O3S: 551.1758; found 552.1844 [(M+H) form],

7- [ 1 -(difluoromethyl)py razol-4-y 1] -3- [ [4-hy d roxy-1 -[(3R,4R)-3 -phe nylpipe ridine-4- carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 146)

Using General Procedure 6 starting from Example 50 as reagent, Example 146 was obtained. HRMS calculated for C28H31F2N7O3: 551.2457; found 552.254 [(M+H) form].

3- [ [1- [(3R,4R)-1 -acetyl-3-phenyl-piperidine-4-carbony 1] -4-hydroxy-4pîperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 147)

Using General Procedure 8 starting from EXAMPLE 101 and acetic acid as reagents, Example 147 was obtained. HRMS calculated for C32H35N5O4: 553.2689; found 554.2757 [(M+H) form],

7-(4-dimethylaminophenyI)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl] -4-piperidyl] methyl] pyrrolo [2,3-d] pyrimidin-4-one (Example 148)

Using General Procedure 6 starting from Example 51 as reagent, Example 148 was obtained. HRMS calculated for C32H38N6O3; 554.3005; found 555.3076 [(M+H) form],

7- [3 -(dimethylamino) phenyl] -3- [ [4-hyd roxy-1 - [(3R,4R)-3-pheny lpiperidine-4carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 149)

Using General Procedure 6 starting from Example 52 as reagent, Example 149 was obtained. HRMS calculated for C32H38N6O3: 554.3005; found 555.3086 [(M+H) form].

-81 “ 7-(1,3-benzodioxol-5-yl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 150)

Using General Procedure 6 starting from Example 53 as reagent, Example 150 was obtained. HRMS calculated for C31H33N5O5: 555.2482; found 556.2556 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-l-methyl-3-phenyl-piperidine-4-carbonyl]-4piperidyl]methyl]-7-(4-methoxyphenyl)pyrroIo[2,3-d]pyrimidin-4-one (Example 151)

Using General Procedure 7 starting from Example 135 and methyl iodide as reagents, Example 151 was obtained. HRMS calculated for C32H37N5O4: 555.2845; found 556.2922 [(M+H) form],

7-(3-chlorophenyl)-3-[[4-hydroxy-l-[(3R,4R)-l-methyl-3-phenyl-piperidine-4carbonyl]-4-piperidyl]methyI]pyrrolo[2,3-d]pyrimidin-4-one (Example 152)

Using General Procedure 7 starting from Example 142 and methyl iodide as reagents, Example 152 was obtained. HRMS calculated for C31H34N5O3CI: 559.235; found 560.2425 [(M+H) form].

7-(4-chlorophenyl)-3-[[4-hydroxy-l-[(3R,4R)-l-methyl-3-phenyl-piperidine-4carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 153)

Using General Procedure 7 starting from Example 143 and methyl iodide as reagents, Example 153 was obtained. HRMS calculated for CîiHuNsChCl: 559.235; found 560.2423 [(M+H) form],

7-[(4-chlorophenyl)methyl]-3-[[4-hydroxy-l-[(3R,4R)-3-phenyIpiperidine-4carbonyI]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 154)

Using General Procedure 6 starting from Example 56 as reagent, Example 154 was obtained. HRMS calculated for Cs^ClNsCh: 559.235; found 560.2418 [(M+H) form],

7-[(3-chlorophenyl)methyl]-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-425 carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 155)

Using General Procedure 6 starting from Example 55 as reagent, Example 155 was obtained. HRMS calculated forCsiHîzjClNsOj: 559.235; found 560.2432 [(M+H) form].

Ο

7- [(2-chlorophenyl)methyl] -3- [ [4-hydroxy-l - [(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 156)

Using General Procedure 6 starting from Example 54 as reagent, Example 156 was obtained. HRMS calculated for C3ÎH34CIN5O3: 559.235; found 560.2429 [(M+H) form].

7-(4-fluoro-3-methoxy-phenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl] -4-piperidyl] methyl] pyrrolo [2,3-d] pyrimidin-4-one (EXAMPLE 157)

Using General Procedure 6 starting from Example 57 as reagent, Example 157 was obtained. HRMS calculated for C31H34FN5O4: 559.2595; found 560.2638 [(M+H) form].

7- [4-(difluoromethy l)pheny 1] -3 - [ [4-hy droxy-1 - [(3R,4R)-3- phenylpiperid ine-4- carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 158)

Using General Procedure 6 starting from Example 58 as reagent, Example 158 was obtained. HRMS calculated for C31H33F2N5O3: 561.2551; found 562.2636 [(M+H) form].

3- [ [4-hy d roxy-1- [(3R,4R)-3-pheny Ipiper idi ne-4-car bonyl] -4-pi per idyl] methyl] -7-(2naphthyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 159)

Using General Procedure 6 starting from Example 60 as reagent, Example 159 was obtained. HRMS calculated forC34H₃5N5O3: 561.274; found 562.2831 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenyIpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(lnaphthyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 160)

Using General Procedure 6 starting from Example 59 as reagent, Example 160 was 20 obtained. HRMS calculated for C34H35N5O3: 561.274; found 562.2827 [(M+H) form].

7-(4-chloro-3-fluoro-phenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 161)

Using General Procedure 6 starting from Example 61 as reagent, Example 161 was obtained. HRMS calculated for C30H31N5O3FCI: 563.21; found 564.2181 [(M+H) form].

3-[[4-hydroxy-l-[(3R₁4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(2trimethylsilylethoxymetliyl)pyrroIo[2,3-d]pyrimidin-4-one (Example 162)

Example 62 (1.6 g, 2.4 mmol) was dissolved in 30 ml DCM, then TFA (3 ml) and formte acid (550 μΙ, 7.2 mmol, 3 eq.) were added. The mixture was stirred at r.t. for 4 days, then potassium carbonate (15 g, 108 mmol) was added. The solution was extrated with DCM and organic phase was dried (MgSCfi) and evaporated to give Example 162. HRMS calculated for C30H43N5O4S1: 565.3084; found 566.3138 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-l-isobutyl-3-phenyl-piperidine-4-carbonyl]-4- piperidy 1] methyl] -7-pheny 1- pyrrolo [2,3-d] pyrimid in-4-o ne (Exa M PL E 163)

Using General Procedure 7 starting from Example 101 and l-bromo-2-methyl-propane as reagents, Example 163 was obtained. HRMS calculated for C34H41N5O3: 567.3209; found 568.328 [(M+H) form].

7-(2,3-dihydro-l,4-benzodioxin-6-yl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine4-carbonyl]-4-piperidyl]methyI]pyrrolo[2_l(3-d]pyrimidin-4-one (Example 164)

Using General Procedure 6 starting from Example 63 as reagent, Example 164 was obtained. HRMS calculated for C32H35N5O5: 569.2638; found 570.2709 [(M+H) form].

l-(2,3-dihydro-l,4-benzodioxin-6-yl)-5-[[4-hydroxy-l-[(3R,4R)-3-pIienylpiperidine4-carbonyl]-4-piperidyl]methyl]pyrazolo[3,4-d]pyrimidin-4-one (Example 165)

Using General Procedure 6 starting from Example 64 as reagent, Example 165 was 20 obtained. HRMS calculated for C31H34N6O5: 570.2591; found 571.2663 [(M+H) form].

3-[[l-[(3R,4R)-l-acetyl-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4piperidyl]methyl]-7-(4-fluorophenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 166)

Using General Procedure 8 starting from Example 130 and acetic acid as reagents, Example 166 was obtained. HRMS calculated for C32H34FN5O4: 571.2595; found

572.2679 [(M+H) form].

7-(3,5-dimethoxyphenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-

4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 167)

-84Usîng General Procedure 6 starting from Example 66 as reagent, Example 167 was obtained. HRMS calculated for C32H37N5O5: 571.2795; found 572.2881 [(M+H) form].

7-(3,4-dimethoxyphenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 168)

Using General Procedure 6 starting from Example 65 as reagent, Example 168 was obtained. HRMS calculated for C32H37N5O5: 571.2795; found 572.2892 [(M+H) form].

5-[[l-[(3R,4R)-l,l-dimethyl-3-phenyl-piperidin-l-iuiu-4-carbonyl]-4-hydroxy-4piperidyl]methyl]-l-(4-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one (Example 169)

Using General Procedure 7 starting from Example 135 and methyl iodide as reagents, Example 169 was obtained. HRMS calculated for C32H39N6O4: 571.3027; found 571.3038 [(M+)form],

3- [ [4-hyd roxy-1 - [(3R,4R)-3-phenylpiper id ine-4-car bony 1] -4-piperidy 1] methyl] -6iodo-7-methyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 170)

Using General Procedure 6 starting from Example 67 as reagent, Example 170 was obtained. HRMS calculated for C25H30IN5O3: 575.1393; found 576.1455 [(M+H) form].

7-(3-chloro-5-methoxy-phenyI)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbony 1] -4-piperidyl] methyl] pyrrolo [2,3-d] pyrimidin-4-one (Example 171 )

Using General Procedure 6 starting from Example 68 as reagent, Example 171 was obtained. HRMS calculated for C3LH34CIN5O4: 575.2299; found 576.2382 [(M+H) form],

7-(4-chloro-3-methoxy-phenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 172)

Using General Procedure 6 starting from Example 69 as reagents, Example 172 was obtained. HRMS calculated for C31H34CIN5O4: 575.2299; found 576.2382 [(M+H) form].

7-(3,5-dichlorophenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 173) (Ί

-85Using General Procedure 6 starting from Example 71 as reagent, Example 173 was obtained. HRMS calculated for C30H31N5O3CI2: 579.1804; found 580.1891 [(M+H) form].

7-(3,4-dichlorophenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 174)

Using General Procedure 6 starting from Example 70 as reagent, Example 174 was obtained. HRMS calculated for C30H31CI2N5O3: 579.1804; found 580.187 [(M+H) form],

3-[[4-hydroxy-1- [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] -7- [4(trifluoromethyl)phenyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 175)

Using General Procedure 6 starting from Example 72 as reagent, Example 175 was 10 obtained. HRMS calculated for C31H32N5O3F3: 579.2457; found 580.2529 [(M+H) form],

3- [ [4-hyd roxy-1 - [(3R,4R)-3-pheny Ipiperidi ne-4-car bonyl] -4-piperidyl] methyl] -7- [3 (trifluoromethyl)phenyI]pyrrolo[2,3-d]pyrimidin-4-one (Example 176)

Using General Procedure 6 starting from Example 73 as reagent, Example 176 was obtained. HRMS calculated for C31H32F3N5O3: 579.2457; found 580.2509 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-l-(2-methylpropanoyl)-3-phenyl-piperidine-4-carbonyl]4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 177)

Using General Procedure 8 starting from Example 101 and 2-methylpropanoic acid as reagents, Example 177 was obtained. HRMS calculated for C34H39N5O4: 581.3002; found 582.3072 [(M+H) form].

3- [ [1 -[(3R,4R)-l-acetyl-3-phenyl-piperidine-4-carbonyI] -4-hydroxy-4piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 178)

Using General Procedure 8 starting from Example 135 and acetic acid as reagents, Example 178 was obtained. HRMS calculated for C33H37N5O5: 583.2795; found 584.2868 [(M+H) form].

3-[[l-[(3R,4R)-l-acetyl-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4piperidyl]methyl]-7-(3-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 179) ( )

- 86Using General Procedure 8 starting from Example 136 and acetic acid as reagents, Example 179 was obtained. HRMS calculated for C33H37N5O5: 583.2795; found 584.2863 [(M+H) form],

3-[[i-[(3R,4R)-l-acetyl-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4- piperidyl]methyl]-7-(3-clilorophenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 180)

Using General Procedure 8 starting from Example 142 and acetic acid as reagents, Example 180 was obtained. HRMS calculated for C32H34CIN5O4: 587.2299; found 588.238 [(M+H) form].

3-[[l-[(3R,4R)-l-acetyl-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4- piperidyl]methyl]-7-(4-chlorophenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 181)

Using General Procedure 8 starting from Example 143 and acetic acid as reagents, Example 181 was obtained. HRMS calculated for C32H34CIN5O4: 587.2299; found 588.2366 [(M+H) form]. '

3-[[4-hydroxy-l-[(3R,4R)-3-phenyIpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-[415 (trifluoromethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 182)

Using General Procedure 6 starting from Example 76 as reagent, Example 182 was obtained. HRMS calculated for C31H32N5O4F3: 595.2407; found 596.2494 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-[3(trifluoromethoxy)phenyI]pyrrolo[2,3-d]pyrimidin-4-one (Example 183)

Using General Procedure 6 starting from Example 75 as reagent, Example 183 was obtained. HRMS calculated for C31H32N5O4F3: 595.2407; found 596.2491 [(M+H) form].

3-[[l-[(3R,4R)-l-(2,2-dimethylpropanoyl)-3-phenyl-piperidine-4-carbonyl]-4hydroxy-4-piperidyl]methyl]-7-pheny!-pyrrolo[2,3-d]pyrimidin-4-one (Example 184)

Using General Procedure 8 starting from Example 101 and 2,2-dimethylpropanoic acid as reagents, Example 184 was obtained. HRMS calculated for C35H41N5O4: 595.3159; found 596.3221 [(M+H) form].

: C)

3-[[4-hydroxy-1- [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] -7-(3- ; morpholinophenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 185)

Using General Procedure 6 starting from Example 77 as reagent, Example 185 was obtained. HRMS calculated for C34H40N6O4: 596.3111; found 597.3187 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7(3,4,5-trimethoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 186)

Using General Procedure 6 starting from Example 78 as reagent, Example 186 was obtained. HRMS calculated for C33H39N5O6: 601.29; found 602.296 [(M+H) form].

3-[[l-[(3R,4R)-l-(3,3-dimethylbutanoyl)-3-phenyl-piperidine-4-carbonyl]-4- hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 187) Using General Procedure 8 starting from Example 101 and 3,3-dimethylbutanoic acid as reagents, Example 187 was obtained. HRMS calculated for C36H43N5O4: 609.3315; found 610.3384 [(M+H) form], .

> 7-(4-benzyloxyphenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-415 piperidyl]methyl]pyrrolo[2,3-d]pyriniidin-4-one (Example 188)

Using General Procedure 6 starting from Example 79 as reagent, Example 188 was obtained. HRMS calculated for C37H39N5O4: 617.3002; found 618.3083 [(M+H) form].

7-(3-benzyloxyphenyl)-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4pipcridyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 189)

Using General Procedure 6 starting from Example 80 as reagent, Example 189 was obtained. HRMS calculated for C37H39N5O4: 617.3002; found 618.3051 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyI]-7-[3[(4-methylpiperazin-l-yl)methyl]phenyl]pyrrolo[2,3-d]pyrimidîn-4-one (Example 190)

Using General Procedure 6 starting from Example 81 as reagent, Example 190 was obtained. HRMS calculated for C36H45N7O3: 623.3584; found 624.3656 [(M+H) form].

3-[[4-hydroxy-l- [(3R,4R)-3-phenylpiperidine-4-carbonyl] -4-piperidyl] methyl] -7- phenyl-thieno[3,4-d]pyrimidin-4-one (Example 191)

Using General Procedure 6 starting from Example 127 as reagent, Example 191 was obtained. HRMS calculated for C30H32N4O3S: 528.2195; found 529.2265 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6iodo-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 192)

Example 74 (647 mg, 0.82 mmol) was dissolved in 13 ml DCM, then TFA (188 μΐ, 2.46 mmol, 3 eq.) and formic acid (356 μΙ, 9.43 mmol, 11.5 eq.) were added. The mixture was stirred at r.t. for 214 hours, then potassium carbonate (1.99 g, 14.3 mmol) was added. The solution was extrated with DCM (2x70 ml) and organic phase (MgSCU) was dried and evaporated to give Example 192. HRMS calculated for C30H42IN5O4SK 691.2051; found 692.2155 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxopyrido[3,2-d]pyrimidin-3yl)methyl]piperidine-l-carbonyl]-3-phenyl-piperidine-l-carboxyIate (Example 193)

Using General Procedure 5 starting from 3/ï-pyrido[3,2-c/]pyrimidin-4-one and Préparation Rlc as reagents, Example 193 was obtained. HRMS calculated for C30H37N5O5: 547.2795; found 548.2870 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrido[3,2-d]pyrimidin-4-one (Example 194)

Using General Procedure 6 starting from Example 193 as reagent, Example 194 was obtained as HCl sait. HRMS calculated for C25H29N5O3: 447.227; found 448.2365 [(M+H)⁺ form].

tert-butyl (3R,4R)-4-[4-[(6-chloro-4-oxo-pyrido[3,2-d]pyrimidin-3-yl)methyl]-4hydroxy-piperidine-l-carbonyl]-3-plienyl-piperidine-l-carboxylate (Example 195)

Using General Procedure 5 starting from 6-chloro-3/7-pyrido[3,2-i/]pyrimidin-4-one and Préparation Rlc as reagents, Example 195 was obtained. HRMS calculated for C30H36CIN5O5: 581.2405; found 604.2239 [(M+Na) form].

6-chloro-3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4piperidyl]methyl]pyrido[3,2-d]pyrimidin-4-one (Example 196)

Using General Procedure 6 starting from Example 195 as reagent, Example 196 was obtained as HCI sait. HRMS calculated for C25H28CIN5O3: 481.1881; found 482.1949 5 [(M+H)⁺ form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(6-methoxy-4-oxo-pyrido[3,2-d]pyrimidin-3yl)methyl]piperïdine-l-carbonyl]-3-phenyI-piperidine-l-carboxylate (Example 197)

Using General Procedure 5 starting from 6-methoxy-3/f-pyrido[3,2-tZ]pyrimidin-4-one and Préparation Rlc as reagents, Example 197 was obtained. HRMS calculated for 10 C31H39N5O6: 577.29; found 578.2976 [(M+H) form].

3-[[4-hydroxy-l-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6methoxy-pyrido[3,2-d]pyrimidin-4-one (Example 198)

Using General Procedure 6 starting from Example 197 as reagent, Example 198 was obtained as HCl sait. HRMS calculated for C26H31N5O4: 477.2376; found 478.2458 15 [(M+H)⁺form].

Ο

-90PHARMACOLOGICAL STUDY

EXAMPLE A: Evaluation of the inhibition of USP7 by the Fluorescence Intensity (FLINT) readings

USP7 activity was measured using Rhodamine-110 c-terminal labelled Ubiquitin as a 5 substrate (Viva Biosciences). 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 p.L volume, in 384 well black solid low binding plates (Corning #3575). The reaction buffer consisted of 100 mM Bicine pH 8.0, 10 0.01 %TritonX100, 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 and the plate read every 3 minutes for 21 minutes to measure the release of Rhodamine-110. Fluorescence Intensity (FLINT) 15 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 (ICso) were determined, from 11-poînt dose response curves, in XL-Fit using a 20 4-Parameter Logistic Model (Sigmoidal Dose-Response Model).

The results presented in Table 1 below show that compounds of the invention inhibit interaction between USP7 protein and the fluorescent peptide described hereinbefore.

-91 EXAMPLE B: In vitro cvtotoxicity

The cytotoxîcity studies were carried out on the MM1S multiple myeloma tumour cell line. The cells are distributed onto microplates and exposed to the test compounds for 96 hours. The cell viability is then quantified by a colorimétrie assay, the Microculture Tétrazolium 5 Assay (Cancer Res., 1987, 47, 939-942).

The results are expressed in IC50 (the concentration of compound that inhibits cell viability by 50%) and are presented in Table 1 below.

The results show that the compounds of the invention are cytotoxic.

Table 1: IC50 of TJSP7 inhibition and of cvtotoxicity for MM1S cells

Example	IC₅., (M) USP7 FLINT	!Cso (M) MÎT MM 1S	Example	IC₃,j(M)USP7 FLINT	1C_;O(M)MTTMMIS
2	1.28E-07	ND	147	4.06E-07	ND
15	2.74E-07	ND	151	5.24E-08	ND
40	4.99E-08	3.15E-08	152	6.48E-08	ND
44	6.15E-08	ND	153	4.86E-08	7.47E-08
57	7.02E-08	ND	157	3.93E-08	ND
64	6.87E-08	ND	163	1.08E-07	ND
101	3.16E-08	2.72E-07	165	1.96E-08	3.00E-07
103	5.29E-08	ND	166	1.02E-07	ND
104	3.94E-07	ND	169	8.60E-07	ND
117	1.20E-06	ND	177	1.03E-07	ND
121	1.40E-07	ND	178	9.61E-08	ND
130	3.77E-08	ND	179	8.84E-08	ND
135	2.87E-08	1.35E-07	180	8.90E-08	ND
136	4.86E-08	ND	181	7.42E-08	ND
141	7.48E-08	ND	184	8.30E-08	ND
142	5.67E-08	ND	187	8.85E-08	ND
143	4.12E-08	ND

ND: not determined

Ο

-92EXAMPLE C: Anti-tumor activity in vivo

The anti-tumour activity of the compounds of the invention is evaluated in a xenograft model of multiple myeloma and/or acute lymphoblastic leukaemia cells.

Human tumour cells are grafted subcutaneously into immunosuppressed mice.

When the tumour volume (TV) reaches about 200 mm³, the mice are treated per os with the varions compounds once a day for 5 days on/2 days off during 3 weeks. The tumour mass is measured twice weekly from the start of treatment.

The compounds of the invention display anti-tumour activities represented by the TGI (tumor growth inhibition) at the end ofthe treatment period. The TGI is defined as follows:

TGI =

Médian (DTV at Dx in treated group) \ ------------------------------------------ I x 100 ,

Médian (DTV at Dx in control group) / with:

DTV (delta tumoral volume) at Dx = (TV at Dx) - (TV at randomization for each animal).

EXAMPLE D: Pharmaceutical composition: Tablets

1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 198.........5g

Wheat starch.....................................................................................................................20g

Maize starch......................................................................................................................20g

Lactose..............................................................................................................................30g

Magnésium stéarate............................................................................................................2g

Silica...................................................................................................................................1g

Hydroxypropylcellulose.....................................................................................................2g

Claims

1. Compound of formula (I):

wherein:

♦ Ri represents an aryl group or a heteroaryl group, ♦ R₂ represents a hydrogen atom or a halogen atom, ♦ R₃ represents a hydrogen atom, a linear or branched (Ci-Cejalkyl group, a linear or branched halo{Ci-C₆)alkyl, a -C(O)-R₈ group, a -C(O)-OR₈ group, ♦ n is an integer equal to 0,1 or 2, ♦ W represents the group

, wherein:

A represents a heteroaryl ring, X represents a carbon atom or a nitrogen atom, Ra represents a hydrogen atom, a halogen atom, a linear or branched (Ci-Cs)alkyl group, a linear or branched (C₂-C5)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, a -Yi-NRgR? group, a -Yi-OR₆ group, a linear or branched halo(Ci-C₆)alkyi group, an oxo group, a -Yi-Cyi group, a -Cyi-R? group, a -Cyi-OR? group, or a -Yi-NR₆-C(O)-R7 group, R₅ represents a hydrogen atom, a halogen atom, a linear or branched (Ci-Ce)aIkyl group, a cyano group, or a -hydroxyfCi-Ceialkyl group, R_e represents a hydrogen atom or a linear or branched (Ci-C₆)alkyl group, or a -Y₂-Si[(Ci-C4)alkyl]₃ group, R? represents a hydrogen atom, a linear or branched (Ci-Csjalkyl group, or a -Y₂-Cy₂ group, Yi and Y₂ independently of one another represent a bond or a linear or branched (Ci-C4)alkylene group, , ♦ R₈ represents a hydrogen atom, or a linear or branched (Ci-Cs)aIkyl group,

5 ♦ Cyi and Cy₂ independently of one another, represent 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

10 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

15 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-C₆)alkyl, linear or branched (C₂-C₅)alkenyl, linear or branched (C₂-C₆)alkynyl, linear or

20 branched halo(Ci-C₆)alkyl, -Yi-OR', -Yi-NR'R, -Yi-S(O)_m-R', oxo (or N-oxide where appropriate), nitro, cyano, -C(O)-R', -C(O)-OR', -O-C(O)-R', -C(O)-NR'R, -Yi-NR'-C(O)-R, -Yi-NR'-C(O)-OR, halogen, cyclopropyl, and pyridiny! which can be substituted by a linear or branched (Ci-Cs)aIkyI group, it being understood that R' and R independently of one another represent a hydrogen

25 atom, a linear or branched (Ci-Cejalkyl group, a linear or branched (C₂-Ce)alkenyl group, a linear or branched (Ci-C₆)alkoxy group, a linear or branched halo(Ci-C_e)aIkyl, a linear or branched hydroxy(Ci-C6)alkyI group, a linear or branched (CiC₆)alkoxy(Ci-C₅)alkyl group, a phenyl group, a cyclopropylmethyl group, a tetrahydropyranyl group,

or the substituents of the pair (R', R) form together with the nitrogen atom carrying them 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 nitrogen in question may be substituted by from 1 to 2 groups 5 representing a hydrogen atom, or a linear or branched (Ci-Ce)alkyl group, and it being understood that 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. Compounds according to claim 1, wherein W represents the group

O

wherein R4, R5 and A are as defined in claim 1.

3. Compounds according to claim 1, wherein W represents the group

O

wherein R

4, R5 and A are as defined in claim 1.

15 4. Compounds according to claim 1, wherein Ri represents a phenyl group.

5. Compounds according to claim 1, wherein R2 represents a hydrogen atom.

6. Compounds according to claim 1, wherein R3 represents a hydrogen atom, a methyl group, a -CH₂-CH(CH3)2 group, a -CH2-CF3 group, a -C(O)-CH₃ group, a -C(O)-CH(CH₃)₂ group, a -C(O)-CH₂-C(CH₃)₃ group, or a -C(O)-OC(CH₃)₃ group.

7. Compounds according to claim 1, wherein R₄ represents a hydrogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a - Yi-NR₆R7 group, a -Yi-OR₆ group, a linear or branched

5 halo(Ci-C₆)alkyl group, a -Yi-Cyi group, a -Cyi-R? group, or a -Cyi-OR? group.

8. Compound according to claim 1, wherein R, represents a hydrogen atom, an iodine atom, a chlorine atom, a methyl group or a -CH₂-0H group.

9. Compounds according to claim 1, wherein Rô represents a hydrogen atom, a methyl group, or a -(CH₂)₂-Si(CH₃)₃ group.

10 10. Compounds according to claim 1, wherein R? represents a hydrogen atom, a methyl group, or a -CH₂-Cy₂ group.

11. Compounds according to claim 1, which are:

- tert-butyl (3S,4S)-4-({4-hydroxy-4-[(4-oxothieno[2,3-d]pyrirnidin-3(4H)y|)methyl]piperidin-l-yl}carbonyl)-3-phenylpiperidine-l-carboxylate;

15 - tert-butyl (3R,4R)-4-[(4-hydroxy-4-{[4-oxo-7-(pyridin-2-yl)-4,7-dihydro-3H-pyrrolo[2,3c/]pyrimidin-3-yl]methyl}piperidin-l-yl)carbonyl]-3-phenylpiperidine-l-carboxylate;

- tert-butyl (3R,4R)-4-[(4-hydroxy-4-{[7-(4-methoxyphenyl)-4-oxo-4,7-dihydro-3Hpyrrolo[2,3-d]pyrimidin-3-yl]methyl}piperidin-l-yl)carbonyl]-3-phenylpiperidine-lcarboxylate;

20 - tert-butyl (3R,4R)-4-[(4-hydroxy-4-{[l-(4-methoxyphenyl)-4-oxo-l,4-dihydro-5Hpyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidin-l-yl)carbonyl]-3-phenylpiperidine-lcarboxylate;

- tert-butyl (3R,4R)-4-[(4-{[7-(4-fluoro-3-methoxyphenyl)-4-oxo-4,7-dihydro-3Hpyrrolo[2,3-d]pyrimidin-3-yl]methyl}-4-hydroxypiperidin-l-yl)carbonyl]-3-

25 phenylpiperidine-l-carboxylate;

- tert-butyl (3R,4R)-4-[(4-{[l-(2,3-dihydro-l,4-benzodioxin-6-yl)-4-oxo-l,4-dihydro-5Hpyrazolo[3,4-t/]pyrimidin-5-yl]methyl}-4-hydroxypiperidin-l-yl)carbonyl]-3phenylpiperidine-l-carboxylate;

- 3-[(4-hydroxy-l-{[(3/?,4/?)-3-phenylpiperidin-4-yl]carbonyl}pîperidin-4-yl)methvl]-7phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

- 5'[(4-hydroxy-l-{[(3R4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-lphenyl-l,5-dihydro-4H-pyrazolo[3,4-d]pyrïmidin-4-orie;

5 - 3-[(4-hydroxy-l-{[(3R,4K)-3-phenylpipeiïdin-4-yl]carbonyl}piperidin-4-yl)meÎhyl]-7(pyridin-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

- 3-[(4-hydroxy-l-{[(3R,4R)-3-phenyl-l-(2,2,2-trifliioroethyl)piperidin-4yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyirolo[2,3-d]pyrimidin-4-one;

- 3-[(4-hydroxy-l-{[(3R,4R)-l-methyl-3-phenylpiperidin-4-yl]carbonyl}ptperidin-4-

10 yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidîn-4-one;

- 7-(4-fluorophenyl)-3-[(4-hydroxy-l-{[(3/î,4/ï)-3-phenylpiperidin-4-yl]carbonyl}piperidin4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-c/]pyrimidin-4-one;

- 3-[(4-hydroxy-l-{[(3fî,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-7-(4methoxyphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

15 - 3-[(4-hydroxy-l-{[(3/?,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-7-(3meÎhoxyphenyl)-3J-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

- 7-(4-fluorophenyl)-3-[(4-hydroxy-l-{[(3/î,4/ï)-l-methyl-3-phenylpiperidin-4yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

- 7-(3-chlorophenyl)-3-[{4-hydroxy-l-{[(3/?,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin20 4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pvrinnidin-4-one;

- 7-(4-chlorophenyl)-3-[(4-hydroxy-l-{[(3R4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

- 3-[(l-{[(3/?,4R)-l-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4yOmethylJ^-phenYl-SJ-dihvdrcMH-pyrroloIXB-a'jpyrÎmidinA-one;

25 - 3-[(4-hydroxy-l-{[(3R,4K)-l-methyl-3-phenylpiperidin-4-yl]carbonyl}piperidin-4yl)methyl]-7-(4-methoxyphenyl)-3,7-dihydro-4H-pyrrolo[2_/3-d]pyrimidin-4-one;

- 7-(3-chlorophenyl)-3-[(4-hydroxy-l-{[(3R,4R)-l-methyl-3-phenylpiperidin-4yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

- 7-(4-εΚΙθΓορήθηγί)-3-[(4-ΚγάΓθχγ-1-{[(3/?_;4/ϊ)-1-ηηθΙήνΙ-3-ρΗ6ηνΙρΐρθπάΐη-4-

30 yl]carbonyl}pÎperidin-4-yl)methyl]-3J-dihydrO-4H-pyrrolo[2,3-d]pyrimÎdin-4-one;

- 7-(4-fluoro-3-methoxyphenyl)-3-[(4-hydroxy-l-{[(3R,4/ï)-3-phenylpipendiri-4yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2_;3-c/]pyrimidin-4-one;

„ 98

() '

- 3-[(4-hydroxy-l-{[(3R,4R)-l-(2-methylpropyl)-3-phenylpiperidin-4-yl]carbonyl} piperidin-4-Yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

- l-(2,3-dihydro-l,4-benzodioxin-6-yl)-5-[(4-hydroxy-l-{[(3/ï,4R)-3-phenylpiperidin-4- yl]carbonyl}piperidin“4-yl)methyl]-l_i5-dihydrO'47/-pYrazolo[3,4-d]pyrimidin-4-one;

5 - 3-[(l-{[(3R,4R)-l-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4yl)methyl]-7-(4-fluorophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pynmidin-4-one;

- (3R,4R)-4-[(4-hydroxy-4-{[l-(4-methoxyphenyl)-4-oxo-l,4-dihydro-5H-pyrazolo[3,4d]pyrimidin-5-yl]methyl}piperidin-l-yl)carbonyl]-l,l-dimethyl-3-phenylpiperidinium;

- 3-[(4-hydroxy-l-{[(3R,4R)-l-(2-methylpropanoyl)-3-phenylpiperidin-4-yl]carbonyl}

10 piperidin-4-yl)methy1]-7-phenyl“3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

- 3-[(l-{[(3R,4R)-l-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxyp!perîdin-4yl)methyl]-7-(4-methoxyphenyl)-37-dihydro-4H-pyrrolo[2,3-c/]pyrimidin-4-one;

- 3-[(l-{[(3R,4R)-l-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4- yl)methyl]-7-(3-methoxyphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

15 - 3-[(l-{[(3R,4R)-l-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4yl)methyl]-7-(3-chlorophenyl)-3,7-dihydro-4H-pyrrolo[2_;3-c/]pyrimidin-4-one;

- 3-[(l-{[(3R_J4R)-l-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4yl)methyl]-7-(4-chlorophenyl)-3,7-dihydro-4H-pyrrolo[2_i3-d]pyrimidin-4-one;

- 3-[(l-{[(3R,4R)-l-(2,2-dimethylpropanoyl)-3-phenyipiperidin-4-yl]carbonyl}-4-

20 hydroxypiperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo[2_/3-a']pyrimidin-4-one;

- 3-[(l-{[(3R,4R)-l-(3,3-dimethylbutanoyl)-3-phenylpiperidin-4-yl]carbonyl}-4hydroxypiperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one.

12. Process for the préparation of a compound of formula (I) according to claim 1, characterised in that there is used as starting material the compound of formula (II):

(^R2)n

wherein R.2 and n are as defined for formula (I), which is subjected to coupling with a compound of formula (III):

wherein Ri is as defined for formula (I), and R3’ represents a -C(O)-ORg group wherein

Rg is as defined for formula (I), to yield the compound of formula (IV):

(R₂)

R1

R₃' (IV) wherein Ri, R2, R3’ and n are as defined hereinbefore, compound of formula (IV) which is further converted to an epoxide compound of formula (V):

(V) wherein Ri, R2, R3’ and n are as defined hereinbefore, compound of formula (V) which is further subjected to coupling with compound of formula (VI):

(VI) wherein W is as defined for formula (I),

100 to yield the compound of formula (I-a), a particular case ofthe compounds of formula (I):

wherein Ri, R2, R3’, n and W are as defined hereinbefore,

5 which compound of formula (I/a) may then, if required, be subjected to a reaction removing the R₃’ group, to yield the compound of formula (I-b), a particular case ofthe compounds of formula (I):

wherein Ri, R2, n and W are as defined hereinbefore,

10 which compound of formula (I/b) may then, if required, be subjected to a coupling reaction with compound of formula R3”-C1 wherein R3” represents a linear or branched (CiCô)alkyl group, a linear or branched halo(Ci-Cô)alkyl, or a -C(O)-Rs group wherein R» is as defined for formula (I), to yield the compound of formula (I-c), a particular case of the compounds of formula (I):

101

13.

14.

15.

OH

W—CH₂ (R₂)n

Ri wherein Ri, R2, R3”, n and W are as defined hereinbefore, which compounds offormulae (I/a)to (I/c), which constitute the totality ofthe 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.

Pharmaceutîcal composition comprising a compound of formula (I) according to any one of daims 1 to 11 or an addition sait thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.

Pharmaceutîcal composition according to claim 13 for use as pro-apoptotic and/or antiproliférative agents.

Pharmaceutîcal composition according to claim 13 for use in the treatment of cancers and of auto-immune and immune system diseases.

16.

Pharmaceutîcal composition according to claim 13 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, ovarîan cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

102

17.

18.

Use of a pharmaceutical composition according to claim 13 in the médicaments for use as pro-apoptotic and/or anti-proliferative agents.

manufacture of manufacture of

Use of a pharmaceutical composition according to claim 13 in the médicaments for use in the treatment of cancers and of auto-immune and immune system diseases.

19. Use of a pharmaceutical composition according to claim 13 in the manufacture of médicaments 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,

10 myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

20. Compound of formula (I) according to any one of claims 1 to 11, or an addition sait thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers ofthe bladder, brain, breast and utérus, chronic lymphoid leukemia, cancer of the colon,

15 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.

21. Use of a compound of formula (I) according to any one of claims 1 to 11 or an addition sait thereof with a pharmaceutically acceptable acid or base, in the manufacture of

20 médicaments 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.

25 22. Combination of a compound of formula (I) according to any one of claims 1 to 11 with anti-cancer agents selected from genotoxic agents, mitotic poisons, anti-métabolites, protéasome inhibitors, kinase inhibitors, protein-protein interaction inhibitors, immunomodulators, E3 ligase inhibitors, chimeric antigen receptor T-cell therapy and antibodies.

....... 19084 _χ 102 /

17. Use of a pharmaceutical composition according to claim 13 in the manufacture of médicaments for use as pro-apoptotic and/or anti-proliferative agents.

18. Use of a pharmaceutical composition according to claim 13 in the manufacture of médicaments for use in the treatment of cancers and of auto-immune and immune system

5 diseases.

19. Use of a pharmaceutical composition according to claim 13 in the manufacture of médicaments for use in the treatment of cancers ofthe bladder, brain, breast and utérus, chronic lymphoid leukemia, cancer of the colon, esophagus and liver, lymphoblastic leukemia, acute myeloid leukemia, lymphomas, melanomas, malignant haemopathies,

20. Compound of formula (I) according to any one of daims 1 to 11, or an addition sait thereof with a pharmaceutically 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,

21. Use of a compound of formula (I) according to any one of daims 1 to 11 or an addition sait thereof with a pharmaceutically acceptable acid or base, in the manufacture of

25 22. Combination of a compound of formula (I) according to any one of daims 1 to 11 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 antibodies.

103

23.

24.

25.

26.

Pharmaceutical composition comprising a combination according to combination with one or more pharmaceuticaîly acceptable excipients.

Combination according to claim 22 for use in the treatment of cancers.

claim 22 in

Use of a combination according to claim 22 in the manufacture of médicaments for use in the treatment of cancers.

Compound of formula (I) according to any one of claims 1 to 11 for use in the treatment of cancers requiring radiotherapy.