OA18644A

OA18644A - New pyrrolo[2,3-d]pyrimidine derivatives as dual DYRK1/CLK1 inhibitors.

Info

Publication number: OA18644A
Application number: OA1201800117
Authority: OA
Inventors: Michaël Frank BURBRIDGE; Andrea Fiumana; Nicolas Foloppe; Stuart Ray; David Walmsley; Francisco Humberto CRUZALEGUI; András Kotschy
Original assignee: Les Laboratoires Servier; Vernalis (R&D) Limited
Priority date: 2015-09-30
Filing date: 2016-09-30
Publication date: 2019-01-31

Abstract

New pyrrolo[2,3-d]pyrimidine derivatives, a process for their preparation and pharmaceutical compositions containing them compounds of formula (I):

Description

NEW PYRROLO[2,3-d]PYRIMIDINE DERIVATIVES, A PROCESS FOR THEIR PREPARATION

AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The présent invention relates to new pyrrolo[2,3-<7]pyrimidine dérivatives, to a process for their préparation and to pharmaceutical compositions containing them.

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

The présent invention relates to the use of dual DYRK1 / CLKl inhibitors in the treatment 10 of cancer, neurodegenerative disorders and metabolic disorders.

In cancer, the dual-specificity tyrosine-phosphorylation-regulated kinases DYRKIA and DYRKIB hâve been demonstrated to control several pathways that enhance cancer cell prolifération, migration and metastasis, induce résistance to cell death and repress responses to conventional and targeted anti-cancer thérapies [Abbassi et al, Pharmacol

Ther. 2015;151:87-98; lonescu et al, Mini Rev Med Chem. 2012; 12( 13): 1315-29; Friedman et al, J Cell Biochem. 2007;102(2):274-9; Yoshida et al, Biochem Pharmacol. 2008;76(l 1):1389-94]. Reported substrates of DYRKIA that are involved in this régulation of cancer progression and résistance to therapy include the transcription factors GLU, STAT3 and FOXO1 [Mao et al, J Biol Chem. 2002;277(38):35156-61; Matsuo et al,

J Immunol Methods 2001;247:141-51; Woods et al, Biochem J. 2001;355(Pt 3):597-607]. DYRKIA is also believed to stabilise cancer-associated tyrosine kinase receptors such as EGFR and FGFR via interaction with the protein Sprouty2 [Ferron et al, Cell Stem Cell. 2010;7(3):367-79; Aranda et al, Mol Cell Biol. 2008;28(19):5899-911]. DYRKIA, and also DYRKIB, hâve been shown to be required for the induction of cell quiescence in response to treatment of cancer cells by chemotherapeutic agents and targeted thérapies. This is important since it is known that quiescent cancer cells are relatively insensitive to most anti-cancer drugs and radiation [Ewton et al, Mol Cancer Ther. 2011 ; 10(11):2104-14; Jin et al, J Biol Chem. 2009;284(34):22916-25]. For example, DYRKIA activâtes the DREAM multisubunit protein complex, which maintains cells in quiescence and protects against apoptosis [Litovchick et al, Genes Dev. 2011 ;25(8):801-13]. DYRKIB has been

-2demonstrated to prevent cell-cycle exit in response to chemotherapy via phosphorylation of Cyclin Dl [Zou et al, J Biol Chem. 2004;279(26):27790-8]. DYRKIB has also been shown to protect against chemotherapy through a réduction in reactive oxygen species content [Hu et al, Genes Cancer. 20 lO;l(8):803-811].

It is thus clear that the use of DYRK1A / DYRKIB inhibitors would constitute a novel anti-cancer treatment in a wide variety of cancers when used either alone or in combination with conventional therapy, radiation or targeted thérapies as a strategy to combat résistance.

The rôle of DYRKIA in neurological disorders is well established. DYRKIA is associated 10 with neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as with Down’s syndrome, mental retardation and motor defects and [Abbassi et al, Pharmacol Ther. 2015;151:87-98; Beker et al, CNS Neurol Disord Drug Targets. 2014;13(l):26-33; Dierssen, Nat Rev Neurosci. 2012 Dec; 13(12):844-58]. DYRKIA has been identified as a major kinase phosphorylating the microtubule15 associated protein TAU, leading to the formation of neurotoxic neurofibrillary tangles and neurodegeneration as seen in Alzheimer’s [Azorsa et al, BMC Genomics. 2010;l 1:25]. DYRKIA also alters the splicing of TAU pre-mRNA leading to an imbalance between TAU isoforms which is sufficient to cause neurodegeneration and dementia [Liu et al, Mol Neurodegener. 2008;3:8]. It is not surprising, therefore, that DYRKIA is believed to be 20 causally involved in the development of Alzheimer-like neurodegenerative diseases in Down Syndrome patients, where three copies of the DYRKIA gene are présent on chromosome 21. In these individuals, increased DYRKIA activity also causes prématuré neuronal différentiation and a decrease in mature neurones [Hâmmerle et al, Development. 2011;138(12):2543-54],

It is thus clear that the use of DYRKIA inhibitors would offer a novel therapeutic approach for the treatment of neurodegenerative disorders, in particular Alzheimer’s disease, as well as for other neurological conditions such as Down’s syndrome.

The CDC2-like kinase (CLK) family contains four isoforms (CLK1-4) which are important in regulating the fonction of the spliceosome complex [Fedorov et al, Chem Biol. 30 2011;18(1 ):67-76]. This complex, comprised of small nuclear RNAs (snRNA) and a large number of associated proteins, régulâtes the splicing of pre-mRNAs to give mature protein-encoding mRNAs. CLK1 is known to regulate the activity of the spliceosome via

-3 phosphorylation of the constituent serine-arginine-rich (SR) proteins [Bullock et al, Structure. 2009; 17(3):352-62]. By controlling the activity of the spliceosome in this way, many genes are able express more than one mRNA leading to diversity in the translated proteins. The alternative protein isoforms transcribed from the same gene will often hâve 5 different activities and physiological functions. Deregulation of alternative splicing has been linked to cancer, where a number of cancer-related proteins are known to be altematively spliced [Druillennec et al, J Nucleic Acids. 2012;2012:639062]. An example of an altematively spliced protein in cancer is Cyclin Dl, important for the progression of cancer cells through the cell cycle [Wang et al, Cancer Res. 2008;68(14):5628-38].

It is thus clear that the use of CLK1 inhibitors would constitute a novel anti-cancer treatment in a wide variety of cancers when used either alone or in combination with conventional therapy, radiation or targeted thérapies.

Alternative splicing regulated by CLK1 has also been described to play a rôle in neurodegenerative diseases, including Alzheimer’s and Parkinson’s, via phosphorylation of 15 the SR proteins of the spliceosome [Jain et al, Curr Drug Targets. 2014;15(5):539-50]. In the case of Alzheimer’s, CLK1 is known to regulate the alternative splicing of the microtubule-associated protein TAU leading to an imbalance between TAU isoforms which is sufficient to cause neurodegeneration and dementia [Liu et al, Mol Neurodegener. 2008;3:8].

It is thus clear that the use of CLK1 inhibitors would offer a novel therapeutic approach for the treatment of neurodegenerative disorders, in particular Alzheimer’s disease, as well as for other neurological conditions such as Parkinson’s.

In the treatment of both cancer and neurological disease, there is thus undoubtedly an urgent need for compounds which potently inhibit the DYRK1 and CLK1 kinases whilst 25 not affecting other closely-related kinases. The DYRK1 and CLK1 kinases are members of the CMGC group, which includes the CDK and the GSK kinases, the chronic inhibition of which is believed to be a cause of toxicity to the patient. For example, common toxicities observed in the clinic with CDK inhibition are similar to those observed with conventional cytotoxic therapy, and include hématologie toxicity (leukopenia and thrombocytopenia), 30 gastrointestinal toxicity (nausea and diarrhea), and fatigue [Kumar et al, Blood.

2015;125(3):443-8]. The présent invention describes a new class of DYRK1 / CLK1

-4inhibitors which are highly sélective for DYRKl and CLKl over these other kinases and which would thus be suitable for use in the treatment of these pathologies.

Diabètes type l and type 2 both involve deficiency of functional pancreatic insulin-producing beta cells. Restoring functional beta-cell mass is thus an important therapeutic goal for these diseases which affect 380 million people worldwide. Recent studies hâve shown that DYRKl A inhibition promûtes human beta-cell prolifération in vitro and in vivo and, following prolonged treatment, can increase glucose-dependent insulin sécrétion [Dirice et al, Diabètes. 20l6;65(6):l660-7l ; Wang et al, Nat Med. 2015;21(4):383-8]. These observations clearly suggest that the use of potent and sélective DYRKIA inhibitors would offer a novel therapeutic approach for the treatment and/or prévention of metabolic disorders including diabètes and obesity.

Some pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d]pyrimidine dérivatives are already known from literature. In particular, WO 2014/001973 and WO 2015/092592 disclose LRRK2 inhibitors exhibiting such a Chemical scaffold, whilst EP 2125803 disclose DYRKIA inhibitors. Ail are of potential value in the treatment of cancer or neurodegenerative disorders. Interestingly, compounds according to the invention display spécifie substitutes and hâve dual DYRKl/CLKl inhibitory properties.

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

wherein:

♦ Ri and R₂, each independently of the other, represent a hydrogen atom, a halogen atom, NR5R5 or a linear or branched (Ci-Côjalkyl group, ♦ W₃ represents a linear or branched (Ci-Cô)alkoxy, -0-(Co-C6)alkylene-Cyi, -O-(C₀-C6)alkylene-Cyi-Cy_2> -NR_aRb, -NR_a-(Co-C₆)alkylene-Cyi,

-NR_a-(C₀-C₆)alkylene-Cyi-Cy₂, -NR_a-(Co-C₆)alkylene-Cyi-0-(Ci-C₆)alkylene-Cy₂, -Cyi, -Cy_r(Co-C₆)alkylene-Cy₂, -Cyi-0-(Co-C6)alkylene-Cy₂, -(Ci-Côjalkylene-Cyi, -(C₂-C6)alkenyleneCyi, -(C₂-Cô)alkynylene-Cyi, -(Ci-Céjalkylene-O-Cyi, it being understood that the alkylene moieties defined hereinbefore may be linear or branched, ♦ W₄ represents a cyano group, a cycloalkyl group, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C2-Cô)alkenyl group, a linear or branched (C2-

Cô)alkynyl group optionally substituted by a cycloalkyl group, ♦ R5 and R5’, each independently of the others, represent a hydrogen atom or a linear or branched (Ct-Cô)alkyl group, ♦ Ra and Rb, each independently of the other, represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group, ♦ Ai and A₂, each independently of the other, represent CH or a nitrogen atom, ♦ Cyi, Cy2 and Cy3, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group, wherein:

- aryl means a phenyl, naphthyl, biphenyl or indenyl group,

- heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen,

- cycloalkyl means any mono- or bi-cyclic, non-aromatic, carbocyclic group containing from 3 to 11 ring members, which may include fused, bridged or spiro ring Systems,

- heterocycloalkyl means any mono- or bi-cyclic, non-aromatic, condensed or spiro group composed of from 3 to 10 ring members and containing from 1 to 3 hetero atoms or groups selected from oxygen, sulphur, SO, SO2 and nitrogen, which may include fused, bridged or spiro ring Systems,

- “-(Co-C6)alkylene-“ refers either to a covalent bond (-Coalkylene-) or to an alkylene group containing 1, 2, 3,4, 5 or 6 carbon atoms, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene to be substituted by from 1 to 4 groups selected from linear or branched (Ci-C6)alkyl, linear or branched (C2-Cô)alkenyl group, linear or branched (C2-Cô)alkynyl group, linear or branched

-6(Ci-Cô)alkoxy optionally substituted by -NRcRd or by from l to 3 halogen atoms, linear or branched (Ci-C6)alkyl-S-, hydroxy, oxo (or TV-oxide where appropriate), nitro, cyano, -C(O)-ORc, -C(O)-R_c, -O-C(O)-R_d, -C(O)-NRcRd, -NRc-C(O)-R_d, -NR^Ru, linear or branched (Ci-C6)polyhaloalkyl, or halogen, it being understood that R_c and Rd 5 independently of one another represent a hydrogen atom or a linear or branched (Ci-Cô)alkyl group, to their enantiomers and diastereoisomers, and to addition salts thereof with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids there may be mentioned, without implying 10 any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonie acid, camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned, without implying 15 any limitation, sodium hydroxide, potassium hydroxide, triethylamine, rert-butylamine etc.

Advantageously, Ri represents a hydrogen and R₂ a -NH₂ group.

In one embodiment of the invention, Ai represents a CH group.

In another embodiment of the invention, Ai represents a nitrogen atom.

In a preferred embodiment of the invention, A₂ represents a nitrogen atom.

Altematively, A₂ represents a CH group. When A₂ represents a CH group, Ai represents preferably a CH group.

In another embodiment of the invention, W3 represents a linear or branched (Ci-Cô)alkoxy, -0-(Co-C₆)alkylene-Cyi, -O-(C₀-C₆)alkylene-Cyi-Cy_2> -NR_a-(Ci-C₆)alkylene-Cyi-Cy₂,

-7 -NR_a-(Co-C6)alkylene-Cyi-0-(Ci-C6)alkylene-Cy2, -Cyi-0-(Co-C6)alkylene-Cy₂,

-(Ci-C6)alkylene-Cyi, -(C2-C6)alkenylene-Cyi, -(C2-C6)alkynylene-Cyi, -(Ci-C6)alkyleneO-Cyi, it being understood that the alkylene moieties defined hereinbefore may be linear or branched.

Altematively, W3 represents a Cyi group selected from: l,3-benzodioxolyl, IH-indolyl, phenyl, pyridinyl, 2,3-dihydro-l,4-benzodioxinyl, l-benzothiophenyl, l-benzofuranyl, 3,4dihydronaphthalenyl, l ,2,3,4-tetrahydronaphthalenyl, 3,4-dihydro-2//-1,4-benzoxazinyl, wherein the preceding groups are optionally substituted according to the définition mentioned previously.

io In an other embodiment, W3 represents: (i) a -NRa-Cyi group, wherein Cyi represents a group selected from: phenyl, 2,3-dihydro-l/f-indene and 1,2,3,4-tetrahydronaphthalene, wherein the preceding groups are optionally substituted according to the définition mentioned previously; or (ii) a -NR_a-(Ci-C6)alkylene-Cyi group, wherein Cyi represents a group selected from: phenyl, pyridinyl, furanyl, thiophenyl, l//-pyrazolyl, 1,3-thiazolyl, 15 1,2-oxazolyl, cyclohexyl, cyclopropyl and l//-indolyl, wherein the preceding groups are optionally substituted according to the définition mentioned previously.

In a spécifie embodiment, W3 represents a -phenylene-(Co-Cô)alkylene-Cy2.

More preferably, W3 represents -O-(Ci-C6)alkylene-Cyi or -NRa-(Ci-C6)alkylene-Cyi, wherein Cyi is a phenyl or a pyridinyl group, these latter group being optionally 20 substituted by one or two groups selected from methoxy, methyl or halogen.

Preferred W4 groups are as follows: methyl ; propan-2-yl ; prop-l-en-2-yl ; ethenyl ; cyano ; ethynyl ; cyclopropyl ; cyclopropylethynyl. Methyl group is even more preferred.

Preferred compounds according to the invention are included in the following group:

- 5-(2-aminopyridin-4-yl)-7V-(2-methoxybenzyl)-2-methyl-7//-pynOlo[2,325 J]pyrimidin-4-amine,

-8- 4-[2-methyl-4-(thiophen-3-ylmethoxy)-7/7-pyrrolo[2,3-i/]pyrimidin-5-yl]pyridin-2amine,

- 5-(2-aminopyridin-4-yl)-jV-(2,6-dichlorobenzyl)-2-methyl-7//-pyrrolo[2,3</]pyrimidin-4-amine,

- 5-(2-aminopyridin-4-yl)-Æ-(2,6-difluorobenzyl)-2-methyl-7/7-pyrrolo[2,3t/]pyrimidin-4-amine, - 5-(2-aminopyridin-4-yl)-2-methyl-V-(2-methylbenzyl)-7/7-pyrrolo[2,3</]pyrimidin-4-amine,

- 5-(2-aminopyridin-4-yl)-A-(2-chloro-6-fluorobenzyl)-2-methyl-7/f-pyrrolo[2,310 d]pyrimidin-4-amine,

- 5-(2-aminopyridin-4-yl)-2-methyl-7V-[(3-methylpyridin-2-yl)methyl]-7/7pyrrolo[2,3-i/]pyrimidin-4-amine,

- 5-(2-aminopyridin-4-yl)-7V-[(3-fluoropyridin-2-yl)methyl]-2-methyl-7/fpyrrolo[2,3-iZ]pyrimidin-4-amine,

- 5-(2-aminopyrimidin-4-yl)W-(2,6-difluorobenzyl)-2-methyl-7/7-pyrrolo[2,3i/]pyrimidin-4-amine, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

The invention relates also to a process for the préparation of compounds of formula (I), 20 which process is characterised in that there is used as starting material the compound of formula (II):

wherein T represents a halogen atom, a methane-sulfanyl group, a cycloalkyl group or a linear or branched (Ci-Cô)alkyl group, and A₂ is as defined in formula (I),

-9which compound is subjected to a nucleophilic substitution in the presence of an appropriate alcohol or amine dérivative, or subjected to coupling with an appropriate boronic acid dérivative, to yield the compound of formula (III) :

(III) wherein T is as defined previously, A₂ and W3 are as defined in formula (I), which compound of formula (III) is either :

(i) converted into its methanesulfonyl dérivative when T represents a methanesulfanyl group, then reacted with NaCN and further subjected to coupling with an appropriate boronic acid dérivative, (ii) or directly subjected to coupling with an appropriate boronic acid dérivative, (iii) or subjected to coupling with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2dioxaborolane to yield :

which compound of formula (ΙΙΓ) is further reacted with the appropriate halide, to yield compound of formula (IV) :

- ιο-

(iv) wherein T’ represents represents a halogen atom, a cyano group, a cycloalkyl group or a linear or branched (Ci-C6)alkyl group, and Ai, A2, Ri, R2 and W3 are as defined in formula (I), which compound of formula (IV):

- may be subjected to coupling with an appropriate alkynyl (or alkenyl) boronic acid dérivative or alkynyl (or alkenyl) (trifluoro)borate dérivative sait, when T’ represents a halogen atom, to yield the compounds of formula (I), which compound of formula (I) may be purified according to a conventional séparation 10 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 time considered appropriate in the course of the abovedescribed process, certain groups (hydroxy, amino...) of the reagents or intermediates of 15 synthesis may be protected and then deprotected according to the requirements of synthesis.

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

(II) wherein W4 and Ai are as defined in formula (I), which compound of formula (II) is subjected to coupling with an appropriate boronic acid dérivative, to yield compound of formula (V):

(V) wherein Ai, A2,Ri, R2, and W4 are as defined in formula (I), which compound of formula (V) is either subjected to a nucleophilic substitution, or subjected to a coupling reaction with an appropriate boronic acid dérivative, or subjected to a coupling with a compound of formula ΞΞΞΞ----^R3 » wherein R3 represents a hydrogen orCyi, to yield the compounds of formula (I), which compound of formula (I) may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that, at any time considered appropriate in the course of the abovedescribed process, certain groups (hydroxy, amino...) of the reagents or intermediates of 5 synthesis may be protected and then deprotected according to the requirements of synthesis.

The compound of formula (II), the alcohol and amino dérivatives, the boronic acid dérivatives, the borate sait dérivatives and ----^R3 mentioned above are either commercially available or can be obtained by the person skilled in the art using 10 conventional Chemical reactions described in the literature.

Pharmacological study of the compounds of the invention has shown that they are powerful DYRK1/CLK1 inhibitors which are highly sélective for DYRK1 and CLK1 over other kinases such as CDK9.

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

Among the cancer treatments envisaged there may be mentioned, without implying any limitation, haematological cancer (lymphoma and leukemia) and solid tumors including carcinoma, sarcoma, or blastoma. There may be mentioned more preferably acute megakaryoblastic leukaemia (AMKL), acute lymphoblastic leukaemia (ALL), ovarian 20 cancer, pancreatic cancer, gastrointestinal stromal tumours (GIST), osteosarcoma (OS), colorectal carcinoma (CRC), neuroblastoma and glioblastoma.

In another embodiment, the compounds of the invention will useful in the treatment of neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as with Down’s syndrome, mental retardation and motor defects.

Altematively, the compounds of the invention could be used in the treatment and/or prévention of metabolic disorders including diabètes and obsesity.

- 13The présent invention relates also to pharmaceutical compositions comprising at least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention there may be 5 mentioned more especially those that are suitable for oral, parentéral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.

The dosage varies according to the sex, âge and weight of the patient, the administration 10 route, the nature of the therapeutic indication, or of any associated treatments, and ranges from 0.01 mg to 5 g per 24 hours in one or more administrations.

Furthermore, the présent invention relates also to the combination of a compound of formula (I) with an anticancer agent selected from genotoxic agents, mitotic poisons, antimetabolites, protéasome inhibitors, kinase inhibitors, signaling pathway inhibitors, 15 phosphatase inhibitors, apoptosis inducers and antibodies, and also to pharmaceutical compositions comprising that type of association 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 administered simultaneously or sequentially. The administration route is preferably the oral 20 route, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingrédients. The compounds of the combination may moreover be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingrédients, or in the form of a single pharmaceutical composition, in which the active ingrédients are in admixture.

The compounds of the invention may also be used in association with radiotherapy in the treatment of cancer.

List of abbreviations
	Abbreviation	Name
	Ac	acetyl
	aq.	Aqueous
5	Bn	benzyl
	Boc	/er/-butyloxycarbonyl protecting group
	dppf	l, l '-bis(diphenylphosphino)ferrocene
	DCM	dichloromethane
	DEAD	diethyl azodicarboxylate
10	DIBAL	diisobutylaluminium hydride
	DMAP	4-diméthylaminopyridine
	DMF	A/V-dimethylformamide
	DMSO	dimethyl sulfoxide
	dtbpf	l, l ’-bis(di-/er/-butylphosphino)ferrocene
15	eq-	équivalent
	Et	ethyl
	IPA	isopropanol
	HPLC-MS	liquid chromatography-mass spectrometry
	LiHMDS	lithium bis(trimethylsilyl)amide
20	mCBPA	we/a-chloroperoxybenzoic acid
	Me	methyi
	NBS	jV-bromosuccinimide
	ⁿBu	w-butyl
	ⁿBuPAd₂	n-butyldiademantylphosphine
25	Pd/C	palladium on carbon
	Ph	phenyl
	PPh₃	triphenylphosphine
	pTSA	pnra-toluenesulfonic acid
	RT	rétention time
30	sat.	saturated

SEM	[2-(trimethylsilyl)ethoxy]methyl
'Bu	/erZ-butyl
TFA	trifuoroacetic acid
THF	tetrahydrofurane

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 with pre- packed silica gel cartridges (Strata SI-l ; 6lÂ, Phenomenex, Cheshire UK or IST Flash II, 54Â, Argonaut, Hengoed, UK) or by automated flash chromatography using a Combiflash Rf apparatus (Teledyne Isco Inc.) using RediSep Rf prepacked silica columns (Teledyne Isco Inc.) or SilaSep pre-packed columns (Silicycle Inc.). Thin layer chromatography was conducted with 5 x 10 cm plates coated with Merck Type 60 F254 silica gel.

The compounds of the présent invention were characterized by high performance liquid 15 chromatography-mass spectroscopy (HPLC-MS) on either an Agitent HP1200 Rapid

Resolution Mass detector 6140 multimode source M/z range 150 to 1000 amu or an Agilent HPl 100 Mass detector 1946D ESI source M/z range 150 to 1000 amu. The conditions and methods listed below are identical for both machines.

Column for 7.5 min run: GeminiNX, 5 pm, C18, 30 x 2.1 mm (Phenomenex) or Zorbax 20 Eclipse Plus, 3.5 pm, C18, 30 x 2.1 mm (Agilent). Température: 35 °C.

Column for 3.75 min run: GeminiNX, 5pm, C18, 30 x 2.1 mm (Phenomenex) or Zorbax Eclipse Plus, 3.5 pm, C18, 30 x 2.1 mm (Agilent). Température: 35 °C.

Column for 1.9 min run: Kinetex, 2.5 pm, C18, 50 x 2.1 mm (Phenomenex) or Accucore, 2.6 pm, Cl8, 50x2.1 mm.

Température: 55 °C.

Mobile Phase: A - H2O + 10 mmol / ammonium formate + 0.08% (v/v) formic acid at pH ca 3.5.

B - 95% Acetonitrile + 5% A + 0.08% (v/v) formic acid.

Injection Volume: 1 pL

Method A Short method gradient table, either positive (pos) or positive and négative (pos / neg) ionisation

Time (min)	Solvent A (%)	Solvent B (%)	Flow (mL/min)
0	95	5	l
0.25	95	5	l
2.50	5	95	l
2.55	5	95	1.7
3.60	5	95	1.7
3.65	5	95	l
3.70	95	5	l
3.75	95	5	l

Method B Super Short method gradient table, either positive (pos) or positive and négative (pos / neg) ionisation

Time (min)	Solvent A (%)	Solvent B (%)	Flow (mL/min)
0	95	5	1.3
0.12	95	5	1.3
1.30	5	95	1.3
1.35	5	95	1.6
1.85	5	95	1.6
1.90	5	95	1.3
1.95	95	5	1.3

Détection: UV détection at 230, 254 and 270 nm.

The compounds of the présent invention were also characterized by Nuclear Magnetic 5 Résonance (NMR). Analysis was performed with a Bruker DPX-400 spectrometer and proton NMR spectra were measured at 400 MHz. The spectral reference was the known Chemical shift of the solvent. Proton NMR data is reported as follows: Chemical shift (δ) in ppm, followed by the multiplicity, where s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, dm = doublet of multiplets, 10 ddd = doublet of double doublets, td = triplet of doublets, qd = quartet of doublets and br = broad, and finally the intégration.

- 17 Some compounds of the invention were purified by préparative HPLC. These were performed on a Waters FractionLynx MS autopurification System, with a Gemini® 5 pm Cl8(2), 100 mm x 20 mm i.d. column from Phenomenex, running at a flow rate of 20 cm³min·' with UV diode array détection (210-400 nm) and mass-directed collection.

At pH 4: solvent A = 10 mM ammonium acetate in HPLC grade water + 0.08% v/v formic acid. Solvent B = 95% v/v HPLC grade acetonitrile + 5% v/v solvent A + 0.08% v/v formic acid.

At pH 9: solvent A = 10 mM ammonium acetate in HPLC grade water + 0.08% v/v ammonia solution. Solvent B = 95% v/v HPLC grade acetonitrile + 5% v/v solvent A + 10 0.08% v/v ammonia solution.

The mass spectrometer was a Waters Micromass ZQ2000 spectrometer, operating in positive or négative ion electrospray ionisation modes, with a molecular weight scan range of 150 to 1000.

Some compounds of the présent invention were characterised using an Agilent 1290 15 Infinity II sériés instrument connected to an Agilent TOF 6230 single quadrupole with an ESI source. High resolution mass spectra were recorded in positive-negative switching mode ionization unless otherwise stated. UV détection was by diode array detector at 230, 254 and 270 nm. Column: Thermo Accucore 2.6 μΜ Cl8, 50x2 mm, at 55 °C column température. Buffer A: Water /10 mM ammonium formate / 0.04% (v/v) formic acid 20 pH=3.5. Buffer B: Acetonitrile / 5.3 % (v/v) A / 0.04% (v/v) formic. (Injection volume: 1 pL).

The following Préparations and Examples illustrate the invention without limiting it in any way.

General Procedure I

General Procedure II

BnOH

SEM

RO OR

In General Procedures I, II and III :

- Ri and R₂ are as defined in formula (I),

- R₃ represents a linear or branched (Ci-Cô)alkyl group, -(Co-Cô)alkylene-Cyi, 5 -(Co-C6)alkylene-Cyi-Cy₂, it being understood that Cyi and Cy₂, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group.

Example 1: 4-methoxy-2-methyl-5-(pyridin-4-yl)-7fl^r-pyrrolo[2,3-i/]pyrimidine

Step 1: 5-bromo-4-chloro-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,31° d]pyrimidine (Préparation 1)

To a solution of 5-bromo-4-chloro-2-methyl-7f/-pyrrolo[2,3-<7]pyrimidine (1 g, 4.06 mmol) in DMF (30 mL) was added NaH (60% in minerai oil, 1 eq) at 0 °C under N₂. The reaction mixture was stirred for 30 min before adding SEM-C1 (1.1 eq) at 0 °C and allowed to warm to room température ovemight under N₂. The reaction mixture was diluted with 15 diethyl ether (100 mL), washed with brine (4 x 50 mL), dried over MgSO₄ and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (1.18 g, 3.13 mmol, 77%) as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.12 (s, IH), 5.65 (s, 2H), 3.67-3.57 (m, 2H), 2.74 (s, 3H), 0.98-0.87 (m, 2H), 0.00 (s, 9H).

LC/MS (method B): RT = 1.59 min; m/z = RT = 1.59 min; m/z = 377 [M+H]⁺

-20Step 2: 5-bromo-4-methoxy-2-methyl·7·{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo [2,3-d]pyrimidine (Préparation 2)

To a suspension ofNaH (60% in minerai oil, 2 eq) in THF (10 mL) was added MeOH (1.3 eq) dropwise at 0 °C under N2. Stirred for IO min before adding a solution of the 5 compound obtained in Step l (0.5 g, 1.3 mmol) in THF (3 mL). The reaction mixture was stirred at 0 °C for 30 min and allowed to warm to room température over l hour. The reaction mixture was diluted with sat. aq. NH4CI solution (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give the product (0.494 g, 1.3 mmol, 100%) as a clear oil. The compound was 10 used without further purification.

Ή NMR (399 MHz, DMSO-d6) Ô 7.75 (s, IH), 5.59 (s, 2H), 4.12 (s, 3H), 3.64-3.55 (m, 2H), 2.65 (s, 3H), 0.97 - 0.87 (m, 2H), 0.00 (s, 9H).

LC/MS (method B): RT = 1.53 min; m/z = 374 [M+H]⁺

Step 3: 4-methoxy-2-methyl-5-(pyridin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H15 pyrrolo[2,3-d]pyrimidine (Préparation 3)

The compound obtained in Step 2 and (pyridin-4-yl)boronic acid (1.5 eq) were dissolved in THF/water (6:1, 5 mL) under N₂. Potassium carbonate (3 eq) and Pd(dtbpf)Ch (10% wt) were added and the resulting mixture was degassed under N2 for 5 minutes. The reaction mixture was heated at 120 °C on a CEM microwave reactor for 1 hour. The reaction 20 mixture was diluted with water (10 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over MgSÛ4 and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (0.11 g, 0.30 mmol, 44%) as an oil.

Ή NMR (399 MHz, DMSO-d6) δ 8.67-8.61 (m, 2H), 8.11 (s, IH), 7.83-7.77 (m, 2H), 25 5.68 (s, 2H), 4.13 (s, 3H), 3.70 - 3.61 (m, 2H), 2.68 (s, 3H), 0.99 - 0.88 (m, 2H), 0.00 (s,

9H).

LC/MS (method A): RT = 1.37 min; m/z = 371 [M+H]⁺

Step 4: 4-methoxy-2-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (Préparation 4) To a solution of the compound obtained in Step 3 (0.11 g, 0.3 mmol) in THF (3 mL) was 30 added ethylenediamine (5 eq) followed by TBAF (IM solution in THF, 5 eq). The reaction

-21 was heated at 120 °C on a CEM microwave reactor for 1 hour. The reaction mixture was diluted with water (10 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over MgSÛ4 and concentrated in vacuo. The residue was then triturated with EtOAc to give the product (15 mg, 0.06 mmol, 21%) as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.33 (s, IH), 8.58 - 8.50 (m, 2H), 7.85 (s, IH), 7.78 7.72 (m, 2H), 4.05 (s, 3H), 2.57 (s, 3H).

LC/MS (method A): RT = 1.49 min; m/z = 241 [M+H]⁺

Example 6: 2-methvl-5-(2-methvlpvridin-4-vD-4-|(37D-piperidin-3-vlmethoxvl-7.Hpyrrolo[2,3-rf] pyrimidine

Step 1: 4-(benzyloxy)-5-bromo-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7Hpyrrolo[2,3 -d]pyrimidine

Starting from 5-bromo-4-chloro-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7/fpyrrolo[2,3-7]pyrimidine (Example 1, Step 1) (5 g, 13.27 mmol) and benzyl alcohol (1.3 eq) following procedure described in Préparation 2, the desired product (5.4 g, 12 mmol, 15 91%) was obtained as a light yellow oil.

Ή NMR (399 MHz, DMSO-d6) δ 7.77 (s, IH), 7.68 - 7.60 (m, 2H), 7.54 - 7.45 (m, 2H), 7.47 - 7.38 (m, IH), 5.67 (s, 2H), 5.60 (s, 2H), 3.65 - 3.55 (m, 2H), 2.67 (s, 3H), 0.97 0.87 (m, 2H), 0.00 (s, 9H).

LC/MS (method A): RT = 3.04 min; m/z = 450 [M+H]⁺

Step 2: 4-(benzyloxy)-2-methyl-5-(2-methylpyridin-4-yl)-7-{[2-(trimethylsilyl)ethoxy] methyl}- 7H-pyrrolo[2,3-d]pyrimidine

Starting from the compound obtained in Step 1 (2 g, 4.46 mmol) and (2-methylpyridin-4-yl)boronic acid (1.2 eq) following procedure described in Préparation 3. The residue was purified via flash chromatography using EtOAc and isohexane as eluent 25 to give the product ( 1.311 g, 2.8 mmol, 64%) as a brown oil.

Ή NMR (399 MHz, DMSO-d6) δ 8.36 (dd, IH), 8.08 (s, IH), 7.66 - 7.40 (m, 7H), 5.67 (s, 2H), 5.63 (s, 2H), 3.69 - 3.60 (m, 2H), 2.71 (s, 3H), 2.31 (s, 3H), 0.99 - 0.90 (m, 2H), 0.00 (s, 9H).

-22Step 3: 2 -methyl-5 -(2 -methylpyridin ~4-yl)-7-{[2 -(trimethylsilyl)ethoxy] methyl} -7Hpyrrolo[2,3-d]pyrimidin-4-ol (Préparation 5)

A suspension of the compound obtained in Step 2 (l.3Il g, 2.8 mmol) and Pd/C (10% in wt) in EtOH (40 mL) was agitated under H₂ at room température for 2h. The suspension 5 was filtered through a plug of celite and concentrated in vacuo. The residue was triturated with isohexane to give the product (0.886 g, 2.39 mmol, 84%) as an off-white solid Ή NMR (399 MHz, DMSO-d6) δ 12.14 (s, IH), 8.47 - 8.40 (m, IH), 8.01 - 7.91 (m, 3H), 5.54 (s, 2H), 3.62 (dd, 2H), 2.53 (s, 3H), 2.43 (s, 3H), 0.92 (dd, 2H), 0.00 (s, 9H).

Step 4: tert-butyl (3R)-3-({[2-methyl-5-(2-methylpyridin-4-yl)-7-{[2-(trimethylsilyl) ethoxy]methyl} -7H-pyrrolo[2,3 -d]pyrimidin -4 -yl]oxy}methyl)piperidine -1 -carboxylate (Préparation 6)

To a solution of the compound obtained in Step 3 (100 mg, 0.27 mmol) and tert-butyl (3J?)-3-(hydroxymethyl)piperidine-l-carboxylate (1.5 eq) in THF( 5 mL) was added PPh₃(1.5 eq) at room température under N₂. The reaction mixture was allowed to stir at room température for 10 minutes and then cooled in an ice-bath before adding DEAD (1.5 eq). The ice-bath was removed and the reaction mixture allowed to stir for 2 hours at room température. The reaction mixture was concentrated in vacuo and the residue purified via flash chromatography using EtOAc and isohexane as eluent to give the product (122 mg, 0.214 mmol, 80%) as a clear oil.

Ή NMR (399 MHz, DMSO-d6) δ 8.51 (d, IH), 8.08 (s, IH), 7.72 (s, IH), 7.61 (d, IH), 5.67 (s, 2H), 4.51 (dd, IH), 4.40 (dd, IH), 3.68 - 3.59 (m, 2H), 3.43 (s, 9H), 2.66 (s, 3H), 2.56 (s, 3H), 1.88 (d, IH), 1.69 (s, 1 H), 1.47 - 1.19 (m, 7H), 0.99 - 0.87 (m, 2H), 0.00 (s, 9H).

Step 5: 2-methyl-5-(2-methylpyridin-4-yl)-4-[(3R)-piperidin-3-ylmethoxy]-7H-pyrrolo[2,325 d]pyrimidine (Préparation 7)

To a solution of the compound obtained in Step 4 (78 mg, 0.137 mmol) in DCM (5 mL) was added TFA (3 mL) under N₂ at room température and stirred for 3 hours. The reaction mixture was loaded directly into a scx-2 column (10 g), washed with MeOH and DCM and eluted with IN NH₃ solution in MeOH. The fractions were concentrated in vacuo and the

-23residue was purified via flash chromatography using 2N NH₃ solution in MeOH and DCM as eluent to give the desired product (18 mg, 0.024 mmol, 17%) as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.24 (s, IH), 8.38 (d, IH), 7.80 (s, IH), 7.66 (d, IH), 7.54 (dd, IH), 4.30 (qd, 2H), 3.05 - 2.96 (m, IH), 2.84 (dt, IH), 2.54 (s, 3H), 2.51 (s, 3H), 5 2.47 - 2.36 (m, IH), 2.32 (dd, IH), 1.97 - 1.86 (m, IH), 1.79 (dd, IH), 1.62 - 1.49 (m,

IH), 1.46- 1.02 (m, 3H).

LC/MS (method A): RT = 1.35 min; m/z = 338 [M+H]⁺

Example 20: 4-|2-methyl-4-(l-phenylethoxy)-7/f-pyrroIo|2,3-</|pyrimidin-5-yl| pyridin-2-amine

Step 1: 4-(4-chloro-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo

[2,3 -d]pyrimidin -5 -yl)pyridin -2 -amine

Starting from 5-bromo-4-chloro-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7//pyrrolo[2,3-i/]pyrimidine (0.91 g, 2.42 mmol) and 4-(tetramethyll,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.1 eq) following procedure described in

Préparation 3, the desired product (0.257 g, 0.659 mmol, 27%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.02 (t, 2H), 6.74 - 6.63 (m, 2H), 6.08 (s, 2H), 5.72 (s, 2H), 3.66 (dd, 2H), 2.76 (s, 3H), 0.99 - 0.88 (m, 2H), 0.00 (s, 9H).

LC/MS (method A): RT = 2.16 min; m/z = 390 [M+H]⁺

Step 2: 4-[2-methyl-4-(l-phenylethoxy)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7Hpyrrolo[2,3 -d]pyrimidin -5 -yl[pyridin -2 -amine

Starting from the compound obtained in Step 1 (100 mg, 0.25 mmol) and 1-phenylethan-l-ol (1.3 eq) following procedure described in Préparation 2, the product (107 mg, 0.224 mmol, 90%) was obtained as an oil.

LC/MS (method B): RT = 1.38 min; m/z = 476 [M+H]⁺

-24Step 3: 4-[2-methyl-4-(1 -phenylethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]pyridin-2-amine Starting from the compound obtained in Step 2 (107 mg, 0.224 mmol) following procedure described in Préparation 4, the desired product (40 mg, 0.115 mmol) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.22 (s, IH), 7.96 (d, IH), 7.67 (s, IH), 7.59 - 7.51 (m, 2H), 7.47 - 7.38 (m, 2H), 7.40 - 7.31 (m, IH), 6.99 - 6.88 (m, 2H), 6.54 (q, IH), 5.86 (s, 2H), 2.6 (s, 3H), 1.76 (d, 3H).

LC/MS (method B): RT = 1.09 min; m/z = 346 [M+H]⁺

Examples 1-28 in the following Table 1 were prepared by methods outlined in General 10 Procedure I-III using appropriate commercially available boronate esters and alcohols.

The compounds of Example 1, 6, 20 are also included.

Table 1: HRMS (TOF, ESI) data

Example	Structure	Mol Formula	Calcd Exact Mass	Found m/z	Adduct
1	4-methoxy-2-methyl-5-(pyridin-4-y 1)-7//pyrrolo[2,3-i/]pyrimidine	C13 H12N4O	240.1011	241.1082	[M + Hf
2	4-(4-methoxy-2-methyl-7/7-pyrrolo[2,3t/]pyrimidin-5-yl)pyridin-2-amine	C13 H13N5 O	255.1120	256.1196	[M + H]⁺
3	5-(2-fluoropyridin-4-yl)-4-methoxy-2-methyl7//-pyrrolo[2,3-<7]pynrnidine	C13 HH F N4 O	258.0917	259.0996	[M + H]⁺
4	4-methoxy-2-methyl-5-(2-methylpyridin-4-yl)7//-pyiTolo[2,3-i/]pynmidine	C14H14N4O	254.1168	255.1238	[M + H]⁺

5	2-methyl-5-(2-methylpyridin-4-yl)-4(thiophen-3-ylmethoxy)-7//-pyiTolo[2,3JJpyrimidine	C18 H16N4OS	336.1045	337.1129	[M + H]⁺
6	2-methyl-5-(2-methylpyridin-4-yl)-4-[(3Æ)piperidin-3-ylmethoxy]-7/7-pyiTolo[2,3iflpyrimidine	C19H23 N5 0	337.1903	338.1982	[M + H]⁺
7	4-(cyclopropylmethoxy)-2-methyl-5-(pyridin4-yl)-7//-pyrrolo[2,3-^pyrirnidine	C16 H16N4O	280.1324	281.1400	[M + H]⁺
8	4-(2-cyclopropylethoxy)-2-methyl-5-(pyridin4-yl)-7/7-pyrrolo[2,3’ô/]pynmidine	C17H18N4O	294.1481	293.1409	[M - H]'
9	4-[2-(l//4ndol-3-yl)ethoxy]-2-methyl-5(pyridin-4-yl)-7//-pyrrolo[2,3-if]pyrimidine	C22H19N5O	369.1590	370.1657	[M + H]⁺
10	2-methyl-4-(2-phenylethoxy)-5-(pyridin-4-yl)7//-pyrrolo[2,3-^]pyrimidine	C20H18N4O	330.1481	331.1547	[M + H]⁺
11	4-(benzyloxy)-2-methyl-5-(pyridin-4-yl)-7//pyrrolo[2,3-d]pyrimidine	C19H16N4O	316.1324	317.1391	[M + H]⁺
12	2-methyl-5-(pyridin-4-yl)-4-[2-(pynOlidin-1 yl)ethoxy]-7//-pyiTolo[2,3-i/]pyrimidine	C18H21 N5 0	323.1746	324.1818	[M + H]⁺
13	2-methy 1 -4-[2-( pi perid i n-1 -y l)ethoxy]-5(pyridin-4-yl)-7//-pyrrolo[2,3-d]pyrimidine	C19H23 N5 0	337.1903	338.1975	[M + H]⁺

I

14	2-methyl·5-(pyridin-4-yl)-4-(tetrahydrofίIran2-ylmethoxy)-7//-pyrrolo[2,3-i/]pynmidine	C17H18N4 02	310.1430	311.1508	[M + H]'
15	4-(cyclopentylmethoxy)-2-methyl-5-(pyridin4-yl)-7//-pyrrolo[2,3-6/]pyrimidine	C18H20 N4O	308.1637	309.1711	[M + H]⁺
16	2-methy l-4-[(5-methyl-1,2-oxazol-3-yl) methoxy]-5-(pyridin-4-yl)-7//-pyirolo[2,3- d]pyrimidine	C17H15N5 02	321.1226	322.1299	[M + H]⁺
17	4-[2-methyl-4-(thiophen-3-ylmethoxy)-7//pyrrolo[2,3-6/]pynmidin-5-yl]pyridin-2-amine	C17H15N5 OS	337.0997	338.1068	[M + H]⁺
18	4-[2-methyl-4-( 1,3-thiazol-5-y lmethoxy)-7//pyrrolo[2,3-t/]pyrimidin-5-yl]pyridin-2-amine	C16H14N6OS	338.0950	339.1025	[M +
19	4-[2-methyl-4-(thiophen-2-ylmethoxy )-7//pyrrolo[2,3-i/]pynmidin-5-yl]pyridin-2-amine	C17H15N5OS	337.0997	338.1072	[M + H]*
20	4-[2-methy 1-4-( 1 -pheny lethoxy )-7//pyrrolo[2,3-i/]pyrimidin-5-yl]pyridin-2-amine	C20H19N5O	345.1590	346.1654	[M + H]⁺
21	4-{ 2-methy l-4-[2-(4-methy 1-1,3-thiazol-5yl)ethoxy]-7//-pyrrolo[2,3-t/]pyrimidin-5yl}pyridin-2-amine	C18H18N6OS	366.1263	367.1343	[M + H]⁺
22	4-[2-methyl-4-(pyridin-3-ylmethoxy )-7//pyrrolo[2,3-i/]pynmidin-5-yl]pyridin-2-amine	C18H16N6O	332.1386	333.1453	[M +

23	4-[2-methyl-4-(pyridin-4-ylmethoxy )-7//pyrrolo[2,3-i/]pyrimidin-5-yl]pyridin-2-amine	C18H16N6O	332.1386	333.1452	[M + H]⁺
24	4-(4-{ [5-(4-fluorophenyl)-1,2-oxazol-3yl]methoxy}-2-methyl-7//-pyrrolo[2,3- </]pyrimidin-5-yl)pyridin-2-amine	C22H17FN6 02	416.1397	417.1459	(M + H]⁺
25	4-({[5-(2-aminopyridin-4-yl)-2-methyl-7//pyirolo[2,3-ô/]pyrimidin-4- y l]oxy} methy l )benzonitri le	C20H16N6O	356.1386	357.1464	(M + H]⁺
26	4-{4-[(4-methoxybenzyl)oxy]-2-methyl-7//pyirolo[2,3-(/]pyrimidin-5-yl}pyridin-2-amine	C20H19N5 02	361.1539	360.1463	[M - H]'
27	4-(2-methyl-4-{[4-(propan-2-yl)benzyl]oxy}7//-pyrrolo[2,3-i/]pyrimidin-5-yl)pyridin-2amine	C22 H23 N5 O	373.1903	374.1972	[M + H]⁺
28	4-[2-methyl-4-( l ,3-thiazol-4-y Imethoxy )-7//pyrrolo[2,3-i/]pyrimidin-5-yl]pyridin-2-amine	C16H14N6OS	338.0950	339.1019	[M + H]⁺

General Procedure V

General Procedure VI

SEM

In General Procedures IV, V and VI:

- Ri and R2 are as defined in formula (I),

- R3 represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, -(Co-Cejalkylene-Cyi, -(Co-Cô)alkylene-Cyi-Cy2, -(Co-C6)alkylene-Cyi-0-(Ci-Cô)alkylene-

Cy2, it being understood that Cyi and Cy2, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group, and R’3 represents a hydrogen atom or a linear or branched (Ci-Cô)alkyl group, or R3 and R’3 form with the nitrogen atom carrying them a heterocycloalkyl or an heteroaryl,

- G represents a group selected from the list of substituents defined in formula (I), it being understood that the phenyl may be substituted by from l to 4 independent G groups.

Example 30: 4-[2-methyl-4-(pyrrolidin-l-yl)-777-pyrrolo[2,3-i/]pyrimidin-5-yl] pyridin-2-amine

Step 1: 4-[2-methyl-4-(pyrrolidin-l-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo [2,3-d]pyrimidin-5-yl]pyridin-2-amine (Préparation 8)

To a solution of 4-(4-chloro-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl} -7Â/-pyrrolo[2,3-i/]pyrimidin-5-yl)pyridm-2-amine (Example 20, Step 1) (50 mg, 0.128 mmol) in THF (3 mL) was added pyrrolidine (3 eq). The reaction mixture was heated at 90 10 °C on a CEM microwave reactor for 1 hour (reaction monitored by LC-MS). The reaction mixture was diluted with DCM (10 mL) and water (10 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo to give the desired product (58 mg, >100%). Purity estimated around 90% by LCMS. The compound was used without further purification.

LC/MS (method A): RT = 2.08 min; m/z = 425 [M+H]⁺

Step 2: 4-[2-methyl~4-(pyrrolidin-l-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]pyridin-2-amine Starting from the compound obtained in Step 1 (58 mg) following procedure described in Préparation 4, the desired product (23 mg, 0.078 mmol, 61% over two steps) was obtained as a white solid.

Ή NMR (DMSO-d6) δ: 11.71 (s, 1H), 7.86 (d, 1H), 7.17 (d, 1H), 6.56 - 6.44 (m, 2H), 5.89 (s, 2H), 3.31 (m, 4H), 2.41 (s, 3H), 1.72 - 1.63 (m, 4H)

Example 32; 5-(2-ammopyridin-4-yl)-/V-benzyl-2-methyl-7Æ-pyrrolo[23-ii]pyrimidin4-amine

Step 1 : N-benzyl -5 -bromo -2 -methyl-7-{[2 -(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo

[2,3-d]pyrimidin-4-amine

Starting from 5-bromo-4-chloro-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7/fpyrrolo[2,3-J]pyrimidine (Example 1, Step /) (1 g, 2.65 mmol) and phenylmethanamine

-30(4 eq) following procedure described in Préparation 8. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (1.08 g, 2.41 mmol, 91%) as a clear oil.

Ή NMR (399 MHz, DMSO-d6) δ 7.55 (s, IH), 7.49 - 7.26 (m, 5H), 7.04 (t, IH), 5.51 (s, 5 2H), 4.85 (d, 2H), 3.62 - 3.53 (m, 2H), 2.47 (s, 3H), 0.99 - 0.85 (m, 2H), 0.00 (s, 9H).

LC/MS (method A): RT = 2.95 min; m/z = 449 [M+H]⁺

Step 2: 5-(2-aminopyridin-4-yl)-N-benzyl-2-methyl-7-{[2-(trimethylsilyl)ethoxy] methyl}7H-pyrrolo[2,3-d]pyrimidin-4-amine

Starting from the compound obtained in Step l (0.702 g, 1.57 mmol) and 10 4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (l.l eq) following procedure described in Préparation 3, the desired product (0.335 g, 0.727 mmol, 46%) was obtained as a light brown oil.

Ή NMR (399 MHz, DMSO-d6) δ 7.97 (dd, IH), 7.50 - 7.34 (m, 5H), 7.35 - 7.26 (m, IH), 6.65 - 6.56 (m, 2H), 6.09 (t, IH), 6.06 (s, 2H), 5.58 (s, 2H), 4.77 (d, 2H), 3.67 - 3.58 (m, 15 2H), 2.51 (s, 3H), 0.98 - 0.84 (m, 2H), 0.00 (s, 9H).

LC/MS (method A): RT = 2.33 min; m/z = 461 [M+H]⁺

Step 3: 5-(2-aminopyridin-4-yl)-N-benzyl-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Starting from the compound obtained in Step 2 (0.335 g, 0.727 mmol) following procedure described in Préparation 4, the desired product (51 mg, 0.154 mmol, 21%) was obtained 20 as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 11.73 (s, IH), 7.89 (d, IH), 7.42 - 7.28 (m, 4H), 7.29 7.19 (m, 2H), 6.60 - 6.49 (m, 2H), 5.92 (d, 3H), 4.70 (d, 2H), 2.42 (s, 3H).

LC/MS (method A): RT = 1.65 min; m/z = 331 [M+H]⁺

Example 52; 5-(2-aminopyridin-4-yl)-/V-(2,6-difluorobenzyl)-2-methyl-7/f25 pyrrolo[2,3-rf]pyrimidin-4-amine

Step 1: 5 -bromo -N ·[(2,6 -difluorophenyl)methyl/ -2 -methyl-7 -{[2 -(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3 -d]pyrimidin -4 -amine

I

-3l -

Starting from 5-bromo-4-chloro-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7/7pyrrolo[2,3-d]pyrimidine (Example 1, Step 1) (1.2 g, 3.19 mmol) and (2,6-difluorophenyl)methanamine (4 eq) following procedure described in Préparation 8. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to 5 give the desired product as a clear oil.

IH NMR (399 MHz, DMSO-d6) δ 7.56 (s, IH), 7.46 (tt, IH), 7.24 - 7.11 (m, 2H), 6.81 (t, IH), 5.51 (s, 2H), 4.92 (d, 2H), 3.62 - 3.53 (m, 2H), 2.49 (s, 3H), 0.97 - 0.85 (m, 2H), 0.00 (s, 9H).

LC/MS (method A): RT = 2.96 min; m/z = 485 [M+H]⁺

Step 2: 5-(2-aminopyridin-4-yl)-N-(2,6-difluorobenzyl)-2-methyl-7-{[2-(trimethylsilyl) ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Starting from the compound obtained in Step 1 (1 g, 2.07 mmol) and 4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.1 eq) following procedure described in Préparation 3, the desired product (0.422 g, 0.849 mmol, 41%) was obtained 15 as a light brown oil.

IH NMR (399 MHz, DMSO-d6) δ 7.99 (dd, IH), 7.52 - 7.39 (m, 2H), 7.22 - 7.11 (m, 2H), 6.61 - 6.53 (m, 2H), 6.05 (d, 3H), 5.57 (s, 2H), 4.85 (d, 2H), 3.66 - 3.57 (m, 2H), 2.53 (s, 3H), 1.00 - 0.86 (m, 2H), 0.00 (s, 9H).

LC/MS (method B): RT = 1.32 min; m/z = 497 [M+H]⁺

Step 3: 5-(2-aminopyridin-4-yl)-N-(2,6-difluorobenzyl)-2-methyl-7H-pyrrolo[2,3-d] pyrimidin-4-amine

Starting from the compound obtained in Step 2 (0.422 g, 0.849 mmol) following procedure described in Préparation 4, the product (0.104 g, 0.284 mmol, 33%) was obtained as a white solid.

IH NMR (399 MHz, DMSO-d6) δ 11.74 (s, IH), 7.90 (d, IH), 7.37 (tt, IH), 7.24 (d, IH), 7.09 (t, 2H), 6.54 - 6.45 (m, 2H), 5.93 (s, 2H), 5.85 (t, IH), 4.77 (d, 2H), 2.43 (s, 3H).

LC/MS (method B): RT = 0.96 min; m/z = 367 [M+H]⁺

-32Example 129: 5-(2-aminopyridin-4-yl)-2-methyI-JV-phenyl-7Zf-pyrroIo[2,3i/]pyrimidin-4-amine

Step 1: 5-bromo-2-methyl-N-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl} -7H-pyrrolo [2,3-d]pyrimidin-4-amine (Préparation 9)

To a solution of 5-bromo-4-chloro-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7/7pyrrolo[2,3-J]pyrimidine (Example 1, Step 7) (0.2 g, 0.53 mmol) in DMF (2 mL) was added aniline (1.2 eq) followed by /-BuOK (2 eq) at room température under N2. The reaction mixture was stirred at room température for 2 hours. The reaction mixture was diluted with water (10 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over MgSÛ4 and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (0.109 g, 0.251 mmol, 47%) as a clear oil.

LC/MS (method B): RT = 1.68 min; m/z = 433 [M+H]⁺

Step 2: tert-butyl N-{4-[2-methyl-4-(phenylamino)-7-{[2-(trimethylsilyl)ethoxy]methyl}

-7H-pyrrolo[2,3 -d]pyrimidin-5 -yl]pyridin-2-yl}carbamate

Starting from the compound obtained in Step 1 (0.109 g, 0.251 mmol) and /er/-butyl 7V-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.2 eq) following procedure described in Préparation 3, the product (0.118 g, 0.215 mmol, 86%) was obtained as clear oil.

LC/MS (method B): RT = 1.68 min; m/z = 547 [M+H]⁺

Step 3: 5-(2-aminopyridin-4-yl)-2-methyl-N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Starting from the compound obtained in Step 2 (0.118 g, 0.215 mmol) following procedure described in Préparation 7, the desired product (37 mg, 0.117 mmol, 54%) was obtained as a pale yellow solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.00 (d, IH), 8.00 (d, IH), 7.72 - 7.65 (m, 3H), 7.45 (d, IH), 7.35 - 7.28 (m, 2H), 7.00 (m, IH), 6.71 (dd, IH), 6.63 (d, IH), 6.25 (s, 2H), 2.53 (s, 3H).

LC/MS (method B): RT = 0.87 min; m/z = 317 [M+H]⁺

-33 Examples 29-146 in the following Table 2 were prepared by methods outlined in General Procedure IV-VI using appropriate commercially available boronate esters and amines. The compounds of Example 30,32,129 are also included.

Table 2: HRMS (TOF, ESI) data

Example	Structure	Mol Formula	Calcd Exact Mass	Found m/z	Adduct
29	5-(2-aminopyridin-4-yl)-AW24riînethyl7//-pyrrolo[2,3-i/]pyrimidin-4-amine	C14H16N6	268.1436	269.1519	[M +
30	4-[2-methy l-4-(pyrrolidin-1 -y 1)-7/7pyrrolo[2,3-<7]pyrimidin-5-yl]pyridin-2amine	C16H18N6	294.1593	295.1672	[M + H]⁺
31	4-{4-[3-(dimethylamino)pyrrolidin-l-yl]-2methyl-7//-pyrrolo[2,3-i/]pyrimidin-5yl}pyridin-2-amine	C18 H23 N7	337.2015	338.2085	[M + H]⁺
32	5-(2-aminopyridin-4-yl)-N-benzyl-2methyl-7//-pyrrolo[2,3-t/]pyrimidin-4amine	C19H18N6	330.1593	331.1661	[M + H]⁺

33	4-[2-methyl-4-(4-methylpiperazin-l-y 1)-7//pyrrolo[2,3-i/]pyrimidin-5-yl]pyndin-2amine	C17H21 N7	323.1858	324.1932	[M + H]⁺
34	5-(2-aminopyridin-4-yl)-2-methyl-jV(pyridin-3-ylmethyl)-7//-pyrrolo[2,3^pyrimidin-4-amine	C18H17N7	331.1545	332.1612	[M + H]⁺
35	5-(2-aminopyridin-4-yl)-7V-(fiiran-3ylmethyl)-2-methyl-7//-pynOlo[2,3i/]pyrimidin-4-amine	C17H16N6O	320.1386	321.1466	[M + H]⁺
36	5-(2-aminopyridin-4-yl)-2-methykV(thiophen-3-ylmethyl)-7//-pyrrolo[2,3J]pyrimidin-4-amine	C17H16N6S	336.1157	337.1231	[M + H]⁺
37	5-(2-aminopyndin-4-yl)-2-methyl-7V(thiophen-2-ylmethyl)-7//-pyrrolo[2,3if]pyrimidin-4-amine	C17H16N6S	336.1157	337.1222	[M + H]⁺

38	5-(2-aminopyridin-4-yl)-2-methyl-W-[(lmethyl-l//-pyrazol-5-yl)methyl]-7/7pyrrolo[2,3-t/]pyrimidin-4-amine	C17H18N8	334.1654	335.1722	[M + H]⁺
39	5-(2-aminopyridin-4-yl)-2-methy 1-M( 1,3thiazol-2-ylmethyl)-7//-pyrrolo[2,3- J]pyrimidin-4-amine	C16H15N7S	337.1110	338.1179	[M + H]⁺
40	5-(2-aminopyridin-4-y l)-2-methy 1-tV-( 1,3thiazol-4-ylmethyl)-7H-pynOlo[2,3-ûQ pyrimidin-4-amine	C16H15N7S	337.1110	338.1189	[M + H]⁺
41	5-(2-aminopyridin-4-yl)-2-methyl-7V-(l,3thiazol-5-ylmethyl)-7//-pyrrolo[2,3-i/] pyrimidin-4-amine	C16H15N7S	337.1110	338.1179	[M + H]⁺
42	/V-benzyl-2-methyl-5-(pyridin-4-yl)-7//pyirolo[2,3-ô/]pyrimidin-4-amine	C19H17N5	315.1484	316.1547	[M + H]⁺

43	A^r-benzyl-2-methyl-5-(2-methylpyridin-4yl)-7//-pyrrolo[2,3-i/]pyrimidin-4-amine	C20H19N5	329.1640	330.1709	[M 4-
44	2-methyi-5-(pyridin-4-yl)-/V-(thiophen-3ylmethyl)-7//-pyrrolo[2_s3-i/]pyrimidin-4amine	C17H15N5 S	321.1048	322.1121	[M 4- H]⁺
45	2-methyl-5-(2-methylpyridin-4-yi)-/V(thiophen-3-yimethyl)-7//-pyrrolo[2,3pyrimidin-4-amine	C18H17N5S	335.1205	336.1283	[M 4- H]+
46	2-methy l-V-[(5-methyI-1,2-oxazol-3yl)methyl]-5-(pyridin-4-yl)-7//-pynOlo[2,3- J]pyrimidin-4-amine	C17H16N6O	320.1386	321.1450	[M + H]⁺
47	2-methy l-N-[(5-methy i-1,2-oxazoi-3-y l) methyl]-5-(2-methylpyridin-4-yl)-7//pyrrolo[2,3-t/]pyrimidin-4-amine	C18H18N6O	334.1542	335.1613	[M + H]*

48	5-(2-aminopyridin-4-yl)-?/(cyclohexyÎmethyl)-2-methyl-7//-pyrrolo 2,3-i/]pyrimidin-4-amine	C19H24 N6	336.2062	337.2134	[Μ + Η]^ψ
49	5-(2-aminopyridin-4-yl)-2-methyl-/V-(lphenylethyl)-7//-pyrrolo[2,3-i/]pyrimidin-4amine	C20 H20 N6	344.1749	345.1814	[M + H]⁺
50	5-(2-aminopyridin-4-yl)-jV-(3fluorobenzyl)-2-methyl-7//-pyrrolo[2,3iZJpyrimidin-4-amine	C19H17FN6	348.1499	349.1567	[Μ + ΗΓ
51	5-(2-aminopyridin-4-yl)-2V-(2fluorobenzyl)-2-methyl-7/7-pyrrolo[2,3- J]pyrimidin-4-amine	C19H17FN6	348.1499	347.1430	[M-H]-
52	5-(2-aminopyridin-4-yl)-7V-(2,6difluorobenzyl)-2-methyl-7//-pyrrolo[2,3- ûflpyrimidin-4-amine	C19H16F2 N6	366.1405	365.1341	[M - H]’

53	5-(2-aminopyridin-4-yl)-2-rnethyl-/V(pyridin-2-ylmethyi)-7//-pyrroio[2,3’ 6Âpyrimidin-4-amine	C18H17N7	331.1545	330.1471	[M - H]'
54	5-(2-aminopyridin-4-yl)-JV-(4fluorobenzyl)-2-methyl-77/-pynOlo[2,3i/]pyrimidin-4-amine	C19H17FN6	348.1499	347.1416	[M - H]’
55	5-(2-aminopyridin-4-yl)-jV-(2- methoxybenzyl)-2-methyl-7//-pyrrolo[2,3i/]pyrimidin-4-amine	C20 H20 N6 0	360.1699	359.1611	[M - H]-
56	5-(2-aminopyridin-4-yl)-2-methyl-jV-(2methylbenzyl)-7//-pyrrolo[2,3-J]pyrimidin4-amine	C20 H20 N6	344.1749	343.1675	[M - H]'
57	5-(2-aminopyridin-4-yl)-7V-(2chlorobenzyl)-2-methyl-7//-pynOlo[2,3iflpyrimidin-4-amÎne	C19H17C1N6	364.1203	363.1139	[M - H]’

58	5-(2-aminopyridin-4-yl)-A42-chloro-6methylbenzyl)-2-methyl-7//-pyrrolo[2,3d]pyrimidin-4-amine	C20H19CIN6	378.1360	377.1292	[M - H]'
59	5-(2-aminopyridin-4-yl)-2-methyl-N-[(5methyl-l,2-oxazol-3-yl)methyl]-7//pyrrolo[2,3-i/]pynmidin-4-amine	C17H17N7O	335.1495	334.1417	[Μ-H]'
60	5-(2-aminopyridin-4-yl)-2-methyl-A^r-[(3methylpyridin-2-yl)methyl]-7//-pynOlo[2,3ôflpyrimidin-4-amine	C19H19N7	345.1702	344.1630	[M - H]'
61	5-(2-aminopyridin-4-yl)-7/-(2,6dichlorobenzyl)-2-methyl-7/7-pyrrolo[2,3- i/]pyrimidin-4-amine	C19H16C12 N6	398.0813	397.0746	[Μ-H]’
62	5-(2-aminopyridin-4-yl)-7V-(2-chloro-6fluorobenzyl)-2-methyl-7//-pyrrolo[2,3d]pyrimidin-4-amine	C19H16C1F N6	382.1109	381.1045	[M - H]'

63	5-(2-aminopyridin-4-yl)-7V-(2,4difluorobenzyl)-2-methyl-7H-pyrrolo[2,3i/]pyrimidin-4-amine	C19H16F2 N6	366.1405	365.1323	[M - H]’
64	5-(2-aminopyridin-4-yl)-2-methykV-[2(trifluoromethyl)benzyl]-7Z/-pynOlo[2,3tflpyrimidin-4-amine	C20H17F3 N6	398.1467	397.1402	[M - H]'
65	5-(2-aminopyridin-4-yl)-//(cyciopropylmethyl)-2-methyi-7//pyrrolo[2,3-J]pynmidin-4-amine	C16H18N6	294.1593	293.1535	[M - H]’
66	5-(2-aminopyridin-4-yl)-2-methyl-7V-[l(pyridin-2-yl)ethyl]-7//-pyirolo[2,36/]pyrimidin-4-amine	C19H19N7	345.1702	344.1636	[M - H]‘
67	5-(2-aminopyridin-4-yi)-2-methyl-/V-[(lS^r) l-phenylethyI]-7//-pyiroIo[2,3-i/]pyrimidin4-amine	C20 H20 N6	344.1749	343.1688	[M - H]'

-4l -

68	5-(2-aminopyridin-4-yl)-2-methyl-N-[(lÆ)l^henylethyl]-7H-pyirolo[2,3-^pyrimidin4-amine	C20 H20 N6	344.1749	343.1680	[M - H]'
69	5-(2-aminopyridin-4-yl)-A42-fluoro-6methoxybenzyl)-2-methyl-7//-pynolo[2,3t/]pyrimidin-4-amine	C20H19FN6O	378.1604	377.1534	[Μ-H]'
70	5-(2-aminopyridin-4-yl)-A42’fluoro-6methylbenzyl)-2-methyl-7//-pyrrolo[2,3J]pyrimidin-4-amine	C20H19FN6	362.1655	361.1593	[Μ-H]'
71	5-(2-aminopyridin-4-yl)-jV-[(3fluoropyridin-2-yl)methyl]-2-methyl-7//pyrrolo[2,3-^pyrimidin-4-amine	C18H16FN7	349.1451	348.1370	[M - H]'
72	5-(2-aminopyridin-4-y 1 //-indoi-6- ylmethyl)-2-methyl-7//-pyrrolo[2,3iflpyrimidin-4-amine	C21 H19N7	369.1702	368.1629	[M - H]’

73	5-(2-aminopyridin-4-yl)-2-methyl-iV-(2,3,5trifluorobenzyl)-7//-pyrrolo[2,3iflpyrimidin-4-amine	C19H15 F3 N6	384.1310	383.1246	[M - H]'
74	5-(2-aminopyridin-4-yl)-7V-(2,3difluorobenzyl)-2-methyl-7//-pyrrolo[2,3- J]pyrimidin-4-amine	C19H16F2 N6	366.1405	365.1328	[Μ-H]'
75	5-(2-aminopyridin-4-yl)-A^r-[4-fluoro-2(trifluoromethyl)benzyl]-2-methyl-7//pyirolo[2,3-i/]pyrimidin-4-amine	C20H16F4 N6	416.1373	415.1297	[Μ-H]'
76	5-(2-aminopyridin-4-y l)-7V-[( 1 ^)-2,3dihydro-1 //-inden-1 -y l]-2-methy I-7Hpyirolo[2,3-d]pyrimidin-4-amine	C21 H20N6	356.1749	355.1685	[M - H]'
77	5-(2-aminopyridin-4-yl)-?/-[(lS)-2,3dihydro-1 //-inden-1 -y l]-2-methy 1-7//pyrrolo[2,3-i/]pyrimidin-4-amine	C21 H20N6	356.1749	355.1677	[M-H]-

78	5-(2-aminopyridin-4-y l)-2-methy 1-jV- {[3(trifluoromethyl)pyridin-2-yl]methyl}-7/7pyrrolo[2,3-6/]pynmidin-4-amine	C19H16 F3 N7	399.1419	398.1370	[M - H]’
79	5-(2-aminopyridin-4-yl)-7V-(2- ethoxybenzyl)-2-methyl-7/7-pyrrolo[2,3ô7]pyrimidin-4-amine	C21 H22 N6O	374.1855	373.1783	[M - H]'
80	5-(2-aminopyridin-4-yl)-7V-[2-methoxy-6(trifluoromethyl)benzyl]-2-methyl-7//py^olo[2,3-i/]pyrimidin-4-amine	C21 H19F3 N6 0	428.1572	427.1491	[Μ-H]'
81	5-(2-aminopyridin-4-yl)-_JV-(2,3dichlorobenzyl)-2-methyl-7//-pyrrolo[2,3- d]pyrimidin-4-amine	C19H16C12 N6	398.0813	397.0744	[M - H]'
82	5-(2-aminopyridin-4-yl)-7V-[ 1-(2,6difluorophenyl)ethyl]-2-methyl-7//pyrrolo[2,3-^pyrimidin-4-amine	C20H18F2 N6	380.1561	379.1500	[M-H]·

83	5-(2-aminopyridin-4-y l)-N-[( l R,2R,4S)bicyclo[2.2.1 ]hept-2-yl]-2-methyl-7//pyrroIo[2,3-tflpyrimidin-4-amine	C19H22 N6	334.1906	333.1845	[M - H]‘
84	5-(2-aminopyridin-4-yl)-7V-(4-fluoro-2methoxybenzyl)-2-methyl-7//-pyrrolo[2,3i/]pyrimidin-4-amine	C20H19FN6O	378.1604	377.1540	[M - H]'
85	5-(2-aminopyridin-4-y Ι)-Λ4( l Æ)methoxyphenyl)ethyl]-2-methyl-7Hpyirolo[2,3-^pyrimidin-4-amine	C2l H22 N6 0	374.1855	373.1791	[M - H]*
86	5-(2-aminopyridin-4-y l)-7V-[( l R)-1 -(2fluorophenyl)ethyl]-2-methyl-7//pyiTolo[2,3-i/]pyrimidin-4-amine	C20H19FN6	362.1655	361.1593	[M - H]'
87	5-(2-aminopyridin-4-yl)-2-methyl-jV-{[5(pyridin-2-yl)thiophen-2-yl]methyl}-7//pyrrolo[2,3-J]pyrimidin-4-amine	C22H19N7S	413.1423	412.1358	[M - H]'

88	5-(2-aminopyridin-4-yi)-2-methyl-/V-[(3phenyl-l,2-oxazoi-5-yl)methyl]-7Z/pyirolo[2,3-i/]pyrimidin-4-amine	C22H19N7O	397.1651	396.1584	[M - H]'
89	5-(2-aminopyridin-4-yl)-2-methyl-7V-[2(trifluoromethoxy)benzyl]-7//-pynolo[2,3tZ]pyrimidin-4-amine	C20H17F3 N6 0	414.1416	413.1342	[M - H]’
90	5-(2-aminopyridin-4-yl)-2V-[(lÆ,27?)-2(benzyloxy)cyclohexyl]-2-methyl-7//pyrrolo[2,3-J]pyrimidin-4-amine	C18H19N7O	428.2325	427.2252	[Μ-H]’
91	5-(2-aminopyridin-4-yI)-2-methykV-[(lÆ)1,2,3,4-tetrahydronaphthalen-1 -y l]-7/A pyrrolo[2,3-i/]pyrimidin-4-amine	C22 H22 N6	370.1906	369.1829	[M-H]-
92	5-(2-aminopyndin-4-yl)-jV-(2,5dichlorobenzyi)-2-methyl-7//-pynOlo[2,3- J]pyrimidin-4-amine	C19H16C12 N6	398.0813	397.0746	[M - H]’

93	5-(2-aminopyridin-4-yl)-7V-cyclohexyl-2methyl-7//-pyiTolo[2,3-i/]pyrimidin-4amine	C18H22 N6	322.1906	321.1830	[M - H]'
94	5-(2-aminopyridin-4-yl)-V-(3-chloro-2methylbenzyl)-2-methyl-7//-pyrrolo[2,3J]pyrimidin-4-amine	C20H19C1N6	378.1360	377.1288	[M - H]’
95	5-(2-aminopyridin-4-yl)-V-[(3,5-dimethyll,2-oxazol-4-yl)methyl]-2-methyl-7//py rrol o [2,3 -d\ py ri m i d i n-4-am i ne	C18H19N7O	349.1651	348.1587	[M - H]'
96	4-(4-(3,4-dihydroisoquinolin-2( l H)-y I )-2methyl-7//-pyrrolo[2,3-i/]pynmidin-5yl]pyridin-2-amine	C2l H20N6	356.1749	355.1680	[M-H]-
97	4-[2-methyl-4-(3-methylpiperidin-l-yl)-7//pynOlo[2,3-tZ]pyrimidin-5-yl]pyridin-2amine	C18H22 N6	322.1906	323.1978	[M - H]⁺

98	5-(2-aminopyridin-4-yl)-?/-[(3- methoxypyridin-2-yl)methyl]-2-methyl-7//pyrrolo[2,3-6Z]pyrimidin-4-amine	C19H19N7O	361.1651	362.1728	[M - H]⁺
99	5-(2-aminopyridin-4-yl)-7V-(2,3-dihydrol//-inden-2-yl)-2-methyl-7?/-pynOlo[2,3tZjpyrimidin-4-amine	C21 H20N6	356.1749	357.1823	[M H- H]⁺
100	5-(2-aminopyridin-4-yl)-2-methyl-/V-(3,3,3trifluoropropyl)-7//-pyrrolo[2,3- J]pyrimidin-4-aniine	C15H15F3 N6	336.1310	335.1250	[M - H]’
101	4-[4-(3-azaspiro[5.5]undec-3-yl)-2-methyI7//-pyrrolo[2,3-j]pynmidin-5-yl]pyndin-2amine	C22 H28 N6	376.2375	375.2309	[M-H]·
102	4-[2-methyl-4-(8-methyl-2-azaspiro[4.5] dec-2-yl)-7/7-pyrrolo[2,3-ô/]pyriinidin-5yl]pyridin-2-amine	C22 H28 N6	376.2375	377.2441	[M - H]⁺

103	4-[2-methy l-4-(2-pheny lazetidin-1 -y 1)-7//pyrrolo[2,3-i/]pyrimidin-5-yl]pyridin-2amine	C21 H20N6	356.1749	357.1821	[M - H]⁺
104	4-[2-methyl·4-(octahydΓoisoquinolin-2(17f)yl)-7//-pyrrolo[2,3-i/]pyrimidin-5yl]pyridin-2-amine	C21 H26N6	362.2219	363.2285	[M - H]⁺
105	4-{2-methyl-4-[4- (trifluoromethy 1 )p iperid in-1 -y 1]-7//pyrrolo[2,3-iZ]pyrimidin-5-yl}pyridin-2amine	C18H19F3 N6	376.1623	375.1563	[M-H]·
106	5-(2-aminopyridin-4-y 1)-jV-[( IS)-1 -(2methoxyphenyl)ethyl]-2-methyl-7//pyrrolo[2,3-/]pyrimidin-4-amine	C21 H22N6O	374.1855	375.1920	[M - H]⁺
107	4-{2-methyl-4-[2- (trifluoromethy l)pyrrolidin-1 -y 1]-7//pyrrolo[2,3-i/\|pynmidin-5-yl}pyridin-2amine	C17H17F3 N6	362.1467	363.1528	[M - H]⁺

108	4-[4-(6,7-dihydrothieno[3,2-c]pyridin5(4//)-yl)-2-methyl-7//-pynOlo[2,3- tZ]pyrimidin-5-yl]pyridin-2-amine	C19H18N6S	362.1314	363.1393	[M - H]⁺
109	4-[4-(2-azaspiro[3.5]non-2-yl)-2-methyl- 7//-pyrrolo[2,3-^pyrimidin-5-yl]pyridin-2amine	C20 H24 N6	348.2062	347.1993	[M-H]'
110	4-{2-methyl-4-[(4aÆ,8aÆ)octahydroisoquinolin-2( 1 pyrroIo[2,3-i7]pyrimidin-5-yl}pyridin-2amine	C21 H26 N6	362.2219	361.2154	[M-H]'
111	4-{2-methyl-4-[(4aÆ,8aS)-octahydro isoquinolin-2(17^-yl]-7//-pynolo[2,3J]pyrimidin-5-yl}pyridin-2-amine	C21 H26N6	362.2219	361.2145	[M-H]'
112	5-(2-aminopyridin-4-yl)-N-(2,3-dihydro-lbenzoiuran-3-ylmethyl)-2-methyl-7//pynolo[2,3-d]pyrimidin-4-amine	C21 H20N6O	372.1699	373.1761	[M - H]*

113	5-(2-aminopyridin-4-yl)-7V-[l-(3methoxypyridin-2-yl)ethyl]-2-methyl-7//pynOlo[2,3-ûGpyrimidin-4-amine	C20 H21 N7O	375.1808	376.1876	[M - H]⁺
114	4-[4-(3,4-dihydroisoquinolin-2(l//)-yl)-2methyl-7//-pyrolo[2,3-<7]pyrirnidin-5yl]pyridine-2,6-diamine	C21 H21N7	371.1858	370.1786	[M - H]'
115	4-{4-[(2,6-difluorobenzyl)amino]-2-methyl77/-pyrrolo[2,3-J]pyrimidin-5-yl}pyridine2,6-diamine	C19H17F2 N7	381.1513	382.1556	[M - H]⁺
116	4-{4-[(2-fluoro-6-methoxybenzyl)amino]-2methyl-7//-pyrrolo[2,3-i/]pyrimidin-5yl}pyridine-2,6-diamine	C20 H20 F N7 0	393.1713	394.1774	[M - H]⁺
117	4-(4-(((15^-1-(2- methoxyphenyl)ethyl]amino}-2-methyl-7//pyrrolo[2,3-i(\|pyrimidin-5-yl)pyridine-2,6diamine	C21 H23 N7O	389.1964	390.2023	[M - H]⁺

-5l -

118	4- {4-[( 1 Æ)-2,3-dihydro-l//-inden-1 ylamino]-2-methyl-7//-pyrrolo[2,3d]pyrimidin-5-yl}pyridine-2,6-diamine	C21 H21 N7	371.1858	372.1936	[M - Hf
119	5-(2-aminopyridin-4-yl)-/V-[(3,5- difluoropyridin-4-yl)methyl]-2-methyl-7/7pynolo[2,3-i/]pyrimidin-4-amine	C18 H15 F2 N7	367.1357	368.1421	[M - H]⁺
120	5-(2-aminopyridin-4-yl)-7V-(2,6difluorobenzyl)-/V,2-dimethyl-7//pyrrolo[23-^pyrimidin-4-amine	C20H18F2 N6	380.1561	381.1629	[M - H]⁺
121	5-(2-aminopyridin-4-yl)-A41-(3fluoropyridin-2-yl)propyl]-2-methyl-7//- pyrrolo[2,3-i/]pyrimidin-4-amine	C20 H20 F N7	377.1764	378.1836	[M - H]⁺
122	5-(2-aminopyridin-4-yl)-/V-[(lS)-l-(3fluoropyridin-2-yl)ethyl]-2-methyl-7//pynOlo[2,3-^]pyrimidin-4-amine	C19H18FN7	363.1608	364.1636	[M - H]⁺

123	5-(2-aminopyridin-4-yl)-?/-(2,2-difluoro-2phenylethyl)-2-methyl-7//-pyrrolo[2,3J]pyrimidÎn-4-amine	C20H18F2 N6	380.1561	381.1635	[M - H]⁺
124	5-(2-aminopyridin-4-yl)-2-methyl-jV-[2(pyridin-2-yl)ethyl]-7//-pynOlo[2,3i/]pyrimidin-4-amine	C19H19N7	345.1702	346.1767	[M - H]⁺
125	4-{4-[(2Æ,6S)-2,6-dimethylmorpholin-4-yl]2-methyl-7//-pyrrolo[2,3-i/]pyrimidin-5yl}pyridin-2-amine + 4-{4-[(2S,6Æ)-2,6-dimethylmorpholin-4-yl]2-methyl-7//-pyrrolo[2,3-ô/]pyrimidin-5yl}pyridin-2-amine	C18H22 N6 0	338.1855	339.1931	[M - H]⁺
126	4-{4-[(2J?,6S)-2,6-dimethylmorpholin-4-yl]2-methyl-7/7-pynOlo[2,3-d]pyrimidin-5yl}pyridine-2,6-diamine + 4-{4-[(2S,6Æ)-2,6-dimethylmorpholin-4-yl]2-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl}pyridine-2,6-diamine	C18H23 N7 0	353.1964	354.2044	[M - H]⁺
127	5-(2-aminopyridin-4-yl)-/V-( 1,3benzodioxol-4-ylmethyl)-2-methyl-7//pyiTolo[2,3-</\|pyrimidin-4-amine	C20H18N6O2	374.1491	375.1494	[M - H]⁺

128	4-{4-[(l,3-benzodioxol-4-ylmethyl)amino]- 2-methyl-7//-pyrrolo[2,3-</]pyrimidin-5- yl }pyridine-2,6-diamine	C20H19N7 02	389.1600	390.1593	[M - H]⁺
129	5-(2-aminopyridin-4-yl)-2-methykVphenyl-7//-pynolo[2,3-(i]pyrimidin-4amine	C18H16N6	316.1436	317.1458	[M - H]*
130	5-(2-aminopyridin-4-yl)-2-methyl-7V-[2(trifluoromethyI)phenyl]-7//-pyrrolo[2,3c(]pyrimidin-4-amine	C19H15F3 N6	384.1310	385.1326	[M - H]⁺
131	4-(2-methyl-4-{[2- (trifluoromethyl)phenyl]amino}-7/7pyirolo[2,3-i/]pyrimidin-5-yl)pyridine-2,6diamine	C19H16F3 N7	399.1419	400.1434	[M - H]⁺
132	5-(2-aminopyridin-4-yl)-A^-( 1,3benzodioxol-5-yl)-2-methyl-7//pyrrolo[2,3-(/\|pyrimidin-4-amine	C19H16N6 02	360.1335	361.1332	[M - H]*

133	4-[4-(4-methoxypiperidin-1 -yl)-2-methy 17//-pyrrolo[2,3-dOpyrimidin-5-yl]pyridin-2amine	C18H22 N6 0	338.1855	339.1871	[M - H]*
134	4-[2-methyl-4-(morpholin-4-y 1)-7//pyrrolo[2,3-i/]pyrimidin-5-yl]pyridin-2amine	C16H18N6O	310.1542	311.1565	[M - H]⁺
135	4-(4-(5,6-dihydroimidazo[ 1,2-a]pyrazin7(8//)-yl)-2-methyl-7//-pyrrolo[2,3d]pyrimidin-5-yl]pyridin-2-amine	C18H18N8	346.1654	347.1663	[M - H]⁺
136	4-(4-(7,8-dihydropyrido[3,4-b]pyrazin6(5//)-yl)-2-methyl-7//-pyiTolo[2,3t/]pyrimidin-5-yl]pyridin-2-amine	C19H18N8	358.1654	359.1659	[M -
137	4-[2-methyl-4-(2-methylmorpholin-4-yl)7//-pynOlo[2,3-</]pyrimidin-5-yl]pyridin-2amine	C17H20 N6 0	324.1699	323.1544	[M - H]’

138	4-[4-(3-methoxypiperidin-l-yl)-2-methyl7//-pyrrolo[2,3-^pyrimidin-5-yl]pyridin-2amine	C18H22 N6O	338.1855	339.1855	[M -
139	4-[4-(4-methoxypiperidin-l-yl)-2-methyl- 7//-pyrrolo[2,3-<\|pyrimidin-5-yl]pyndine- 2,6-diamine	C18H23 N7O	353.1964	354.1972	[M - H]⁺
140	4-[2-methyl-4-(morpholin-4-yl)-7//pynOlo[2,3-d]pyrimidin-5-yl]pyridine-2,6diamine	C16H19N7O	325.1651	326.1724	[M - H]⁺
141	4-(4-(5,6-dihydroimidazo[l,2-α]pyΓazin7(8/n.yl)-2-methyl-7/f-pyπΌlo[2,3iflpyrimidin-5-yl]pyridine-2,6-diamine	C18H19N9	361.1763	362.1764	[M - H]*
142	4-(4-(7,8-dihydropyrido[3,4-6]pyrazin- 6(5//)-yl)-2-methyl-7//-pyrrolo[2,3à(]pyrimidin-5-yl]pyridine-2,6-diamine	C19H19N9	373.1763	374.1760	[M - H]⁺

143	4-[2-methyl-4-(2-methylmorpholin-4-yl)7//-pyrrolo[2,3-ô/]pyrimidin-5-yi]pyridine- 2,6-diamine	C17H21 N7 0	339.1808	340.1845	[M - H]⁺
144	4-[4-(3-methoxypiperidin-l-yl)-2-methyl7//-pyrrolo[2,3-iZ]pynmidin-5-yl]pyndine- 2,6-diamine	C18H23 N7 0	353.1964	354.1978	[M - H]+
145	N-[2-methoxy-6-(trifluoromethyl)benzyl]-2methyl-5-(pyridin-4-yl)-7//-pynolo[2,3iflpyrimidin-4-amine	C21 H18F3 N5 0	413.1463	414.1468	[M - H]⁺
146	N-[2-methoxy-6-(trifluoromethyl)benzyl]-2methyl-5-(2-methylpyridin-4-yl)-7//pynOlo[2,3-i/]pyrimidin-4-amine	C22 H20 F3 N5 O	427.1620	428.1633	[M - Hf

-58General Procedure IX

General Procedure X

NeCH

G

In General Procedures VII, VIII, IX and X:

- Ri and R₂ are as defîned in formula (I),

- Rî represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, -(Co-C6)alkylene-Cyi, -(Co-C6)alkylene-Cyi-Cy2, -(Co-C6)alkylene-Cyi-0-(Ci-C6)alkyleneCy2, it being understood that Cyi and Cy2, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group, and Rb represents a hydrogen atom or a linear or branched (Ci-Cô)alkyl group, or R3 and R’3 form with the nitrogen atom carrying them a heterocycloalkyl or an heteroaryl,

- R4 represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group or a cycloalkyl group,

Example 148: 5-(2-aminopyridin-4-yl)-A-(2,6-difluorobenzyl)-2-ethynyl-7/7pyrrolo[2,3-7]pyrimidin-4-amine

Step 1: 5-bromo-2-chloro-N-[(2,6-difluorophenyl)methyl]-7-{[2-(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3-d]pyrimidin-4 -amine

Starting from 5-bromo-2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7//-pynOlo [2,3-J]pyrimidine (prepared following procedure described in WO2007/104944} (1 g, 2.52 mmol) and (2,6-difluorophenyl)methanamine (2 eq) following procedure described in

Préparation 8. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (1.25 g, 2.48 mmol, 98%) as a clear oil.

LC/MS (method B): RT = 3.0 min; m/z = 505 [M+H]⁺

Step 2: tert-butyl N-[4-(2-chloro-4-{[(2,6-difluorophenyl)methyl]amino}-7-{[2(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3 -d]pyrimidin -5 -yl)pyridin -2 -yl/ carbamate

Starting from the compound obtained in Step 1 (1.25 g, 2.48 mmol) and /er/-butyl A-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.2 eq) following procedure described in Préparation 3, the desired product (1.063 g, 1.72 mmol, 69%) was obtained as an off-white solid.

-60Ή NMR (399 MHz, DMSO-d6) δ 9.93 (s, IH), 8.30 (d, IH), 7.95 (d, IH), 7.76 (s, IH), 7.44 (tt, IH), 7.19 - 7.06 (m, 3H), 6.78 (t, IH), 5.57 (s, 2H), 4.82 (d, 2H), 3.67 - 3.57 (m, 2H), l .54 (s, 9H), 0.98 - 0.84 (m, 2H), 0.00 (s,9H).

LC/MS (method B): RT = l.7l min; m/z = 617 [M+H]⁺

Step 3: 4-{2-[2-(tert-butyldimethylsilyl)ethynyl]-4-{[(2,6-difluorophenyl)methyl]amino} -7 -{[2 -(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-2 -amine (Préparation 10)

The compound obtained in Step 2 (0.5 g, 0.81 mmol) and rer/-butyldimethyl[2-(tetramethyl-l,3,2-dioxaborolan-2-yl)ethynyl]silane (1.2 eq) were dissolved in 1,4-dioxane (10 mL) under N2. 2M Na2CÛ3 aq. solution (1 mL) and tetrakis(triphenylphosphine)palladium (0.08 mmol) were added and the resulting mixture was degassed under N2 for 5 minutes. The reaction mixture was heated at 160 °C on a CEM microwave reactor for 1 hour. The reaction mixture was filtered through a plug of celite. The filtrate was diluted with water (10 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (0.379 g) as a yellow oil. Purity estimated around 50% by LCMS. The compound was used without further purification.

LC/MS (method A): RT = 2.84 min; m/z = 621 [M+H]⁺

Step 4: 5-(2-aminopyridin-4-yl)-N-(2,6-difuorobenzyl)-2-ethynyl-7H-pyrrolo[2,3d]pyrimidin-4-amine

Starting from the compound obtained in Step 3 (0.379 g) following procedure described in Préparation 4, the desired product (13 mg, 0.003 mmol) was obtained as a white solid.

Ή NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1 H), 7.97 (d, IH), 7.54 - 7.41 (m, 2H), 7.19 (q, 2H), 6.62 - 6.54 (m, 2H), 6.09 (t, 1 H), 6.03 (s, 2H), 4.86 (d, 2H), 4.06 (s, 1 H).

LC/MS (method B): RT = 0.99 min; m/z = 377 [M+H]⁺

-6I -

Example 153: 4-(4-(1,3-benzodioxol-5-yl)-2-(cyclopropylethynyl)-7Æ-pyrrolo[2,3i/]pyrimidin-5-yi]pyridin-2-amine

Step 1: 4-(1,3-benzodioxol-5-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine

Starting from 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 5.32 mmol) and 5 (l,3-benzodioxol-5-yl)boronic acid (1.05 eq) following procedure described in Préparation 3, the desired product (1.45 g, 3.84 mmol) was obtained as a pale yellow solid. Purity estimated around 70% by LCMS. The compound was used without further purification.

LC/MS (method B): RT = 1.2 min; m/z = 274 [M+H]⁺

Step 2: 4-(l,3-benzodioxol-5-yl)-2-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7Hpyrrolo[2,3-d]pyrimidine

Starting from the compound obtained in Step 1 (1.45 g, 3.84 mmol) following procedure described in Préparation 1, the desired product (1.005 g, 2.49 mmol, 65%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 7.92 (d, IH), 7.85 (dd, IH), 7.73 (d, IH), 7.21 (d, IH), 7.12 (d, IH), 6.25 (s, 2H), 5.68 (s, 2H), 3.73 - 3.53 (m, 2H), 0.99 - 0.83 (m, 2H), 0.00 (s, 9H).

LC/MS (method B): RT = 1.57 min; m/z = 404 [M+H]⁺

Step 3: 4-(l,3-benzodioxol-5-yl)-2-(cyclopropylethynyl)-7-{[2-(trimethylsilyl)ethoxy] 20 methyl}-7H-pyrrolo[2,3-d]pyrimidine

Starting from the compound obtained in Step 2 (0.45 g, 1.11 mmol) and potassium (2cyclopropyl-ethyn-l-yl)-trifluoroborate (prepared from Org. Lett., 2010, 12, 3272-3275) (1.4 eq) following procedure described in Préparation 10, the desired product (0.22 g, 0.512 mmol, 46%) was obtained as a red oil.

Ή NMR (399 MHz, DMSO-d6) δ 7.95 (dd, IH), 7.89 - 7.77 (m, IH), 7.73 (dd, IH), 7.26 - 7.03 (m, 2H), 6.27 - 6.18 (m, 2H), 5.71 (s, 2H), 3.74 - 3.58 (m, 2H), 1.50 (m, IH), 1.01 - 0.83 (m, 6H), 0.00 (s, 9H).

LC/MS (method B): RT = 1.61 min; m/z = 434 [M+H]⁺

-62Step 4: 4-(1,3 -benzodioxol-5 -yl) -5 -bromo -2 -(cyclopropylethynyl) -7 -{[2 (trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3-d]pyrimidine (Préparation 11)

To a solution of the compound obtained in Step 3 (0.22 g, 0.512 mmol) in DMF (10 mL) was added NBS (1.05 eq) 0 °C under N₂ and the reaction was allowed to warm to room température over 3 hours. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (0.147 g, 0.286 mmol, 56%) as a brown oil. Ή NMR (399 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.32 - 7.22 (m, 2H), 7.13 (d, 1H), 6.20 (s,

2H), 5.66 (s, 2H), 3.67 - 3.58 (m, 2H), 1.69 (tt, 1H), 1.04 - 0.99 (m, 2H), 0.95 - 0.86 (m,

4H), 0.00 (s, 9H).

LC/MS (method B): RT = 1.64 min; m/z = 512 [M+H]⁺

Step 5: tert-butyl N-{4-[4-(l,3-benzodioxol-5-yl)-2-(cyclopropylethynyl)-7-{[2(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3-d]pyrimidin-5-yl]pyridin-2-yl}carbamate

Starting from the compound obtained in Step 4 (0.110 g, 0.21 mmol) and tert-butyl 7V-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.1 eq) following procedure described in Préparation 3, the desired product (96 mg, 0.153 mmol, 71%) was obtained as an off-white solid.

LC/MS (method B): RT = 1.63 min; m/z = 626 [M+H]⁺

Step 6: 4-[4-(l,3-benzodioxol-5-yl)-2-(cyclopropylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-5yl7pyridin-2-amine

Starting from the compound obtained in Step 5 (96 mg, 0.153 mmol) following procedure described in Préparation 7, the desired product (34 mg, 0.083 mmol, 54%) was obtained as an off-white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.83 (s, 1H), 7.61 (d, 1H), 6.96 (d, 1H), 6.88 - 6.80 (m, 1H), 6.74 (d, 1H), 6.15 (t, 1H), 6.02 (s, 2H), 6.04 - 5.98 (m, 1H), 5.68 (s, 2H), 1.63 (tt, 1H), 1.07-0.90 (m, 2H), 0.91-0.79 (m, 2H).

LC/MS (method B): RT = 0.99 min; m/z = 396 [M+H]⁺

-63Example 157; 5-(2-aminopyridin-4-yI)-4-[(2,6-difluorobenzyl)amino]-7fl'-pyrroIo[2,3d] py rimidine-2-carbonitriIe

Step 1: 5 -bromo -N-[(2,6-difluorophenyl)methyl/ -2 -(methylsulfanyl) -7-{[2 -(trimethylsilyl) ethoxy] methyl} -7H-pyrrolo[2,3 -d]pyrimidin-4-amine

Starting from 5-bromo-4-chloro-2-(methylsulfanyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}7/f-pyrrolo[2,3-iZ]pyrimidine (prepared following procedure described in WO2007/104944) (0.77 g, 1.88 mmol) and 2,6-difluorobenzylamine (3 eq) following procedure described in Préparation 8, the desired product (0.856 g, 1.66 mmol, 88%) was obtained as a pale yellow oil.

Ή NMR (399 MHz, DMSO-d6) δ 7.49 (m, 2H), 7.18 (t, 2H), 6.97 (s, IH), 5.49 (s, 2H), 4.94 (d, 2H), 3.58 (m, 2H), 2.55 (s, 3H), 0.98 - 0.87 (m, 2H), 0.00 (s, 9H).

LC/MS (method B): RT = 1.7 min; m/z = 515 [M+H]⁺

Step 2: 5 -bromo -N-[(2,6 -difluorophenyl)methyl] -2 -methanesulfonyl-7-{[2 -(trimethylsilyl) ethoxy]methyl} -7H-pyrrolo[2,3 -d]pyrimidin -4 -amine (Préparation 12)

To a solution of the compound obtained in Step 1 (0.856 g, 1.66 mmol) in DCM (20 mL) was added mCBPA (2.5 eq) portion wise at 0°C under N2. The reaction mixture was stirred at the same température for 1 hour before allowed to warm to room température over 2 hours. The reaction mixture was diluted with sat. aq. NaHCO₃ (20 mL) solution and DCM (20 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo to give the product (0.831 g, 1.51 mmol, 92%) as a yellow oil. The compound was used without further purification.

LC/MS (method B): RT = 1.53 min; m/z = 549 [M+H]⁺

Step 3: 5 -bromo -4 -{[(2,6 -difluorophenyl)methyl]amino} -7-{[2 -(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3 -d]pyrimidine -2 -carbonitrile (Préparation 13)

To a solution of the compound obtained in Step 2 (0.660 g, 1.11 mmol) in DMF (15 mL) was added sodium cyanide (2.5 eq) under N₂ at room température. The reaction mixture was heated at 90 °C for 2 hours. The reaction mixture was cooled to room température, diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified via

-64flash chromatography using EtOAc and isohexane as eluent to give the product (0.453 g, 0.916 mmol, 76%) as a clear oil.

Ή NMR (399 MHz, DMSO-d6) δ 7.97 (s, IH), 7.55 - 7.41 (m, 2H), 7.19 (t, 2H), 5.58 (s, 2H), 4.93 (d, 2H), 3.63 - 3.53 (m, 2H), 0.99 - 0.83 (m, 2H), 0.00 (s, 9H).

LC/MS (method A): RT = 2.94 min; m/z = 496 [M+H]⁺

Step 4: tert-butyl N-[4-(2-cyano-4-{[(2,6-difluorophenyl)methyl]amino}-7-{[2(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3 -d]pyrimidin -5 -yl)pyridin -2 -yl]carbamate Starting from the compound obtained in Step 3 (0.225 g, 0.46 mmol) and terr-butyl A-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (l.l eq) following procedure described in Préparation 3, the desired product (0.135 g, l.5l mmol, 49%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 9.96 (s, IH), 8.32 (d, IH), 8.03 (s, IH), 7.97 (d, IH), 7.45 (t, IH), 7.19 - 7.08 (m, 3H), 6.94 (t, IH), 5.67 (s, 2H), 4.84 (d, 2H), 3.63 (t, 2H), 0.99 - 0.85 (m, 2H), 0.00 (s, 9H).

LC/MS (method A): RT = 2.98 min; m/z = 608 [M+H]⁺

Step 5: 5-(2-aminopyridin-4-yl)-4-[(2,6-difluorobenzyl)amino]-7H-pyrrolo[2,3d]pyrimidine-2-carbonitrile

Starting from the compound obtained in Step 4 (0.135 g, l.5l mmol) following procedure described in Préparation 7, the desired product (17 mg, 0.04 mmol) was obtained as a 20 white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.56 (s, IH), 7.92 (d, IH), 7.64 (s, IH), 7.40 (tt, IH), 7.11 (t, 2H), 6.54 - 6.43 (m, 3H), 5.98 (s, 2H), 4.77 (d, 2H).

LC/MS (method B): RT = l .03 min; m/z = 378 [M+H]⁺

Example 158: 4-(l,3-benzodioxol-5-yl)-5-(2,6-diaminopyridin-4-yl)-7H-pyrrolo|2,325 J]pyrimidine-2-carbonitrile

Step 1: 4 -(1,3-benzodioxol -5 -yl) -2 -(methylsulfanyl)-7-{[2-(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3-d]pyrimidine

-65Starting from 4-chloro-2-(methylsulfanyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}7//-pyrrolo[2,3-iZ]pyrimidine (prepared following procedure described in WO2007/104944) (0.411 g, 1.25 mmol) and (l,3-benzodioxol-5-yl)boronic acid (1.1 eq) following procedure described in Préparation 3, the desired product (0.462 g, 1.11 mmol, 5 89%) was obtained as a pale yellow oil.

’H NMR (399 MHz, DMSO-d6) δ 7.84 (dd, IH), 7.78 - 7.69 (m, 2H), 7.20 (d, IH), 6.99 (d, IH), 6.24 (s, 2H), 5.68 (s, 2H), 3.68 (m, 2H), 2.71 (s, 3H), 1.00 - 0.86 (m, 2H), 0.00 (s, 9H).

LC/MS (method B): RT = 1.63 min; m/z = 416 [M+H]⁺

Step 2: 4-(l,3-benzodioxol-5-yl)-2-methanesulfonyl-7-{[2-(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3-d]pyrimidine

Starting from the compound obtained in Step 1 (0.462 g, 1.11 mmol) following procedure described in Préparation 12, the desired product (0.475 g, 1.06 mmol, 95%) was obtained as a pale orange oil.

’H NMR (399 MHz, DMSO-d6) δ 8.19 (d, IH), 8.01 - 7.92 (m, 2H), 7.86 (d, IH), 7.29 (d, IH), 6.27 (s, 2H), 5.81 (s, 2H), 3.73 - 3.61 (m, 2H), 3.57 (s, 3H), 1.01 - 0.92 (m, 2H), 0.00 (s, 9H).

LC/MS (method A): RT = 2.7 min; m/z = 448 [M+H]⁺

Step 3: 4-(1,3 -benzodioxol -5 -yl) -7 -{[2 -(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo

[2,3 -djpyrimidine -2 -carbonitrile

Starting from the compound obtained in Step 2 (0.260 g, 0.58 mmol) following procedure described in Préparation 13, the desired product (0.200 g, 0.51 mmol, 87%) was obtained as a dark oil.

LC/MS (method A): RT = 2.84 min; m/z = 395 [M+H]⁺

Step 4: 4-(l,3-benzodioxol-5-yl)-5-bromo-7-{[2-(trimethylsilyl)ethoxyJmethyl}-7Hpyrrolo[2,3 -d]pyrimidine -2 -carbonitrile

Starting from the compound obtained in Step 3 (0.200 g, 0.51 mmol) following procedure described in Préparation 11, the desired product (0.183 g, 0.386 mmol, 76%) was obtained as a pale yellow solid.

-66Ή NMR (399 MHz, DMSO-d6) δ 8.45 (s, IH), 7.40 - 7.28 (m, 2H), 7.17 (d, IH), 6.22 (s, 2H), 5.74 (s, 2H), 3.71 - 3.57 (m, 2H), 0.97 - 0.89 (m, 2H), 0.00 (s, 9H).

LC/MS (method B): RT = l .59 min; m/z = 473 [M+H]⁺

Step 5: tert-butyl N-[6-(tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-l,3,25 dioxaborolan-2-yl)-2-pyridyl]carbamate (Préparation 14) (4-bromo-6-/err-butoxycarbonylamino-pyridin-2-yl)-carbamicacid terf-butyl ester (prepared following procedure described in J. Org. Chem. 2004, 69, 543-548) (10 g, 25.27 mmol), bis(pinacolato)diboron (1.5 eq), Pd(OAc)2 (0.05 eq), 1,1'bis(diphenylphosphino)ferrocene (0.05 eq) and KOAc (3 eq) were dissolved in 1,4-dioxane 10 (160 mL) under N2 at room température. The reaction mixture was stirred at 80 °C ovemight under N2. The reaction mixture was cooled to room température, filtered through celite and washed with warm 1,4-dioxane. Solvent was removed in vacuo. The residue was purified via flash chromatography using EtOAc and DCM as eluent to give the product (7.099 g, 16.3 mmol, 63%) as an off-white solid.

Ή NMR (399 MHz, CDCh) δ 8.16 (brs, 2H), 7.92 (s, 2H), 1.54 (s, 18H), 1.34 (s, 12H).

Step 6: 4-(1,3-benzodioxol-5-yl)-5-(2,6-diaminopyridin-4-yl)- 7H-pyrrolo[2,3d]pyrimidine-2-carbonitrile

The procedure described in Préparation 3 was applied starting from the compound obtained in Step 4 (0.183 g, 0.386 mmol) and the compound obtained in Step 5 (1.1 eq).

The crude reaction mixture was concentrated in vacuo and the residue dissolved in DCM (2mL) and TFA (1.5 mL) following procedure described in Préparation 7, the desired product (8.4 mg, 0.022 mmol, 6%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 13.07 (s, IH), 8.02 (s, IH), 7.09 - 6.97 (m, 2H), 6.79 (d, IH), 6.04 (s, 2H), 5.32 (s, 2H), 5.21 (s, 4H).

LC/MS (method B): RT = 0.92 min; m/z = 372 [M+H]⁺

Examples 147-158 in the following Table 3 were prepared by methods outlined in General Procedure VII-X using appropriate commercially available boronate esters and amines. The compounds of Example 148,153,157,158 are also included.

-67Table 3: HRMS (TOF, ESI) data

Example	Structure	Mol Formula	Calcd Exact Mass	Found m/z	Adduct
147	5-(2-aminopyridin-4-yl)-2-cyclopropyl-?/(2,6-difluorobenzyl)-7//-pyrrolo[2,3c/]pyrimidin-4-amine	C21 H18F2N6	392.1561	391.1494	[M - H]’
148	5-(2-aminopyridin-4-yl)-//-(2,6difluorobenzyl)-2-ethynyl-7//-pyrrolo[2,3- t/\|pyrimidin-4-amine	C20H14F2 N6	376.1248	375.1193	[M - H]’
149	5-(2-aminopyridin-4-yl)-A^r-(2,6difluorobenzy l)-2-(prop-1 -en-2-y 1)-7//pyrrolo[2,3-J\|pyrimidin-4-amine	C21 H18 F2N6	392.1561	391.1479	[M - H]'
150	5-(2-aminopyridin-4-yl)-7V-(2,6difluorobenzyl)-2-(propan-2-yl)-7//pynolo[2,3-d]pyrimidin-4-amine	C21 H20F2N6	394.1718	393.1650	[M - H]’
151	5-(2-aminopyridin-4-yl)-A42,6- difluorobenzyl)-2-ethenyl-7//-pyrrolo[2,3cflpyrimidin-4-amine	C20H16F2 N6	378.1405	377.1342	[M - H]'

152	5-(2-aminopyridin-4-yl)-2(cyclopropylethynyl)-N-(2,6difluorobenzyl)-7//-pyrrolo[2,3- iflpyrimidin-4-amine	C23H18F2 N6	416.1561	417.1618	[M - H]⁺
153	4-[4-( 1,3-benzodioxol-5-y l)-2(cyclopropylethynyl)-7//-pynOlo[2,3- J]pyrimidin-5-yl]pyridin-2-amine	C23H17N5 02	395.1382	396.1383	[M - Hf
154	4-[4-( 1,3-benzodioxol-5-y l)-2(cyclopropylethynyl)-7//-pyrrolo[2,3- ^pyrimidin-5-yl]pyridine-2,6-diamine	C23 H18N6 02	410.1491	411.1546	[M-H]⁺
155	4-[4-( 1,3-benzodioxol-5-y l)-2-ethyny 1-7//pyirolo[2,3-d]pyrimidin-5-yl]pyridine-2,6diamine	C20H14N6 02	370.1178	371.1182	[M - H]*
156	4-[4-(l,3-benzodioxol-5-yl)-2-ethynyl-7//pyrrolo[2,3-6/]pynmidin-5-yl]pyndin-2amine	C20H13N5 02	355.1069	356.1108	[M - H]⁺

157	5-(2-aminopyridin-4-yl)-4-[(2,6difluorobenzyl)amino]-7//-pyrrolo[2,3- ûf]pyrimidine-2-carbonitrile	C19H13F2 N7	377.1200	378.1242	[M - Hf
158	4-(l,3-benzodioxol-5-y 1)-5-(2,6diaminopyndin-4-yl)-7//-pyrrolo[2,3- iZ]pyrimidine-2-carbonitrile	C19H13N7 02	371.1131	370.1036	[M - H]'

Example 150 was prepared from Example 149 using method described in Préparation 5.

General Procedure XI

SEM

General Procedure XII

General Procedure XIV

-71 General Procedure XVII

BOC

In General Procedures XI to XVII:

- Ri and R₂ are as defined in formula (I),

- R₃ represents a hydrogen atom, a linear or branched (Ci-C6)alkyl group,

-(Co-Cô)alkylene-Cyi, -(Co-C6)alkylene-Cyi-Cy₂, -(Co-C6)alkylene-Cyi-0-(Ci-Cô)alkyleneCy₂, it being understood that Cyi and Cy₂, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group, and R’₃ represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, or R₃ and R’₃ form with the nitrogen atom carrying them a heterocycloalkyl or an heteroaryl,

- G represents a group selected from the list of substituents defined in formula (I), it being understood that the phenyl may be substituted by from 1 to 4 independent G groups.

-72General Procedure XVIII

B oc

wherein R3 represents a hydrogen, a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group.

Example 162: 4-[4-(3-fluoro-5-methoxyphenyl)-2-methyl-7H-pyrrolo[2,3-i/] pyrimidin-5-yl]pyridin-2-amine

Step 1: tert-butylN-{4-[4-(3-fluoro-5-methoxyphenyl)-2-methyl-7-{[2-(trimethylsilyl) ethoxy]methyl} -7H-pyrrolo[2,3 -d]pyrimidin -5 -yl]pyridin -2 -yl}carbamate

Starting from tert-butyl V-[4-(4-chloro-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}10 7/f-pynOlo[2,3-i/]pyrimidin-5-yl)pyridin-2-yl]carbamate (prepared following the procedure described in Example 20, Step 1 using tert-butyl V-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate) (100 mg, 0.2 mmol) and (3-fluoro-5-methoxyphenyl)boronic acid (1.1 eq) following procedure described in Préparation 3, the desired product (104 mg, 0.179 mmol, 88%) was obtained as an off15 white solid.

Ή NMR (399 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.15 (s, 1H), 8.06 (d, 1H), 7.52 (s, 1H), 6.94 - 6.79 (m, 2H), 6.72 (dd, 1H), 6.66 (dd, 1H), 5.77 (s, 2H), 3.70 (dd, 2H), 3.5 (s, 3H), 2.82 (s, 3H), 1.49 (s, 9H), 1.00-0.81 (m, 2H), 0.00 (s, 9H).

LC/MS (method B): RT = 1.66 min; m/z = 580 [M+H]⁺

-73Step 2: 4-[4-(3-fl uoro -5 -methoxyphenyl) -2 -methyl-7H -pyrrolo[2,3 -d]pyrimidin -5 -yl/ pyridin-2-amine (Préparation 15)

To a solution of the compound obtained in Step 1 (104 mg, 0.179 mmol) in DCM (2 mL) was added boron trifluoride diethyl etherate (2 eq) drop wise at 0 °C under N₂ and the 5 reaction mixture was allowed to warm to room température over 4 hours. The reaction mixture was diluted with sat. aq. NaHCO₃ (20 mL) solution and DCM (20 mL). The organic layer was separated and concentrated in vacuo. The residue was dissolved in MeCN (2 mL), ammonium hydroxide solution (28% ammonia in water, 2 mL) was added and the mixture stirred at room température for 2 hours. The reaction mixture was 10 concentrated in vacuo and the residue was triturated with diethyl ether to give the product (8.7 mg, 0.024 mmol, 14%) as a pale yellow powder.

'H NMR (399 MHz, DMSO-d6) δ 12.39 (s, IH), 7.74 (s, IH), 7.59 (d, IH), 6.89 (ddd, IH), 6.81 (dt, IH), 6.66 (dd, IH), 6.20 - 6.14 (m, IH), 5.99 (dd, IH), 5.68 (s, 2H), 3.51 (s, 3H), 2.72 (s, 3H).

LC/MS (method B): RT = 0.9 min; m/z = 350 [M+H]⁺

Example 164; 4-(4-(2,2-difluoro-l,3-benzodioxol-5-yl)-2-methyl-7/f-pyrrolo[2,3-i/) pyrimidin-5-yl]pyridin-2-amine

Step 1: 4 -(2,2 -difluoro -1,3 -benzodioxol -5 -yl) -2 -methyl-7H-pyrrolo[2,3-d]pyrimidine (Préparation 16)

4-chloro-2-methyl-7/f-pyrrolo[2,3-7]pyrimidine (0.511 g, 3.05 mmol) and (2,2-difluoro-l,3-benzodioxol-5-yl)boronic acid (1.02 eq) were dissolved in THF/water (10:1, 10 mL) under N₂. Césium carbonate (2 eq) and Pd(dppf)C12 (10% wt) were added and the resulting mixture was degassed under N₂ for 5 minutes. The reaction mixture was heated at 140 °C on a CEM microwave reactor for I hour. The mixture was diluted with water ( 150 mL) and the resulting precipitated was collected by filtration to give the product (0.88 g, 3.04 mmol, 99%) as an off-white solid.

LC/MS (method B): RT = 1.27 min; m/z = 290 [M+H]⁺

Step 2: tert-butyl 5-bromo-4-(2,2-difluoro-l,3-benzodioxol-5-yl)-2-methyl

-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (Préparation 17)

-74To a solution of the compound obtained in Step l (0.88 g, 3.04 mmol) in DMF (15 mL) was added NBS (l.l eq) portion wise at 0 °C under N₂ and the reaction mixture was allowed to warm to room température over 2 hours (reaction monitored by LCMS). Dirert-butyl dicarbonate (1.2 eq), DMAP (0.01 eq) and trimethylamine (2 eq) were added to the mixture and stirred ovemight under N₂ at room température. The reaction mixture was diluted with water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over MgSÛ4 and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (0.681 g, 1.45 mmol, 48%) as a pale yellow oil.

Ή NMR (399 MHz, DMSO-d6) δ 8.05 (s, IH), 7.72 (d, IH), 7.59 (d, IH), 7.50 (dd, IH), 2.75 (s, 3H), 1.64 (s, 9H).

LC/MS (method B): RT = 1.6 min; m/z = 470 [M+H]⁺

Step 3: 4-[4-(2,2 -difl uoro -1,3 -benzodioxol -5 -yl) -2 -methyl-7H-pyrrolo[2,3 -d]pyrimidin 5-yl]pyridin-2-amine (Préparation 18)

The compound obtained in Step 2 (0.681 g, 1.45 mmol) and terr-butyl N-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.1 eq) were dissolved in THF/water (3:1, 20 ml) under N₂. Potassium carbonate (3 eq) and Pd(dtbpf)Cl₂ (10% wt) were added and the resulting mixture was degassed under N₂ for 5 minutes. The reaction mixture was heated at 65 °C ovemight under N₂, cooled to room température and diluted with water (10 mL) and DCM (50 mL). The organic layer was separated, washed with brine, dried over MgSÛ4 and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the desired coupled compound. The compound was dissolved in 2 M HCl solution in MeOH (4 mL) and heated at 90 °C on a CEM microwave reactor for 1 hour. The reaction mixture was concentrated in vacuo and diluted with 10% IPA in DCM (20 ml), washed with sat. aq. NaHCOj, dried over MgSO4 and concentrated in vacuo. The residue was purified via flash chromatography using MeOH and DCM as eluent to give, after trituration with diethyl ether, the product (99 mg, 0.26 mmol, 26%) as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.39 (s, IH), 7.74 (s, IH), 7.58 (d, IH), 7.36 (d, IH), 30 7.27 (d, IH), 7.19 (dd, IH), 6.07 (t, IH), 6.00 (dd, IH), 5.68 (s, 2H), 2.72 (s, 3H).

LC/MS (method B): RT = 0.96 min; m/z = 382 [M+H]⁺

-75Example 168: 4-{2-methyl-4-[3-(trifluoromethyl)plienyl]-77f-pyrroIo[23-</] pyrimidin-5-yl}pyridin-2-amine

Step 1: 7 -(benzenesulfonyl) -5 -bromo -2 -methyl -4 -[3 -(trifluoromethyl)phenyl/ -7H-pyrrolo [2,3-d]pyrimidine (Préparation 19)

To a solution of 2-methyl-4-[3-(trifluoromethyl)phenyl]-7#-pynOlo[2,3-<7]pyrimidine (prepared following the procedure described in Example 164, Step 1 using 3-(trifluoromethyl)phenyl]boronic acid) (186 mg, 0.67 mmol) in DMF (5 mL) was added NBS (1.1 eq) at 0 °C under N2 and the reaction was allowed to warm to room température over 2 hours. The reaction mixture was cooled to 0 °C, NaH (60% in minerai oil, 1.4 eq) was added and stirred for 5 minutes before adding benzenesulfonyl chloride (1.1 eq) under N2. The reaction mixture was allowed to warm to room température overnight, diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (201 mg) as a brown oil. Purity estimated around 70% by LCMS. The compound was used without further purification.

LC/MS (method B): RT = 1.57 min; m/z = 496 [M+H]⁺

Step 2: 4 -[7-(benzenesulfonyl) -2 -methyl -4 [3 -(trifluoromethyl)phenyl/ -7H-pyrrolo

[2,3-d]pyrimidin-5 -yl]pyridin-2-amine

Starting from the compound obtained in Step 1 (201 mg) and /er/-butyl jV-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.1 eq) following procedure described in Préparation 3, the desired product (106 mg, 0.177 mmol, 26% over two steps) was obtained as a yellow oil.

LC/MS (method B): RT = 1.22 min; m/z = 510 [M+H]⁺

Step 3: 4-{2-methyl-4-[3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl} pyridin-2-amine (Préparation 20)

To a solution of the compound obtained in Step 2 (106 mg, 0.177 mmol) in MeOH (5 mL) was added K2CO3 (5 eq) and the resulting suspension was stirred at room température i

-76ovemight. The suspension was filtered, concentrated in vacuo and the residue was purified via flash chromatography using MeOH and DCM as eluent to give the product (10 mg, 0.027 mmol, 15%) as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.42 (s, IH), 7.87 - 7.79 (m, IH), 7.74 (d, 2H), 7.56 (s,

2H), 7.61 - 7.47 (m, IH), 6.17 - 6.11 (m, IH), 5.90 (dd, IH), 5.64 (s, 2H), 2.74 (s, 3H).

LC/MS (method B): RT = 0.94 min; m/z = 370 [M+H]⁺

Example 169: 4-(2-methyl-4-{4-[(4-methylpiperazin-l-yl)methyl]phenyl}-7Æ-pyrrolo [2,3-7] pyrimidin-5-yl)pyridin-2-amine

Step 1: tert-butyl 5-(2-{[(tert-butoxy)carbonyl]amino}pyridin~4-yl)-2-methyl-4I ° {4-[(4 -methylpiperazin -1 -yl)methyl]phenyl} -7H-pyrrolo[2,3 -d]pyrimidine-7 -carboxylate (Préparation 21)

To a solution of Zeri-butyl 5-(2-{[(/err-butoxy)carbonyl]amino}pyridin-4-yl)-4(4-formylphenyl)-2-methyl-7/7-pynOlo[2,3-7]pyrimidine-7-carboxylate (prepared following the procedure described in Example 164 using (4-formylphenyl)boronic acid) (200 mg, 0.38 mmol) in MeOH (5 mL) was added 1-methylpiperazine (2 eq) followed by sodium cyanoborohydride (1.5 eq) at room température under N2. The reaction mixture was stirred overnight. Then, it was diluted with sat aq. NaHCOj solution (10 mL) and DCM (10 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified via flash chromatography using MeOH and DCM as eluent to give the product (86 mg, 0.14 mmol, 37%) as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 9.67 (s, IH), 8.02 - 7.93 (m, 2H), 7.34 (s, IH), 7.23 (d, 2H), 7.06 (d, 2H), 6.75 (dd, IH), 3.44 (s, 2H), 2.78 (s, 3H), 2.5 - 2.2 (m, 8H), 2.18 (s, 3H), 1.67 (s, 9H), 1.44 (s, 9H).

LC/MS (method B): RT = 1.26 min; m/z = 614 [M+H]⁺

Step 2: 4-(2-methyl-4-{4-[(4-methylpiperazin-l -yl)methyl]phenyl}-7H-pyrrolo[2,3-d] pyrimidin-5-yl)pyridin-2-amine (Préparation 22)

The compound obtained in Step 1 (86 mg, 0.14 mmol) was dissolved in 2 M HCl in MeOH solution (4 mL) and heated at 80 °C on a CEM microwave reactor for 1 hour. The mixture

-77 was concentrated in vacuo and the residue was triturated with diethyl ether to give the product (58 mg, O.l 19 mmol) as an HCl sait.

Ή NMR (399 MHz, DMSO-d6) δ 13.71 (brs, IH), 13.23 (brs, IH), l l.9l (brs, IH), 8.25 (d, IH), 7.77 (m, 4H), 7.56 (d, 2H), 6.48 (dd, IH), 6.39 (d, IH), 4.7 - 3.2 (m, 13H), 2.81 (s, 5 3H).

LC/MS (method B): RT = 0.7 min; m/z = 414 [M+H]⁺

Example 174: 4-(2-methyl-4-{3-[3-(morpholin-4-yl)propoxy]phenyl}-7/f-pyrrolo [2,3-i/]pyrimidin-5-yl)pyridin-2-amine (Préparation 23)

To a solution of 4-{4-[3-(3-chloropropoxy)phenyl]-2-methyl-7/7-pyrrolo[2,3-J] pyrimidin-5-yl}pyridin-2-amine (prepared following the procedure described in Example 168 using 2-[3-(3-chloropropoxy)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (US2007/0004675)) (50 mg, 0.13 mmol) in MeCN (2 mL) was added Nal (4 eq), K2CO3 (6 eq) and morpholine (4 eq). The reaction mixture was heated at 150 °C on a CEM microwave reactor for 30 minutes. The reaction mixture was diluted with 10% MeOH in

DCM (5 ml), filtered through a phase separator column and concentrated in vacuo. The residue was purified via flash chromatography using MeOH and DCM as eluent to give, after trituration with MeCN, the product (30 mg, 0.067 mmol, 53%) as an off-white solid. Ή NMR (399 MHz, DMSO-d6) δ 12.33 (s, IH), 7.70 (s, IH), 7.51 (d, IH), 7.21 (t, IH), 7.12 (dt, IH), 6.95 - 6.87 (m, IH), 6.85 - 6.79 (m, IH), 6.19 (d, IH), 5.91 (dd, IH), 5.63 (s, 2H), 3.67 (t, 2H), 3.55 (t, 4H), 2.71 (s, 3H), 2.36 (s, 6H), 1.81 - 1.72 (m, 2H).

LC/MS (method B): RT = 0.617 min; m/z = 445 [M+H]⁺

Example 178; 4-(4-(2,3-dihydro-lZ/-indol-l-ylmethyl)-2-methyl-7H-pyrroIo[2,3-i/| pyrimidin-5-yl]pyridin-2-amine

Step 1: ethyl 2 -methyT7H-pyrrolo[2,3 -d]pyrimidine -4 -carboxylate (Préparation 24)

4-chloro-2-methyl-7/f-pyrrolo[2,3-</|pyrimidine (4 g, 23.87 mmol), sodium acetate (2 eq), Pd(OAc)2 (0.07 eq) and l,T-bis(diphenylphosphino)ferrocene (0.07 eq) in éthanol (140 mL) were combined in a Parr reaction bottle under N2. The System was purged three times with carbon monoxide and pressurized to 28 psi. The reactor was warmed to 70 °C and

-78shaken ovemight in a Parr shaker hydrogenator apparatus. The reactor was cooled to room température, carbon monoxide removed by vacuum and the reaction mixture was filtered through a plug of celite. The filtrate was concentrated in vacuo and the residue was triturated with water and diethyl ether to give the product (3.811 g, 18.58 mmol, 78%) as a 5 pale brown solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.24 (s, IH), 7.69 (d, IH), 6.81 (d, IH), 4.43 (q, 2H), 2.71 (s, 3H), l.39(t,3H).

LC/MS (method B): RT = 0.92 min; m/z = 206 [M+H]⁺

Step 2: ethyl 7-(benzenesulfonyl)-5-bromo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine 10 -4-carboxylate

Starting from the compound obtained in Step l (1.83 g, 3.8 mmol) following procedure described in Préparation 19, the desired product (1.63 g, 3.8 mmol, 60%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.36 (s, IH), 8.25 - 8.17 (m, 2H), 7.85 - 7.74 (m, IH), 15 7.74 - 7.64 (m, 2H), 4.44 (q, 2H), 2.75 (s, 3H), 1.34 (t, 3H).

LC/MS (method B): RT = 1.41 min; m/z = 423 [M+H]⁺

Step 3: 7 -(benzenesulfonyl) -5 -bromo -2 -methyl-7H-pyrrolo[2,3 -d]pyrimidine -4 carbaldehyde (Préparation 25)

To a solution of the compound obtained in Step 2 (0.5 g, 1.18 mmol) in THF (13 mL) was 20 added DIBAL (IM in THF solution, 3 eq) at -78 °C under N2. The reaction mixture was stirred at the same température for 1 hour and allowed to warm to room température over 2 hours. Cooled to -78 °C, the mixture was quenched with water (1 mL) and 2N NaOH solution (0.5 mL) and allowed to warm to room température. MgSCM was added to the mixture, filtered through a plug of celite and concentrated in vacuo to give the product (1.2 25 g, >100%). The compound was used without further purification.

LC/MS (method B): RT = 1.31 min; m/z = 413, [M+H]⁺ not found

Step 4: l-{[7 -(benzenesulfonyl) -5 -bromo -2 -methyl-7H-pyrrolo[2,3 -d]pyrimidin -4 -yl/ methyl) -2,3-dihydro -IH-indole

-79Starting from the compound obtained in Step 3 (1.2 g) and indoline (1.2 eq) following procedure described in Préparation 21, the desired product (0.193 g, 0.399 mmol, 34% over two steps) was obtained as a white solid.

LC/MS (method B): RT = 1.57 min; m/z = 482 [M+H]⁺

Step 5: 4-[7-(benzenesulfonyl)-4-(2,3-dihydro-lH-indol-l-ylmethyl)-2-methyl-7H-pyrrolo [2,3 -d]pyrimidin -5 -yl/pyridin -2 -amine

Starting from the compound obtained in Step 4 (0.193 g, 0.399 mmol) and tert-butyl /V-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.1 eq) following procedure described in Préparation 3, the desired product (0.133 g, 0.267 mmol, 67%) 10 was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.28 - 8.20 (m, 2H), 7.96 - 7.88 (m, 2H), 7.83 - 7.74 (m, IH), 7.75 - 7.64 (m, 2H), 6.93 (dd, IH), 6.79 (td, IH), 6.70 (dd, IH), 6.56 (dd, IH), 6.50 (td, IH), 6.09- 5.99 (m, 3H), 4.36 (s, 2H), 3.03 (t, 2H), 2.69 (d, 5H).

LC/MS (method B): RT = 1.16 min; m/z = 497 [M+H]⁺

Step 6: 4-[4-(2,3-dihydro-lH-indol-l-ylmethyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin -5 -yl]pyridin -2 -amine

Starting from the compound obtained in Step 5 (0.133 g, 0.267 mmol) following procedure described in Préparation 20, the product (41 mg, 0.114 mmol, 43%) was obtained as an off-white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.18 (d, IH), 7.89 (d, IH), 7.54 (d, IH), 6.94 (dd, IH), 6.81 (td, IH), 6.65 (dd, IH), 6.57 - 6.45 (m, 2H), 6.17 (d, IH), 5.92 (s, 2H), 4.45 (s, 2H), 3.10 (t, 2H), 2.71 (t, 2H), 2.64 (s, 3H).

LC/MS (method B): RT = 0.89 min; m/z = 357 [M+H]⁺

Example 193: 4-(2-methyl-4-{(2-(trifluoromethyl)phenoxy]methyl}-7Æ-pyrrolo[23-</] 25 pyrimidin-5-yl)pyridin-2-amine

Step 1: {5-bromo-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}methanol (Préparation 26)

To a solution of ethyl 5-bromo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylate (prepared following the procedure described in Example 153, Step 4 starting from ethyl

-802-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylate (Préparation 24)) (0.500 g, 1.76 mmol) in THF (10 mL) was added LiBH₄ (2 eq) portion wise at 0 °C under N₂. The reaction mixture was allowed to warm to room température overnight. The reaction mixture was diluted with sat. aq. NaHCCL (10 mL) solution and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified via flash chromatography using MeOH and DCM as eluent to give the product (0.237 g, 0.98 mmol, 56%) as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.29 (s, IH), 7.67 (s, IH), 5.23 (t, IH), 4.96 (d, 2H), 2.65 (s, 3H).

LC/MS (method B): RT = 0.51 min; m/z = 243 [M+H]⁺

Step 2: tert-butyl 5-bromo-4-(hydroxymethyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine7 -carboxylate

To a solution of the compound obtained in Step l (0.237 g, 0.98 mmol) was added di-tertbutyl dicarbonate (1.2 eq), DMAP (0.01 eq) and trimethylamine (2 eq) following procedure described in Préparation 17. The desired product (0.345 g, >100%) was obtained as a white solid. Purity estimated around 70% by LC-MS. The compound was used without further purification.

LC/MS (method B): RT = 1.23 min; m/z = 342 [M+H]⁺

Step 3: tert-butyl 5-bromo-2-methyl-4-{[2-(trifluoromethyl)phenoxy]methyl}-7H20 pyrrolo[2,3 -d]pyrimidine-7 -carboxylate

Starting from the compound obtained in Step 2 (0.345 g) and 2-(trifluoromethyl)phenol (1.1 eq) following procedure described in Préparation 6, the desired product (0.63 g, >100%) was obtained as a yellow oil. Purity estimated around 45% by LC-MS. The compound was used without further purification.

LC/MS (method B): RT = 1.58 min; m/z = 485 [M+H]⁺

Step 4: tert-butyl 5-(2-{[(tert-butoxy)carbonyl]amino}pyridin-4-yl)-2-methyl4 -{[2-(trifluoromethyl)phenoxy] methyl} -7H-pyrrolo[2,3 -d]pyrimidine -7 -carboxylate

Starting from the compound obtained in Step 3 (0.63 g) and /ert-butyl JV-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.1 eq) following

-8l procedure described in Préparation 18, the desired product (62 mg, 0.155 mmol) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.34 (s, IH), 7.67 (s, IH), 7.62 - 7.53 (m, 3H), 7.22 (d, IH), 7.09 (t, IH), 6.63 (dd, IH), 6.51 (t, IH), 5.75 (d, 2H), 5.31 (s, 2H), 2.66 (s, 3H).

LC/MS (method B): RT = 0.99 min; m/z = 400 [M+H]⁺

Example 198: 4-[4-(cyclopropylethynyl)-2-methyl-7/f-pyrrolo[2,3-</]pyrimidin-5-yl] pyridin-2-amine

Step 1: tert-butyl 5-bromo-4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate Starting from 4-chloro-2-methyl-7//-pyrrolo[2,3-i/]pyrimidine (10.53 g, 59.67 mmol) following procedure described in Préparation 17, the product (14.43 g, 41.63 mmol, 93%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.11 (s, IH), 2.69 (s, 3H), 1.62 (s, 9H).

Step 2: tert-butyl 5-(2-{[(tert-butoxy)carbonyl]amino}pyridin-4-yl)-4-chloro-2-methyl7H-pyrrolo[2,3 -d]pyrimidine-7 -carboxylate

Starting from the compound obtained in Step 1 (1 g, 2.89 mmol) and /er/-butyi ?/-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.1 eq) following procedure described in Préparation 3, the desired product (1.059 g, 2.3 mmol, 80%) was obtained as a pale yellow solid.

Ή NMR (399 MHz, DMSO-d6) δ 9.89 (s, IH), 8.31 (dd, IH), 8.02 (s, IH), 7.97 (t, IH), 20 7.20 (dd, 1 H), 2.71 (s, 3H), 1.64 (s, 9H), 1.48 (s, 9H).

LC/MS (method B): RT = 1.49 min; m/z = 460 [M+H]⁺

Step 3: tert-butyl 5-(2-{[(tert-butoxy)carbonyl]amino}pyridin-4-yl)-4-(cyclopropyl ethynyl) -2 -methyl-7H-pyrrolo[2,3 -d]pyrimidine -7-carboxylate (Préparation 2 7)

To a solution of the compound obtained in Step 2 (100 mg, 0.22 mmol) in EtîN (4 ml) and

THF (1 mL) was added ethynylcyclopropane (3 eq) and Cul (0.3 eq) at room température. The solution was purged with N₂ for 5 minutes before adding Pd(PPh3)2Ch (0.3 eq) and the reaction mixture was stirred at 80 °C for 5 hours on a CEM micro wave reactor. The reaction mixture cooled to room température and concentrated in vacuo. The residue was

-82purified via flash chromatography using MeOH and DCM as eluent to give the product (70 mg, 0.143 mmol, 66%) as a white solid.

LC/MS (method B): RT = l .51 min; m/z = 490 [M+H]⁺

Step 4: 4-[4 -(cyclopropylethynyl) -2 -methyi-7H-pyrrolo[2,3 -d]pyrimidin-5 -yl]pyridine

-2-amine

Starting from the compound obtained in Step 3 (70 mg, 0.143 mmol) following procedure described in Préparation 7, the desired product (32 mg, O.l l mmol, 77%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.27 (s, IH), 7.91 (d, IH), 7.67 (d, IH), 6.67 (dd, IH), 10 6.59 (t, IH), 5.91 (s, 2H), 2.60 (s, 3H), l .50 (tt, IH), 0.85 (m, 2H), 0.66 (m, 2H).

LC/MS (method B): RT = 0.76 min; m/z = 290 [M+H]⁺

Examples 159-204 in the following Table 4 were prepared by methods outlined in General Procedure XI-XVIII using appropriate commercially available boronate ester, alcohol, amines and ethynyl. The compounds of Example 162, 164, 168, 169, 174, 178, 15 193, 198 are also included.

Table 4: HRMS (TOF, ESI) data

Example	Structure	Mol Formula	Calcd Exact Mass	Found m/z	Adduct
159	4-{2-methyl-4-[(£)-2-phenylethenyl]-7//pyrrolo[2,3-i/]pyrimidin-5-yl}pyridin-2amine	C20H17N5	327.1484	328.1564	[M - H]⁺

160	4-[2-methyl-4-(2-phenylethyl)-7//pyirolo[2,3-/]pyrimidin-5-yl]pyridin-2-amine	C20H19N5	329.1640	328.1574	[M - H]'
161	4-[4-(l//-indol-2-yl)-2-methyl-7//pyrrolo[2,3-i/]pyrimidin-5-yl]pyridin-2-ainine	C20H16N6	340.1436	341.1519	[M - H]⁺
162	4-[4-(3-fluoro-5-methoxyphenyl)-2-methyl7/7-pyrrolo[2,3-t/]pynmidin-5-yl]pyridin-2amine	C19H16FN5O	349.1339	348.1269	[M - H]'
163	4-(2-methyl-4-phenyl-7//-pyrroIo[2,3c/]pyrimidin-5-yl)pyridin-2-amine	C18H15N5	301.1327	302.1396	[M - H]⁺
164	4-[4-(2,2-difluoro-l,3-benzodioxol-5-yl)-2methyl-7//-pyiTolo[2,3-i/]pyrimidin-5yl]pyridin-2-amine	C19H13F2 N5 02	381.1037	380.0972	[M-H]·

165	4-{2-methyl-4-[4-(pyrrolidin-l-ylmethyl) phenyl]-7//-pyrrolo[2,3-iZ]pyrimidin-5yl}pyridin-2-amine	C23 H24 N6	384.2062	385.2135	[Μ-ΗΓ
166	4-{4-[(2,6-difluorophenoxy)methyi]-2methyl-7//-pynOlo[2,3-6/]pyrimidin-5yl}pyridin-2-amine	C19H15F2 N5 0	367.1245	366.1172	[M - H]'
167	4-[4-(3-methoxyphenyl)-2-methyl-7//pyrrolo[2,3-</\|pyrimidin-5-yl]pyridin-2-amine	C19H17N5 O	331.1433	330.1369	[M-H]-
168	4-{2-methyl-4-[3-(trifluoromethyl)phenyl]7//-pyrrolo[2,3-t/]pyrimidin-5-yi}pyridin-2amine	C19H14F3 N5	369.1201	368.1140	[Μ-H]’
169	4-(2-methyl-4-{4-[(4-methylpiperazin-lyl)methyl]phenyl}-7//-pynolo[2,3t/]pyrimidin-5-yl)pyridin-2-amine	C24 H27 N7	413.2328	412.2268	[M - H]’

170	4-[4-(5-fluoropyridin-3-yl)-2-methyl-7//pyrrolo[2,3-i/]pyrimidin-5-yl]pyndin-2-amine	C17H13 FN6	320.1186	319.1112	[M - H]'
171	4-{2-methyl-4-[3-(pyrrolidin-l-yl)phenyl]7//-pynOlo[2,3-£/]pyrimidin-5-yl}pyridm-2amine	C22 H22 N6	370.1906	369.1839	[M - H]’
172	4-[4-(4-ethoxyphenyl)-2-methyl-7//pynolo[2,3-ô/]pyrimidm-5-yl]pyridin-2-amine	C20H19N5O	345.1590	346.1656	[M + H]⁺
173	4-[4-(2,3-dihydro-l,4-benzodioxin-6-yl)-2methyl-7//-pynOlo[2,3-i/]pyrimidm-5yl]pyridin-2-amine	C20H17N5 02	359.1382	360.1440	[M + H]⁺
174	4-(2-methyl-4-{3-[3-(morpholin-4yl)propoxy]phenyl}-7//-pyrrolo[2,3iZ]pyrimidin-5-yl)pyridin-2-amine	C25 H28 N6 02	444.2274	445.2250	[M + H]⁺

175	4-[5-(2-aminopyridin-4-yl)-2-methyl-7//pyrro lo [2,3 -d\ py ri mi d i n-4-y 1] -2fluorobenzonitrile	C19H13 FN6	344.1186	343.1119	[M + H]'
176	4-{4-[(3,3-difluoropynOlidin-l-yl)methyl]-2methyl-7//-pyrrolo[2,3-i/]pyrimidin-5yl}pyridin-2-amine	C17H18F2 N6	344.1561	343.1486	[M + H]'
177	4-{4-[(3,3-difluoropiperidin-l-yl)rnethyi]-2methyl-77/-pyrrolo[2,3-ô/]pyrimidin-5- yl}pyridin-2-amine	C18H20 F2 N6	358.1718	357.1622	[M + H]-
178	4-[4-(2,3-dihydro-1 //-indol-1 -y Imethy l)-2methyl-7//-pyrrolo[2,3-i/]pyrimidin-5yl]pyridin-2-amine	C21 H20 N6	356.1749	355.1683	[M + H]’
179	4-[4-(l,3-benzodioxol-5-yl)-2-methyl-7//pyrrolo[2,3-</]pyrimidin-5-yl]pyridin-2-amine	C19H15N5 02	345.1226	344.1127	[M + H]’

180	4-[4-(3,5-difluorophenyl)-2-methyl-7Z/pyrrolo[2,3-^]pyrimidin-5-yl]pyridin-2-amine	C18H13F2 N5	337.1139	336.1057	1 [M + H]'
181	4-{2-methyl-4-[3-(trifluoromethoxy)phenyl]7//-pyrrolo[2,3-<flpyrimidin-5-yl}pyridin-2amine	C19H14F3 N5 0	385.1150	384.1086	[M + H]-
182	4-[4-(l-benzothiophen-2-yl)-2-methyl-7//pyiTolo[23-^pyrimidin-5-yl]pyridin-2-amine	C20H15N5 S	357.1048	356.0969	[M + H]’
183	4-[4-(l-benzofuran-2-yl)-2-methyl-7?/pyrrolo[2,3-ôZ]pynmidin-5-yl]pyridin-2-amine	C20H15N5 0	341.1277	340.1217	[M + H]’
184	4-[2-methyl-4-(5-methyl-l-benzothiophen-2yl)-7//-pyrrolo[2,3-</]pyrimidin-5-yl]pyridin2-amine	C21 H17N5S	371.1205	372.1210	[M + Hf

185	4-[4-(7-chloro-l-benzothiophen-2-y 1)-2methyl-7//-pyrrolo[2,3-t/]pynmidin-5yl]pyridin-2-amine	C20H14C1 N5 S	391.0658	392.0712	[M +
186	4-[2-methy 1-4-(1-methyl-l//-indol-2-y 1)-7//pyrrolo[2,3-i/]pyrimidin-5-yl]pyridin-2-amine	C21 H18N6	354.1593	353.1534	[M + H]’
187	4-[4-(3,4-dihydronaphthalen-2-yl)-2-methyI7//-pyrrolo[2,3-i/]pyrimidin-5-yl]pyridin-2amine	C22H19N5	353.1640	352.1583	[M + H]'
188	4-[2-methy 1-4-( 1,2,3,4-tetrahydronaphthalen2-yl)-7//-pyrrolo[2,3-6Z]pyrimidin-5yl]pyridin-2-amine	C22 H21 N5	355.1797	354.1732	[M + H]’
189	4-{2-methyl-4-[(2S)-l,2,3,4- tetrahydronaphthalen-2-yl]-7//-pyrrolo[2,3û(]pyrimidin-5-yl}pyridin-2-amine	C22 H21 N5	355.1797	354.1716	[M + H]’

190	4-{2-methyl-4-[(2/?)-l, 2,3,4- tetrahydronaphthalen-2-yl]-7//-pyrrolo[2,3c/]pyrimidin-5-yl}pyridin-2-amine	C22 H21 N5	355.1797	354.1728	[M + H]'
191	4-[4-(7-fluoro-l,3-benzodioxol-5-yl)-2methyl-7//-pyrrolo[2,3-ô/]pyrimidin-5yl]pyridin-2-amine	C19H14FN5 02	363.1132	362.1022	[M + H]'
192	4-[4-(l,3-benzodioxol-5-yl)-2-methy 1-7/7pynOlo[2,3-i/]pyriniidin-5-yl]pyridine-2,6diamine	C19H16N6 02	360.1335	361.1420	[M + H]⁺
193	4-(2-methyl-4-{[2-(trifluoromethyl) phenoxy] methyl }-7//-pyrrolo[2,3iflpyrimidin-5-yl)pyridin-2-amine	C20H16F3 N5 0	399.1307	398.1246	[M + H]'
194	4-{4-[(2-fluorophenyl)ethynyi]-2-methyl-7/7pynolo[2,3-i/]pyrimidin-5-yl}pyridin-2amine	C20H14FN5	343.1233	342.1116	[M + H]'

195	4-[2-methy 1-4-(5,6,7,8-tetrahydronaphthalen2-yl)-7//-pyiTolo[2,3-i/]pyrimidin-5yl]pyridin-2-amine	C22 H21 N5	355.1797	356.1805	[M + H]⁺
196	4-[4-(cyclopropylethynyl)-2-methyl-7//pyrrolo[2,3-ô/]pyrimidin-5-yl]pyridine-2,6diamine	C17H16N6	304.1436	305.1458	[M + H]⁺
197	4-{4-[(2-methoxyphenyl)ethynyl]-2-methyl7//-pyrrolo[2,3-6/]pyrimidin-5-yl}pyridin-2amine	C21 H17N5O	355.1433	356.1442	[M + H]⁺
198	4-[4-(cyclopropylethynyl)-2-methyl-7//pyiTolo[2,3-6/]pyrimidin-5-yl]pyridin-2-amine	C17H15N5	289.1327	288.1228	[M + H]'
199	4-(2-methyl-4-{3-[3-(piperidin-lyl)propoxy]phenyl}-7/7-pyrrolo[2,3cflpyrimidin-5-yl)pyridin-2-amine	C26 H30 N6 0	442.2481	443.2474	[M + H]⁺

200	4-(2-methyl-4-{3-[3-(4-methylpiperazin-lyl)propoxy]phenyl}-77/-pyrrolo[2,3- ^pyrimidin-5-yl)pyridin-2-amine	C26 H31 N7O	457.2590	456.2477	[M + H]'
201	4-{4-[3-(2-chloroethoxy)phenyl]-2-methyl7//-pyrrolo[2,3-d]pynmidin-5-yl}pyridin-2amine	C20H18C1 N5 O	379.1200	378.1140	[M + H]-
202	4-(2-methyl-4-{3-[2-(pyrrolidin-lyl)ethoxy]phenyl}-7//-pyrrolo[2,3if\|pyrimidin-5-yl)pyridin-2-amine	C24 H26 N6 O	414.2168	415.2165	[M + H]⁺
203	4-(4-{3-[2-(dimethylamino)ethoxy]phenyl}2-methyl-7//-pyrrolo[2,3-i/]pyrimidin-5yl)pyridin-2-amine	C22 H24 N6 O	388.2012	389.1996	[M + H]⁺
204	4-(2- methy 1 -4- {3 - [2-( morpho 1 i n-4yl)ethoxy]phenyl}-7//-pyrrolo[2,3e/]pyrimidin-5-yl)pyridin-2 -amine	C24 H26 N6 02	430.2117	431.2096	[M + H]⁺

Example 160 was prepared from Example 159 using method described in Préparation 5.

Example 188 was prepared from Example 187 using method described in Préparation 5.

Example 189 and 190 were prepared from Example 188 by préparative HPLC with a chiral stationary phase. Example 191 was prepared from

2-(7-fluoro-l,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane prepared from

-926-bromo-4-fluoro-l,3-benzodioxole following the procedure described in Préparation 14. Ή NMR (399 MHz, Chloroform-d) δ 7.18 (d, IH), 7.08 (s, IH), 6.05 (s, 2H), 1.35 (s, 12H).

General Procedure XIX

R3_, R'3 N H

General Procedure XX

G

General Procedure XXI

R3^„R'3 N H

CH₂u ^SnBu,

In General Procedures XIX, XX and XXI:

- Ri and R₂ are as defined in formula (I),

- R3 represents a hydrogen atom, a linear or branched (Ci-C6)alkyl group, 5 -(Co-Cô)alkylene-Cyi, -(Co-Cô)alkylene-Cyi-Cy_2> -(Co-C6)alkylene-Cyi-0-(Ci-C6)alkylene-

Cy2, it being understood that Cyi and Cy₂, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group, and R’3 represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, or R3 and R’3 form with the nitrogen atom carrying them a heterocycloalkyl or an 10 heteroaryl,

- G represents a group selected from the list of substituents defined in formula (I), it being understood that the phenyl may be substituted by from I to 4 independent G groups.

-94Example 206: 5-(2-aminopyrimidin-4-yl)-7V-(2,6-difluorobenzyl)-2-methyl-7/fpyrrolo[2,3-d]pyrimidin-4-amine

Step 1: 7-(benzenesulfonyl) -5 -bromo -4 -chloro -2 -methyl-7H-pyrrolo[2,3-d]pyrimidine

Starting from 4-chloro-2-methyl-7/7-pyrrolo[2,3-J]pyrimidine (1 g, 4.06 mmol) following 5 procedure described in Préparation 19, the desired product (1.264 g, 3.27 mmol, 81%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.31 (s, IH), 8.24 - 8.16 (m, 2H), 7.85 - 7.78 (m, IH), 7.73 - 7.65 (m, 2H), 2.69 (s, 3H).

LC/MS (method B): RT = 1.46 min; m/z = 387 [M+H]⁺

Step 2: 7-(benzenesulfonyl)-5-bromo-N-[(2,6-difluorophenyl)methyl]-2-methyl-7H-pyrrolo [2,3 -d]pyrimidin -4 -amine

Starting from the compound obtained in Step 1 (1.2 g, 3.10 mmol) and (2,6-difluorophenyl)methanamine (2 eq) following procedure described in Préparation 8, the desired product (1.410 g, 2.86 mmol, 92%) was obtained as a white solid.

LC/MS (method B): RT = 1.52 min; m/z = 493 [M+H]⁺

Step 3: 7-(benzenesulfonyl) -N-[(2,6-difluorophenyl)methyl] -2-methyl-5-(tetramethyl-l,3,2dioxaborolan -2 -yl)-7H-pyrrolo[2,3 -djpyrimidin -4-amine (Préparation 28)

To a solution of the compound obtained in Step 2 (1 g, 2.03 mmol) in THF (5 mL) was added bis(pinacolato)diboron (1.2 eq), KOAc (3 eq) and PdCh(PPh3)2 (10% wt). The 20 resulting mixture was degassed under Ni for 5 minutes before heated at 140 °C on a CEM microwave reactor for 1 hour. The reaction mixture was filtered through a plug of celite, washed with EtOAc. The organic layer was washed with brine, dried over MgSO₄ and conc. in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the desired product (0.675 g, 1.25 mmol, 62%) as a white solid. 25 LC/MS (method B): RT = 1.63 min; m/z = 541 [M+H]⁺

-95Step 4: 5-(2-aminopyrimidin-4-yl)-N-(2,6-difluorobenzyl)-2-methyl-7-(benzenesulfonyl)7H-pyrrolo[2,3-d]pyrimidin-4-amine

Starting from the compound obtained in Step 3 (0.915 g, 1.69 mmol) and 4-chloropyrimidin-2-amine (1.5 eq) following procedure described in Préparation 3, the 5 product (0.551 g, l .08 mmol, 64%) was obtained as a pale brown solid.

IH NMR (399 MHz, DMSO-d6) δ 10.79 (t, IH), 8.44 (s, IH), 8.29 (d, IH), 8.20 - 8.13 (m, 2H), 7.80 (m, IH), 7.65 (t, 2H), 7.40 - 7.24 (m, 2H), 7.01 (t, 2H), 6.70 (s, 2H), 4.90 (d, 2H), 2.38 (s, 3H).

LC/MS (method B): RT = 1.41 min; m/z = 508 [M+H]⁺

Step 5: 5-(2-aminopyrimidin-4-yl)-N-(2,6-difluorobenzyl)-2-methyl-7H-pyrrolo[2,3d]pyrimidin-4-amine

Starting from the compound obtained in Step 4 (0.551 g, 1.08 mmol) following procedure described in Préparation 20, the desired product (0.159 g, 0.432 mmol, 40%) was obtained as a pale orange solid.

IH NMR (399 MHz, DMSO-d6) δ 11.97 (s, IH), 10.63 (s, 1 H), 8.14 (d, IH), 8.04 (s, IH), 7.33 (m, IH), 7.12 (d, IH), 7.06 (q, 2H), 6.35 (s, 2H), 4.91 (d, 2H), 2.36 (s, 3H).

। LC/MS (method B): RT = 0.96 min; m/z = 368 [M+H]⁺

I

Example 208: 5-(2-aminopyrimidin-4-yl)-/V-(l,3-benzodioxol-4-ylmethyl)-2-methyl7J7-pyrrolo[2,3-</]pyrimidin-4-amine

Step 1: 7-(benzenesulfonyl)-5-bromo-4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine Starting from 4-chloro-2-methyl-7/7-pyrrolo[2,3-d]pyrimidine (1 g, 4.06 mmol) following procedure described in Préparation 19, the desired product (1.264 g, 3.27 mmol, 81%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.31 (s, IH), 8.24 - 8.16 (m, 2H), 7.85 - 7.78 (m, IH), 25 7.73 - 7.65 (m, 2H), 2.69 (s, 3H).

LC/MS (method B): RT = 1.46 min; m/z = 387 [M+H]⁺

-96Step 2: 7 -(benzenesulfonyl) -N-(1,3 -benzodioxol -4 -ylmethyl) -5 -bromo -2 -methyl -7Hpyrrolo[2,3 -d]pyrimidin -4 -amine

Starting from the compound obtained in Step 1 (0.5 g, 1.29 mmol) and l,3-benzodioxol-4-ylmethanamine (2 eq) following procedure described in Préparation 8, 5 the desired product (0.562 g, 1.12 mmol, 87%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.19 - 8.11 (m, 2H), 7.82 - 7.72 (m, 2H), 7.66 (dd, 2H), 7.10 (t, IH), 6.86 - 6.71 (m, 3H), 6.03 (s, 2H), 4.69 (d, 2H), 2.41 (s, 3H).

LC/MS (method B): RT = 1.52 min; m/z = 501 [M+H]⁺

Step 3: 7 -(benzenesulfonyl) -N-(1,3-benzodioxol -4-ylmethyl) -2-methyl-5-(tetramethyl 10 l,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Préparation 28)

To a solution of the compound obtained in Step 2 (0.25 g, 0.5 mmol) in THF (5 mL) was added bis(pinacolato)diboron (1.2 eq), KOAc (3 eq) and PdCh(PPh3)2 (10% wt). The resulting mixture was degassed under N2 for 5 minutes before heated at 140 °C on a CEM microwave reactor for 1 hour. The reaction mixture was filtered through a plug of celite, 15 washed with EtOAc. The organic layer was washed with brine, dried over MgSÛ4 and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (0.227 g, 0.414 mmol, 83%) as a white solid. LC/MS (method B): RT = 1.61 min; m/z = 549 [M+H]⁺

Step 4: 4 -[7 -(benzenesulfonyl) -4-[(1,3 -benzodioxol -4 -ylmethyl)amino] -2 -methyl-7H20 pyrrolo[2,3 -d]pyrimidin -5 -yl]pyrimidin -2 -amine

Starting from the compound obtained in Step 3 (227 mg, 0.414 mmol) and 4-chloropyrimidin-2-amine (1.5 eq) following procedure described in Préparation 3, the desired product (85 mg, 0.165 mmol, 40%) was obtained as a pale brow solid.

Ή NMR (399 MHz, DMSO-d6) δ 9.54 (s, 2H), 8.26 - 8.17 (m, 2H), 7.82 - 7.72 (m, IH), 25 7.72 - 7.64 (m, 3H), 7.54 (s, 2H), 6.80 - 6.63 (m, 3H), 6.51 (t, IH), 5.93 (s, 2H), 4.60 (d,

2H), 2.44 (s, 3H).

LC/MS (method B): RT = 1.44 min; m/z = 549 [M+H]⁺

-97Step 5: 5-(2-aminopyrimidin-4-yl)-N-(l,3-benzodioxol-4-ylmethyl)-2-methyl-7H-pyrrolo[2,3d]pyrimidin-4-amine

Starting from the compound obtained in Step 4 (85 mg, 0.165 mmol) following procedure described in Préparation 20, the desired product (25 mg, 0.066 mmol, 40%) was obtained 5 as a pale orange solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.00 (s, IH), 10.55 (t, IH), 8.14 (d, IH), 8.06 (d, IH),

7.13 (d, IH), 6.91 -6.72 (m, 3H), 6.22 (s, 2H), 6.03 (s, 2H), 4.81 (d, 2H), 2.37 (s, 3H).

LC/MS (method B): RT = 0.935 min; m/z = 376 [M+H]⁺

Example 210: 4-(4-(2,2-difluoro-l,3-benzodioxol-5-yl)-2-methyl-7Æ-pyrrolo[23-</] 10 pyrimidin-5-yl]pyrimidin-2-amine

Step 1: tert-butyl 4-(2,2-difluoro-l,3-benzodioxol-5-yl)-2-methyl-5-(4,4,5,5-tetramethyl

-1,3,2 -dioxaborolan -2 -yl) -7H-pyrrolo[2,3 -d]pyrimidine-7 -carboxylate

Starting from ZerZ-butyl

5-bromo-4-(2,2-difluoro-l,3-benzodioxol-5-yl)-2-methyl-7//-pyrrolo[2,3-7]pyrimidine-7-c 15 arboxylate (see Example 164, Step 2) (240 mg, 0.51 mmol) following procedure described in Préparation 28, the desired product (75 mg, 0.145 mmol, 28%) was obtained as a white solid.

LC/MS (method B): RT = 1.62 min; m/z = 516 [M+H]⁺

Step 2: 4-[4 -(2,2 -difluoro -1,3 -benzodioxol -5 -yl) -2 -methyl-7H-pyrrolo[2,3 -d]pyrimidin 20 5 -yl/pyrimidin -2 -amine

Starting from the compound obtained in Step 1 (75 mg, 0.145 mmol) and 4-chloropyrimidin-2-amine (1.5 eq) following procedure described in Préparation 18, the desired product (7 mg, 0.018 mmol, 13%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.52 (s, IH), 8.01 - 7.92 (m, 2H), 7.40 (d, IH), 7.32 25 (m, 1 H), 7.22 (dd, 1 H), 6.21 (d, 1 H), 6.10 (s, 2H), 2.72 (s, 3H).

LC/MS (method B): RT = 1.02 min; m/z = 383 [M+H]⁺

-98Example 211: 4-(4-(3,4-dihydroisoquinolin-2(l£0-yl)-2-ethynyl-7H-pyrrolo[2,3-d] pyrimidin-5-yl|pyrimidin-2-amine

Step 1: 2 -[7 -(benzenesulfonyl) -5 -bromo -2 -chloro-7H-pyrrolo[2,3 -d]pyritnidin -4 -yl]

-1,2,3,4 -tetrahydroisoquinol ine

Starting from 7-(benzenesulfonyl)-5-bromo-2,4-dichloro-7H-pynOlo[2,3-d]pyrimidine (prepared following procedure described in WO2007/042299) (0.875 g, 2.15 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.5 eq) following procedure described in Préparation 8, the desired product (1.044 g) was obtained as a pale yellow solid (purity around 80% by LC-MS). The compound was used without further purification.

LC/MS (method B): RT = 1.69 min; m/z = 505 [M+H]

Step 2: 1 -[7-(benzenesulfonyl)-2-chloro-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-7H-pyrrolo [2,3 -d]pyrimidin-5 -yl] ethan-1 -one (Préparation 29)

The compound obtained in Step 1 (0.52 g, 1.03 mmol), LiCI (2.5 eq), tetrakis(triphenylphosphine)palladium (0.1 eq) and tributyl(l-ethoxyvinyl)tin (1.2 eq) were 15 dissolved in 1,4-dioxane (10 mL) under N₂ at room température. The reaction mixture was stirred at 100 °C overnight under N₂. The reaction mixture was cooled to room température, 2N HCl (5 mL) solution was added and the reaction mixture stirred for 1 hour. The reaction mixture was diluted with sat. aq. NaHCOj (20 mL) solution and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over MgSÛ4 and 20 concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (0.448 g). Purity around 70% by LC-MS. The compound was used without further purification.

LC/MS (method B): RT = 1.55 min; m/z = 467 [M+H]⁺

Step 3: Potassium tertAi\Ay\à\methy\[2-(trifluoroboranyl)ethynyl]silane (Préparation 30) 25 To a solution of ter/-butyldimethyl[2-(tetramethyl-l,3,2-dioxaborolan-2-yl)ethynyl]silane (0.973 g, 3.65 mmol) in acetone (15 mL) was added a solution of potassium biflouride (4 eq) in water (5mL) at 0 °C and the suspension was allowed to warm to room température overnight. The reaction mixture was concentrated in vacuo and the residue was triturated

-99with warm acetone to give the product (0.705 g, 2.86 mmol) as a white solid which was used without further purification.

Ή NMR (399 MHz, DMSO-d6) δ 0.89 (s, 9H), 0.00 (s, 6H).

Step 4: 1 -[7 -(benzenesulfonyl) -2-[2-(tert-butyldimethylsilyl)ethynyl] -4-(l ,2,3,4-tetra hydroisoquinolin -2 -yl) -7H-pyrrolo[2,3 -d]pyrimidin -5 -yl] ethan -1 -one

Starting from the compound obtained in Step 2 (0.400 g, 0.86 mmol) and potassium tert-butyldimethyl[2-(trifluoroboranyl)ethynyl]silane (1.78 eq) following procedure described in Préparation 10, the desired product (0.220 g, 0.35 mmol, 45%) was obtained as yellow oil.

LC/MS (method B): RT = 1.75 min; m/z = 571 [M+H]⁺

Step 5.· 1 -[7-(benzenesulfonyl) -2 -[2 -(tert-butyldimethylsilyl)ethynyl] -4 -(1,2,3,4-tetrahydro isoquinolin -2 -yl) -7H-pyrrolo[2,3 -d]pyrimidin -5 -yl/ -3 -(dimethylamino)prop -2 -en -1 -one (Préparation 31)

To a solution of the compound obtained in Step 4 (0.220 g, 0.35 mmol) in DMF (5 mL) was added A,7V-dimethylformamide dimethyl acetal (6 eq) at room température under N₂. The reaction mixture was stirred at 90 °C for 3 hours. The mixture was cooled to room température, diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over MgSÜ4 and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the product (84 mg, 0.134 mmol, 35%) as a yellow oil.

LC/MS (method B): RT = 1.69 min; m/z = 626 [M+H]⁺

Step 6: 4-[4-(3,4-dihydroisoquinolin-2(lH)-yl)-2-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-5yl]pyrimidin-2-amine (Préparation 32)

To a solution ofthe compound obtained in Step 5 (84 mg, 0.134 mmol) in THF (3 mL) was added TBAF (IM in THF solution, 1.1 eq) at 0 °C under N₂. The reaction mixture was allowed to warm to room température over 1 hour. The mixture was diluted with DCM (10 mL), washed with sat. aq. NaHCOa solution, dried over MgSÜ4 and concentrated in vacuo. The residue was dissolved in butan-l-ol (3 mL), guanidine carbonate (1.5 eq) and sodium methoxide (4 eq) were added and the reaction mixture was stirred at 130 °C on a CEM

- ιοο microwave reactor for 30 minutes. The mixture was poured into water (10 mL) and DCM (10 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with 10% MeOH in DCM followed by préparative HPLC at pH = 4 to 5 afford the product (l.4 mg, 0.004 mmol, 3%) as a yellow solid.

Ή NMR (399 MHz, DMSO-zfe) δ 12.39 (s, IH), 8.13 (d, IH), 7.77 (s, IH), 7.18 - 7.06 (m, 3H), 7.02 - 6.94 (m, IH), 6.75 (d, IH), 6.54 (s, 2H), 4.56 (s, 2H), 4.05 (s, IH), 3.64 (t, 2H), 2.76 (t, 2H).

LC/MS (method B): RT = I.l3 min; m/z = 368 [M+H]⁺

Examples 205-212 in the following Table 5 were prepared by methods outlined in General Procedure XIX, XXI using appropriate commercially available boronate ester, amines and ethynyl. The compounds of Example 208,210,211 are also included.

Table 5: HRMS (TOF, ESI) data

Example	Structure	Mol Formula	Calcd Exact Mass	Found m/z	Adduct
205	5-(2-amino-6-methylpyrimidin-4-yl)-N-(2,6difluorobenzyl)-2-methyl-7//-pyrrolo[2,3i/]pyrimidin-4-amine	C19H17F2 N7	381.1513	382.1569	[M + H]⁺
206	5-(2-aminopyrimidin-4-yl)-7V-(2,6difluorobenzyl)-2-methyl-7//-pyrrolo[2,3- i/]pyrimidin-4-amine	C18H15F2 N7	367.1357	368.1413	[M + H]⁺

- ΙΟΙ -

207	4-(4-( 1 -benzothiophen-2-y l)-2-methy 1-7//pyrrolo[2,3-i/]pyrimidin-5-yl]pynmidin-2amine	C19H14N6S	358.1001	359.1020	(M + H]⁺
208	5-(2-aminopyrimidin-4-y 1)-7/-( 1,3benzodioxol-4-ylmethyl)-2-methy 1-7//pynolo[2,3-i/]pyrimidin-4-amine	C19H17N7 02	375.1444	374.1375	[M + H?
209	4-(4-( 1,3-benzodioxol-5-y l)-2-methy 1-7//pyrrolo[2,3-ô/]pyrimidin-5-yl]pyrimidin-2amine	C18H14N6 02	346.1178	347.1190	[M + H]⁺
210	4-(4-(2,2-difluoro-l, 3-benzodioxol-5-yl)-2methyl-7//-pyrrolo[2,3-6/\|pyrimidin-5yl]pyrimidin-2-amine	C18 H12F2 N6 02	382.0990	381.0912	[M + H]'
211	4-(4-(3,4-dihydroisoquinolin-2(l//)-yl)-2ethynyl-7//-pyrrolo[2,3-i7]pyrimidin-5yl]pyrimidin-2-amine	C21 H17N7	367.1545	366.1442	[M + H]-

- )02-

212

5-(6-aminopyrimidin-4-yl)-A^r-(2,6difluorobenzyl)-2-methyl-7//-pynOlo[2,3cZ]pyrimidin-4-amine

C18H15F2N7

367.1357

368.1376

[M + H]⁺

General Procedure XXII

- 103 General Procedure XXIII

RO OR

B

HO. .OH

PhSO2

General Procedure XXIV

RO CR 8

- 104 General Procedure XXV

General procedure XXVI

In General Procedures XXII to XXIV:

- Ri and R₂ are as defined in formula (I),

- R3 represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, -(Co-C6)alkylene-Cyi, -(Co-C6)alkylene-Cyi-Cy₂, -(Co-Cô)alkylene-Cyi-0-(Ci-C6)alkylene5 Cy₂, it being understood that Cyi and Cy₂, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group, and R’3 represents a hydrogen atom or a linear or branched (Ci-Cô)alkyl group, or R3 and R’3 form with the nitrogen atom carrying them a heterocycloalkyl or an heteroaryl,

- R4 represents a hydrogen atom, a linear or branched (Ci-C6)aikyl group or a cycloalkyl group,

- 105 -

Example 213: 3-(2-aminopyridin-4-yl)-A-(2,6-difluorobenzyl)-6-methyl-l//py rrolo [2,3-6] pyridin-4-amine

Step 1: N-[(2,6-difluorophenyl)methyl] -6-methyl-lH-pyrrolo[2,3-b]pyridin-4-amine (Préparation 33)

To a solution of 4-chloro-6-methyl-17f-pyrrolo[2,3-6]pyridine (0.5 g, 3 mmol) in MeCN (15 mL) was added 2,6-difluorobenzylamine (2 eq) and pTSA.HiO (2 eq) under N2 at room température. The reaction mixture was heated at 150 °C in a CEM microwave reactor 10 for 4 hours. The mixture was diluted with sat. aq. NaHCO? (20 mL) solution and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over MgSÛ4 and concentrated in vacuo. The residue was purified via flash chromatography using MeOH and DCM as eluent to give the product (0.521 g, 1.90 mmol, 63%) as yellow solid.

Ή NMR (399 MHz, DMSO-d6) δ 10.96 (s, IH), 7.43 (tt, IH), 7.20 - 7.08 (m, 2H), 6.95 (d, IH), 6.77 (t, IH), 6.53 (d, IH), 6.15 (s, IH), 4.44 (d, 2H), 2.35 (s, 3H).

LC/MS (method A): RT = 1.82 min; m/z = 274 [M+H]⁺

Step 2: tert-butyl 3-bromo-4-{[(2,6-difluorophenyl)methyl]amino}-6-methyl-lH-pyrrolo [2,3 -b]pyridine -1 -carboxylate

Starting from the compound obtained in Step 1 (0.415 g, 1.51 mmol) following procedure described in Préparation 17, the desired product (0.280 g, 0.61 mmol, 40%) was obtained as a solid.

‘H NMR (399 MHz, Chloroform-d) δ 7.36 (s, IH), 7.33 - 7.23 (m, IH), 6.95 (t, 2H), 6.46 (s, IH), 6.20 (d, IH), 4.57 (d, 2H), 2.59 (s, 3H), 1.65 (s, 10H).

LC/MS (method A): RT = 2.53 min; m/z = 452 [M+H]⁺

Step 3: tert-butyl 3-(2-aminopyridin-4-yl)-4-{[(2,6-difluorophenyl)methyl]amino}-6-methyl -lH-pyrrolo[2,3 -b]pyridine -1 -carboxylate

Starting from the compound obtained in Step 2 (0.280 g, 0.61 mmol) and /er/-butyl Æ-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.4 eq) following

- I06- procedure described in Préparation 3, the desired product (0.154 g, 0.33 mmol, 53%) was obtained as an off-white solid.

LC/MS (method B): RT = 0.99 min; m/z = 466 [M+H]⁺

Step 4: 3-(2-aminopyridin-4-yl)-N-(2,6-difluorobenzyl)-6-methyl-lH-pyrrolo[2,3-b] 5 pyridin-4-amine

Starting from the compound obtained in Step 3 (0.I54 g, 0.33 mmol) following procedure described in Préparation 7, the product (O.llO g, 0.30 mmol, 91%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 11.43 (s, IH), 7.85 (d, IH), 7.42 (tt, IH), 7.20 - 7.07 10 (m, 3H), 6.51 - 6.43 (m, 2H), 6.29 (s, IH), 5.89 (s, 2H), 5.23 (t, IH), 4.49 (d, 2H), 2.39 (s,

3H).

LC/MS (method A): RT = 1.58 min; m/z 366 [M+H]⁺

Example 214: 4-[4-(5-fluoropyridin-3-yl)-6-methyl-lH-pyrrolo[2,3-6]pyridin-3-yl] pyridin-2-amine

Step 1: l-(benzenesulfonyl)-3-bromo-4-chloro-6-methyl-lH-pyrrolo[2,3-b]pyridine Starting from 4-chloro-6-methyl-l/7-pyrrolo[2,3-6]pyridine (0.713 g, 4.27 mmol) following procedure described in Préparation 19, the desired product (0.493 g, 1.28 mmol, 30%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.21 - 8.13 (m, 3H), 7.81 - 7.72 (m, IH), 7.70 - 7.62 20 (m, 2H), 7.41 (s, IH), 2.56 (s, 3H).

LC/MS (method B): RT = 1.52 min; m/z = 386 [M+H]⁺

Step 2: 4-[l -(benzenesulfonyl) -4 -chloro -6 -methyi-1 H-pyrrolo[2,3 -b]pyridin -3 -yl] pyridin -2 -amine

Starting from the compound obtained in Step 1 (0.493 g, 1.28 mmol) and

4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.4 eq) following procedure described in Préparation 3, the desired product (0.200 g, 0.501 mmol, 39%) was obtained as a pale yellow solid.

-107-

Ή NMR (399 MHz, DMSO-d6) δ 8.27 - 8.17 (m, 2H), 8.00 - 7.91 (m, 2H), 7.81 - 7.63 (m, 3H), 7.38 (s, IH), 6.64 (dd, IH), 6.57 (d, IH), 5.99 (s, 2H), 2.57 (s, 3H).

LC/MS (method B): RT = 1.13 min; m/z = 399 [M+H]⁺

Step 3: 4-[l -(benzenesulfonyl) -4 -(5 -fluoropyridin -3 -yl)-6-methyl-lH-pyrrolo[2,3-b] pyridin -3 -ylJpyridin -2 -amine

Starting from the compound obtained in Step 2 (0.133 g, 0.33 mmol) and (5-fluoropyridin-3-yl)boronic acid (1.1 eq) following procedure described in Préparation 3, the product (97 mg, 0.211 mmol, 63%) was obtained as a pale brown solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.48 (d, IH), 8.31 - 8.23 (m, 2H), 8.19 (t, IH), 7.97 (s,

IH), 7.82 - 7.73 (m, IH), 7.73 - 7.63 (m, 2H), 7.62 - 7.44 (m, 4H), 7.33 (s, IH), 6.16 (m, IH), 5.89 (dd, IH), 5.77 (s, 2H), 2.65 (s, 3H).

LC/MS (method B): RT = 1.1 min; m/z = 460 [M+H]⁺

Step 4: 4-[4-(5 -fluoropyridin -3 -yl) -6 -methyl -lH-pyrrolo[2,3-b]pyridin -3 -yl]pyridin -2 amine

Starting from the compound obtained in Step 3 (97 mg, 0.211 mmol) following procedure described in Préparation 20, the desired product (20 mg, 0.06 mmol, 30%) was obtained as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.06 (s, IH), 8.49 (d, IH), 8.26 (d, IH), 7.63 (s, IH), 7.56 - 7.46 (m, 2H), 7.10 (s, IH), 6.08 (d, IH), 5.87 (dd, IH), 5.62 (s, 2H), 2.61 (s, 3H).

LC/MS (method A): RT = 1.67 min; m/z = 320 [M+H]⁺

Example 215: 4-[6-(cyclopropylethynyl)-4-(2,3-dihydro-l,4-benzodioxin-6-yl)-lZfpyrrolo[2,3-ô]pyridin-3-yl]pyridin-2-amine

Step 1:1 -benzoyl-4-chloro-6-(cyclopropylethynyl)-lH-pyrrolo[2,3-b]pyridine

Starting from l-benzoyl-6-bromo-4-chloro-l/7-pyrrolo[2,3-ô]pyridine (prepared following 25 procedure described on WO2009/087225) (1.12g, 3.72 mmol) and ethynylcyclopropane (3 eq) following procedure described in Préparation 27, the desired product (1.053 g, 3.28 mmol, 88%) was obtained as a pale brown solid.

LC/MS (method B): RT = 1.52 min; m/z = 321 [M+H]⁺

- 108 -

Step 2: 6-(cyclopropylethynyl)-4-(2,3 -dihydro -1,4 -benzodioxin -6 -yl) -1 H-pyrrolo[2,3-b] pyridine

Starting from the compound obtained in Step 1 (0.5 g, 1.56 mmol) and (2,3-dihydro-l,4-benzodioxin-6-yl)boronic acid (1.2 eq) following procedure described in 5 Préparation 3, the desired product (0.234 g, 0.74 mmol, 47%) was obtained as a brown solid.

LC/MS (method B): RT = 1.35 min; m/z = 316 [M+H]⁺

Step 3: tert-butyl 3-bromo-6-(cyclopropylethynyl)-4-(2,3-dihydro-l,4-benzodioxin-6-yl) -lH-pyrrolo[2,3 -b]pyridine -1 -carboxylate

Starting from the compound obtained in Step 2 (0.234 g, 0.74 mmol) following procedure described in Préparation 17, the desired product (0.326 g, 0.658 mmol, 89%) was obtained as a pale yellow solid.

LC/MS (method B): RT = 1.7 min; m/z = 497 [M+H]⁺

Step 4: tert-butyl 3-(2-{[(tert-butoxy)carbonyl]amino}pyridin-4-yl)-6-(cyclopropyl 15 ethynyl)-4 -(2,3 -dihydro -1,4 -benzodioxin -6 -yl) -lH-pyrrolo[2,3 -b]pyridine -1 -carboxylate

Starting from the compound obtained in Step 3 (0.326 g, 0.658 mmol) and tert-butyl 7V-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.1 eq) following procedure described in Préparation 3, the desired product (0.211 g, 0.347 mmol, 53%) was obtained as a pale yellow solid.

LC/MS (method A): RT = 3.05 min; m/z = 609 [M+H]⁺

Step 5: 4 -[6-(cyclopropylethynyl) -4-(2,3 -dihydro -1,4 -benzodioxin -6 -yl) -IH-pyrrolo

[2,3-b]pyridin -3 -yl]pyridin -2 -amine

Starting from the compound obtained in Step 4 (0.211 g, 0.347 mmol) following procedure described in Préparation 7, the desired product (54 mg, 0.132 mmol, 38%) was obtained 25 as a white solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.08 (s, IH), 7.72 (s, IH), 7.50 (d, IH), 7.07 (s, IH), 6.73 - 6.60 (m, 3H), 6.05 (m, IH), 5.89 (dd, IH), 5.52 (s, 2H), 4.20 (ddd, 4H), 1.60 (tt, IH), 0.98 - 0.87 (m, 2H), 0.87 - 0.76 (m, 2H).

- 109LC/MS (method A): RT = 2.16; m/z = 409 [M+H]⁺

Example 216: 3-(2-aminopyridin-4-yl)-6-(cyclopropylethynyl)-7V-(2,6-difluorobenzyl)l//-pyrrolo[2,3-6]pyridin-4-amine

Step 1: 4-chloro-6-(cyclopropylethynyl)-lH-pyrrolo[2,3-b]pyridine (Préparation 34)

To a solution of l-benzoyl-6-bromo-4-chloro-lH-pyrrolo[2,3-è]pyridine (prepared following procedure described in WO2009/087225) (1.52 g, 4.54 mmol) in EtsN (15 ml) and THF (3 mL) was added ethynylcyclopropane (3 eq) and Cul (0.3 eq) at room température. The solution was purged with N₂ for 5 minutes before adding Pd(PPh3)2Ch (0.3 eq) and the reaction mixture was stirred at room température overnight. Water (1 mL) 10 was added to the reaction mixture and heated at 80 °C on CEM microwave reactor for 1 hour. The mixture was diluted with water (20 mL) and DCM (20 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified via flash chromatography using MeOH and DCM as eluent followed by trituration with isohexane to give the product (0.652 g, 3 mmol, 66%) as an off-white 15 solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.04 (s, IH), 7.65 (d, IH), 7.24 (s, IH), 6.50 (d, IH), 1.59 (tt, IH), 1.01-0.85 (m, 2H), 0.89-0.72 (m, 2H).

LC/MS (method B): RT = 1.31 min; m/z = 217 [M+H]⁺

Step 2: 6 -(cyclopropylethynyl) -N-[(2,6 -difluorophenyl)methyl] -1H-pyrrolo [2,3-b] pyridin-4-amine ( Préparation 35)

The compound obtained in Step 1 (0.3 g, 1.38 mmol), 2,6-difluorobenzylamine (1.2 eq), BrettPhos (0.01 eq) and BrettPhos precatalyst (0.01 eq) were added into a microwave vial. The vial was sealed with a teflon screw-cap, then evacuated and backfilled with N2. LiHMDS (IM solution in THF, 2 eq) was added at room température under N2. The 25 reaction mixture was heated at 65 °C in a CEM microwave reactor for 4 hours. The reaction mixture was quenched with IN HCl (2 mL) solution and diluted with DCM (50 mL). The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified via flash chromatography using MeOH and DCM as eluent to give the product (0.429 g, 1.32 mmol, 96%) as a pale brown solid.

- IIO-

Ή NMR (399 MHz, DMSO-d6) δ 11.13 (t, IH), 7.43 (tt, IH), 7.20 - 7.06 (m, 3H), 6.94 (t, IH), 6.59 (dd, IH), 6.33 (s, IH), 4.44 (d, 2H), 1.53 (tt, IH), 0.96 - 0.81 (m, 2H), 0.80 0.66 (m, 2H).

LC/MS (method B): RT = 1.12 min; m/z = 324 [M+H]⁺

Step 3: tert-butyl 3-bromo-6-(cyclopropylethynyl)-4-{[(2,6-difluorophenyl)methyl] amino} -lH-pyrrolo[2,3 -b]pyridine -1 -carboxylate

Starting from the compound obtained in Step 2 (0.429 g, 1.32 mmol) following procedure described in Préparation 17, the desired product (0.463 g, 0.921 mmol, 69%) was obtained as an off-white solid.

Ή NMR (399 MHz, Chloroform-d) δ 7.42 (s, IH), 7.29 (m, IH), 7.01 - 6.92 (m, 2H), 6.69 (s, IH), 6.19 (t, IH), 4.56 (d, 2H), 1.64 (s, 9H), 1.50 (m, IH), 1.00 - 0.86 (m, 4H).

LC/MS (method B): RT = 1.61 min; m/z = 502 [M+H]⁺

Step 4: tert-butyl 3-(2-{[(tert-butoxy)carbonyl]amino}pyridin-4-yl)-6-(cyclopropyl ethynyl) -4 -{[(2,6-difluorophenyl)methyl]amino}-! H -pyrrolo[2,3 -b]pyridine-1 -carboxylate

Starting from the compound obtained in Step 3 (0.463 g, 0.921 mmol) and ZerZ-butyl Æ-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.1 eq) following procedure described in Préparation 3, the desired product (0.233 g, 0.378 mmol, 41%) was obtained as a pale yellow solid.

Ή NMR (399 MHz, Chloroform-d) δ 8.25 - 8.19 (m, IH), 8.06 (d, IH), 7.48 (s, IH), 7.42 20 (s, IH), 7.27 - 7.21 (m, IH), 7.02 (dd, IH), 6.95 - 6.85 (m, 2H), 6.72 (s, IH), 4.86 (t, IH),

4.45 (d, 2H), 1.67 (s, 9H), 1.55 (s, 9H), 1.53 - 1.48 (m, IH), 0.97-0.82 (m, 4H).

LC/MS (method B): RT = 1.64 min; m/z = 616 [M+H]⁺

Step 5: 3-(2-aminopyridin-4-yl)-6-(cyclopropylethynyl)-N-(2,6-difluorobenzyl)-lHpyrrolo[2,3-b]pyridin-4-amine

Starting from the compound obtained in Step 4 (0.233 g, 0.378 mmol) following procedure described in Préparation 7, the desired product (88 mg, 0.211 mmol, 56%) was obtained as a white solid.

- 111 Ή NMR (399 MHz, DMSO-d6) δ l l.6l (s, IH), 7.85 (d, IH), 7.48 - 7.36 (m, IH), 7.32 (s, IH), 7.14 (t, 2H), 6.50 - 6.42 (m, 3H), 5.91 (s, 2H), 5.31 (t, IH), 4.48 (d, 2H), 1.56 (tt, IH), 0.91 (m, 2H), 0.80 - 0.71 (m, 2H).

LC/MS (method B): RT = 1.09 min; m/z = 416 [M+H]⁺

Example 223: 3-(2-aminopyridin-4-yl)-4-(l,3-benzodioxol-5-yl)-lZf-pyrrolo[2,3-/>] pyridine-6-carbonitrile

Step 1: 4-(1,3-benzodioxol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

Starting from 4-chloro-lJf-pyrrolo[2,3-à]pyridine-6-carbonitrile (prepared from Synthesis, 2008, (2), 201-204) (100 mg, 0.56 mmol) and (l,3-benzodioxol-5-yl)boronic acid (1.1 eq) following procedure described in Préparation 3, the desired product (84 mg, 0.32 mmol, 57%) was obtained as a yellow solid.

Ή NMR (399 MHz, DMSO-d6) δ 12.38 (s, IH), 7.93 - 7.82 (m, IH), 7.75 (s, IH), 7.43 7.31 (m, 2H), 7.12 (d, IH), 6.78 (dd, IH), 6.14 (s, 2H).

LC/MS (method B): RT = 1.23 min; m/z = 264 [M+H]⁺

Step 2: tert-butyl 4-(l,3-benzodioxol-5-yl)-3-bromo-6-cyano-lH-pyrrolo[2,3-b] pyridine -1 -carboxylate

Starting from the compound obtained in Step 1 (0.289 g, 1.1 mmol) following procedure described in Préparation 17, the desired product (0.373 g, 0.84 mmol, 77%) was obtained as a yellow solid.

Ή NMR (399 MHz, DMSO-d6) δ 8.33 (s, IH), 7.87 (s, 1 H), 7.14 - 7.04 (m, 2H), 6.98 (dd, IH), 6.14 (s, 2H), 1.64 (s, 9H).

Step 3: 3 -(2 -aminopyridin -4 -yl) -4-(1,3 -benzodioxol-5 -yl) -1H-pyrrolo [2,3 -b]pyridine -6 carbonitrile

Starting from the compound obtained in Step 2 (0.180 g, 0.41 mmol) and rerr-butyl

7V-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.1 eq) following procedure described in Préparation 3. The crude reaction mixture was concentrated in vacuo and the residue dissolved in DCM (2mL) and TFA (1.5 mL) following procedure described in Préparation 7. The crude reaction mixture was concentrated in vacuo and the

- 112 residue was triturated with MeOH to give the product (49 mg, 0.137 mmol, 34%) as a TFA sait.

Ή NMR (399 MHz, DMSO-d6) δ 13.10 (d, 2H), 8.38 (d, IH), 7.79 (s, IH), 7.67 (t, 3H), 6.98 (d, IH), 6.85 (d, IH), 6.71 (dd, IH), 6.49 - 6.30 (m, 2H), 6.05 (s, 2H).

LC/MS (method B): RT = 0.97 min; m/z = 356 [M+H]⁺

Examples 213-225 in the following Table 6 were prepared by methods outlined in General Procedure XXII-XXVI using appropriate commercially available boronate ester, amines and ethynyl. The compounds of Example 213,214,215,216,223 are also included.

Table 6: HRMS (TOF, ESI) data

Example	Structure	Mol Formula	Calcd Exact Mass	Found m/z	Adduct
213	3-(2-aminopyridin-4-yl)-7V-(2,6-difluoro benzyl)-6-methyl-l//-pynOlo[2,3-Z>]pyridin4-amine	C20H17F2 N5	365.1452	366.1514	[M + H]⁺
214	4-[4-(5-fluoropyridin-3-yl)-6-methyl-l//pyrrolo[2,3-ô]pyridin-3-yl]pyridin-2-amine	C18H14FN5	319.1233	320.1299	[M + H]⁺
215	4-[6-(cyclopropylethyny 1)-4-(2,3-dihydro1,4-benzodioxin-6-yl)- l/7-pyrrolo[2,36]pyridin-3-yl]pyridin-2-amine	C25 H20 N4 02	408.1586	409.1618	[M + H]*

- 113 -

216	3-(2-aminopyridin-4-yl)-6-(cyclopropyl ethynyl)-A42,6-difluorobenzyl)-l/7pyrrolo[2,3-ô]pyridin-4-amine	C24H19F2N5	415.1609	416.1638	[M + H]⁺
217	4-[4-(2,3-dihydro-l,4-benzodioxin-6-yl)-6methyl-17/-pyrrolo[2,3-ô]pyridin-3- yl]pyridin-2-amine	C21 H18N4 02	358.1430	359.1428	[M + H]⁺
218	4-[4-( 1,3-benzodioxol-5-y l)-6(cyclopropylethynyl)-l//-pyrrolo[2,3- ô]pyridin-3-yl]pyridine-2,6-diamine	C24H19N5 02	409.1539	410.1570	[M + H]⁺
219	4- [4-( 1,3-benzodioxol-5-y l)-6(cyclopropylethynyl)-l//-pynOlo[2,3- ^]pyridin-3-yl]pyridin-2-amine	C24H18N4 02	394.1430	395.1430	[[M + H]⁺
220	4-[4-( 1,3-benzodioxol-5-y l)-6-ethy ny 1-1Hpyrrolo[2,3“ô]pyridin-3-yl]pyridin-2-amine	C21 H14N4 02	354.1117	355.1120	[M + H]⁺

- 114 -

221	4-(4-( 1,3-benzodioxol-5-y l)-6-ethy ny 1-1Hpyrrolo[2,3-ô]pyridin-3-yl]pyridine-2,6diamine	C21 H15N5 02	369.1226	368.1146	[M + H]’
222	4-(4-( l,3-benzodioxol-5-yl)-6-methyl- 1HpyrroIo[2,3-ô]pyridin-3-yl]pyridin-2-amine	C20H16N4 02	344.1273	343.1191	[M + H]'
223	3-(2-aminopyridin-4-y 1)-4-( 1,3-benzodioxol5-yl)-l//-pyrrolo[2,3-6]pyridine-6- carbonitrile	C20H13N5 02	355.1069	354.1014	[M + H]'
224	4-( 1,3-benzodioxol-5-y 1)-3-(2,6-diamino pyridin-4-yl)-l/7-pynOlo[2,3-ô]pyridine-6carbonitrile	C20H14N6 02	370.1178	371.1170	[M + H]⁺
225	4-[6-methyl-4-(4-methyI-3,4-dihydro-2//l,4-benzoxazin-6-y!)-l//-pyrrolo[2,3ô]pyridin-3-yl]pyridin-2-amine	C22 H21 N5 0	371.1746	372.1738	[M + H]⁺

- 115 -

PHARMACOLOGICAL STUDY

EXAMPLE A: Kinase TR-FRET assays

Inhibition of the enzymatic activity of human kinases was evaluated in a Time-Resolved Fluorescence Résonance Energy Transfer (TR-FRET) assay in 384-well reaction plates. In 5 this assay, full-length human kinases from Cama Biosciences - DYRKIA (NM_00l396, ref. 04-130; 2.0 ng/μΙ), DYRKIB (NM_0047l4, ref. 04-131; 1.2 ng/μΐ), CLKl (NM-001162407, ref. 04-126; 0.7 ng/μΐ), CDK9 (NM_001261, ref. 04-110; 0.9 ng/μΐ), or GSK3p (NM_001146156, ref. 04-141; 2.0 ng/μΐ) - were incubated for 40 minutes (DYRKIA and DYRKIB) or 100 minutes (CLKl, CDK9 and GSK3p) at room 10 température with ATP (Sigma A2383, 10 μΜ) and a t/Light™-labelled human Myelin

Basic Protein (MBP) peptide substrate (Perkin Elmer TRF0109, 100 nM) in a reaction buffer composed of 50 mM HEPES pH7.4, 1 mM EGTA, 10 mM MgCh, 2 mM DTT and 0.01% Tween20. Test compounds of the invention were added in reaction buffer at a range of concentrations from 0.1 nM to 30 μΜ. Following addition of EDTA (Sigma E7889, 10 15 mM) to stop the reaction, Europium-labelled mouse monoclonal antibody recognizing phospho-Thr232 in MBP (Perkin Elmer TRF0201, 1 nM) was added. After one hour, the reaction plates were read using a fluorescence reader (EnVision®, Perkin Elmer) at 620nm and 665 nm (excitation at 340 nm): when the Europium donor fluorophore is excited by light at 340 nm, an energy transfer (620 nm) to the accepter occurs, which will then émit light at 665 nm. The activity, and hence inhibition, of DYRKIA kinase activity is thus measured by the relative intensity of the emitted light. The IC50 was calculated from the concentration-activity curve as the concentration of the test compound required for 50% inhibition of kinase activity. The results are presented in Table 1.

EXAMPLE B: Kinase ADP assays

The activity of His-TEV-DYRKIA Kinase domain (aal27-485) was measured using the accumulation of ADP produced during the the phosphorylation of the peptide substrate Woodtide (Zinnsser Analytic) using ATP (Sigma Aldrich A7699). The enzyme reaction was conducted in assay buffer (pH 7.4), containing 15 mM Hepes; 20 mM NaCl; 1 mM EGTA; 10 mM MgC12; 0.02% Tween20 and 0.1 mg/ml Bovine-y-globulin. Test 30 compounds of the invention were added in reaction buffer in a range of concentrations for

- lieΙΟ minutes at 3O°C in the presence of20 nM DYRKIA enzyme, 40 μΜ peptide substrate and 20 μΜ ATP. Détection reagents (DiscoveRx 90-0083), ADP Hunter Plus Reagent A and then ADP Hunter Plus Reagent B were added. After a following 20 minutes incubation at 30°C, ADP Hunter Plus Stop Solution was added. The fluorescence intensity was 5 measured at 590nm. The ICso was calculated from the concentration-activity curve as the concentration of the test compound required for 50% inhibition of kinase activity. The results are presented in Table l.

EXAMPLE C: Cellular DYRKIA autophosphorvlation assay

On day 0, human U2-OS osteosarcoma cells were seeded in 12-well culture plates 10 (100,000 cells per well) and incubated at 37°C in the presence of 5% CO₂ in 1 ml McCoy's

5A (Modified) medium containing GlutaMAX™ (Gibco 36600), supplemented with 50 units/ml penicillin, 50 pg/ml streptomycin, 10 mM Hepes buffer, pH = 7.4, and 10% foetal calf sérum (FCS, Sigma F7524). On day 1, medium was replaced with 500 μ! Optimem medium containing GlutaMAX™ (Gibco 51985), 150 ng of a pcDNA3.1 plasmid 15 (Invitrogen) containing a sequence coding for full-length, wild-type human DYRKIA (NM_001396) with an HA tag, 0.3 % lipofectamine (Invitrogen 18324-020), and 0.6 % Plus reagent (Invitrogen Cat N°11514-015). After 5 hours, medium was replaced with 900 μΐ McCoy's 5A (Modified) medium containing GlutaMAX™ (Gibco 36600). On day 2, cells were exposed to a range of concentrations of the test compounds of the invention for 20 5 hours. Cells were then washed in phosphate-buffered saline solution and cell lysed in lysis buffer comprised of 150 mM NaCI, 20 mM Tris-HCI pH 7.4, 1% triton X-100, 1 mM EGTA, 1 mM EDTA and protease (1% v/v; 539134; Calbiochem) and phosphatase (1% v/v; 524625; Calbiochem) inhibitor cocktails (50 μΙ lysis buffer/well). The relative levels of phospho-Ser520-DYRKl A were assayed using either western blotting or the Mesoscale 25 ELISA platform. For analysis by western blot, lysâtes were diluted into Laemmli sample buffer (Bio-Rad) containing 5% v/v β-mecaptoethanol, heated for 5 min at 95°C, and resolved on Tris-glycine gels or NuPage Bis-Tris gels (Novex; Invitrogen). Biotinylated molecular weight standards (Cell Signaling Technology) were included in ail gels. Proteins were transferred to nitrocellulose membranes (Hybond, ECL; Amersham), which were 30 blocked in Tris-buffered saline / 0.1% tween 20 (TBST) containing 5% milk, and probed at 4°C ovemight with anti-phospho-Ser520-DYRKlA antibody (Eurogentec SE6974-75;

- 117 -

0.23 pg/ml in 5% BSA) or anti DYRKIA antibody (Abnova H00001859; 0.5 pg/ml in 5% milk). Peroxidase-conjugated secondary antibodies were diluted into 5% milk and applied to membranes for Ih at 20°C. Chemiluminescence détection was performed using the ECL plus western blotting détection kit (Amersham) and was recorded on ECL plus hyperfilm 5 (Amersham). Blots were scanned using the Bio-Rad GS-800 calibrated densitometer and quantitative analysis of western blots was performed using TotalLab software (Amersham). IC50 values for inhibition of phospho-Ser520-DYRKl A were calculated from dose-response curves plotting the ratio between phospho-Ser520-DYRKlA and total DYRKIA signais at each concentration. For analysis by Mesoscale ELISA, lysâtes were transferred to BSA-blocked ELISA plates with pre-bound anti-HA capture antibodies (Novus biological NB600-364; 15 pg/ml) for 1 hour with shaking at RT. Anti-phosphoSer520-DYRKlA antibody (Eurogentec SE6974-75; 2.3 - 3.0 mg/ml) and anti DYRKIA antibody (Abnova H00001859; 3 pg/ml) was then added for 1 hour at RT, followed by addition of Sulfa-TAG anti-rabbit détection antibody (ref MSD R32AB; 1 pg/ml) and

Sulfa-TAG anti-mouse détection antibody (ref MSD R32-AC-1; 1 pg/ml). After a further 1 hour, Read Buffer was added and plates were read on the Sector Imager 2400 (Mesoscale). IC50 values for inhibition of phospho-Ser520-DYRK!A were calculated from dose-response curves. The results showed that the compounds of the invention are powerful inhibitors of cellular DYRKIA Ser520 autophosphorylation. The results are presented in Table 1.

EXAMPLE D: Pharmacodynamie assay in tumor xenografts for inhibition of DYRKIA autophosphorylation

For pharmacodynamies studies of inhibition of DYRKIA autophosphorylation, female

SCID mice were injected subcutaneously with RS4;11 human acute lymphoblastic 25 leukemia cells. When tumors reached a size of 200 - 300 mm³, mice were randomized into homogeneous groups of 3 and given a single oral administration of the compounds of the invention at doses of up to 100 mg/kg. At various times after treatment, typically 2 hours and 6 hours, treated and control mice were sacrificed, tumors were excised and proteins were extracted in tissue lysis buffer comprised of 150 mM NaCl, 20 mM Tris-HCl pH 7.4, 30 1% triton X-100, 1 mM EGTA, 1 mM EDTA and protease (1% v/v; 539134; Calbiochem) and phosphatase (1% v/v; 524625; Calbiochem) inhibitor cocktails. The relative levels of

- ns- phospho-Ser520-DYRKIA were assayed using western blotting. For this, lysâtes were diluted into Laemmli sample buffer (Bio-Rad) containing 5% v/v β-mecaptoethanol, heated for 5 min at 95°C, and resolved on Tris-glycine gels or NuPage Bis-Tris gels (Novex; Invitrogen). Biotinylated molecular weight standards (Cell Signaling Technology) 5 were included in ail gels. Proteins were transferred to nitrocellulose membranes (Hybond,

ECL; Amersham), which were blocked in Tris-buffered saline / 0.1% tween 20 (TBST) containing 5% milk, and probed at 4°C ovemight with anti-phospho-Ser520-DYRKlA antibody (Eurogentec SE6974-75; 0.23 pg/ml in 5% BSA) or anti DYRKIA antibody (Abnova H00001859; 0.5 pg/ml in 5% milk). Peroxidase-conjugated secondary antibodies were diluted into 5% milk and applied to membranes for Ih at 20°C. Chemiluminescence détection was performed using the ECL plus western blotting détection kit (Amersham) and was recorded on ECL plus hyperfilm (Amersham). Blots were scanned using the BioRad GS-800 calibrated densitometer and quantitative analysis of western blots was performed using TotalLab software (Amersham). The percentage inhibition of phospho-

Ser520-DYRKlA as compared to the control tumors was calculated using the ratio between phospho-Ser520-DYRK!A and total DYRKIA signais at each dose. The results showed that the compounds of the invention are powerful inhibitors of tumor DYRKIA Ser520 autophosphorylation.

EXAMPLE E: Efficacy studies in tumor xenografts

For anti-tumor efficacy studies, female nude NCr nu/nu mice were injected subcutaneously with U87-MG human glioblastoma cells. When tumors reached a size of approximately 150 mm³, mice were randomized into homogeneous groups of 8 and treated orally with the compounds of the invention at doses of at doses of up to 200 mg/kg once daily for up to 3 weeks. Anti-tumor efficacy was monitored by at least twice-weekly measurement of tumor sizes using calipers, and body weights were recorded in order to document potential general toxicity. Percentage tumor growth inhibition (TGI) on a given day was calculated using the formula: (l-[RTV(treated)/RTV(untreated)])xlOO, where RTV = relative tumor volume on the given day versus start of treatment. The results showed that the compounds of the invention are powerful inhibitors of tumor growth.

- 119 Table 1: ICso of Dyrkl/Clkl inhibitor

	IC₅₀ (μΜ) DyrklA TR-FRET assay	ICso (μΜ) DyrklA ADP assay	IC₅o (μΜ) DyrkIB TR-FRET assay	ICso(pM)Clkl TR-FRET assay	IC₅₀ (μΜ) CDK9 TR-FRET assay	IC50 (μΜ) P-Ser520Dyrkl A -Cell assay
Example 1		0,047
Example 2	0,018	0,023	0,0222		4,41	0,48
Example 3		0,241
Example 4	0,0253	0,044	0,044		10
Example 5	0,0094	0,015	0,0005		10
Example 6		0,07
Example 7		0,039
Example 8		0,038
Example 9		0,06
Example 10		0,085
Example 11	0,0173	0,012	0,0132		10
Example 12		2,041
Example 13		1,373
Example 14		0,043
Example 15	0,0355	0,032	0,0143		10
Example 16	0,0149	0,011	0,0178	0,0328	10	0,1402
Example 17	0,009	0,006	0,0013	0,0166	1,8543	0,0093
Example 18	0,0151	0,012	0,0003	0,024	10	0,0663
Example 19		0,025
Example 20	0,0197	0,013
Example 21	0,0102	0,023	0,0091		3,7762
Example 22		0,018
Example 23		0,015
Example 24		0,066
Example 25	0,0031	0,012	0,0079	0,0177	10	0,036
Example 26		0,029
Example 27	0,0444	0,04	0,0522		10
Example 28		0,011

- 120 -

I	IC₅₀ (μΜ) DyrklA TR-FRET assay s	IC50 (μΜ) DyrklA ADP assays	Κ2₅₀(μΜ) DyrklB TR-FRET assays	IC₅₀^M)Clkl TR-FRET assays	IC50 (μΜ) CDK9 TR-FRET assays	IC_5Û (μΜ) P-Ser520Dyrk 1A -Cell assay
Example 29		0,062
Example 30		0,827
Example 31		1,068
Example 32	0,0056	0,015	0,0012		10	0,323
Example 33		0,165
Example 34		0,278
Example 35	0,0248	0,043	0,0094		10	0,8865
Example 36	0,0091	0,027	0,0062		5,5232	0,4857
Example 37	0,007	0,025	0,0005		10	0,358
Example 38		0,149
Example 39		0,084
Example 40		0,051
Exampie 41		0,158
Example 42		0,233
Example 43		0,278
Example 44		0,249
Example 45	0,2005	0,496			30	0,6864
Example 46		0,369
Example 47		0,372
Example 48	0,043	0,044			10	0,208
Example 49		0,127
Example 50		0,045
Example 51	0,0029	0,013			10	0,126
Example 52	0,0043	0,007	0,0027	0,0167	10	0,0232
Example 53	0,0233	0,021			10	0,2375
Example 54	0,0129	0,032			10	0,5105
Example 55	0,0102	0,009	0,0043	0,0157	1,3025	0,0058
Example 56	0,0114	0,012			2,5354	0,0117
Example 57	0,0026	0,015	0,0098	0,0233	8,0604	0,0497
Example 58	0,0215	0,01	0,0175	0,0245	10	0,0337
Example 59	0,0102	0,042	0,0191		10	0,2587

- I2l -

	ICso (μΜ) Dyrkl A TR-FRET assays	ICso (μΜ) Dyrkl A ADP assays	IC50 (μΜ) DyrklB TR-FRET assays	ICso(pM)Clkl TR-FRET assays	IC₅₀^M)CDK9 TR-FRET assays	IC₅₀ (μΜ) P-Ser520DyrklA -Cell assay
Example 60	0,003	0,011			10	0,0206
Example 61	0,0062	0,01	0,0029	0,0129	10	0,0115
Example 62	0,0186	0,008	0,0002	0,0162	10	0,021
Example 63	0,0107	0,014			10	0,0408
Example 64	0,0059	0,015	0,0093		10	0,2335
Example 65	0,0709	0,069			30	0,8984
Example 66	0,0107	0,045			10	0,3
Example 67		0,094
Example 68		0,059
Example 69	0,0016	0,006	0,0011		0,6478	0,0036
Example 70	0,0025	0,009	0,0015	0,0152	1,5031	0,027
Example 71	0,0051	0,008	0,0074	0,0237	10	0,031
Example 72	0,021	0,013			10	0,3
Example 73	0,0059	0,038			10	0,3
Example 74	0,0012	0,014		0,0184	10	0,1115
Example 75	0,0143	0,037			10	0,3
Example 76	0,0063	0,01	0,0005		10	0,0672
Example 77		0,057
Example 78	0,0013	0,01	0,0145	0,0293	10	0,0721
Example 79	0,0021	0,008	0,008		10	0,105
Example 80	0,0059	0,004	0,0106		10	0,0156
Example 81	0,0085	0,014	0,0141		10	0,1659
Example 82	0,001	0,045	0,0199		10
Example 83	0,0006	0,081	0,0404		10
Example 84		0,006				0,0097
Example 86		0,121
Example 87		1,939
Example 88		2,091
Example 89	0,0492	0,077			30
Example 90		10

- 122-

	ICso (μΜ) Dyrkl A TR-FRET assays	IC» (μΜ) DyrklA ADP assays	IC50 (μΜ) DyrklB TR-FRET assays	Ι0₅ο(μΜ)ΟΙ TR-FRET assays	1C_5O^M)CDK9 TR-FRET assays	IC₅₀ (μΜ) P-Ser520Dyrkl A -Cell assay
Example 91		0,038
Example 92		0,087
Example 93		0,176
Example 94	0,0077	0,019	0,0112	0,0378	3	0,1549
Example 95	0,0979	0,066			30	0,5344
Example 96	0,0023	0,009	0,0315	0,0151	3	0,0119
Example 97		0,063
Example 98		0,022		0,0241		0,1923
Example 99	0,0086	0,029	0,0293	0,0549	3	0,1921
Example 100		0,161
Example 101		0,034				0,3
Example 102		0,293
Example 103		0,694
Example 104	0,0081	0,015	0,0167	0,0225	3	0,1055
Example 105		0,121
Example 106		0,018		0,0171		0,1769
Example 107		0,666
Example 108	0,0027	0,009	0,0092	0,0283	3	0,0491
Example 109		0,524
Example 110		0,048
Example 111		0,013
Example 112		0,234
Example 113		0,114
Example 114		0,009		0,0162		0,006
Example 115	0,0031	0,005	0,0094	0,0172	3	0,0185
Example 116		0,005		0,0136		0,0009
Example 117	0,0059	0,01	0,0093	0,0195		0,0377
Example 118		0,011
Example 119	0,0066	0,02	0,0192	0,0828	3	0,2317
Example 120		0,115
Example 121		0,066

- 123 -

	ICso(gM) DyrklA TR-FRET assays	IC50 (μΜ) DyrklA ADP assays	ICso(gM)DyrklB TR-FRET assays	ICso(gM)Clkl TR-FRET assays	IC₅₀(pM) CDK9 TR-FRET assays	IC50 (μΜ) P-Ser520DyrklA -Cell assay
Example 122		0,05
Example 123		0,071		0,0615		0,3
Example 124		0,296
Example 125	0,053	0,073			3,72
Example 126		0,418
Example 127		0,011				0,0169
Example 128		0,009				0,0093
Example 129		0,072
Example 130		0,26
Example 131		0,6
Example 132	0,0338	0,122			30
Example 133		0,269
Example 134		0,848
Example 135		0,091
Example 136		0,169
Example 137		0,336
Example 138		0,407
Example 139		0,883
Example 140		1,223
Example 141		0,417
Example 142		0,512
Example 143		1,057
Example 144		0,545
Example 145		0,042				0,4706
Example 146		0,172
Example 147		0,17
Example 148	0,0042	0,007	0,0144	0,0303	10	0,0335
Example 149		0,734
Example 150	0,0034	0,74			1,1651
Example 151		0,028
Example 152		0,012				0,0101

- 124-

	1C₅o(rM) DyrklA TR-FRET assays	IC50 (μΜ) DyrklA ADP assays	lC₅o(pM) DyrklB TR-FRET assays	ICso^M)Clkl TR-FRET assays	ΐε₅ο(μΜ)σϋΚ9 TR-FRET assays	IC50 (μΜ) P-Ser520DyrklA -Cell assay
Example 153		0,011				0,0146
Example 154		0,013				0,053
Example 155		0,024				0,3
Example 156		0,029
Example 157		0,26
Example 158	0,0655	0,15			30
Example 159		0,012				0,0187
Example 160		0,184
Example 161	0,0091	0,028	0,0252	0,1222	3	0,1501
Example 162		0,014
Example 163		0,026		0,1041		0,1974
Example 164		0,015				0,0883
Example 165		0,301
Example 166		0,025		0,2476		0,1179
Example 167		0,015		0,042		0,0444
Example 168		0,01
Example 169		0,216
Example 170		1,824				0,3
Example 171		0,033
Example 172		0,037
Example 173	0,0045	0,013	0,0051	0,0334	3	0,0497
Example 174		0,07
Example 175		0,146
Example 176		0,196
Example 177		0,532
Example 178	0,0052	0,013	0,0141	0,1795	3	0,0782
Example 179	0,0031	0,014	0,0115	0,0425	10	0,0365
Example 180		0,079
Example 181		0,019				0,15
Example 182		0,013				0,0142
Example 183		0,006				0,029

- 125 -

	IC$o (μΜ) Dyrkl A TR-FRET assays	IC50 (μΜ) Dyrkl A ADP assays	IC₅₀ (μΜ) DyrklB TR-FRET assays	ICso(gM)Clkl TR-FRET assays	ΙΟ$₀(μΜ) CDK9 TR-FRET assays	ICso (μΜ) P-Ser520DyrklA -Cell assay
Example 184		0,012				0,0319
Example 185	0,0048	0,011	0,0158	0,0631	10	0,012
Exampie 186	0,0053	0,017	0,0211	0,0927	10	0,0855
Example 187	0,003	0,013	0,0081	0,0649	11,639	0,0342
Example 188		0,07
Example 189		0,062				0,3
Example 190		0,419
Example 191		0,006				0,0443
Example 192		0,008				0,048
Example 193		0,116
Example 194		0,007				0,017
Example 195		0,008				0,0071
Example 196		0,023				0,1715
Exampie 197		0,009
Exampie 198		0,017				0,1193
Example 199		0,148
Example 200		0,027
Example 201		0,012
Example 202		0,144
Example 203		0,155
Example 204		0,089
Example 205		0,055
Exampie 206	0,0071	0,008	0,0133	0,0238	10	0,0015
Exampie 207	0,0049	0,01	0,0181	0,0545	7,8293	0,0694
Example 208		0,01				0,0041
Example 209		0,032				0,1571
Example 210		0,05				0,3
Example 211		0,027
Example 212		0,009
Example 213	0,0026	0,008	0,0092	0,0172	3	0,057
Example 214		0,242

- 126-

	IC₅o (μΜ) Dyrkl A TR-FRET assay s	ICso(pM) Dyrkl A ADP assays	IC₅₀ (μΜ) DyrklB TR-FRET assays	IC₅o^M)Clkl TR-FRET assays	IC₅₀ (μΜ) CDK9 TR-FRET assays	Κ\)(μΜ) P-Ser520DyrklA-Cell assay
Example 215		0,019				0,1032
Example 216	0,0145	0,021	0,0219	0,1212	10	0,0807
Example 217	0,0027	0,01	0,0077	0,0261	10	0,0385
Example 218		0,015				0,0289
Example 219		0,019				0,0325
Example 220		0,034				0,1933
Example 221		0,016				0,1323
Example 222		0,008				0,0442
Example 223		0,043				0,3
Example 224		0,03				0,2249
Example 225		0,037

EXAMPLE F: Pharmaceutical composition: Tablets

1000 tablets containing a dose of 5 mg of a compound selected from Examples l to 225 5g

Wheat starch............................................................................................................ 20g

Maize starch............................................................................................................. 20g

Lactose..................................................................................................................... 30g

Magnésium stéarate................................................................................................. 2g

Silica........................................................................................................................ Ig

Hydroxypropylcellulose.......................................................................................... 2g

- 127-

Claims

L Compound of formula (I):

wherein:

♦ Ri and R₂, each independently of the other, represent a hydrogen atom, a halogen atom, -NR5R5 or a linear or branched (C j-C₆)alkyl group, ♦ W3 represents a linear or branched (Ci-Cô)alkoxy, -0-(Co-C6)alkylene-Cyi, -0-(Co-C6)alkylene-Cyi-Cy₂, -NR_aRb, -NR_a-(Co-C6)alkylene-Cyi, -NR_a-(Co-C₆)alkylene-Cy ] -Cy₂, -NR_a-(C₀-C₆)alkylene-Cy । -O-(C i -C₆)alky lene-Cy₂, -Cyi, -Cyi-(Co-C₆)alkylene-Cy_2> -Cyi-0-(Co-C₆)alkylene-Cy₂, -(C|-C₆)alkyleneCyi, -(C₂-C6)alkenylene-Cyi, -(C₂-C6)alkynylene-Cyi, -(Ci-Côjalkylene-O-Cyi, it being understood that the alkylene moieties defined hereinbefore may be linear or branched, ♦ W₄ represents a cyano group, a cycloalkyl group, a linear or branched (Cj-Côjalkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂Cô)alkynyl group optionally substituted by a cycloalkyl group, ♦ R5 and Rs’, each independently of the others, represent a hydrogen atom or a linear or branched (C]-C₆)alkyl group, ♦ R_a and Rb, each independently of the other, represent a hydrogen atom or a linear or branched (C]-C6)alkyl group, ♦ Ai and A₂, each independently of the other, represent CH or a nitrogen atom, ♦ Cyi and Cy₂, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group,

- 128 wherein:

- aryl means a phenyl, naphthyl, biphenyl or indenyl group,

- heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from l to 4 hetero

5 atoms selected from oxygen, sulphur and nitrogen,

- cycloalkyl means any mono- or bi-cyclic, non-aromatic, carbocyclic group containing from 3 to 11 ring members, which may include fused, bridged or spiro ring Systems,

- heterocycloalkyl means any mono- or bi-cyclic, non-aromatic, condensed or spiro

10 group composed of from 3 to 10 ring members and containing from l to 3 hetero atoms or groups selected from oxygen, sulphur, SO, SO2 and nitrogen, which may include fused, bridged or spiro ring Systems,

- “-(Co-C6)alkylene-“ refers either to a covalent bond (-Coalkylene-) or to an alkylene group containing l, 2, 3,4, 5 or 6 carbon atoms,

15 it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene to be substituted by from l to 4 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched (C2-Cô)alkenyl group, linear or branched (C2-Cô)alkynyl group, linear or branched (Ci-Cô)alkoxy optionally substituted by -NRcRd or by from l to 3 halogen atoms, linear or

20 branched (Ci-Cô)alkyl-S-, hydroxy, oxo (or A-oxide where appropriate), nitro, cyano, -C(O)-ORc, -C(O)-R_c, -O-C(O)-Rd, -C(O)-NRcRd, -NR_c-C(O)-Rd, -NRcRd, linear or branched (Ci-Cô)polyhaloalkyl, or halogen, it being understood that R_c and Rd independently of one another represent a hydrogen atom or a linear or branched (Ci-Cô)alkyl group,

25 to their enantiomers and diastereoisomers, and to addition salts thereof with a pharmaceutically acceptable acid or base.
2. Compound of formula (I) according to claim 1, wherein Ri represents a hydrogen and R2 a -NH2 group.

- I29-
3. Compound of formula (I) according to claim l or 2, wherein Ai represents a CH group.
4. Compound of formula (I) according to claim l or 2, wherein Ai represents a 5 nitrogen atom.
5. Compound of formula (I) according to one of claims l to 3, wherein A2 represents a nitrogen atom.
6, Compound of formula (I) according to one of claims l to 3, wherein A2 represents a CH group.

10
7. Compound of formula (I) according to claim 6, wherein A2 represents a CH group and Ai represents a CH group.
8, Compound of formula (I) according to one of claims l to 7, wherein W3 represents a linear or branched (Ci-Cô)alkoxy, -0-(Co-Cô)alkylene-Cyi, -0-(Co-C6)alkylene-Cyi-Cy2, -NRa-(Ci-C6)alkylene-Cyi-Cy2, -NRa-(Co-C6)alkylene-Cyi-0-(Ci-C6)alkylene-Cy2, 15 -Cyi-0-(Co-Cô)alkylene-Cy2, -(Ci-Cô)alkylene-Cyi, -(C2-C6)alkenylene-Cyi, -(C2-Cô)alkynylene-Cyi, -(Ci-Cô)alkylene-O-Cyi, it being understood that the alkylene moieties defined hereinbefore may be linear or branched.
9. Compound of formula (I) according to one of claims 1 to 7, wherein W3 represents a Cyi group selected from: 1,3-benzodioxolyl, l//-indolyl, phenyl, pyridinyl, 2,3-dihydro20 1,4-benzodioxinyl, 1-benzothiophenyl, 1-benzofuranyl, 3,4-dihydronaphthalenyl, 1,2,3,4tetrahydronaphthalenyl, 3,4-dihydro-2/f-l,4-benzoxazinyl, wherein the preceding groups are optionally substituted according to the définition of claim 1.
10. Compound of formula (I) according to one of claims 1 to 7, wherein W3 represents: (i) a -NRa-Cyi group, wherein Cyi represents a group selected from: phenyl, 2,3-dihydro25 1/7-indene and 1,2,3,4-tetrahydronaphthalene, wherein the preceding groups are optionally

- 130 substituted according to the définition of claim l; or (ii) a -NRa-(Ci-C6)alkylene-Cyi group, wherein Cyi represents a group selected from: phenyl, pyridinyl, furanyl, thiophenyl, l//-pyrazolyl, l,3-thiazolyl, l,2-oxazolyl, cyclohexyl, cyclopropyl and \Hindolyl, wherein the preceding groups are optionally substituted according to the définition of claim 1.
11. Compound of formula (I) according to one of daims 1 to 7, wherein W3 represents a -phenylene-(Co-Cô)alkylene-Cy2.
12. Compound of formula (I) according to one of daims 1 to 7, wherein W3 represents -O-(Ci-C6)alkylene-Cyi or -NR_a-(Ci-C6)alkylene-Cyi, wherein Cyi is a phenyl or a pyridinyl group, these latter group being optionally substituted by one or two groups selected from methoxy, methyl or halogen.
13. Compound of formula (I) according to one of daims 1 to 12, wherein W₄ groups are as follows: methyl ; propan-2-yl ; prop-l-en-2-yl ; ethenyl ; cyano ; ethynyl ; cyclopropyl ; cyclopropylethynyl.
14. Compound of formula (I) according to daim 13, wherein W₄ is a methyl group.
15. Compound of formula (I) according to claim 1, selected from the following group:

- 5-(2-aminopyridin-4-yl)-jV-(2-methoxybenzyl)-2-methyl-7//-pyrrolo[2,3J]pyrimidin-4-amine,

- 4-[2-methyl-4-(thiophen-3-ylmethoxy)-7//-pynOlo[2,3-J]pyrimidin-5-yl]pyridin-2amine,

- 5-(2-aminopyridin-4-yl)-7V-(2,6-dichlorobenzyl)-2-methyl-7//-pynOlo[2,37]pyrimidin-4-amine,

- 5-(2-aminopyridin-4-yl)-7V-(2,6-difluorobenzyl)-2-methyl-7//-pyrrolo[2,3d\ pyrim idin-4-am ine,

- 5-(2-aminopyridin-4-yl)-2-methyl-?/-(2-methylbenzyl)-7J7-pyrrolo[2,3J]pyrimidin-4-amine,

- I3l -

- 5-(2-aminopyridin-4-yl)-A42-chloro-6-fluorobenzyl)-2-methyl-7/Apyrrolo[2,3i7]pyrimidin-4-amine,

- 5-(2-aminopyridin-4-yl)-2-methyl-7V-[(3-methylpyridin-2-yl)methyl]-7/7pyrrolo[2,3-i/]pyrimidin-4-amine,

5 - 5-(2-aminopyridin-4-yl)-/V-[(3-fluoropyridin-2-yl)methyl]-2-methyl-7/7pyrrolo[2,3-i/]pyrimidin-4-amine, - 5-(2-aminopyrimidin-4-yl)-N-(2,6-difluorobenzyl)-2-methyl-7/7-pynOlo[2,3d]pyrimidin-4-amine, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically 10 acceptable acid or base.
16. Compound of formula (I) according to claim 1 which is 5-(2-aminopyridin-4-yl)-Æ(2,6-dichlorobenzyl)-2-methyl-7Jf-pynOlo[2,3-d]pyrimidin-4-amine.
17. Compound of formula (I) according to claim 1 which is 5-(2-aminopyridin-4-yl)-JV(2,6-difluorobenzyl)-2-methyl-7/f-pynOlo[2,3-i/]pyrimidin-4-amine.

15
18. Compound of formula (I) according to claim 1 which is 5-(2-aminopyridin-4-yl)-7V(2-chloro-6-fluorobenzyl)-2-methyl-7//-pyrrolo[2,3-<7]pyrimidin-4-amine.
19. Compound of formula (I) according to claim 1 which is 5-(2-aminopyridin-4-yl)-2methyl-7V-[(3-methylpyridin-2-yl)methyl]-7/7-pyrrolo[2,3-</]pyrimidin-4-amine.
20, Compound of formula (I) according to claim 1 which is 5-(2-aminopyridin-4-yl)-7V-

20 [(3-fluoropyridin-2-yl)methyl]-2-methyl-7Jf-pyrrolo[2,3-i/]pyrimidin-4-amine.
21. Compound of formula (I) according to claim 1 which is 5-(2-aminopyrimidin-4-yl)7V-(2,6-difluorobenzyl)-2-methyl-7//-pyrrolo[2,3-i/]pyrimidin-4-amine.

-13222» Process for the préparation of compounds of formula (I) according to claim l, which process is characterised in that there is used as starting material the compound of formula (II):

(H)

5 wherein T represents a halogen atom, a methane-sulfanyl group, a cycloalkyl group or a linear or branched (Ci-C6)alkyl group, and A₂ is as defined in formula (I), which compound is subjected to a nucleophilic substitution in the presence of an appropriate alcohol or amine dérivative, or subjected to coupling with an appropriate boronic acid dérivative,

10 to yield the compound of formula (III) :

(III) wherein T is as defined previously, A₂ and W3 are as defined in formula (I), which compound of formula (III) is either :

(ii) converted into its methanesulfonyl dérivative when T represents a

15 methanesulfanyl group, then reacted with NaCN and further subjected to coupling with an appropriate boronic acid dérivative, (iv) or directly subjected to coupling with an appropriate boronic acid dérivative, (v) or subjected to coupling with 4,4,4',4',5,5,5',5^,-octamethyl-2,2'-bi-l,3,2dioxaborolane to yield :

- 133-

(III') which compound of formula (ΙΙΓ) is further reacted with the appropriate halide, to yield compound of formula (IV) :

(iv)

5 wherein T’ represents represents a halogen atom, a cyano group, a cycloalkyl group or a linear or branched (Ci-Cô)alkyl group, and Ai, A2, Ri, R2 and W3 are as defîned in formula (I), which compound of formula (IV):

- may be subjected to coupling with an appropriate alkynyl (or alkenyl) boronic acid to dérivative or alkynyl (or alkenyl) (trifluoro)borate dérivative sait, when T’ represents a halogen atom, to yield the compounds of formula (I),

- 134- which compound of formula (I) may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique,

5 it being understood that, at any time considered appropriate in the course of the abovedescribed process, certain groups (hydroxy, amino...) of the reagents or intermediates of synthesis may be protected and then deprotected according to the requirements of synthesis.
23. Process for the préparation of compounds of formula (I) according to claim l, 10 which process is characterised in that there is used as starting material the compound of formula (II):

wherein W4 and A₂ are as defined in formula (I), which compound of formula (II) is subjected to coupling with an appropriate boronic acid

15 dérivative, to yield compound of formula (V):

I

wherein Ai, A2, Ri, R2, and W4 are as defined in formula (I), which compound of formula (V) is either subjected to a nucleophilic substitution, or subjected to a coupling reaction with an appropriate boronic acid dérivative, or subjected to a coupling with a compound of formula ----R₃ , wherein R3 represents a hydrogen

5 or Cyi, to yield the compounds of formula (I), which compound of formula (I) may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a lO conventional séparation technique, it being understood that, at any time considered appropriate in the course of the abovedescribed process, certain groups (hydroxy, amino...) of the reagents or intermediates of synthesis may be protected and then deprotected according to the requirements of synthesis.

15
24. Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 21, or an addition sait thereof with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients.

- 136 -
25. Pharmaceutical composition according to claim 24 for use in the treatment of cancer, neurodegenerative disorders or metabolic disorders.
26. Pharmaceutical composition for use according to claim 25, wherein the cancer is selected from acute megakaryoblastic leukaemia (AMK.L), acute lymphoblastic leukaemia (ALL), ovarian cancer, pancreatic cancer, gastrointestinal stromal tumours (GIST), osteosarcoma (OS), colorectal carcinoma (CRC), neuroblastoma and glioblastoma.
27. Pharmaceutical composition for use according to claim 25, wherein the neurodegenerative disorders are selected from Alzheimer’s, Parkinson’s and Huntington’s diseases, Down’s syndrome, mental retardation and motor defects.
28. Compound of formula (I) according to one of daims l to 21, or an addition sait thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancer, neurodegenerative disorders or metabolic disorders.
29. Use of a compound of formula (I) according to one of daims l to 21, or an addition sait thereof with a pharmaceutically acceptable acid or base, in the manufacture of a médicament intended for the treatment of cancer, neurodegenerative disorders or metabolic disorders.
30. Combination of a compound of formula (I) according to any one of daims l to 21 with an anticancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, protéasome inhibitors, kinase inhibitors, signaling pathway inhibitors, phosphatase inhibitors, apoptosis inducers and antibodies.
31. Pharmaceutical composition comprising a combination according to claim 30 in combination with one or more pharmaceutically acceptable excipients.
32. Combination according to claim 30 for use in the treatment of cancer.

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33. Use of a combination according to claim 30 in the manufacture of a médicament for use in the treatment of cancer.
34. Compound of formula (I) according to any one of claims l to 21 for use in in the treatment of cancer necessitating radiotherapy.
35. Use according to claim 32, wherein the cancer is selected from acute megakaryoblastic leukaemia (AMKL), acute lymphoblastic leukaemia (ALL), ovarian cancer, pancreatic cancer, gastrointestinal stromal tumours (GIST), osteosarcoma (OS), colorectal carcinoma (CRC), neuroblastoma and glioblastoma.