OA18645A

OA18645A - New imidazo[4,5-b]pyridine derivatives as dual DYRK1/CLK1 inhibitors.

Info

Publication number: OA18645A
Application number: OA1201800120
Authority: OA
Inventors: Michaël Frank BURBRIDGE; Nicolas Foloppe; David Walmsley; Francisco Humberto CRUZALEGUI; Melinda SIPOS; Csaba WÉBER; András Kotschy; Balázs BALINT
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 imidazo[4,5-b]pyridine derivatives, a process for their preparation and pharmaceutical compositions containing them compounds of formula (I): <img file="OA18645A_A0001.tif"/> wherein R 1 , R2, R3, R4, and R5 are as defined in the description.medicaments.

Description

NEW IMIDAZO[4,5-B]PYRIDINE DERIVATIVES AS DUAL DYRK1/CLK1 INHIBITORS

The présent invention relates to new imidazo[4,5-ô]pyridine dérivatives, to a process for 5 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 / CLK1 inhibitors in the treatment of cancer, neurodegenerative disorders and metabolic disorders.

In cancer, the dual-specificity tyrosine-phosphorylation-regulated kinases DYRK1A and DYRK1B 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 DYRK1A that are involved in this régulation of cancer progression and résistance to therapy include the transcription factors GLI1, 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].

DYRK1A 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 ]. DYRK1A, and also DYRK1B, 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. 201 l;10(l 1):2104-14; Jin et al, J Biol Chem. 2009;284(34):22916-25]. For example, DYRK1A activâtes the

I

-2DREAM multisubunit protein complex, which maintains cells in quiescence and protects against apoptosis [Litovchick et al, Genes Dev. 201l;25(8):801-13]. DYRK1B has been demonstrated to prevent cell-cycle exit in response to chemotherapy via phosphorylation of Cyclin DI [Zou et al, J Biol Chem. 2004;279(26):27790-8]. DYRK1B has also been 5 shown to protect against chemotherapy through a réduction in reactive oxygen species content [Hu et al, Genes Cancer. 2010; 1(8):803-811].

It is thus clear that the use of DYRKIA / DYRK1B 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 10 résistance.

The rôle of DYRKIA in neurological disorders is well established. DYRKIA is associated 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 15 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 microtubuleassociated protein TAU, leading to the formation of neurotoxic neurofibrillary tangles and neurodegeneration as seen in Alzheimer’s [Azorsa et al, BMC Genomics. 2010; 11:25]. DYRKIA also alters the splicing of TAU pre-mRNA leading to an imbalance between 20 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 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 25 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 function of the spliceosome complex [Fedorov et al, Chem Biol. 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

-3protein-encoding mRNAs. CLKl is known to regulate the activity of the spliceosome via 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 5 proteins. The alternative protein isoforms transcribed from the same gene will often hâve different activities and physiological fonctions. 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 10 cancer cells through the cell cycle [Wang et al, Cancer Res. 2008;68( 14):5628-38].

It is thus clear that the use of CLKl 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 CLKl has also been described to play a rôle in 15 neurodegenerative diseases, including Alzheimer’s and Parkinson’s, via phosphorylation of the SR proteins of the spliceosome [Jain et al, Curr Drug Targets. 2014; 15(5):539-50]. In the case of Alzheimer’s, CLKl 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. 20 2008;3:8].

It is thus clear that the use of CLKl 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 25 urgent need for compounds which potently inhibit the DYRK1 and CLKl kinases whilst not affecting other closely-related kinases. The DYRK1 and CLKl 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 30 cytotoxic therapy, and include hématologie toxicity (leukopenia and thrombocytopenia), 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 / CLKl

-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 1 and type 2 both involve deficiency of fonctional pancreatic insulinproducing beta cells. Restoring functional beta-cell mass is thus an important therapeutic 5 goal for these diseases which affect 380 million people worldwide. Recent studies hâve shown that DYRK1A inhibition promotes human beta-cell prolifération in vitro and in vivo and, following prolonged treatment, can increase glucose-dependent insulin sécrétion [Dirice et al, Diabètes. 2016;65(6): 1660-71; Wang et al, Nat Med. 2015;21(4):383-8]. These observations clearly suggest that the use of potent and sélective DYRKl A inhibitors 10 would offer a novel therapeutic approach for the treatment and/or prévention of metabolic disorders including diabètes and obesity.

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

(D wherein:

♦ R] represents a cyano group, a halogen atom, or a linear or branched (Ci-Cô)alkyl 15 group optionally substituted by from one to three halogen atoms, ♦ R₂ represents a hydrogen, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C2-Ce)alkenyl group, a linear or branched (C2-Cô)alkynyl group, Cyj, -(Ci-C6)alkylene-[O]_n-Cyi group, -(Ci-C6)alkenylene-[O]_n-Cyi group, -(Ci-Cô)alkylene-NR-Cyi group, -(Ci-Cé)alkylene-S-Cyi group, 20 -(Co-C6)alkylene-Cy2-Cyi group, or -Cy2-(Ci-C6)alkylene-Cyi group, it being

-5understood that the alkyl and alkylene moieties defined hereinbefore may be linear or branched, ♦ R represents a hydrogen or a linear or branched (Ci-Cô)aLkyl group, ♦ n is an integer equals to 0 or l, ♦ Rj represents a hydrogen atom, a halogen atom, -NR^Rj ,-NH-(Co-C6)alkylene-Cy3,

-NH-CO-(Co-C6)alkylene-Cy₃,-NH-CO-(Co-C₆)alkylene-0-Cy3, ♦ R4 and R5, each independently of the others, represent a hydrogen or a halogen atom, ♦ Re and R5’, each independently of the others, represent a hydrogen or a linear or branched (Ci-Ce)alkyl group, ♦ Cyi, Cy₂ and Cy3, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group, it being understood that:

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

- heteroaryl means any mono- or bi-cyclic group composed of from 5 to IO ring members, having at least one aromatic moiety and containing from l 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 l to 3 hetero atoms 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 to be substituted by from 1 to 4 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched (C₂-Cô)alkenyl group, 30 linear or branched (C₂-Cô)alkynyl group, linear or branched (Ci-Ce)alkoxy, linear or branched (Ci-Cejalkyl-S-, hydroxy, oxo (or /V-oxide where appropriate), nitro,

-6cyano, -C(O)-OR’, -C(O)-R’, -O-C(O)-R’, -C(O)-NR’R”, -NR’-C(O)-R”, -NR’R”, linear or branched (Ci-Côjpolyhaloalkyl, difluoromethoxy, trifluoromethoxy, or halogen, it being understood that R’ and R” independently of one another represent a hydrogen atom or a substituted 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 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, methanesulphonic acid, camphoric acid etc.

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

Advantageously, Ri represents a methyl or a cyano group.

In another embodiment of the invention, R4 and R5 each represent a hydrogen atom

Preferably, R3 represents a NH2 group.

Altematively, R3 represents a hydrogen atom.

In one embodiment, R2 represents a hydrogen, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C₂-Câ)alkenyl group, a linear or branched (C2-Ce)alkynyl group, -(Ci-Côjalkylene-O-Cyi group, -(Ci-C6)alkenylene-[O]_n-Cyi group, -(Ci-C₆)alkylene-NR-Cyi group, -(Ci-Cô)alkylene-S-Cyi group, -(Co-C6)alkylene-Cy₂-Cyi group, or -Cy2-(C2-C6)alkylene-Cyi group, it being understood that the alkyl and alkylene moieties defined hereinbefore may be linear or branched.

-7In another embodiment of the invention, R₂ represents Cy_l5 a -(Ci-Cô)alkylene-Cyi group, (Co-Cô)alkylene-Cy₂-Cyi group, or -Cy₂-(Ci-C6)alkylene-Cyi group. More preferably, R₂represents:

- a cycloalkyl group,

- or a-(Ci-Côjalkylene-cycloalkyl or a-(Cj-Cejalkylene-phenyl group,

- or a -cycloalkylene-phenyl group or a -cycloalkylene-(Ci-C6)alkylene-phenyl group, wherein the cycloalkyl, cycloalkylene and phenyl groups so defined can be optionally substituted according to the définitions mentioned previously. Halogens, methoxy and 10 methyl groups are the preferred substituents for the preceding groups.

In a third embodiment, R₂ represents a linear or branched (Ci-Céjalkyl group, wherein the alkyl group so defined can be optionally substituted according to the définitions mentioned previously. Halogens and CH3-S- are the preferred substituents for the alkyl group.

In a fourth embodiment, R₂ represents -(Ci-Ce)alkylene-O-Cyi group. More preferably, R₂ represents a -(Ci-Côjalkylene-O-pyridinyl group, wherein the pyridinyl group so defined can be optionally substituted according to the définitions mentioned previously. Halogens and linear or branched (Ci-Côjpolyhaloalkyl groups are the preferred substituents for the pyridinyl group.

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

- 4-[2-methyl-3-(3-phenylcyclobutyl)-3//-imidazo[4,5-6]pyridin-5-yl]pyridine-2,6diamine, • 4-[3-(3,3-difluorocyclobutyl)-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine,

- 4-(3- {2-[(6-fluoropyridin-2-yl)oxy]ethyl} -2-methyl-37/-imidazo[4,5-b]pyridin-5- yl)pyridine-2,6-diamine,

- 4-{3-[(lÆ,2Æ)-2-benzylcyclopropyl]-2-methyl-3/7-imidazo[4,5-b]pyridin-5yl} pyridine-2,6-diamine,

- 4-[3-(3-fluorocyclobutyl)-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl]pyridine-2,6diamine,

- 4-(3-hexyl-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine,

-8- 4-(3-cyclobutyl-2-methyl-3/7-imidazo[4,5-/>]pyridin-5-yl)pyridine-2,6-diamine,

- 4-[3-(2-{[6-(difluoromethyl)pyridin-2-yl]oxy}ethyl)-2-methyl-3//-imidazo[4,5ô]pyridin-5-yl]pyridine-2,6-diamine,

- 4-[3-(5-methoxy-2,3-dihydro-l/7-inden-2-yl)-2-methyl-3//-imidazo[4,5-ô]pyridin5-yl]pyridine-2,6-diamine,

- 4-(3-ethyl-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine,

- 4-[2-methyl-3-(2- {[6-(trifluoromethyl)pyridin-2-yl]oxy} ethyl)-3/7-imidazo[4,5Z>]pyridin-5-yl]pyridine-2,6-diamine,

- 4-{3-[2-(2-methoxycyclohexyl)ethyl]-2-methyl-3/7-imidazo[4,5-6]pyridin-5yl}pyridine-2,6-diamine,

- 4-(2-methyl-3-pentyl-3//-imidazo[4,5-à]pyridin-5-yl)pyridine-2,6-diamine,

- 4-(3-cyclohexyl-2-methyl-3/7-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine,

- 4-{2-methyl-3-[3-(methylsulfanyl)propyl]-3.W-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine, * 4- (3-[( lJ?,20)-2-benzylcyclopropyl]-2-methyl-3/7-imidazo[4,5-6]pyridin-5- yl} pyridiiie-2,6-diamine,

- 4- {2-methyl-3-[2-(2-methylphenyl)ethyl]-3/7-imidazo[4,5-6]pyridin-5-yl} pyridine-

2,6-diamine,

- 4-(3- {2-[(6-chloropyridin-2-yl)oxy]ethyl} -2-methyl-3/7-imidazo[4,5-ô]pyridin-5yl)pyridine-2,6-diamine,

- 4-(3- {(2/î)-2-[(6-fluoropyridin-2-yl)oxy]propyl} -2-methyl-3//-imidazo[4,5-

ό]pyrίdin-5-yl)pyridme-2,6-diamίne,

- 4-[2-methyl-3-(2,2,2-trifluoroethyl)-3Z7-irnidazo[4,5-ô]pyridin-5-yl]pyridine-2,6diamine,

- 3-cyclopentyl-5-(2,6-diaminopyridin-4-yl)-3/7-imidazo[4,5-à]pyridine-2carbonitrile,

- 4-(3-cyclopropyl-2-methyl-3/f-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

-9The invention relates also to a 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):

(U) wherein A represents a halogen atom, or a linear or branched (Ci-Ce)alkyl group optionally substituted by from one to three halogen atoms, X represent a halogen atom, and R₂ is as defined in formula (I), which compound of formula (II) is subjected to coupling with a compound of formula (III):

(ΠΙ) wherein:

- Rbi and Rb2 represent a hydrogen, a linear or branched (Ci-Cô) alkyl group, or Rbi and Rb2 form with the oxygen atoms carrying them an optionally methylated ring,

- Rbî represents a hydrogen or group NH₂,

- Ri and Rs are as defined in formula (I), to yield compound of formula (IV):

- lOA

wherein A represents a halogen atom, or a linear or branched (Ci-Cô)alkyl group optionally substituted by from one to three halogen atoms, Rbs represents a hydrogen or group NH₂, and R₂, R4 and Rs are as defîned in formula (I), which compound of formula (IV):

- may be reacted with Et₄NCN when A represents a halogen to yield the compounds of formula (I) wherein Ri=-CN, or

- may be subjected to an aromatic nucleophilic substitution when R₂ represents a linear or branched HO-(Ci-Ce)alkylene group, and/or

ÎO - may be subjected to an acylation in the presence of an acid dérivative, 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 15 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.

- 11 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 (ΙΓ):

wherein A’ represents a linear or branched (Ci-Cô)alkyl group optionally substituted by from one to three halogen atoms, and X represents a halogen atom, which compound of formula (ΙΓ) is subjected to coupling with a compound of formula (ΠΙ):

wherein:

- Rbj represents a hydrogen or group NH₂,

- R4 and R5 are as defined in formula (I), to yield compound of formula (IV’):

wherein:

- A’ represents a linear or branched (Ci-Côjalkyl group optionally substituted by from one to three halogen atoms,

- Rb3 represents a hydrogen or group NH₂,

- R4 and R5 are as defined in formula (1), which compound of formula (IV’) is :

A) either subjected to a nucleophilic substitution in the presence of a compound of formula R₂-NH₂, wherein R₂ is as defined in formula (I) to yield the compound of formula (V’) :

A'

- 13wherein:

- A’ represents a linear or branched (Ci-Cô)alkyl group optionally substituted by from one to three halogen atoms,

- Rb3 represents a hydrogen or group NH₂,

- R₂, R4 and R5 are as defined in formula (I), which compound of formula (V’) is submitted to an intramolecular reaction (ring closure) in acidic medium, to yield the compound of formula (I),

B) or converted into the corresponding imino sulfonate dérivative of formula (VI’):

A'

wherein:

- R is a linear or branched (Ci-Cô)alkyl group, an optionally substituted aryl, or a linear or branched polyhalogenated (Ci-Cejalkyl group,

- Rb3 represents a hydrogen or group NH₂,

- R4 and R5 are as defined in formula (I), which compound of formula (VI’) is further subjected to a nucleophilic substitution in the presence of a compound of formula R₂-NH₂, wherein R₂ is as defined in formula (I), to yield the compound of formula (Vif) :

wherein:

- Rbî represents a hydrogen or group NH₂,

- R₂, R4 and R5 are as defined in formula (I), which compound of formula (VII’) is submitted to an intramolecular organometallic coupling reaction, to yield the compound of formula (I) wherein the définition of R] is limited to the one of A’, 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 above15 described process, certain groups (hydroxy, amino...) of the reagents or intermediates of synthesis may be protected and then deprotected according to the requirements of synthesis.

- 15The compounds of formulae (II), (ΙΓ), (III) and the amine R2-NH2 are either commercially available or can be obtained by the person skilled in the art using conventional Chemical reactions described in the literature.

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

More especially, the compounds according to the invention will be usefiil in the treatment 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 cancer, pancreatic cancer, gastrointestinal stromal tumours (GIST), osteosarcoma (OS), colorectal carcinoma (CRC), neuroblastoma and glioblastoma.

In another embodiment, the compounds of the invention will usefiil 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.

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

Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parentéral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets

-16or 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 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, phosphatase inhibitors, apoptosis inducers and antibodies, and also to pharmaceutical compositions comprising that type of combination and their use in the manufacture of médicaments for use in the treatment of cancer.

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

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

List of abbreviations

Abbreviation

Ac

CDI

DCM

DME

DMF

Naine acetyl

1,1 -carbonyldiimidazole dichloromethane

1,2 -dimethoxyethane MA-Dimethylformamide

DMSO	dimethyl sulfoxide
eq. Et	équivalent ethyl
HPLC-MS	liquid chromatography-mass spectrometry
Me	methyl
ⁿBu	w-butyl
ⁿBuPAd₂	n-butyldiademantylphosphine
Ph	phenyl
PPh₃'Bu	triphenylphosphine iert-butyl
TEA	triethylamine
TFA	trifuoroacetic acid
THF	tetrahydrofùrane

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

General procedure I

Step A·.

eq. of the appropriate halide dérivative, 1.2 eq. teri-butyl N-[6-(terte butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2pyridyl]carbamate (Préparation 1) and 3 eq. K2CO3 were dissolved in 1,2dimethoxyethane-water 7:1 (8 mL/mmol). Then 0.05 eq. palladium acetate and 0.1 eq. BuPAd2 were added and the mixture was heated at 100°C under nitrogen in a microwave reactor until no further conversion was observed. Celite was added to the reaction mixture and the volatiles were evaporated under reduced pressure. The solid residue was purified via flash chromatography on silica gel using MeOH -containing 1% NH3- and DCM as eluents.

- 18Step B :

The product obtained in Step A was stirred in a mixture of DCM (5 mL/mmol) and TFA (5 mL/mmol) until no further conversion was observed. The volatiles were evaporated under reduced pressure, the solid residue was dissolved in ammonia solution (7N in methanol, 20 mL/mmol) and the volatiles were evaporated under reduced pressure again. The crude product was purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure II

Préparation 2a R'=Me for Examples 9-143 and Examples 149-155

Préparation 2b R*=Bu for Ex amples 144-147

Préparation 2c R'=Et for Examples 156-159

Préparation 2d R'=Pr for Examples 160-163

Step A:

1.0 eq. of the appropriate amide (Préparation 2a, Préparation 2b, Préparation 2c or Préparation 2d) and 5.0 eq. 2,6-lutidine were dissolved in dry DCM (0.10 M solution for Préparation 2). The DCM solution was cooled to 0°C under nitrogen and DCM solution 15 of 5.0 eq. nonafluorobutanesulfonic anhydride (1.5 M) was added dropwise. The reaction mixture was allowed to warm up to room température over 1 hour then 5 eq. of the appropriate amine was added in one portion and the mixture was stirred until no further conversion was observed. The DCM mixture was washed with water, dried over Na₂SO₄, concentrated under reduced pressure and purified via flash chromatography using 20 dichloromethane and methanolic ammonia as eluents to give the amidine intermediate.

Step B:

1. eq. amidine intermediate from Step A was dissolved in 1,2-dimethoxyethane (0.15 M solution). 0.2 eq. Pd(OAc)₂, 0.4 eq. PBuAd₂, and 2 eq. K3PO4 were added and the reaction mixture was stirred under nitrogen at 115°C in a microwave reactor until no further

- 19conversion was observed. The reaction mixture was concentrated under reduced pressure and purified via flash chromatography using dichloromethane and methanoiic ammonia as eluents to yield the appropriate Boc-protected example.

Step C:

Starting from the product of Step B following General procedure I Step B the appropriate example was obtained.

General procedure III

R=H Préparation 3a R=Me Préparation 3b

Step A:

To the solution of 1 eq. of Préparation 3a or Préparation 3b in dry DMF (0.25 M) under nitrogen 3 eq. sodium hydride was added and the resulting mixture was stirred at 0°C for 15 min. Following the addition of 2 eq. of the appropriate aryl halide the mixture was stirred at 50°C for 5 hours. If formation of the expected product was not observed by HPLC-MS at this point the reaction température was raised to 120 °C and stirring continued until no further conversion was observed. After cooling water was added to the reaction mixture and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous MgSO₄ and solvent was removed under reduced pressure. The crude product was purified by flash chromatography using DCM and MeOH as eluents to give the Boc-protected example.

Step B:

Starting from the product of Step A following General procedure I Step B the appropriate example was obtained.

-20General procedure IV

Step A:

l eq. ierz-butyi N-[6-(ier/-butoxycarbonylamino)-4-[3-(2-hydroxyethyl)-2-methyl5 imidazo[4,5-à]pyridin-5-yl]-2-pyridyl]carbamate (Préparation 3a), 2 eq. of the appropriate phénol dérivative, 2 eq. PPhj, and 2 eq. diierzbutyl azodicarboxylate was dissolved in THF (10 mL/mmol of Préparation 3a). and the mixture was stirred at 60°C until no further conversion was observed. Celite was added to the reaction mixture and the volatiles were evaporated under reduced pressure. The solid residue was purified via flash chromatography on silica gel using MeOH -containing 1% NH3- and DCM as eluents to give the appropriate Boc-protected example.

Step B:

General procedure V

CDI

Pd(PPh₃)₄, K₃PO₄

DME, H₂0,100°C

-2l -

Step A:

The mixture of 1 eq. 2,6-dibromo-3-nitro-pyridine, 3.2 eq. K2CO3, and 1.05 eq. of the appropriate amine in 1,2-dichloroethane (0.17 M for the bromopyridine) was stirred at 50°C until no further conversion was observed. Water was added to the mixture and the 5 aqueous phase was separated and extracted three times with DCM. The combined organic layers were dried over MgSO₄, solvent was removed under reduced pressure and the crude product was purified by flash chromatography using dichloromethane and methanol as eluents to give the appropriate 2-amino-3-nitro-6-bromopyridine.

Step B:

1 eq. of the appropriate 2-amino-3-nitro-6-bromopyridine, 5 eq. Fe powder and 0.2 eq.

NH₄C1 were stirred in a mixture of EtOH and water (3:1, 0.1M for 2-amino-3-nitro-6bromopyridine) at 90°C until no further conversion was observed. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure to give the appropriate 2,3-diamino-6-bromopyridine that was used without further purification.

Step C:

The mixture of 1 eq. of the appropriate 7V²-substituted 2,3-diamino-6-bromopyridine and 1.5 eq. CDI were stirred in dry THF (0.05M solution for 2,3-diamino-6-bromopyridine) until no further conversion was observed. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography using 20 dichloromethane and methanol as eluents to give the appropriate 5-bromo-2-oxo-lHimidazo[4,5-6]pyridine.

Step D:

The mixture of 1 eq. 3-substituted-5-bromo-2-oxo-l/f-imidazo[4,5-Z>]pyridine and POCI3 (5ml) was stirred at 108°C until no further conversion was observed. POC13 was removed 25 under reduced pressure. Dichloromethane and brine were added, organic phase was separated and the aqueous phase was extracted 2 times with dichloromethane. The combined organic layers were dried over MgSO₄, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography using dichloromethane and methanol as eluents to give the appropriate 3-substituted-5-bromo-230 chloro-imidazo[4,5-/>]pyridine.

-22Step E:

Starting from the appropriate 3-substituted-5-bromo-2-chIoro-imidazo[4,5-ô]pyridine and following the procedure described for Préparation 3a the the appropriate 3-substituted-5(2,6-bis(teri-butoxycarbamoyl)pyridin-4-yl)-2-chloro-imidazo[4,5-6]pyridine was obtained.

Step F:

The mixture of l eq. of the appropriate 3-substituted-5-(2,6-bis(tertbutoxycarbamoyl)pyridin-4-yl)-2-chloro-imidazo[4,5-à]pyridine and l .05 eq. tetraethylammonium cyanide was stirred in DMSO (0.03M solution for imidazopyridine) until no further conversion was observed. The reaction mixture was poured onto water, the solid was filtered off, and the aqueous phase was extracted with chloroform. The organic layers were combined, dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography using dichloromethane and ethyl acetate as eluents to give the appropriate 3-substituted-5-(2,6bis(ieri-butoxycarbamoyl)pyridin-4-yl)-2-cyano-imidazo[4,5-à]pyridine.

Step G:

Starting from the product of Step F following General procedure 1 Step B the appropriate example was obtained.

General procedure VI

Step A:

eq. 6-chloro-2-methylamino-3-aminopyridine (Préparation 4) and 2.5 eq. of the appropriate acetic acid dérivative were dissolved in toluene (1 mL/mmol) and the mixture was stirred at 85°C until no further conversion was observed. The volatiles were evaporated under reduced pressure and the solid residue was purified via flash

-23chromatography on silica gel using methanol and DCM as eluents to give 5-chloro-3methyl-2-(trifluoromethyl)imidazo[4,5-ô]pyridine 'H NMR (500 MHz, DMSO-dé) δ 8.39 (d, IH), 7.57 (d, IH), 3.95 (s, 3H)or 5-chloro-2(difluoromethyl)-3-methyl-imidazo[4,5-ô]pyridine - 'H NMR (500 MHz, DMSO-dé) δ 5 8.27 (d, IH), 7.46 (d, IH), 7.44 (t, IH), 3.9 (s, 3H).

Step B:

l eq. of the product obtained in Step A, 1.3 eq. tert-butyl jV-[6-(tert-butoxycarbonylamino)4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridyl]carbamate (Préparation 1), and 2 eq. K3PO4 were dissolved in 1,2-dimethoxyethane (6 mL/mmol) then 0.1 eq Pd(PPh3)₄ was added and the resulting mixture was heated at 100°C under nitrogen using microwave irradiation until no further conversion was observed. Celite was added to the reaction mixture and the volatiles were evaporated under reduced pressure. The solid residue was purified via flash chromatography on silica gel using MeOH and DCM as eluents to give the Boc-protected example.

StepC:

General procedure VII

1.05 eq. of the appropriate acid chloride dérivative was added dropwise at -78°C to the solution of 1 eq. 4-(3-butyl-2-methyl-3H-imidazo[4,5-h]pyridin-5-yl)pyridine-2,6-diamine (Example 148) and 3 eq. triethylamine in THF (16 mL/mmol of Example 148). The resulting mixture was allowed to warm up to room température and stirred until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude product was purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to give the appropriate example.

-24General procedure VIII

Step A:

The mixture of l eq. 3-acetamino-2-fluoro-6-bromopyridine and 5 eq. of the appropriate amine in éthanol (2 M for the amine) was stirred at 50°C until no further conversion was 5 observed. Solvent and excess amine were removed under reduced pressure and the crude 3acetamino-2-amino-6-bromopyridine dérivative was used in the next step without further purification.

Step B:

The solution of the crude 3-acetamino-2-amino-6-bromopyridine dérivative in acetic acid 10 (1.2 mL/mmol of starting 3-acetamino-2-fluoro-6-bromopyridine) was heated at 120°C until no further conversion was observed. The solvent was removed under reduced pressure, the residue was taken up in EtOAc, the organic phase was washed with 10% K2CO3, brine, it was dried over anhydrous MgSÛ4 and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography using 15 heptane and EtOAc as eluents to give the appropriate 3-substituted 5-bromo-2-methylimidazo[4,5-6]pyridine dérivative.

General procedure IX

To the solution of 1 eq. of the appropriate aryl halide dérivative in 1,2-dimethoxyethane20 water 7:1 (8 mL/mmol), 1.1 eq 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2amine, 3 eq. K3PO4, 0.05 eq. Pd(OAc)2, and 0.1 eq. BuPAd2 were added, and the mixture was stirred at 90°C under argon atmosphère until no further conversion was observed. The mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous

NH4HCO3 solution and MeCN as eluents to give the appropriate example.

-25General procedure X

Br

Pd(OAc)₂BuPAd, K,PO₄DME

Br

Pd(PPhj)₄, Κ,ΡΟ₄DME, H₂O

Step A:

A mixture of l eq. the appropriate 3-substituted 5-bromo-2-methyl-imidazo[4,5-ô]pyridine 5 dérivative, 2.4 eq. 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)1,3,2-dioxaborolane, 0.1 eq. Pd(OAc)2, 0.2 eq. bis(l-adamantyl)-butyl-phosphane, and 3 eq. K3PO4 was dispensed in 1,2-dimethoxyethane (0.25 M solution for the imidazopyridine dérivative) and the resulting mixture was stirred at 90°C under nitrogen atmosphère until no further conversion was observed. The reaction mixture was filtered through celite and 10 the celite was washed with 1,2-dichloroethane. Organic layers were combined, dried over MgSO4, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography using dichloromethane and methanol as eluents to give appropriate 3-substituted-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)imidazo[4,5-ô]pyridine.

Step B:

A mixture of 1 eq. of the 3-substituted-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)imidazo[4,5-6]pyridine, 1.05 eq. of the 4-bromopyridine dérivative, 0.1 eq. Pd(OAc)2, 0.2 eq. bis(l-adamantyl)-butyl-phosphane and 4 eq. K3PO4 was dispensed in 1,2-dimethoxyethane (0.17 M solution for the imidazopyridine dérivative). The the reaction mixture was stirred at 90°C under nitrogen atmosphère until no further conversion was observed. The reaction mixture was filtered through celite and the celite was washed with 1,2-dichloroethane. Organic layers were combined, dried over MgSÛ4, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography using dichloromethane and methanol as eluents to give the expected product.

-26Préparation 1: tert-butyl 7V-[6-(iert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-2-pyridyl]carbamate

109.7 g (4-bromo-6-teri-butoxycarbonylamino-pyridin-2-yl)-carbamicacid tert-butyl ester (283 mmol), prepared following J. Org. Chem. 2004, 69, 543-548, 107.7 g 5 bis(pinacolato)diboron (424 mmol), 0.29 g Pd(OAc)₂ (1.27 mmol), 0.70 g 1,1’bis(diphenylphosphino)ferrocene (1.27 mmol) and 83.2 g KOAc (848 mmol) were added to 1100 mL previously degassed 1,4-dioxane, and the mixture was stirred at 80 °C under argon atmosphère until no further conversion was observed. Then the reaction mixture was filtered; the solid was washed with dioxane. 5.5 g charcoal was added to the filtrate, and it 10 was-stirred for 2 minutes at reflux température. The mixture was filtered, washed with warm 1,4-dioxane and the volatiles were evaporated under reduced pressure. The residue was crystallised from tert-butyl-methyl-ether to give Préparation 1 as a white crystalline solid.

'H NMR (500 MHz, CDC1₃) δ : 8.16 (brs, 2H), 7.92 (s, 2H), 1.54 (s, 18H), 1.34 (s, 12H).

Préparation 2a tert-butyl Æ-[6-(tert-butoxycarbonylamino)-4-[6-chloro-5-(acetylamino)2-pyridyl]-2-pyridyl]carbamate

Step A: N-(6-bromo-2-chloro-3-pyridyl)acetamide

31.4 g 6-bromo-2-chloro-pyridin-3-amine (151.3 mmol) was dissolved in 200 ml glacial 20 acetic acid, 15 mL acetic anhydride (158.9 mmol) was added to this solution dropwise and the reaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic phase was washed with 10% aqueous K₂CÜ3 and brine. Following drying over Na₂SO₄ removal of the solvents under reduced pressure gave 25 7V-(6-bromo-2-chloro-3-pyridyl)acetamide.

HPLC-MS: (M-H) = 247.0; 249.0

Step B: tert-butyl N-[6-(tert-butoxycarbonylamino)-4-[6-chloro-5-(acetylamino)-2pyridyl]-2-pyridyl]carbamate

13.1 g A-(6-bromo-2-chloro-3-pyridyl)acetamide (52.5 mmol), 24.0 g. tert-butyl A/-[630 (tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2pyridyl]carbamate (Préparation 1) (55.13 mmol) and 33.4 g K3PO4 (157.3 mmol) were

-27 dissolved in l ,2-dimethoxyethane-water 4:l (250 mL). Then 304 mg tetrakis(triphenylphosphine)palladium(0) (0.26 mmol) was added and the mixture was heated under nitrogen at 90 °C until no further conversion was observed. Then the mixture was diluted with 250 mL water and extracted with EtOAc. The organic layer was dried over Na₂SO₄, the volatiles were removed under reduced pressure and the residue was recrystallized from EtOAc to obtain zerz-butyl 7V-[6-(zerz-butoxycarbonylamino)-4-[6chloro-5-(acetylamino)-2-pyridyl]-2-pyridyl]carbamate.

'H NMR (500 MHz, DMSO-d6) δ: 9.80 (s, IH), 9.51 (s, 2H), 8.40 (d, IH), 8.00 (s, 2H), 7.92 (d, IH), 2.18 (s, 3H), 1.49 (s, 18H).

Préparation 2b zerz-butyl A-[6-(zerZ-butoxycarbonylamino)-4-[6-chloro-5(pentanoylamino)-2-pyridyl]-2-pyridyl]carbamate

Step A: N-(6-bromo-2-chloro-3-pyridyl)pentanamide

3.0 g 6-bromo-2-chloro-pyridin-3-amine (14.5 mmol) and 2.4 mL triethylamine (17.4 mmol) were dissolved in 60 mL DCM. The solution was cooled to 0°C and 2.1 ml pentanoyl chloride (17.4 mmol) was added dropwise over 30 minutes. On completion of the addition the reaction mixture was allowed to warm up to room température whereit was stirred until no further conversion was observed. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography using DCM as eluent to give N-(6-bromo-2-chloro-3pyridyl)pentanamide, a pale pink solid.

HPLC-MS: (M-H) = 289.0; 291.0

Step B: tert-butyl N-[6-(tert-butoxycarbonylamino)-4-[6-chloro-5-(pentanoylamino)-2pyridyl/-2-pyridyl]carbamate

Starting from jV-(6-bromo-2-chloro-3-pyridyl)pentanamide following Step B of Préparation 2a, zerz-butyl 7V-[6-(zerz-butoxycarbonylamino)-4-[6-chloro-5(pentanoylamino)-2-pyridyl]-2-pyridyl]carbamate was obtained.

'H NMR (500 MHz, DMSO-d6) Ô: 9.70 (s, IH), 9.45 (s, 2H), 8.37 (d, IH), 8.00 (s, 2H), 7.91 (d, IH), 2.47 (t, 2H), 1.6 (m, 2H), 1.49 (s, 18H), 1.36 (m, 2H), 0.91 (t, 3H).

-28Préparation 2c tert-butyl N- [6-(tert-butoxycarbony lamino)-4-[6-chloro-5(propanoylamino)-2-pyridyl]-2-pyridyl]carbamate

Step A: N-(6-bromo-2-chloro-3-pyridyl)propanatnide

3.0 g 6-bromo-2-chloro-pyridin-3-amine (14.5 mmol) and 2.4 mL triethylamine (17.4 mmol), were dissolved in 60 ml DCM. The solution was cooled to 0°C and 1.5 ml propanoyl chloride was added dropwise over 30 minutes. On completion of the addition the reaction mixture was allowed to warm up to room température where it was stirred until no further conversion was observed. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography using DCM as eluent to give A-(6-bromo-2-chloro-3pyridyl)propanamide.

HPLC-MS: (M-H) = 261.0; 263.0

Step B: tert-butyl N-[6-(tert-butoxycarbonylamino)-4-[6-chloro-5-(propanoylamino)-2pyridyl/-2-pyridyl]carbamate

Starting from A-(6-bromo-2-chloro-3-pyridyl)propanamide following Step B of Préparation 2a, tert-butyl A-[6-(tert-butoxycarbonylamino)-4-[6-chloro-5(propanoylamino)-2-pyridyl]-2-pyridyl]carbamate was obtained.

'H NMR (500 MHz, DMSO-d6) Ô: 9.68 (s, IH), 9.45 (s, 2H), 8.40 (d, IH), 8.00 (s, 2H), 7.91 (d, IH), 2.48 (q, 2H), 1.49 (s, 18H), 1.11 (t, 3H).

Préparation 2d tert-butyl A-[6-(tert-butoxycarbonylamino)-4-[6-chloro-5(butanoylamino)-2-pyridyl]-2-pyridyl]carbamate

Step A: N-(6-bromo-2-chloro-3-pyridyl)butanamide g 6-bromo-2-chloro-pyridin-3-amine (14.46 mmol) and 2.4 ml triethylamine (17.35 mmol, 1.2 eq.), were dissolved in 60 ml DCM. This solution was cooled down to 0°C and 1.8 ml (17.35 mmol, 1.2 eq.) butanoyl chloride was added dropwise over 30 minutes. On completion of the addition the reaction mixture was allowed to warm up to room température where it was stirred until no further conversion was observed. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure.

-29The residue was purified via flash chromatography using DCM as eluent to give N-(6bromo-2-chloro-3-pyridyl)butanamide.

HPLC-MS: (M-H) = 275.0; 277.0

Step B: tert-butyl N-[6-(tert-butoxycarbonylamino)-4-[6-chloro-5-(butanoylamino)-25 pyridyl]-2-pyridyl]carbamate

Starting from //-(6-bromo-2-chloro-3-pyridyl)butanamide following Step B of Préparation 2a, tert-butyl 2V-[6-(tert-butoxycarbonylamino)-4-[6-chloro-5-(butiroylamino)-2-pyridyl]2-pyridyl]carbamate was obtained.

'H NMR (500 MHz, DMSO-d6) δ: 9.70 (s, IH), 9.46 (s, 2H), 8.37 (d, IH), 8.00 (s, 2H), 10 7.91 (d, IH), 2.45 (t, 2H), 1.64 (m, 2H), 1.49 (s, 18H), 0.95 (t, 3H).

Préparation 3a zerz-butyl N-[6-(zerz-butoxycarbonylamino)-4-[3-(2-hydroxyethyl)-2methyl-imidazo[4,5-ô]pyridin-5-yi]-2-pyridyl]carbamate eq. 5-chloro-3-(2-hydroxyethyl)-2-methyl-imidazo[4,5-ô]pyridine, 1.1 eq. zerz-butyl N15 [6-(ZerZ-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2pyridyl]carbamate (Préparation 1), 0.1 eq. Pd(OAc)₂, 0.2 eq. PBuAd₂, and 3.0 eq. K₂COj were suspended in DME (0.2 M) and the mixture was stirred under nitrogen at 100°C in a microwave reactor until no further conversion was observed. The volatiles were removed under reduced pressure and the crude product was purified via flash chromatography using 20 dichloromethane and methanolic ammonia as eluents to give tert-butyl 7V-[6-(tertbutoxycarbonylamino)-4-[3-(2-hydroxyethyl)-2-methyl-imidazo[4,5-6]pyridin-5-yl]-2pyridyl]carbamate as a white solid.

'H NMR (400 MHz, DMSO-d6) δ : 9.34 (s, 2H), 8.03 (d, IH), 8.02 (s, 2H), 7.68 (d, IH), 4.97 (t, IH), 4.34 (t, 2H), 3.81 (q, 2H), 2.63 (s, 3H), 1.49 (s, 18H).

Préparation 3b zerz-butyl N-[6-(tert-butoxycarbonylamino)-4-[3-(2-hydroxypropyl)-2methyl-imidazo[4,5-6]pyridin-5-yl]-2-pyridyl]carbamate

Step A: 3-amino-2-fluoro-6-bromopyridine eq. 3-amino-2-fluoropyridine was dissolved in DCM (0.6 M solution), 1.05 eq. N30 bromosuccinimide was added and the reaction mixture was stirred at room température until no further conversion was observed. Water was added, the organic phase was

-30separetad, dried over anhydrous MgSO₄ and concentrated under reduced pressure to give 3-amino-2-fluoro-6-bromopyridine.

'H NMR (400 MHz, DMSO-d6) δ : 7.22 (dd, IH), 7.11 (dd, IH), 5.62 (brs, 2H).

Step B: 3-acetamino-2-fluoro-6-bromopyridine

To a solution of 1 eq. 3-amino-2-fluoro-6-bromopyridine in acetic acid (0.9 M) 1.05 eq. acetic anhydride was added and the reaction mixture was stirred at room température until no further conversion was observed. The solvents were removed reduced pressure, the crude product was dissolved in DCM and washed with 10% K2CO3. The organic layer was dried over anhydrous MgSO₄, and concentrated under reduced pressure to give 3acetamino-2-fluoro-6-bromopyridine.

'H NMR (400 MHz, DMSO-d6) δ: 10.03 (brs, IH), 8.42 (dd, IH), 7.56 (d, IH), 2.11 (s, 3H).

Step C: 3-acetamino-2-(2-hydroxypropylamino)-6-bromopyridine

The mixture of 1 eq. 3-acetamino-2-fluoro-6-bromopyridine, 2.2 eq. l-aminopropan-2-ol, and triethylamine (0.27 mL/mmol of the fluoropyridine) was stirred at 60°C until no further conversion was observed. Solvent and excess amine were removed under reduced pressure and the crude 3-acetamino-2-(2-hydroxypropylamino)-6-bromopyridine was used in the next step without purification.

MS: (M+H)⁺= 288.2

StepD: 5-bromo-3-(2-hydroxypropyl)-2-methyl-imidazo[4,5-b]pyridine

The solution of 1 eq. 3-acetamino-2-(2-hydroxypropylamino)-6-bromopyridine in acetic acid (13.6 mL/g of the crude amide) was heated at 130°C until no further conversion was observed. The solvent was removed under reduced pressure, the residue was taken up in methanol:water (5:1, 7 mL/g of residue) containing LiOH*H₂O (0.27 g/g of residue) and the mixture was stirred at ambient température for 2 hours than poured into water. The precipitate was filtered off, washed with water and dried to give 5-bromo-3-(2hydroxypropyl)-2-methyl-imidazo[4,5-6]pyridine.

'H NMR (400 MHz, DMSO-d6) δ: 7.87 (d, IH), 7.36 (d, IH), 4.97 (d, IH), 4.19-3.94 (m, 3H), 2.57 (s, 3H), 1.21 (d, 3H).

-31Step E:

eq. 5-bromo-3-(2-hydroxypropyl)-2-methyl-imidazo[4,5-è]pyridine, 1.0 eq. rerZ-butyl N[6-(tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyi-l,3,2-dioxaboiOlan-2-yi)-2pyridyi]carbamate (Préparation 1), 0.05 eq. tetrakis(triphenyiphosphine)palladium(0), and 5 3 eq. K3PO4 were suspended in DME (5 mL/mmoi for the bromo compound) and the mixture was stirred under nitrogen at 100°C in a microwave reactor until no further conversion was observed. The volatiles were removed under reduced pressure and the crude product was purified via flash chromatography using dichloromethane and methanolic ammonia as eluents to give tert-butyl 7V-[6-(tert-butoxycarbonylamino)-4-[3-(210 hydroxypropyl)-2-methyl-imidazo[4,5-Z>]pyridin-5-yl]-2-pyridyl]carbamate as a white solid.

’H NMR (500 MHz, DMSO-d6) δ: 9.42 (s, 2H), 8.10 (s, 2H), 8.03 (d, IH), 7.70 (d, IH), 5.03 (d, IH), 4.28 (dd, IH), 4.18 (m, IH), 4.10 (dd, IH), 2.64 (s, 3H), 1.50 (s, 18H), 1.19 (d, 3H).

Préparation 4 6-chloro-V²-methyl-pyridine-2,3-diamine

Step A: 6-chloro-N-methyl-3-nitro-pyridin-2-amine

3.86 g 2,6-dichloro-3-nitro-pyridine (20 mmol) was dissolved in 80 ml DCM, 6.9 g K2CO3 (50 mmol, 2.5 eq.) was added and the reaction mixture was cooled down to -20°C. At this 20 température 3.1 ml of methylamine (33% solution in éthanol, 28.6 mmol, 1.43 eq.) was added dropwise then cooling was stopped and the reaction mixture was allowed to warm up to ambient température where it was stirred until no further conversion was observed. The reaction mixture was filtered, the filtrate was washed with water, the organic layer was dried on MgSO4 then concentrated under reduced pressure to give 6-chloro-#-methyl-325 nitro-pyridin-2-amine as a solid.

'H NMR (500 MHz, DMSO-d6) δ: 8.72 (d, IH), 8.42 (d, IH), 6.77 (d, IH), 3.08 (d, 3H).

Step B: 6-chloro-2-methylamino-3-aminopyridine

3.0 g 6-chloro-jV-methyl-3-nitro-pyridin-2-amine (16 mmol) was dissolved in the mixture of 30 ml éthanol and 15 ml water then 4.47 g iron powder (80 mmol, 5 eq.) was added. To 30 this mixture 1.2 ml glacial acetic acid was added dropwise then the reaction mixture was refluxed until no further conversion was observed. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified via flash

-32chromatography using DCM as eluent to give 6-chloro-2-methylamino-3-aminopyridine. MS(M+H)= 158.2

Préparation 5 4-(3-butyl-2-methyl-imidazo[4,5-ô]pyridin-5-yl)-7V²-triphenylmethylpyridine-2,6-diamine

8.35 mL triethylamine (6.07 g, 60.0 mmol) and 8.36 g triphenylmethyl chloride (30.0 mmol) were added at room température to a stirred solution of 2.96 g 4-(3-butyl-2-methyl3//-imidazo[4,5-Z>]pyridin-5-yl)pyridine-2,6-diamine (Example 148) (10.0 mmol) in 100 mL THF and the mixture was stirred until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude product was purified via reversed phase flash chromatography using water and MeCN as eluents to obtain 4-(3butyl-2-methyl-imidazo[4,5-Z>]pyridin-5-yl)-?7^?,?/-di(triphenylmethyl)-pyridine-2,6diamine as an intermediate. This intermediate was dissolved in 400 mL methanol, 20 mL TFA was added at room température and the mixture was stirred at room température until the total amount of the fos-triphenylmethylated intermediate was converted to the desired product. Then 16.0 g NH4HCO3 (202.4 mmol) was added with stirring and the formed precipitate was removed by filtration to obtain the crude product, which was recrystallized from methanol to give 4-(3-butyl-2-methyl-imidazo[4,5-Z>]pyridin-5-yl)-A^?triphenylmethyl-pyridine-2,6-diamine (Préparation 5).

'H NMR (500 MHz, CDCI3) δ : 7.84 (d, IH), 7.42-7.35 (m, 6H), 7.33-7.25 (m, 6H), 7.237.16 (m, 3H), 7.20 (d, IH), 6.33 (s, IH), 6.26 (brs, IH), 6.03 (s, IH), 5.45 (brs, 2H), 4.12(t, 2H), 2.58 (s, 3H), 1.64 (m, 2H), 1.16 (m, 2H), 0.85 (t, 3H).

Préparation 6a 5-bromo-3-butyl-2-methyl-imidazo[4,5-Z>]pyridine

Following General procedure VIII and using butylamine as the appropriate amine dérivative 5-bromo-3-butyl-2-methyl-imidazo[4,5-b]pyridine was obtained.

’H NMR (500 MHz, DMSO-d6) δ: 7.89 (d, IH), 7.38 (d, 1 H), 4.18 (t, 2H), 2.58 (s, 3H),

1.71 (quint, 2H), 1.38-1.22 (m, 2H), 0.91 (t, 3H).

-33 Préparation 6b 5-bromo-3-(2-cyclohexylethyl)-2-methyl-imidazo[4,5-6]pyridine

Following General procedure VIII and using (2-aminoethyl)-cyclohexane as the appropriate amine dérivative 5-bromo-3-(2-cyclohexylethyl)-2-methyl-imidazo[4,5ô]pyridine was obtained.

'H NMR (500 MHz, DMSO-d6) δ: 7.88 (d, IH), 7.38 (d, IH), 4.19 (t, 2H), 2.57 (s, 3H), 1.79 (d, 2H), 1.66 (d, 2H), 1.62-1.57 (m, IH), 1.59 (q, 2H), 1.29-1.08 (m, 4H), 0.94 (q, 2H).

Préparation 6c 5-bromo-3-(cyclopropylmethyl)-2-methyl-imidazo[4,5-6]pyridine

Following General procedure VIII and using cyclopropyl-methylamine as the appropriate amine dérivative 5-bromo-3-(cyclopropylmethyl)-2-methyl-imidazo[4,5-Z>]pyridine was obtained.

'H NMR (400 MHz, DMSO-d6) δ: 7.77 (d, IH), 7.31 (d, IH), 4.10 (d, 2H), 2.66 (s, 3H), ml.33-1.19 (m, IH), 0.64-0.43 (m, 4H).

Préparation 6d 5-bromo-3-but-3-enyl-2-methyl-imidazo[4,5-6]pyridine

Following General procedure VIII and using l-amino-3-butene as the appropriate amine dérivative 5-bromo-3-but-3-enyl-2-methyl-imidazo[4,5-6]pyridine was obtained.

'H NMR (500 MHz, DMSO-d6) δ: 7.88 (d, IH), 7.38 (d, IH), 5.86-5.71 (m, IH), 5.014.94 (m, 2H), 4.26 (t, 2H), 2.57 (s, 3H), 2.52 (q, 2H).

Préparation 6e 5-bromo-3-(3,3-difluorocyclobutyl)-2-methyl-imidazo[4,5-6]pyridine

Following General procedure VIII and using 3,3-difluoro-cycIobutanamine as the appropriate amine dérivative 5-bromo-3-(3,3-difluorocycIobutyl)-2-methyl-imidazo[4,56]pyridine was obtained.

'H NMR (500 MHz, DMSO-d6) δ: 7.91 (d, IH), 7.42 (d, IH), 5.05-4.92 (m, IH), 3.883.69 (m, 2H), 3.22-3.09 (m, 2H), 2.60 (s, 3H).

-34Préparation 6f 5-bromo-3-cyclopropyl-2-methyl-imidazo[4,5-6]pyridine

Following General procedure VIII and using cyclopropylamine as the appropriate amine dérivative 5-bromo-3-cyclopropyl-2-methyl-imidazo[4,5-ô]pyridine was obtained.

'H NMR (500 MHz, DMSO-d6) δ: 7.86 (d, IH), 7.37 (d, IH), 3.33-3.28 (m, IH), 2.60 (s, 5 3H), 1.18-l.H (m,4H).

Example 1 4-(3-cyclopentyl-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl)pyridine-2,6diamine

Starting from 6-chloro-3-cyclopentyl-2-methyl-imidazo[4,5-6]pyridine as the appropriate halide and following General procedure I Example 1 was obtained. HRMS (TOF, ESI) 10 m/z: Calcd for Ci₇H₂₀N₆ 308.1749, Found: 309.1821 [M+H]⁺.

Example 2 4-(2-methyl-3-propyl-377-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine Starting from 3-propyl-6-chloro-2-methyl-imidazo[4,5-6]pyridine as the appropriate halide and following General procedure I Example 2 was obtained. HRMS (TOF, ESI) m/z: Calcd for Ci₅Hi₈N₆ 282.1593, Found: 283.1662 [M+H]⁺.

Example 3 2-(5-(2,6-diaminopyridin-4-yl)-2-methyl-377-imidazo[4,5-6]pyridin-3yl]ethanol

Starting from 6-chloro-3-(2-hydroxyethyl)-2-methyl-imidazo[4,5-6]pyridine as the appropriate halide and following General procedure I Example 3 was obtained. HRMS (TOF, ESI) m/z: Calcd for Ci₄Hi₆N₆O 284.1386, Found: 285.1473 [M+H]⁺.

Example 4 4-(2,3-dimethyl-3//-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine

Starting from 6-chloro-2,3-dimethyl-imidazo[4,5-ô]pyridine as the appropriate halide and following General procedure I Example 4 was obtained. HRMS (TOF, ESI) m/z: Calcd for C|₃H]₄N₆ 254.1280, Found: 255.1361 [M+H]⁺.

Example 5 4-[2-methyl-3-(pyridin-4-ylmethyl)-3/7-imidazo[4,5-ô]pyridin-5-yl]pyridine25 2,6-diamine

Starting from 6-chloro-3-(4-pyridylmethyl)-2-methyl-imidazo[4,5-6]pyridine as the appropriate halide and following General procedure I Example 5 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₎₈H_I7N₇ 331.1545, Found: 332.1623 [M+H]⁺.

-35Example 6 4-[2-methyl-3-(pyridin-2-ylmethyl)-3//-imidazo[4,5-6]pyridin-5-yl]pyridine2,6-diamine

Starting from 6-chloro-3-(2-pyridylmethyl)-2-methyl-imidazo[4,5-à]pyridine as the appropriate halide and following General procedure I Example 6 was obtained. HRMS (TOF, ESI) m/z: Calcd for Ci₈H_i7N₇ 33l.l545, Found: 332.1625 [M+H]⁺.

Example 7 4-[2-methyl-3-(pyridin-3-ylmethyl)-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

Starting from 6-chloro-3-(3-pyridylmethyl)-2-methyl-imidazo[4,5-6]pyridine as the appropriate halide and following General procedure I Example 7 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₁₈H_I7N₇ 331.1545, Found: 332.1625 [M+H]⁺.

Example 8 4-(3-benzyl-2-methyl-3//-imidazo[4,5-à]pyridin-5-yl)pyridine-2,6-diamine

Starting from 3-benzyl-6-chloro-2-methyl-imidazo[4,5-6]pyridine as the appropriate halide and following General procedure I Example 8 was obtained. HRMS (TOF, ESI) m/z: Calcd for C_I9H_I8N₆ 330.1593, Found: 331.1673 [M+H]⁺.

Example 9 4-(3-cyclopropyl-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl)pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using cyclopropylamine as the appropriate amine Example 9 was obtained. HRMS (TOF, ESI) m/z: Calcd for C_i5Hi₆N₆ 280.1436, Found: 281.1518 [M+H]⁺.

Example 10 4-[3-(4-fluorobenzyl)-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using 4fluorobenzylamine as the appropriate amine Example 10 was obtained. HRMS (TOF, ESI) m/z: Calcd for C_I9H₁₇N₆F 348.1499, Found: 349.1565 [M+H]⁺.

Example 11 4-[3-(cyclopropylmethyl)-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

-36Starting from Préparation 2a following General procedure II and using cyclopropylmethylamine as the appropriate amine Example 11 was obtained, HRMS (TOF, ESI) m/z: Calcd for Ci₆Hi₈N₆ 294.1593, Found: 295.1665 [M+H]⁺.

Example 12 4-[3-(2,3-dihydro-lH-inden-2-yl)-2-methyl-3//-imidazo[4,5-ô]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2,3-dihydro-l//inden-2-amine as the appropriate amine Example 12 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₂iH₂₀N₆ 356.1749, Found: 357.1822 [M+H]⁺.

Example 13 1 - {3-[5-(2,6-diamùiopyridin-4-yl)-2-methyl-3//-imidazo[4,5-6]pyridin-3yl]propyl} pyrrolidin-2-one

Starting from Préparation 2a following General procedure II and using l-(3aminopropyl)pyrrolidin-2-one as the appropriate amine Example 13 was obtained. HRMS (TOF, ESI) m/z: Calcd for Ci₉H₂₃N₇O 365.1964, Found: 366.2035 [M+H]⁺.

Example 14 4-[3-(but-3-en-l-yl)-2-methyl-3/f-imidazo[4,5-h]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using 4-amino-l-butene as the appropriate amine Example 14 was obtained. HRMS (TOF, ESI) m/z: Calcd for Ci₆Hi8N₆ 294.1593, Found: 295.1672 [M+H]⁺.

Example 15 4-[3-(2-cyclohexylethyl)-2-methyl-3//-imidazo[4,5-&]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using (2-aminoethyl)cyclohexane as the appropriate amine Example 15 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₂₀H₂₆N₆ 350.2219, Found: 351.2298 [M+H]⁺.

Example 16 4-[2-methyl-3-[(lS,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1 ]hept-3-yl]-3Himidazo[4,5-ô]pyridin-5-yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using (1S,25,3S,5/?)2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine as the appropriate amine Example 16 was

-37obtained. HRMS (TOF, ESI) m/z: Calcd for C₂₂H₂₈N₆ 376.2375, Found: 377.2456 [M+H]⁺.

Example 17 4-[3-(2-cyclopropylethyl)-2-methyl-3/7-imidazo[4,5-6]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 2cyclopropylethanamine as the appropriate amine Example 17 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₁₇H₂₀N₆ 308.1749, Found: 309.1828 [M+H]⁺.

Example 18 4-[3-(2-ethylbutyl)-2-methyl-3/f-imidazo[4,5-Z>]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using 2-ethylbutan-lamine as the appropriate amine Example 18 was obtained. HRMS (TOF, ESI) m/z: Calcd for Ci₈H₂4N₆ 324.2062, Found: 325.2139 [M+H]⁺.

Example 19 4-{3-[2-(furan-2-yl)ethyl]-2-methyl-3//-imidazo[4,5-/>]pyridin-5-yl}pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(2furyl)ethanamine as the appropriate amine Example 19 was obtained. HRMS (TOF, ESI) m/z: Calcd for C]₈H₁₈N₆O 334.1542, Found: 335.1618 [M+H]⁺.

Example 20 4-[2-methyl-3-(thiophen-2-ylmethyl)-377-imidazo[4,5-6]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2thienylmethanamine as the appropriate amine Example 20 was obtained. HRMS (TOF, ESI) m/z: Calcd for Ci₇Hi₆N₆S 336.1157, Found: 337.1224 [M+H]⁺.

Example 21 4-{2-methyl-3-[2-(l-phenyl-l//-pyrazol-4-yl)ethyl]-3#-imidazo[4,5à]pyridin-5-yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(l-phenylpyrazol4-yl)ethanamine as the appropriate amine Example 21 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₂₃H₂₂N₈ 410.1967, Found: 411.2038 [M+H]⁺.

-38Example 22 4- {2-methyl-3-tricyclo[3.3.1.1³’⁷]dec-l-ylmethyl-3//-imidazo[4,5-ô]pyridin5-y 1} pyridine-2,6-diamme

Starting from Préparation 2a following General procedure II and using 1adamantylmethanamine as the appropriate amine Example 22 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₂₃H₂₈N₆ 388.2375, Found: 389.2542 [M+H]⁺.

Example 23 4-(3-cyclobutyl-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using cyclobutylamine as the appropriate amine Example 23 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₁₆Hi₈N₆ 294.1593, Found: 295.1665 [M+H]⁺.

Example 24 N-(4-{2-(5-(2,6-diaminopyridin-4-yl)-2-methyl-3//-imidazo[4,5-/>]pyridin-3yl]ethyl} phenyl)acetamide

Starting from Préparation 2a following General procedure II and using N-[4-(2aminoethyl)phenyl]acetamide as the appropriate amine Example 24 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₂₂H₂₃N₇O 401.1964, Found: 402.2039 [M+H]⁺.

Example 25 4-(3-tert-butyl-2-methyl-3H-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine Starting from Préparation 2a following General procedure II and using tert-butylamine as the appropriate amine Example 25 was obtained. HRMS (TOF, ESI) m/z: Calcd for CiôH₂oN6 296.1479, Found: 240.1125 [M+H-C^e]*. Fragment ion formula: Ci₂H|₂Nô no molecular ion was detected due to extensive fragmentation.

Example 26 4-{2-methyl-3-[2-(thiophen-2-yl)ethyl]-3H-imidazo[4,5-6]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2thienylethaneamine as the appropriate amine Example 26 was obtained. HRMS (TOF, ESI) m/z: Calcd for Ci₈Hi₈N₆S 350.1314, Found: 351.1385 [M+H]⁺.

Example 27 4- {2-methyl-3-[2-(naphthalen- l-yloxy)ethyl]-3A-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

-39Starting from Préparation 2a following General procedure II and using 2-(naphthalen-lyloxy)ethanamine as the appropriate amine Example 27 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₂₄H₂₂N₆O 410.1855, Found: 411.1923 [M+H]⁺.

Example 28 4-[2-methyl-3-(2,2,2-trifluoroethyl)-3f7-imidazo[4,5-b]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 2,2,2trifluoroethylamine as the appropriate amine Example 28 was obtained. HRMS (TOF, ESI) m/z: Calcd for Ci₄H₁₃N₆F₃ 322.1154, Found: 323.1238 [M+H]⁺.

Example 29 4- {2-methyl-3-[2-(thiophen-3-yl)ethyl]-3/7-imidazo[4,5-6]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 3thienylethaneamine as the appropriate amine Example 29 was obtained. HRMS (TOF, ESI) m/z: Calcd for C,₈Hi₈N₆S 350.1314, Found: 351.1379 [M+H]⁺.

Example 30 4-(3-(2,2-dimethylpropyl)-2-methyl-3/f-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 2,2dimethylpropan-1-amine as the appropriate amine Example 30 was obtained. HRMS (TOF, ESI) m/z: Calcd for C₁₇H₂2N₆ 310.1906, Found: 311.2010 [M+H]⁺.

Example 31 4-[2-methyl-3-(2-methylpropyl)-3f/-imidazo[4,5-/>]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using 2-methylpropan-lamine as the appropriate amine Example 31 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₁₆H₂oN₆ 296.1749, Found: 297.1824 [M+H]⁺

Example 32 4- {2-methyl-3-[( 1 A)-1 -(2-methylpyridin-4-yl)ethyl]-3ff-imidazo[4,5à]pyridin-5-yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using (lR)-l-(2-methyl-4pyridyl)ethanamine as the appropriate amine Example 32 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C₂₀H₂iN₇ 359.1858, Found: 360.1934 [M+H]⁺

-40Example 33 4-[3-(butan-2-yl)-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using butan-2-amine as the appropriate amine Example 33 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C_I6H₂oN₆ 296.1749, Found: 297.1826 [M+H]⁺

Example 34 4-[2-methyl-3-(2-methylbutyl)-3/f-imidazo[4,5-6]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using 2-methylbutan-lamine as the appropriate amine Example 34 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for Ci₇H₂₂N₆ 310.1906, Found: 311.1983 [M+H]⁺

Example 35 ethyl 4-[5-(2,6-diaminopyridin-4-yl)-2-methyl-3/7-imidazo[4,5-h]pyridin-3yl]piperidine-l-carboxylate

Starting from Préparation 2a following General procedure II and using ethyl 4aminopiperidine-l-carboxylate as the appropriate amine Example 35 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₀H₂₅N₇O₂ 395.2070, Found: 396.2152 [M+H]⁺

Example 36 4-[2-methyl-3-(5,6,7,8-tetrahydroquinolin-5-yl)-3/7-imidazo[4,5-6]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 5,6,7,8tetrahydroquinolin-5-amine as the appropriate amine Example 36 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C₂iH₂iN₇ 371.1858, Found: 372.1939 [M+H]⁺

Example 37 3-[5-(2,6-diaminopyridin-4-yl)-2-methyl-3//-imidazo[4,5-Z>]pyridin-3yl]propane-1,2-dio 1

Starting from Préparation 2a following General procedure II and using 3-aminopropane1,2-diol as the appropriate amine Example 37 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for Ci₅H|₈N₆O₂ 314.1491, Found: 315.1559 [M+H]⁺

Example 38 l-{4-[5-(2,6-diaminopyridin-4-yl)-2-methyl-3J7-imidazo[4,5-6]pyridin-3y l]piperidin-1 -yl} -2-methylpropan-1 -one

-4l Starting from Préparation 2a following General procedure II and using l-(4-amino-lpiperidyl)-2-methyl-propan-l-one as the appropriate amine Example 38 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C21H27N7O 393.2277, Found: 394.2356 [M+H]⁺

Example 39 4-[3-(4-chloro-2-methoxybenzyl)-2-methyl-3//-imidazo[4,5-6]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using (4-chloro-2methoxy-phenyl)methanamine as the appropriate amine Example 39 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C₂oHi₉N₆OCl 394.1309, Found: 395.1387 [M+H]⁺

Example 40 4- {[5-(2,6-diaminopyridin-4-yl)-2-methyl-3//-imidazo[4,5-6]pyridin-3yl]methyl} benzonitrile

Starting from Préparation 2a following General procedure II and using 4(aminomethyl)benzonitrile as the appropriate amine Example 40 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C20H17N7 355.1545, Found: 356.1612 [M+H]⁺

Example 41 4-[2-methyl-3-(tetrahydrofuran-3-ylmethyl)-3.W-imidazo[4,5-à]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using tetrahydrofuran-3ylmethanamine as the appropriate amine Example 41 was obtained. HRMS (ΓΓ-TOF, ESI) m/z: Calculated for C_l7H2oN₆0 324.1699, Found: 325.1787 [M+H]⁺

Example 42 4-[3-(furan-3-ylmethyl)-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 3furylmethanamine as the appropriate amine Example 42 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C_I7H_I6N₆O 320.1386, Found: 321.1467 [M+H]⁺

Example 43 4- {3-[4-(difluoromethoxy)benzyl]-2-methyl-3//-imidazo[4,5-ô]pyridin-5y 1} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using [4(difluoromethoxy)phenyl]methanamine as the appropriate amine Example 43 was

-42obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C2oHi8N₆OF₂ 396.1510, Found:

397.1581 [M+H]⁺

Example 44 4- {2-methyl-3-[3-(methylsulfanyl)propyl]-3//-imidazo[4,5-6]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 3methylsulfanylpropan-l-amine as the appropriate amine Example 44 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for Ci₆H₂oN₆S 328.1470, Found: 329.1551 [M+H]⁺

Example 45 4-{2-methyl-3-[(l,3,5-trimethyl-l//-pyrazol-4-yl)methyl]-3//-imidazo[4,5Z>]pyridin-5-y 1} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using (1,3,5-trimethyll/7-pyrazol-4-yl)methanamine as the appropriate amine Example 45 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C₁₉H22N8 362.1967, Found: 363.2037 [M+H]⁺

Example 46 4-[3-(2,5-difluorobenzyl)-2-methyl-3/7-imidazo[4,5-6]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using (2,5difluorophenyl)methanamine as the appropriate amine Example 46 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C_]9H₁₆N₆F2 366.1405, Found: 367.1483 [M+H]⁺

Example 47 4-[3-(2-chlorobenzyl)-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using (2chlorophenyl)methanamine as the appropriate amine Example 47 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C,₉H_I7N₆C1 364.1203, Found: 365.1279 [M+H]⁺

Example 48 4-[3-(3-chloroben2yl)-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl]pyridme-2,6diamine

Starting from Préparation 2a following General procedure II and using (3chlorophenyl)methanamine as the appropriate amine Example 48 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for Ci₉H_i7N₆C1 364.1203, Found: 365.1277 [M+H]⁺

-43Example 49 4-[2-methyl-3-(tetrahydro-27/-pyran-4-yl)-3#-imidazo[4,5-ô]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using tetrahydro-2//pyran-4-amine as the appropriate amine Example 49 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₇H₂oN₆0 324.12699, Found: 325.1790 [M+H]⁺

Example 50 4-{3-[2-fluoro-5-(trifluoromethoxy)benzyl]-2-methyl-3//-imidazo[4,5Δ] pyr idin-5-y 1} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using [2-fluoro-5(trifluoromethoxy)phenyl]methanamine as the appropriate amine Example 50 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₀Hi₆N₆OF₄ 432.1322, Found: 433.1416 [M+H]⁺

Example 51 4-[2-methyl-3-(prop-2-en-1 -yl)-3//-imidazo[4,5-Z>]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using prop-2-en-l-amine as the appropriate amine Example 51 was obtained. HRMS (TOF, ESI) m/z: Calculated for C_]5H]₆N₆ 280.1436, Found: 281.1524 [M+H]⁺

Example 52 4-[3-(3,3-dimethylbutyl)-2-methyl-3//-imidazo[4,5-à]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 3,3-dimethylbutan1-amine as the appropriate amine Example 52 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₁₈H₂₄N₆ 324.2062, Found: 325.2153 [M+H]⁺

Example 53 4-[2-methyl-3-(propan-2-yl)-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using propan-2-amine as the appropriate amine Example 53 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₅H₁₈N₆ 282.1593, Found: 283.1675 [M+H]⁺

Example 54 4-(3-cyclohexyl-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6diamine

-44Starting from Préparation 2a following General procedure II and using cyclohexanamine as the appropriate amine Example 54 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₈H₂₂N₆ 323.1921, Found: 323.1994 [M+H]⁺

Example 55 4-(3-( cyclohexylmethyl)-2-methyl-3/7-imidazo[4,5-6]pyridin-5-yl]pyridine5 2,6-diamine

Starting from Préparation 2a following General procedure II and using 1cyclohexylmethanamine as the appropriate amine Example 55 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₉H₂₄N₆ 336.2062, Found: 337.2151 [M+H]⁺

Example 56 4-{2-methyl-3-tricyclo[3.3.1.1³’⁷]dec-l-yl-3//-imidazo[4,5-Z>]pyridin-510 yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 1-adamantylamine as the appropriate amine Example 56 was obtained. HRMS (TOF, ESI) m/z: Calculated for C2₂H₂₆N₆ [M+H]⁺ 374.2219, Found: 375.2307.

Example 57 4-(3-(2,5-dichlorobenzyl)-2-methyl-3//-imidazo[4,5-b]pyridin-5-yl]pyridine15 2,6-diamine

Starting from Préparation 2a following General procedure II and using (2,5dichlorophenyl)methanamine as the appropriate amine Example 57 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₉H_I6N₆C1₂ 398.0814, Found: 399.0896 (M+H]⁺

Example 58 4- {3-(2-(3,4-dichlorophenyl)ethyl]-2-methyl-3H-imidazo[4,5-ô]pyridin-520 yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(3,4dichlorophenyl)ethanamine as the appropriate amine Example 58 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂oH,₈N₆Cl₂ 412.0970, Found: 413.1053 [M+H]⁺

Example 59 4- {3-(2-(2,4-dichlorophenyl)ethyl]-2-methyl-3/7-imidazo[4,5-à]pyridin-525 yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(2,4dichlorophenyl)ethanamine as the appropriate amine Example 59 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂oHi₈N₆C1₂ 412.097, Found: 413.1056 [M+H]⁺

-45Example 60 4-[2-methyl-3-(2-phenylpropan-2-yl)-3//-imidazo[4,5-ô]pyridin-5yl]pyridine-2,6-diamine and

Example 61 4-(2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-phenylpropan-2amine as the appropriate amine Example 60 was obtained. HRMS (TOF, ESI) m/z: Calculated for C21H22N6 358.1906, Found: 359.1988 [M+H]⁺ From the same reaction Example 61 was also isolated. HRMS (TOF, ESI) m/z: Calculated for C12H12N6 240.1123, Found: 241.1206. [M+H]⁺

Example 62 4-[2-methyl-3-( 1,2,3,4-tetrahydronaphthalen-l-yl)-3//-imidazo[4,5-ô]pyridin5-yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 1,2,3,4tetrahydronaphthalen-1-amine as the appropriate amine Example 62 was obtained. HRMS (TOF, ESI) m/z: Calculated for C22H22N6 370.1906, Found: 371.1989 [M+H]⁺

Example 63 4-{2-methyI-3-[2-(2-methyIphenyI)ethyl]-3//-imidazo[4,5-b]pyridin-5y 1} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(otolyl)ethanamine as the appropriate amine Example 63 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂iH₂2N₆ 358.1906, Found: 359.1985 [M+H]⁺

Example 64 4-[2-methyl-3-(pentan-2-yl)-3//-imidazo[4,5-/j]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using pentan-2-amine as the appropriate amine Example 64 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₇H₂2N₆ 310.1906, Found: 311.1980 [M+H]⁺

Example 65 4-(2-methyl-3-pentyl-3#-imidazo[4,5-6]pyridin-5-yl)pyridine-2,6-diamine Starting from Préparation 2a following General procedure II and using pentan-1-amine as the appropriate amine Example 65 was obtained. HRMS (TOF, ESI) m/z: Calculated for Cl₇H₂₂N₆ 310.1906, Found: 311.1983 [M+H]⁺

-46Example 66 4-[2-methyl-3-(tetrahydro-277-thiopyran-4-yl)-3/7-imidazo[4,5-6]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using tetrahydro-2//thiopyran-4-amine as the appropriate amine Example 66 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₇H₂₀N₆S 340.147, Found: 341.1545 [M+H]⁺

Example 67 4-[2-methyl-3-(l-phenylpropyl)-3//-imidazo[4,5-6]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using 1-phenylpropan-lamine as the appropriate amine Example 67 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂iH₂₂N₆ 358.1906, Found: 359.1979 [M+H]⁺

Example 68 4-[2-methyl-3-(pentan-3-yl)-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using pentan-3-amine as the appropriate amine Example 68 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₇H₂₂N₆ 310.1906, Found: 311.1985 [M+H]⁺

Example 69 4- {3-[3-(2-methoxyphenyl)propyl]-2-methyl-3//-imidazo[4,5-6]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 3-(2methoxyphenyl)propan-l-amine as the appropriate amine Example 69 was obtained.

HRMS (TOF, ESI) m/z: Calculated for C₂₂H₂₄N₆O 388.2012, Found: 389.2095 [M+H]⁺

Example 70 4-[5-(2,6-diaminopyridin-4-yl)-2-methyl-3//-imidazo[4,5-à]pyridin-3yl]butan-l-ol

Starting from Préparation 2a following General procedure II and using 4-aminobutan-l-ol as the appropriate amine Example 70 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₆H₂₀N₆O 312.1699, Found: 313.1767 [M+H]⁺

Example 71 4-[2-methyl-3-(4,4,4-trifluorobutyl)-3/7-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

-47Starting from Préparation 2a following General procedure II and using 4,4,4trifluorobutan-l-amine as the appropriate amine Example 71 was obtained. HRMS (TOF, ESI) m/z: Calculated for C|₆H_I7N₆F₃ 350.1467, Found: 351.1533 [M+H]⁺i

Example 72 4- {3-[(2-methoxypyridin-4-yl)methyl]-2-methyl-3//-imidazo[4,5-h]pyridin-55 yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using (2-methoxy-4pyridyl)methanamine as the appropriate amine Example 72 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₉H_]9N₇O 361.1651, Found: 362.1726 [M+H]⁺

Example 73 4- {3-[2-( 1,3-benzodioxol-5-yl)ethyl]-2-methyl-3/Z-imidazo[4,5-6]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(l,3-benzodioxol5-yl)ethanamine as the appropriate amine Example 73 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂iH₂oN₆02 388.1648, Found: 389.1728 [M+H]⁺

Example 74 4-{3-[(2,2-dichlorocyclopropyl)methyl]-2-methyl-3.W-imidazo[4,5-ô]pyridin5-yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using (2,2dichlorocyclopropyl)methanamine as the appropriate amine Example 74 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₆Hi₆N₆C12 362.0814, Found: 363.0883 [M+H]⁺

Example 75 4-[2-methyl-3-(3-methylbutyl)-3/7-imidazo[4,5-à]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2a following General procedure II and using 3-methylbutan-lamine as the appropriate amine Example 75 was obtained. HRMS (TOF, ESI) m/z: Calculated for C_I7H₂₂N₆ 310.1906, Found: 311.1990 [M+H]⁺

Example 76 4-[2-methyl-3-(tetrahydro-2/7-pyran-3-ylmethyl)-3//-imidazo[4,5-ô]pyridin5-yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using tetrahydro-2//pyran-3-ylmethanamine as the appropriate amine Example 76 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci8H₂2N₆O 338.1855, Found: 339.1941 [M+H]⁺

-48Example 77 4- {3-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]-2-methyl-377-imidazo[4,5/>]pyridin-5-yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(2,3-dihydro-1,4benzodioxin-6-yl)ethanamine as the appropriate amine Example 77 was obtained. HRMS (TOF, ESI) m/z: Calculated for C22H22N6O2 402.1804, Found: 403.1888 [M+H]⁺

Example 78 4- {2-methyl-3-[2-(tetrahydro-2//-pyran-4-yl)ethyl]-377-imidazo[4,5h]pyridin-5-yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-tetrahydro-2//pyran-4-ylethanamine as the appropriate amine Example 78 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₉H₂₄N₆O 352.2012, Found: 353.2080 [M+H]⁺

Example 79 4-(2-methyl-3-{2-[2-(trifluoromethyl)phenyl]ethyl}-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-[2(trifluoromethyl)phenyl]ethanamine as the appropriate amine Example 79 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂iHi₉N₆F₃ 412.1623, Found: 413.1708 [M+H]⁺

Example 80 4-[2-methyl-3-(tetrahydro-2//-pyran-4-yLmethyl)-3//-imidazo[4,5-/>]pyridin5-yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using tetrahydro-2Hpyran-4-ylmethanamine as the appropriate amine Example 80 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₈H₂₂N₆O 338.1855, Found: 339.1929 [M+H]⁺

Example 81 4-{3-[2-(2-methoxyphenyl)ethyl]-2-methyl-3//-imidazo[4,5-ô]pyridin-5y 1} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(2methoxyphenyl)ethanamine as the appropriate amine Example 81 was obtained. HRMS (TOF, ESI) m/z: Calculated for C21H22N6O 374.1855, Found: 375.1924 [M+H]⁺

Example 82 4-{3-(1-( furan-2-yl)propan-2-yl]-2-methyl-3/f-imidazo[4,5-b]pyridin-5yl} pyridine-2,6-diamine

-49Starting from Préparation 2a following General procedure II and using l-(2-furyl)propan2-amine as the appropriate amine Example 82 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci9H₂₀N₆O 348.1699, Found: 349.1772 [M+H]⁺

Example 83 4-[2-methyl-3-(2-phenylethyl)-3/7-imidazo[4,5-ô]pyridin-5-yl]pyridine-2,65 diamine

Starting from Préparation 2a following General procedure 11 and using 2-phenylethylamine as the appropriate amine Example 83 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₀H₂₀N₆ 344.1749, Found: 345.1829 [M+H]⁺

Example 84 4- {3-[(2-fIuoropyridin-4-yl)methyl]-2-methyl-3/7-imidazo[4,5-Z)]pyridin-510 yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using (2-fluoro-4pyridyl)methanamine as the appropriate amine Example 84 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₈H,₆N₇F 349.1451, Found: 350.1531 [M+H]⁺

Example 85 4- {2-methyl-3-[2-(tetrahydrofuran-2-yl)ethyl]-3 A-imidazo[4,5-ô]pyridin-515 yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-tetrahydrofùran2-ylethanamine as the appropriate amine Example 85 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₈H₂₂N₆O 338.1855, Found: 339.1930 [M+H]⁺

Example 86 4- {2-methyl-3-[(2-methylcyclopropyl)methyl]-3/7-imidazo[4,5-/>]pyridin-520 yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using l-(2methylcyclopropyl)methanamine as the appropriate amine Example 86 was obtained.

HRMS (TOF, ESI) m/z: Calculated for C_i7H₂₀N₆ 308.1749, Found: 309.1822 [M+H]⁺

Example 87 4-(2-methyl-3-{2-[3-(propan-2-yloxy)phenyl]ethyl}-3A-imidazo[4,525 ô]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(3isopropoxyphenyl)ethanamine as the appropriate amine Example 87 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₃H₂₆N₆O 402.2168, Found: 403.2153 [M+H]⁺

-50Example 88 4-{3-[(l-ethylcyclopropyl)methyl]-2-methyl-37/-imidazo[4,5-6]pyridin-5y l} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using l-(lethylcyclopropyl)methanamine as the appropriate amine Example 88 was obtained.

HRMS (TOF, ESI) m/z: Calculated for C_I8H₂2N₆ 322.1906, Found: 323.1988 [M+H]⁺

Example 89 4-[3-(cyclopentylmethyl)-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using cyclopentylmethanamine as the appropriate amine Example 89 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₈H₂₂N₆ 322.1906, Found: 323.1987 [M+H]⁺

Example 90 4- {3-[2-(3-ethoxyphenyl)ethyl]-2-methyl-3//-imidazo[4,5-ô]pyridin-5yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(3ethoxyphenyl)ethanamine as the appropriate amine Example 90 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₂H₂₄N₆O 388.2012, Found: 389.1953 [M+H]⁺

Example 91 4-(2-methyl-3-{2-[3-(trifluoromethyl)phenyl]ethyl}-3#-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-[3(trifluoromethyl)phenyl]ethanamine as the appropriate amine Example 91 was obtained.

HRMS (TOF, ESI) m/z: Calculated for C₂jH_i9N₆F₃ 412.1623, Found: 413.1683 [M+H]⁺

Example 92 4-[3-(2-cyclopentylethyl)-2-methyl-37/-imidazo[4,5-6]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 2cyclopentylethanamine as the appropriate amine Example 92 was obtained. HRMS (TOF,

ESI) m/z: Calculated for C_I9H₂₄N₆ 336.2062, Found: 337.2012 [M+H]⁺

Example 93 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2-methyl-3//imidazo[4,5-6]pyridin-5-yl]pyridine-2,6-diamine

-5l Starting from Préparation 2a following General procedure II and using 5-methoxytetralin2-amine as the appropriate amine Example 93 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂3H₂4N₆O 400.2012, Found: 401.1963 [M+H]⁺

Example 94 4-(3-hexyl-2-methyl-3//-imidazo[4,5-Z?]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using hexan-1-amine as the appropriate amine Example 94 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₁₈H₂4N₆ 324.2062, Found: 325.2014 [M+H]⁺

Example 95 4- {3-[2-(2-methoxycyclohexyl)ethyl]-2-methyl-3Æ-imidazo[4,5-ô]pyridin-5y I} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(2methoxycyclohexyl)ethanamine as the appropriate amine Example 95 was obtained.

HRMS (TOF, ESI) m/z: Calculated for C₂iH2₈N₆O 380.2325, Found: 381.2378 [M+H]⁺

Example 96 4- {3-[2-(4-fluorophenyl)ethyl]-2-methyl-3//-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(4fluorophenyl)ethanamine as the appropriate amine Example 96 was obtained. HRMS (TOF, ESI) m/z: Calculated for C2oHi₉N₆F 362.1655, Found: 363.1726 [M+H]⁺

Example 97 4-{2-methyl-3-[(2-phenylcyclopropyl)methyl]-3/7-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using l-(2phenylcyclopropyl)methanamine as the appropriate amine Example 97 was obtained.

HRMS (TOF, ESI) m/z: Calculated for C22H22N6 370.1906, Found: 371.1976 [M+H]⁺

Example 98 4-[3-(5-methoxy-2,3-dihydro-l//-inden-2-yl)-2-mcthyl-3/7-imidazo[4,5Z>]pyridin-5-yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 5-methoxyindan-2amine as the appropriate amine Example 98 was obtained. HRMS (TOF, ESI) m/z: Calculated for C22H₂2N₆O 386.1855, Found: 387.1818 [M+H]⁺

-52Example 99 4-{3-[(2,2-dimethylcyclopropyl)methyl]-2-methyl-3//-imidazo[4,5-ô]pyridin5-yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 1-(2,2dimethylcyclopropyl)methanamine as the appropriate amine Example 99 was obtained. HRMS (TOF, ESI) m/z: Calculated for C_I8H₂2N₆ 322.1906, Found: 323.1978 [M+H]⁺

Example 100 4-[2-methyl-3-(3-phenylcyclobutyl)-3//-imidazo[4,5-6]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 3phenylcyclobutanamine as the appropriate amine Example 100 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₂H₂₂N₆ 370.1906, Found: 371.1978 [M+H]⁺

Example 101 4-[3-(3,3-difluorocyclobutyl)-2-methyl-3H-imidazo[4,5-ô]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 3,3difluorocyclobutanamine as the appropriate amine Example 101 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₁₆H_I6N₆F₂ 330.1405, Found: 331.1463 [M+H]⁺

Example 102 4- {2-methyl-3-[2-(2-methylcyclohexyl)ethyl]-3Z7-imidazo[4,5-Z>]pyridin-5y 1} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(2methylcyclohexyl)ethanamine as the appropriate amine Example 102 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂iH₂₈N₆ 364.2375, Found: 365.2447 and 365.2436 [M+H]⁺ for the two diastereoisomers.

Example 103 4-[3-(3-fluorocyclobutyl)-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 3fluorocyclobutanamine as the appropriate amine Example 103 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₆H|₇N₆F 312.1499, Found: 313.1566 [M+H]⁺

Example 104 4- {2-methyl-3-[(27?)-1 -phenoxypropan-2-yl]-3//-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

-53and

Example 105 4-{2-methyl-3-[(2_lS)-l-phenoxypropan-2-yl]-3//-imidazo[4,5-à]pyridin-5y 1} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 1-phenoxypropan2-amine as the appropriate amine a mixture of Example 104 and Example 105 was obtained. The enantiomers were separated on CHIRALCEL OK column using MeOH + 0.1% DEA as eluent to obtain Example 104 as the first eluting enantiomer. HRMS (TOF, ESI) m/z: Calculated for C₂₁H₂₂N₆O 374.1855, Found: 375.1913 [M+H]⁺ ee>99.8% (El). Example 105 was obtained as the second eluting enantiomer. HRMS (TOF, ESI) m/z: Calculated for C₂iH₂₂N₆O 374.1844, Found: 375.1917 [M+H]⁺ ee=98.4% (E2)

Example 106 4- {2-methyl-3-[(27?)-2-phenoxypropyl]-3/7-imidazo[4,5-&]pyridin-5yl} pyridine-2,6-diamine and

Example 107 4-{2-methyl-3-[(2S)-2-phenoxypropyl]-3//-imidazo[4,5-6]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-phenoxypropan1-amine as the appropriate amine a mixture of Example 106 and Example 107 was obtained. The enantiomers were separated on CHIRALCEL OK column using MeOH+0.1% DEA as eluent to obtain Example 106 as the first eluting enantiomer. HRMS (TOF, ESI) m/z: Calculated for C₂iH₂₂N₆O 374.1855, Found: 375.1924. [M+H]⁺ee>99.8% (El). Example 107 was obtained as the second eluting enantiomer. HRMS (TOF, ESI) m/z: Calculated for C₂iH₂₂N₆O 374.1855, Found: 375.1922 [M+H]⁺ ee>99.8% (E2)

Example 108 4-[2-methyl-3-(3,3,3-trifluoropropyl)-3f/-imidazo[4,5-ô]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 3,3,3trifluoropropan-l-amine as the appropriate amine Example 108 was obtained. HRMS (ITTOF, ESI) m/z: Calculated for Ci₅Hi₅N₆F₃ 336.131, Found: 337.1381 [M+H]⁺

Example 109 4-(2-methyl-3-{[(lS,2S)-2-phenylcyclopropyl]methyl}-3//-imidazo[4,5Z>] pyridin-5 -y l)pyridine-2,6-diamine

-54and

Example 110 4-(2-methyl-3- {[( 17?, 2/?)-2-pheny I cyclopropyl] met hyl} -3//-imidazo[4,5à]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using [l,2-trans-25 phenylcyclopropyl]methanamine as the appropriate amine a mixture of Example 109 and Example 110 was obtained. The enantiomers were separated on CHIRALCEL OD-H column using 40:60 1-PrOH/heptane+0.1% DEA as eluent to obtain Example 109 as the fïrst eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C22H22N6 370.1906, Found: 371.1981 [M+H]⁺ ee>99.8% (El). Example 110 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C22H22N6 370.1906, Found: 371.1984 [M+H]⁺ ee>99.8% (E2).

Example 111 4-{2-methyl-3-[(2E)-3-phenylprop-2-en-l-yl]-37/'-imidazo[4,5-6]pyridin-5yi}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using (E)-3-phenylprop15 2-en-l-amine as the appropriate amine Example 111 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C₂iH₂oN₆ 356.1749, Found: 357.1828 [M+H]⁺

Example 112 4-[3-(bicyclo[4.2.0]octa-l,3,5-trien-7-ylmethyI)-2-methyl-3//-imidazo[4,56]pyridin-5-yl]pyridine-2,6-diamine and

Example 113 4-[3-(bicyclo[4.2.0]octa-l,3,5-trien-7-yImethyl)-2-methyl-3//-imidazo[4,5Z>]pyridin-5-yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 1(bicyclo[4.2.0]octa-l,3,5-trien-7-ylmethanamine as the appropriate amine a mixture of Example 112 and Example 113 was obtained. The enantiomers were separated on

CHIRALPAK AS-H column using 50:50 EtOH/heptane+0.1% DEA as eluent to obtain Example 112 as the fïrst eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C21H20N6 356.1749, Found: 357.1818 [M+H]⁺ ee > 99.8% (El). Example 113 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C₂iH₂oN₆ 356.1749, Found: 357.1810 [M+H]⁺ ee = 99.6% (E2).

-55Example 114 4-(3-(2,3-dihydro-l//-inden-2-ylmcthyl)-2-mcthyl-3//-imidazo[4,56]pyridin-5-yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using indan-2ylmethanamine as the appropriate amine Example 114 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C22H22N6 370.1906, Found: 371.1962 [M+H]⁺

Example 115 4-(3-(2,2-difluoroethyl)-2-methy l-3J/-imidazo[4,5-6]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 2,2difluoroethanamine as the appropriate amine Example 115 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci4Hi₄N₆F₂ 304.1248, Found: 305.1318 [M+H]⁺

Example 116 4-[2-methyl-3-(2-methyl-2-phenoxypropyl)-3//-imidazo[4,5-6]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-methyl-2phenoxy-propan-1-amine as the appropriate amine Example 116 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C22H24N6O 388.2012, Found: 389.2069 [M+H]⁺

Example 117 4- {3-[(2S)-2-(2-chlorophenoxy)propyl]-2-methyl-3//-imidazo[4,5-6]pyridin5 -y 1} pyridine-2,6-diamine and

Example 118 4- {3-[(2/î)-2-(2-chlorophenoxy)propyl]-2-methyl-3//-imidazo[4,56]pyridin-5-yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(2chlorophenoxy)propan-l-amine as the appropriate amine a mixture of Example 117 and Example 118 was obtained. The enantiomers were separated on CHIRALPAK AS-H column using 50:50 EtOH/heptane+0.1 % DEA as eluent to obtain Example 117 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C21H21N6OCI 408.1465, Found: 409.1558 [M+H]⁺ ee>99.8% (El). Example 118 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C21H21N6OCI 408.1465, Found: 409.1538 [M+H]⁺ ee=99.8% (E2).

-56Example 119 4-{2-methyl-3-[(2₁S)-2-phenoxybutyl]-3J7-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine and

Example 120 4-{2-methyl-3-[(2J?)-2-phenoxybutyl]-3//-imidazo[4,5-6]pyridin-55 yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-phenoxybutan-lamine as the appropriate amine a mixture of Example 119 and Example 120 was obtained. The enantiomers were separated on CHIRALPAK AS-V column using 40:60 EtOH/heptane + 0.05% DEA as eluent to obtain Example 119 as the first eluting enantiomer. HRMS (TOF, ESI) m/z: Calculated for C22H24N6O 388.2012, Found: 389.2084 [M+H]⁺ ee>99.8% (El). Example 120 was obtained as the second eluting enantiomer. HRMS (TOF, ESI) m/z: Calculated for C22H24N6O 388.2012, Found: 389.2093 [M+H]⁺ ee=99.2% (E2).

Example 121 4-(2-methyl-3- {(2/?)-2-[methyl(phenyl)amino]propyl}-3//-imidazo[4,515 b]pyridin-5-yl)pyridine-2,6-diamine and

Example 122 4-(2-methyl-3- {(2S)-2-[methyl(phenyl)amino]propyl}-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using N²-methyl-N²20 phenyl-propane-l,2-diamine as the appropriate amine a mixture of Example 121 and Example 122 was obtained. The enantiomers were separated on CHIRALPAK IA column using 20:80 EtOH/heptane+0.1% DEA as eluent to obtain Example 122 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C22H25N7 387.2171, Found: 388.2253 [M+H]⁺ ee>99.8% (El). Example 121 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C22H25N7 387.2171, Found: 388.2232 [M+H]⁺ ee>99.8% (E2)

Example 123 4-{3-[(2S)-2-(3-fluorophenoxy)propyl]-2-methyl-3/7-imidazo[4,5-ô]pyridin5-y 1} pyridine-2,6-diamine and

Example 124 4-{3-[(2J?)-2-(3-fluorophenoxy)propyl]-2-methyl-3J7-imidazo[4,5-Z>]pyridin5-yl} pyridine-2,6-diamine

-57Starting from Préparation 2a following General procedure II and using 2-(3fluorophenoxy)propan-l-amine as the appropriate amine a mixture of Example 123 and Example 124 was obtained. The enantiomers were separated on CHIRALCEL OJ-H column using EtOH + 0.1% DEA as eluent to obtain Example 123 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C21H21N6OF 392.1761, Found: 393.1850 [M+H]⁺ ee>99.8% (El). Example 124 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C₂iH₂iN₆OF 392.1761, Found: 393.1828 [M+H]⁺ ee=99.8% (E2).

Example 125 4-{3-[(2S)-2-(3-methoxyphenoxy)propyl]-2-methyl-3/7-imidazo[4,56]pyridin-5-yl} pyridine-2,6-diamine and

Example 126 4- {3-[(27?)-2-(3-methoxyphenoxy)propyl]-2-methyl-3//-imidazo[4,5Z?]pyridin-5-yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(3methoxyphenoxy)propan-l-amine as the appropriate amine a mixture of Example 125 and Example 126 was obtained. The enantiomers were separated on CHIRALPAK AS-H column to obtain Example 125 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C22H₂₄N₆O2 404.1961, Found: 405.2040 [M+H]⁺ ee>99.8% (El). Example 126 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C22H₂₄N₆O₂ 404.1961, Found: 405.2048 [M+H]⁺ ee=99.6% (E2).

Example 127 4-{2-methyl-3-[(2S)-2-(3-methylphenoxy)propyl]-3//-imidazo[4,5b]pyridin-5-yl} pyridine-2,6-diamine and

Example 128 4-{2-methyl-3-[(2R)-2-(3-methylphenoxy)propyl]-3/f-imidazo[4,5b]pyridin-5-yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(3methylphenoxy)propan-l-amine as the appropriate amine a mixture of Example 127 and Example 128 was obtained. The enantiomers were separated on CHIRALPAK AS-V column using 50:50 EtOH/heptane + 0.05% DEA as eluent to obtain Example 127 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C22H2₄NôO 388.2012, Found: 389.2088. [M+H]⁺ ee>99.8% (El). Example 128 was obtained as the second

-58eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C22H24N6O 388.2012, Found: 389.2079. [M+H]⁺ ee=99.2% (E2).

Example 129 4- {3-[(2S)-2-(4-fluorophenoxy)propyl]-2-methyl-3A-imidazo[4,5-ô]pyridin5-yl} pyridine-2,6-diamine and

Example 130 4- {3-[(2Æ)-2-(4-fluorophenoxy)propyl]-2-methyl-3//-imidazo[4,5-à]pyridin5 -y 1} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(4fluorophenoxy)propan-l-amine as the appropriate amine a mixture of Example 129 and Example 130 was obtained. The enantiomers were separated on CHIRALPAK AS-V column using 50:50 EtOH/heptane + 0.05% DEA as eluent to obtain Example 129 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C21H21N6OF 392.1761, Found: 393.1832. [M+H]⁺ ee>99.8% (El). Example 130 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C21H21N6OF 392.1761, Found: 393.1834. [M+H]⁺ ee=99.8% (E2).

Example 131 4- {2-methyl-3-[(2<S)-2-(2-methylphenoxy)propyl]-3//-imidazo[4,5ô]pyridin-5-yl}pyridine-2,6-diamine and

Example 132 4- {2-methyl-3-[(2/?)-2-(2-methylphenoxy)propyl]-3//-imidazo[4,5à]pyridin-5-yl}pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(2methylphenoxy)propan-l-amine as the appropriate amine a mixture of Example 131 and Example 132 was obtained. The enantiomers were separated on OJ column using EtOH + 0.05% DEA as eluent to obtain Example 131 as the first eluting enantiomer. HRMS (ITTOF, ESI) m/z: Calculated for C₂₂H24N₆O 388.2012, Found: 389.2103 [M+H]⁺ ee>99.8% (El). Example 132 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C22H₂4N₆O 388.2012, Found: 389.2081 [M+H]⁺ ee=99.0% (E2).

Example 133 4- {3-[(2S)-2-(2-fluorophenoxy)propyl]-2-methyl-3/7-imidazo[4,5-ô]pyridin5-yl} pyridine-2,6-diamine and

-59Example 134 4- {3-[(2/?)-2-(2-fluorophenoxy)propyl]-2-methyl-377-imidazo[4,5-h]pyridin5-yl) pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(2fluorophenoxy)propan-l -amine as the appropriate amine a mixture of Example 133 and Example 134 was obtained. The enantiomers were separated on CHIRALPAK AS-V column using 70:30 EtOH/heptane + 0.05% DEA as eluent to obtain Example 133 as the first eluting enantiomer. HRMS (1T-TOF, ESI) m/z: Calculated for C21H21N6OF 392.1761, Found: 393.1836 [M+H]⁺ ee>99.8% (El). Example 134 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C21H21N6OF 392.1761, Found: 393.1852. [M+H]⁺ ee=99.6% (E2).

Example 135 4- {2-methyl-3-[(25)-2-(phenylsulfanyl)propyl]-3//-imidazo[4,5-6]pyridin-5y 1} pyridine-2,6-diamine and

Example 136 4- {2-methyl-3-[(2J?)-2-(phenylsulfanyl)propyl]-3//-imidazo[4,5-ô]pyridin-5y 1} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2phenylsulfanylpropan-1-amine as the appropriate amine a mixture of Example 135 and Example 136 was obtained. The enantiomers were separated on CHIRALPAK AS-V column using 40:60 EtOH/heptane + 0.05% DEA as eluent to obtain Example 135 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C21H22N6S 390.1627, Found: 391.1701 [M+H]⁺ ee>99.8% (El). Example 136 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C21H22N6S 390.1627, Found: 391.1711 [M+H]⁺ ee=99.4% (E2).

Example 137 4-{3-((15,2J?)-2-benzylcyclopropyl]-2-methyl-3J/-imidazo[4,5-£]pyridin-5yl} pyridine-2,6-diamine and

Example 138 4- {3-((15,25)-2-benzylcyclopropyl]-2-methyl-3#-imidazo[4,5-b]pyridin-5yl} pyridine-2,6-diamine and

Example 139 4-{3-[(lÆ,2./î)-2-benzylcyclopropyl]-2-methyl-3/f-imidazo[4,5-6]pyridm-5yl} pyridine-2,6-diamine

-60and

Example 140 4-{3-[(l.Æ,2S)-2-benzylcyclopropyl]-2-methyl-3//-imidazo[4,5-£]pyridin-5y l} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 25 benzylcyclopropanamine as the appropriate amine a mixture of the czs-products (Example 137,Example 138) and the mixture of the irans-products (Example 139 ,Example 140) were obtained. The enantiomers of these mixtures were separated on CHIRALCEL OD column using 50:50 EtOH/heptane + 0.05% DEA as eluent.

We obtained Example 137 as the first eluting enantiomer of the cis-mixture. HRMS (IT10 TOF, ESI) m/z: Calculated for C₂₂H₂2N₆ 370.1906, Found: 371.1966 [M+H]⁺ ee>99.8 % (El). Example 138 was obtained as the second eluting enantiomer of the cis-mixture. HRMS (IT-TOF, ESI) m/z: Calculated for C22H22N6 [M+H]⁺ 370.1906, Found: 371.1981 ee>99.8 % (E2).

We obtained Example 139 as the first eluting enantiomer of the trans-mixture. HRMS (IT15 TOF, ESI) m/z: Calculated for C₂₂H₂2N6 370.1906, Found: 371.1983 [M+H]⁺ ee=99.6 % (El). Example 140 was obtained as the second eluting enantiomer ofthe trans-mixture. HRMS (IT-TOF, ESI) m/z: Calculated for C22H22N6 370.1906, Found: 371.1988 [M+H]⁺ee=99.8 % (E2).

Example 141 4- {3-[(2S)-2-(2-methoxyphenoxy)propyl]-2-methyl-3/f-imidazo[4,520 Z>]pyridin-5-yl} pyridine-2,6-diamine and

Example 142 4- {3-[(2Æ)-2-(2-methoxyphenoxy)propyl]-2-methyl-3/7-imidazo[4,5ô] pyr idin-5-y 1} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(225 methoxyphenoxy)propan-l-amine as the appropriate amine a mixture of Example 141 and Example 142 was obtained. The enantiomers were separated on CHIRALPAK AS-H column using 50:50 l-PrOH/heptane+0.1% DEA as eluent to obtain Example 141 as the first eluting enantiomer. HRMS (TOF, ESI) m/z: Calculated for C22H₂4N6O2 404.1961, Found: 405.2041 [M+H]⁺. Example 142 was obtained as the second eluting enantiomer.

HRMS (TOF, ESI) m/z: Calculated for C22H₂4N₆O₂ 404.1961, Found: 405.2038 [M+H]⁺

-61 Example 143 4-[2-methyl-3-(3-phenoxypropyl)-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 3-phenoxypropan1-amine as the appropriate amine Example 143 was obtained. HRMS (TOF, ESI) m/z: Calculated for C2iH₂₂N₆O 374.1855, Found: 375.1946 [M+H]⁺

Example 144 4-(2,3-dibutyl-3//-imidazo[4,5-6]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2b following General procedure II and using butan-l-amine as the appropriate amine Example 144 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci9H₂₆N6 338.2219, Found: 339.2289 [M+H]⁺

Example 145 4-(2-butyl-3-cyclopentyl-377-imidazo[4,5-Z>]pyridin-5-yl)pyridine-2,6diamine

Starting from Préparation 2b following General procedure II and using cyclopentanamine as the appropriate amine Example 145 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₀H₂₆N₆ 350.2219 Found: 351.2270 [M+H]⁺

Example 146 4-[2-butyl-3-(2-phenoxyethyl)-3/7-imidazo[4,5-è]pyridin-5-yl]pyridine-2,6diamine

Starting from Préparation 2b following General procedure II and using 2phenoxyethanamine as the appropriate amine Example 146 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₃H₂₆N₆O 402.2168 Found: 403.2235 [M+H]⁺

Example 147 4-(2-butyl-3-methyl-37/-imidazo[4,5-Z?]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2b following General procedure II and using methanamine as the appropriate amine Example 147 was obtained. HRMS (TOF, ESI) m/z: Calculated for C|₆H₂₀N₆ 296.1749, Found: 297.1824 [M+H]⁺

Example 148 4-(3-butyl-2-methyl-37/-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using butan-l-amine as the appropriate amine Example 148 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₆H₂₀N₆ 296.1749, Found: 297.1842 [M+H]⁺

-62Example 149 4-{3-[(lR)-l-(2-fluoropyridin-4-yl)ethyl]-2-methyl-3F/-imidazo[4,5Z>]pyridin-5-yl} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using (lR)-l-(2-fluoro-4pyridyl)ethanamine as the appropriate amine Example 149 was obtained. HRMS (TOF, ESI) m/z: Calculated for C_I9H₎₈N₇F 363.1608, Found: 364.1674 [M+H]⁺

Example 150 4-[3-(3-methoxypropyl)-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 3-methoxypropan1-amine as the appropriate amine Example 150 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₆H₂oN₆0 312.1699, Found: 313.1761 [M+H]⁺

Example 151 4-[3-(4-methoxybutyl)-2-methyl-37/-imidazo[4,5-à]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 4-methoxybutan-lamine as the appropriate amine Example 151 was obtained. HRMS (TOF, ESI) m/z: Calculated for C|₇H₂₂N₆O 326.1855, Found: 327.1919 [M+H]⁺

Example 152 4- {3-[2-(3-methoxyphenyl)ethyl]-2-methyl-3H-imidazo[4,5-6]pyridin-5y I} pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using 2-(3methoxyphenyl)ethanamine as the appropriate amine Example 152 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₎H₂₂N₆O 374.1855, Found: 375.1919 [M+H]⁺

Example 153 4-[2-methyl-3-(2-phenoxyethyl)-3H-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2a following General procedure II and using 2phenoxyethanamine as the appropriate amine Example 153 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₀H₂₀N₆O 360.1699, Found: 361.1774. [M+H]⁺

Example 154 4-(3-ethyl-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine

-63Starting from Préparation 2a following General procedure II and using ethanamine as the appropriate amine Example 154 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₄Hi₆N₆ 268.1436, Found: 269.1510 [M+H]⁺

Example 155 4-[3-(bicyclo[2.2.1 ]hept-2-yl)-2-methyl-3//-imidazo[4,5-ô]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2a following General procedure II and using norboman-2-amine as the appropriate amine Example 155 was obtained. HRMS (TOF, ESI) m/z: Calculated for C_I9H₂₂N₆ 334.1906, Found: 335.1981 [M+H]⁺

Example 156 4-(3-cyclopentyl-2-ethyl-3//-imidazo[4,5-6]pyridin-5-yl)pyridine-2,6diamine

Starting from Préparation 2c following General procedure II and using cyclopentanamine as the appropriate amine Example 156 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₈H₂2N₆ 322.1906, Found: 323.1993 [M+H]⁺

Example 157 4-(3-butyl-2-ethyl-3Ff-imidazo[4,5-5]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2c following General procedure II and using butan-1-amine as the appropriate amine Example 157 was obtained. HRMS (TOF, ESI) m/z: Calculated for C_I7H₂₂N₆ 310.1906, Found: 311.1982 [M+H]⁺

Example 158 4-[3-(2,3-dihydro-l//-inden-2-yl)-2-ethyl-37/-imidazo[4,5-ô]pyridin-5yl]pyridine-2,6-diamine

Starting from Préparation 2c following General procedure II and using indan-2-amine as the appropriate amine Example 158 was obtained. HRMS (TOF, ESI) m/z: Calculated for C2₂H₂₂N₆ 370.1906, Found: 371.1992 [M+H]⁺

Example 159 4-(2-ethyl-3-methyl-3H-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2c following General procedure II and using methanamine as the appropriate amine Example 159 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₄H_i6N₆ 268.1436, Found: 269.1512 [M+H]⁺

-64Example 160 4-(3-cyclopentyl-2-propyl-3//-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6diamine

Starting from Préparation 2d following General procedure II and using cyclopentanamine as the appropriate amine Example 160 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₉H₂₄N₆ 336.2062 Found: 337.2150 [M+H]⁺

Example 161 4-(3-butyl-2-propyl-3//-imidazo[4,5-/>]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2d following General procedure II and using butan-1-amine as the appropriate amine Example 161 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₈H₂₄N₆ 324.2062, Found: 325.2145 [M+H]*

Example 162 4-[3-(2-phenoxyethyl)-2-propyl-3/f-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

Starting from Préparation 2d following General procedure II and using 2phenoxyethanamine as the appropriate amine Example 162 was obtained. HRMS (ITTOF, ESI) m/z: Calculated for C₂₂H₂₄N₆O 388.2012 Found: 389.2081 [M+H]⁺

Example 163 4-(3-methyl-2-propyl-3//-imidazo[4,5-à]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 2d following General procedure II and using methanamine as the appropriate amine Example 163 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₅Hi₈N₆ 282.1593, Found: 283.1663 [M+H]⁺

Example 164 4-(3- {2-[(5-chloropyridin-2-yl)oxy]ethyl}-2-methyl-37/-imidazo[4,5Z>]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3a following General procedure III and using 2-fluoro-5chloropyridine as the appropriate aryl halide Example 164 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C_i9Hi₈N₇OC1 395.1261, Found: 396.1326 [M+H]⁺

Example 165 4-(3- {2-[(6-chloropyridin-2-yl)oxy]ethyl}-2-methyl-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3a following General procedure III and using 2-fluoro-6chloropyridine as the appropriate aryl halide Example 165 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for Ci₉H_I8N₇OC1 395.1261, Found: 396.1331. [M+H]⁺

-65Example 166 4-(3-{2-[(3-chloropyridin-2-yl)oxy]ethyl}-2-methyl-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3a following General procedure ΙΠ and using 2-fluoro-3chloropyridine as the appropriate aryl halide Example 166 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C_I9H₁₈N₇OCl 395.1261, Found: 396.1319 [M+H]⁺

Example 167 4-(3- {2-[(6-fluoropyridin-2-yl)oxy]ethyl} -2-methyl-3/7-imidazo[4,5/>]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3a following General procedure III and using 2,6difluoropyridine as the appropriate aryl halide Example 167 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₁₉H,₈N₇OF 379.1557, Found: 380.1635 [M+H]⁺

Example 168 4-(3-{2-[(6-bromopyridin-2-yl)oxy]ethyl}-2-methyl-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3a following General procedure ΙΠ and using 2-fluoro-6bromopyridine as the appropriate aryl halide Example 168 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C,₉H₁₈N₇OBr 439.0756, Found: 440.0823 [M+H]⁺

Example 169 4-(3-{2-[(3-bromopyridin-2-yl)oxy]ethyl}-2-methyl-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3a following General procedure ΙΠ and using 2-fluoro-3bromopyridine as the appropriate aryl halide Example 169 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C_l9H₁₈N₇OBr 439.0756, Found: 440.0817 [M+H]⁺

Example 170 4-(3-{2-[(5-bromopyridin-2-yl)oxy]ethyl}-2-methyl-3Z7-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3a following General procedure III and using 2-fluoro-5bromopyridine as the appropriate aryl halide Example 170 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C₁₉Hi₈N₇OBr 439.0756, Found: 440.0811 [M+H]⁺

Example 171 4-(3- {2-[(5-fluoropyridin-2-yl)oxy]ethyl} -2-methyl-3/7-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

-66Starting from Préparation 3a following General procedure III and using 2,5difluoropyridine as the appropriate aryl halide Example 171 was obtained. HRMS (ITTOF, ESI) m/z: Calculated for C₁₉H₁₈N₇OF 379.1557, Found: 380.1617 [M+H]⁺

Example 172 4-(3-(2- {[6-(fluoromethyl)pyridin-2-yl]oxy) ethyl)-2-methyl-3//5 imidazo[4,5-ô]pyridin-5-yl]pyridine-2,6-diamine

Starting from Préparation 3a following General procedure III and using 2-fluoro-6fluoromethylpyridine as the appropriate aryl halide Example 172 was obtained. HRMS (TOF, ESI) m/z: Calculated for C20H20FN7O 393.1713, Found: 394.1784 [M+H]⁺

Example 173 4-(3-(2- {[6-(difluoromethyl)pyridin-2-yl]oxy} ethyl)-2-methyl-3//10 imidazo[4,5-6]pyridin-5-y l]pyridine-2,6-diamine

Starting from Préparation 3a following General procedure III and using 2-fluoro-6difluoromethylpyridine as the appropriate aryl halide Example 173 was obtained. HRMS (TOF, ESI) m/z: Calculated for C2oHi9F₂N₇0 411.1619, Found: 412.1686 (M+H]⁺

Example 174 4-{2-methyl-3-[(2S)-2-(pyridin-2-yloxy)propyl]-3//-imidazo[4,5-Z?]pyridin15 5-yl}pyridine-2,6-diamine and

Example 175 4- {2-methyl-3-[(2R)-2-(pyridin-2-yloxy)propyl]-3//-imidazo(4,5-6]pyridin5-yl) pyridine-2,6-diamine

Starting from Préparation 3b following General procedure III and using 2-fluoropyridine as 20 the appropriate aryl halide a mixture of Example 174 and Example 175 was obtained. The enantiomers were separated on CHIRALCEL OK column using 50:50 EtOH/heptane + 0.05% DEA as eluent to obtain Example 174 as the fïrst eluting enantiomer. HRMS (ITTOF, ESI) m/z: Calculated for C₂₀H₂₁N₇O 375.1808, Found: 376.1867 [M+H]⁺ ee>99.8% (El). Example 175 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) 25 m/z: Calculated for C20H21N7O 375.1808, Found: 376.1872 (M+H]⁺ ee>99.8% (E2).

Example 176 4-(3-{(2S)-2-[(6-chloropyridin-2-yl)oxy]propyl)-2-methyl-37/-imidazo[4,5ô]pyridin-5-yl)pyridine-2,6-diamine and

-67Example 177 4-(3-{(27?)-2-[(6-chloropyridin-2-yl)oxy]propyl}-2-methyl-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3b following General procedure III and using 2-fluoro-6chloropyridine as the appropriate aryl halide a mixture of Example 176 and Example 177 was obtained. The enantiomers were separated on OJ column using EtOH + 0.05% DEA as eluent to obtain Example 176 as the earlier eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C20H20N7OCI 409.1418, Found: 410.1469 [M+H]⁺ ee>99.8% (El).

Example 177 was obtained as the later eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C20H20N7OCI 409.1418, Found: 410.1482 [M+H]⁺ ee=98.8% (E2)

Example 178 4-(3- {(2S)-2-[(5-fluoropyridin-2-yl)oxy]propyl}-2-methyl-3//-imidazo[4,5ô]pyridin-5-yl)pyridine-2,6-diamine and

Example 179 4-(3-{(2R)-2-[(5-fluoropyridin-2-yl)oxy]propyl}-2-methyl-3//-imidazo[4,5b]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3b following General procedure III and using 2,5difluoropyridine as the appropriate aryl halide a mixture of Example 178 and Example 179 was obtained. The enantiomers were separated on AS column using 50:50 1PrOH/heptane + 0.1% DEA as eluent to obtain Example 178 as the earlier eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C20H20N7O 393.1713, Found: 394.1780 [M+H]⁺ ee=99.4% (El).Example 179 was obtained as the later eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C20H20N7O 393.1713, Found: 394.1774 [M+H]⁺ ee=98.6% (E2).

Example 180 4-(3-{(2<S)-2-[(6-bromopyridin-2-yl)oxy]propyl}-2-methyl-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine and

Example 181 4-(3- {(27?)-2-[(6-bromopyridin-2-yl)oxy]propyl)-2-methyl-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3b following General procedure III and using 2-fluoro-6bromopyridine as the appropriate aryl halide a mixture of Example 180 and Example 181 was obtained. The enantiomers were separated on CHIRALPAK AS-H column using 40:60 EtOH/heptane+0.1% DEA as eluent to obtain Example 180 as the earlier eluting

-68enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for 02οΗ₂οΝ70Βγ 453.0913, Found: 454.0970 [M+H]⁺ ee>99.8% (El). Example 181 was obtained as the later eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C2oH2oN70Br 453.0913, Found: 454.0967 [M+H]⁺ ee=99.0% (E2).

Example 182 4-(3-{(2S)-2-[(3-bromopyridin-2-yl)oxy]propyl}-2-methyl-3/7-imidazo[4,5Z>]pyridin-5-yl)pyridine-2,6-diamine and

Example 183 4-(3-{(2R)-2-[(3-bromopyridin-2-yl)oxy]propyl)-2-methyl-3/7-imidazo[4,5à]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3b following General procedure III and using 2-fluoro-3bromopyridine as the appropriate aryl halide a mixture of Example 182 and Example 183 was obtained. The enentiomers were separated on CHIRALPAK AS-H column using 70:30 2-PrOH/heptane+0.1% DEA as eluent to obtain Example 182 as the earlier eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C2oH2oN70Br 453.0913, Found:

454.0963 [M+H]⁺ ee>99.8% (El). Example 183 was obtained as the later eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C2oH2oN70Br 453.0913, Found: 454.0968 [M+H]⁺ ee=99.0% (E2).

Example 184 4-(3-{(2S)-2-[(5-chloropyridin-2-yl)oxy]propyl}-2-methyl-3#-imidazo[4,5Z>]pyridin-5-yl)pyridine-2,6-diamine and

Example 185 4-(3-{(2R)-2-[(5-chloropyridin-2-yl)oxy]propyl}-2-methyl-3/7-imidazo[4,5Z>]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3b following General procedure III and using 2-fluoro-5chloropyridine as the appropriate aryl halide a mixture of Example 184 and Example 185 was obtained. The enantiomers were separated on OJ column using 50:50 EtOH/heptane + 0.05% DEA as eluent to obtain Example 184 as the earlier eluting enantiomer. HRMS (ITTOF, ESI) m/z: Calculated for C20H20N7OCI 409.1418, Found: 410.1469. [M+H]⁺ee>99.8% (El). Example 185 was obtained as the later eluting enantiomer. HRMS (TOF, ESI) m/z: Calculated for C20H20CIN7O 409.1418, Found: 410.1471 [M+H]⁺ ee99.8% (E2).

-69Example 186 4-(3- {(25)-2-[(5-bromopyridin-2-yl)oxy]propyl) -2-methyl-3/7-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine and

Example 187 4-(3- {(2Æ)-2-[(5-bromopyridin-2-yl)oxy]propyl} -2-methyl-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3b following General procedure III and using 2-fluoro-5bromopyridine as the appropriate aryl halide a mixture of Example 186 and Example 187 was obtained. The enentiomers were separated on OJ column using 60:40 EtOH/heptane + 0.05% DEA as eluent to obtain Example 186 as the earlier eluting enantiomer. HRMS (ITTOF, ESI) m/z: Calculated for C₂oH₂oN₇OBr 453.0913 Found: 454.0967 [M+H]⁺ee>99.8% (El). Example 187 was obtained as the later eluting enantiomer. HRMS (ITTOF, ESI) m/z: Calculated for C₂₀H₂₀N₇OBr 453.0913 Found: 454.0983 [M+H]⁺ee=99.2% (E2).

Example 188 4-(3-{(2S)-2-[(6-fluoropyridin-2-yl)oxy]propyl}-2-methyl-3f/-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine and

Example 189 4-(3- {(2J?)-2-[(6-fluoropyridin-2-yl)oxy]propyl) -2-methyl-3//-imidazo[4,5ô]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3b following General procedure III and using 2,6difluoropyridine as the appropriate aryl halide a mixture of Example 188 and Example 189 was obtained. The enantiomers were separated on CHIRALCEL OJ-H column using EtOH+0.1% DEA as eluent to obtain Example 188 as the earlier eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C₂₀H₂₀N₇OF 393.1713, Found: 394.1779 [M+H]⁺ ee>99.8% (El). Example 189 was obtained as the later eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C₂₀H₂₀N₇OF 393.1713, Found: 394.1773 [M+H]⁺ ee=99.6% (E2).

Example 190 4-(3- {(25)-2-[(3-chloropyridin-2-yl)oxy]propyl} -2-methyl-3//-imidazo[4,5Z>]pyridin-5-yl)pyridine-2,6-diamine and

Example 191 4-(3-{(2Æ)-2-[(3-chloropyridin-2-yl)oxy]propyl}-2-methyl-3f7-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

-70Starting from Préparation 3b following General procedure III and using 2-fluoro-3chioropyridine as the appropriate aryl halide a mixture of Example 190 and Example 191 was obtained. The enantiomers were separated on CHIRALPAK AS-V column using 70:30 2-PrOH/heptane + 0.05% DEA as eluent to obtain Example 190 as the earlier eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C20H20N7OCI 409.1418, Found: 410.1477 [M+H]⁺ ee>99.8% (El). Example 191 was obtained as the later eluting enantiomer. HRMS (IT-TOF, ESI) m/z: Calculated for C20H20N7OCI 409.1418, Found: 410.1492 [M+H]⁺ ee>99.8% (E2)

Example 192 4-(3- {(2S)-2-[(3,6-difluoropyridin-2-yl)oxy]propyl) -2-methyl-3FA imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine and

Example 193 4-(3- {(2R)-2-[(3,6-difluoropyridin-2-yl)oxy]propyl) -2-methyl-3//imidazo[4,5-6]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3b following General procedure III and using 2,3,615 trifluoropyridine as the appropriate aryl halide a mixture of Example 192 and Example 193 was obtained. The enantiomers were separated on CHIRALCEL OK column using 60:40 EtOH/heptane + 0.05% DEA as eluent to obtain Example 192 as the earlier eluting enantiomer. HRMS (TOF, ESI) m/z: Calculated for C20H19F2N7O 411.1699, Found: 412.1694 [M+H]⁺ ee>99.8% (El). Example 193 was obtained as the later eluting enantiomer. HRMS (TOF, ESI) m/z: Calculated for C2oHj9F2N₇0 411.1619, Found: 412.1700 [M+H]⁺ ee>99.8% (E2).

Example 194 4-[2-methy 1-3-(2- {[6-(trifluoromethyl)pyridin-2-yl]oxy) ethyl)-3//imidazo[4,5-Z>]pyridin-5-yl]pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 6-trifluoromethyl25 2-pyridone as the appropriate phénol analog Example 194 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C2oH₁₈N₇OF₃ 429.1525, Found: 430.1608 [M+H]⁺

Example 195 4-(2-methyl-3-{2-[(6-methylpyridin-2-yl)oxy]ethyl}-3//-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

-71 Starting from Préparation 3a following General procedure IV and using 6-methyl-2pyridone as the appropriate phénol analog Example 195 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₀H_2lN₇O 375.1808, Found: 376.1872 [M+H]⁺

Example 196 4-(3-{2-[(6-aminopyridin-2-yl)oxy]ethyl}-2-methyl-3Z7-imidazo[4,56]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 6-amino-2pyridone as the appropriate phénol analog Example 196 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for Ci₉H₂₀N₈O 376.1760, Found: 377.1826 [M+H]⁺

Example 197 6- {2-(5-(2,6-diaminopyridin-4-yl)-2-methyl-3.H-imidazo[4,5-Z>]pyridin-3yl]ethoxy} pyridine-2-carbonitrile

Starting from Préparation 3a following General procedure IV and using 6-cyano-2pyridone as the appropriate phénol analog Example 197 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C₂₀H]₈N₈O 386.1604, Found: 387.1655 [M+H]⁺

Example 198 4- {3-[2-(4-fluorophenoxy)cthyl]-2-methyl-3//-imidazo[4,5-6]pyridin-5y 1} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 4-fluorophenol as the appropriate phénol analog Example 198 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₀H]₉N₆OF 378.1604, Found: 379.1683 [M+H]⁺

Example 199 4- {3-[2-(3-fluorophenoxy)ethyl]-2-methyl-3J7-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 3-fluorophenol as the appropriate phénol analog Example 199 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₀H₁₉N₆OF 378.1604, Found: 379.1621 [M+H]⁺

Example 200 4- {3-[2-(3-chlorophenoxy)ethyl]-2-methyl-3//-imidazo[4,5-à]pyridin-5y 1} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 3-chlorophenol as the appropriate phénol analog Example 200 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₀H|₉N₆OC1394.1309, Found: 395.1308 [M+H]⁺

-72Example 201 4- {2-methyl-3-[2-(3-methylphenoxy)ethyl]-3//-imidazo[4,5-ô]pyridin-5yl}pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 3-methylphenol as the appropriate phénol analog Example 201 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂iH₂₂N₆O 374.1855, Found: 375.1908 [M+H]⁺

Example 202 4- {3-[2-(3-methoxyphenoxy)ethyl]-2-methyl-3//-imidazo[4,5-ô]pyridin-5y 1} pyridine-2,6-d iamine

Starting from Préparation 3a following General procedure IV and using 3-methoxyphenol as the appropriate phénol analog Example 202 was obtained. HRMS (TOF, ESI) m/z: Calculated for C2iH₂₂N₆O₂ 390.1804, Found: 391.1810 [M+H]⁺

Example 203 4- {3-[2-(2-fluorophenoxy)ethyl]-2-methyl-3/7-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 2-fluorophenol as the appropriate phénol analog Example 203 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂oHi₉N₆OF 378.1604, Found: 379.1685 [M+H]⁺

Example 204 4- {3-[2-(2-chlorophenoxy)ethyl]-2-methyl-3//-imidazo[4,5-Z>]pyridin-5yl) pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 2-chlorophenol as the appropriate phénol analog Example 204 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂oH_I9N₆OC1 394.1309, Found: 395.1387 [M+H]⁺

Example 205 4- (2-methyl-3-[2-(2-methylphenoxy)ethyl]-3//-imidazo[4,5-ô]pyridin-5y 1} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 2-methylphenol as the appropriate phénol analog Example 205 was obtained. HRMS (TOF, ESI) m/z: Calculated for C_2IH₂₂N₆O 374.1855, Found: 375.1929 [M+H]⁺

Example 206 4- {3-[2-(2-methoxyphenoxy)ethyl]-2-methyl-3/7-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

I

-73Starting from Préparation 3a following General procedure IV and using 2-methoxyphenol as the appropriate phénol analog Example 206 was obtained. HRMS (TOF, ESI) m/z: Calculated for C2iH₂2N₆O₂ 390.1804, Found: 391.1888 [M+H]⁺

Example 207 4- {3-[2-(4-chlorophenoxy)ethyl]-2-methyl-3//-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 4-chlorophenol as the appropriate phénol analog Example 207 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₀Hi₉N₆OCl 394.1309, Found: 395.1389 [M+H]⁺

Example 208 4- {2-methyl-3-[2-(4-methylphenoxy)ethyl]-3//-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 4-methylphenol as the appropriate phénol analog Example 208 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂iH₂2N₆O 374.1855, Found: 375.1937 [M+H]⁺

Example 209 4- {3-[2-(4-methoxyphenoxy)ethyl]-2-methyl-3Æ-imidazo[4,5-ô]pyridin-5yl}pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 4-methoxyphenol as the appropriate phénol analog Example 209 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₁H₂₂N₆O₂ 390.1804, Found: 391.1883 [M+H]⁺

Example 210 4- {3-[2-(l//-indol-5-yloxy)ethyl]-2-methyl-3//-imidazo[4,5-6]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using l//-indol-5-ol as the appropriate phénol analog Example 210 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂₂H₂iN₇O 399.1808, Found: 400.1848 [M+H]⁺

Example 2114- {3-[2-(2-methoxy-5-methylphenoxy)ethyl]-2-methyl-377-imidazo[4,56]pyridin-5-yl} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 2-methoxy-5methylphenol as the appropriate phénol analog Example 211 was obtained. HRMS (TOF, ESI) m/z: Calculated for C22H24N6O2 404.1961, Found: 405.2022 [M+H]⁺

-74Example 212 4- {3-(2-(2,6-difluorophenoxy)ethyl]-2-methyl-37/-imidazo[4,5-à]pyridin-5y 1} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 2,6-difluorophenol as the appropriate phénol analog Example 212 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂oH_I8N₆OF2 396.1510, Found: 397.1570 [M+H]⁺

Example 213 4- {3-(2-(2,6-dimethoxyphenoxy)ethyl]-2-methyl-3//-imidazo[4,5-6]pyridin5-yl} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 2,6dimethoxyphenol as the appropriate phénol analog Example 213 was obtained. HRMS (TOF, ESI) m/z: Calculated for C22H24N6O3 420.1910, Found: 421.1979 [M+H]⁺

Example 214 4-(2-methyl-3-{2-[2-(propan-2-yioxy)phenoxy]cthyl}-3//-imidazo[4,5à]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 2isopropoxyphenol as the appropriate phénol analog Example 214 was obtained. HRMS (TOF, ESI) m/z: Calculated for C23H₂₆N₆O2 418.2117, Found: 419.2195 [M+H]⁺

Example 215 4- {3-[2-(2-ethoxyphenoxy)ethyl]-2-methyl-3//-imidazo(4,5-ô]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 2-ethoxyphenol as the appropriate phénol analog Example 215 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂2H₂₄N₆O2 404.1961, Found: 405.2030 (M+H]⁺

Example 216 4- {2-methyl-3-[2-(pyridin-3-yloxy)ethyl]-3//-imidazo[4,5-Z>]pyridin-5y l} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 3-hydroxypyridine as the appropriate phénol analog Example 216 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₉H₁₉N₇O 361.1651, Found: 362.1724 [M+H]⁺

Example 217 4- {2-methyl-3-[2-(pyridin-2-yloxy)ethyl]-3//-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

-75Starting from Préparation 3a following General procedure IV and using 2-pyridone as the appropriate phénol analog Example 217 was obtained. HRMS (TOF, ESI) m/z: Calculated for C]₉Hi₉N₇O 361.1651, Found: 362.1731 [M+H]⁺

Example 218 4-(2-methyl-3-{2-[(l-methyl-l/7-pyrazol-5-yl)oxy]ethyl)-3/7-imidazo[4,5ô]pyridin-5-yl)pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using 1-methyl-1/7pyrazol-5-ol as the appropriate phénol analog Example 218 was obtained. HRMS (TOF, ESI) m/z: Calculated for C|₈H₂₀N₈O 364.1760, Found: 365.1822 [M+H]⁺

Example 219 4- {2-methyl-3-[2-(pyrimidin-2-yloxy)ethyl]-3//-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine

Starting from Préparation 3a following General procedure IV and using pyrimidin-2(177)one as the appropriate phénol analog Example 219 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₎₈H_I8N₈O 362.1604, Found: 363.1675 [M+H]⁺

Example 220 4-(2-chloro-3-cyclopentyl-3//-imidazo[4,5-6]pyridin-5-yl)pyridine-2,6diamine

Following General procedure V using cyclopentanamine and as the appropriate amine and omitting Step F Example 220 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₆H_i7N₆C1 328.1203, Found: 329.1272 [M+H]⁺

Example 221 3-cyclopentyl-5-(2,6-diaminopyridin-4-yl)-3//-imidazo[4,5-Z>]pyridine-2carbonitrile

Following General procedure V and using cyclopentanamine as the appropriate amine Example 221 was obtained. HRMS (TOF, ESI) m/z: Calculated for Cj₇Hi₇N₇ 319.1545, Found: 320.1623 [M+H]⁺

Example 222 5-(2,6-diaminopyridin-4-yl)-3-(2-phenoxyethyl)-3/7-imidazo[4,5-6]pyridine2-carbonitrile

Following General procedure V and using 2-phenoxyethanamine as the appropriate amine Example 222 was obtained. HRMS (TOF, ESI) m/z: Calculated for C₂oH]₇N₇0 371.1495, Found: 372.1575 [M+H]⁺

-76Example 223 5-(2,6-diaminopyridin-4-yl)-3-ethyl-3//-imidazo[4,5-/>]pyridine-2carbonitrile

Following General procedure V and using ethanamine as the appropriate amine Example 223 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C14H13N7 279.1232, Found: 280.1315 [M+H]⁺

Example 224 3-cyclopropyl-5-(2,6-diaminopyridin-4-yl)-37Y-imidazo[4,5-à]pyridine-2carbonitrile

Following General procedure V and using cyclopropanamine as the appropriate amine Example 224 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C15H13N7 291.1232, Found: 292.1303 [M+H]⁺

Example 225 5-(2,6-diaminopyridin-4-yl)-3-(prop-2-en-1 -yl)-3//-imidazo[4,5-ô]pyridine2-carbonitrile

Following General procedure V and using prop-2-en-l-amine as the appropriate amine Example 225 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C15H13N7 291.1232, Found: 292.1300 [M+H]⁺

Example 226 5-(2,6-diaminopyridin-4-yl)-3-(4,4,4-trifluorobutyl)-3//-imidazo[4,56]pyridine-2-carbonitrile

Following General procedure V and using 4,4,4-trifluorobutan-l-amine as the appropriate amine Example 226 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C16H14N7F3 361.1263, Found: 362.1338 [M+H]⁺

Example 227 5-(2,6-diaminopyridin-4-yl)-3-methyl-3J/-imidazo[4,5-Z>]pyridine-2carbonitrile

Following General procedure V and using methanamine as the appropriate amine Example 227 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for CbHhN? 265.1076, Found: 266.1139 [M+H]⁺

Example 228 4-[2-(difluoromethyl)-3-methyl-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine2,6-diamine

-77 Following General procedure VI starting from Préparation 4 and using ethyl difluoroacetate as the appropriate acetic acid dérivative Example 228 was obtained. HRMS (TOF, ESI) m/z: Calculated for C_BH₁₂N₆F₂ 290.1092, Found: 291.1161 [M+H]⁺

Example 229 4-[3-methyl-2-(trifluoromethyl)-377-imidazo[4,5-h]pyridin-5-yl]pyridine5 2,6-diamine

Following General procedure VI starting from Préparation 4 and using trifluoroacetic acid as the appropriate acetic acid dérivative Example 229 was obtained. HRMS (TOF, ESI) m/z: Calculated for CbHhNôFs 308.0997, Found: 309.1078 [M+H]⁺

Example 230 jV-[6-amino-4-(3-butyl-2-methyl-3/7-imidazo[4,5-6]pyridin-5-yl)pyridin-210 yl]-2-phenoxyacetamide

To a solution of 200 mg of 4-(3-butyl-2-methyl-imidazo[4,5-6]pyridin-5-yl)-jV²triphenylmethyl-pyridine-2,6-diamine (Préparation 5) (0.37 mmol, 1 eq.) and 155 pL triethyl amine (1.11 mmol, 3 eq.) in 4 mL dry THF, 41 pL 2-chloroacetyl chloride (0.51 mmol, 1.4 eq.) was added and the mixture was stirred until no further conversion was observed. The volatiles were removed under reduced pressure, the residue was dissolved in 5 mL dry DMF and then 70 mg phénol (0.74 mmol, 2 eq.) and 154 mg potassium carbonate (1.11 mmol, 3 eq.) were added. The resulting mixture was stirred until no further conversion was observed. It was diluted with brine and extracted with DCM. The combined organic phases were dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was fïrst purified by flash chromatography on silica column using DCM / MeOH ( 1.2% NH₃) as eluents during which the trityl group wa also removed, followed by préparative reversed phase chromatography using 5 mM aqueous NH₄HCO₃ solution and MeCN as eluents to give Example 230. HRMS (TOF, ESI) m/z: Calculated for C₂₄H₂₆N₆O₂ 430.2117, Found: 431.2195 [M+H]⁺

Example 2317V-benzyl-4-(3-butyl-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl)pyridine-2,6diamine

To a solution of 269 mg of 4-(3-butyl-2-methyl-imidazo[4,5-6]pyridin-5-yl)-A²triphenylmethyl-pyridine-2,6-diamine (Préparation 5) (0.5 mmol, 1 eq.) and 159 mg benzaldehyde (1.5 mmol, 3 eq.) in DMF/MeOH (3/2 mL) 113 mg sodium borohydride (3 30 mmol, 6 eq.) was added in small portions. The resulting mixture was stirred at 60°C in the

-78presence of 100 pL acetic acid until no further conversion was observed. The pH was set to 5 with 2 M aqueous HCl solution and the resulting mixture was stirred until no further conversion (detritylation) was observed. The mixture was neutralized with 10% aqueous K2CO3 solution, diluted with brine, and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to give Example 231. HRMS (TOF, ESI) m/z: Calculated for C₂3H₂₆N₆ 386.2219, Found: 387.2295 [M+H]⁺

Example 232 7V-[6-amino-4-(3-butyl-2-methyl-3J/-imidazo[4,5-6]pyridin-5-yl)pyridin-2yl]-2-cyclohexylacetamide

Starting from Example 148 following General procedure VII using cyclohexylacetyl chloride as the appropriate acid chloride Example 232 was obtained. HRMS (TOF, ESI) m/z: Calculated for C24H32N6O 420.2638, Found: 421.2719 [M+H]⁺

Example 233 7V-[6-amino-4-(3-butyl-2-methyl-3/Z-imidazo[4,5-6]pyridin-5-yl)pyridin-2yl]-2-chlorobenzamide

Starting from Example 148 following General procedure VII using 2-chlorobenzoyl chloride as the appropriate acid chloride Examplé 233 was obtained. HRMS (TOF, ESI) m/z: Calculated for C23H23N6OCI 434.1622, Found: 435.1702 [M+H]⁺

Example 234 V-[6-amino-4-(3-butyl-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl)pyridin-2yl]cyclohexanecarboxamide

Starting from Example 148 following General procedure VII using cyclohexanoyl chloride as the appropriate acid chloride Example 234 was obtained. HRMS (TOF, ESI) m/z: Calculated for C23H30N6O 406.2481, Found: 407.2557 [M+H]⁺

Example 235 /'/-[6-amino-4-(3-butyl-2-methyl-3//-imidazo[4,5-/>]pyridin-5-yl)pyridin-2yl]-2-phenylacetamide

Starting from Example 148 following General procedure VII using phenylacetyl chloride as the appropriate acid chloride Example 235 was obtained. HRMS (TOF, ESI) m/z: Calculated for C24H₂6N₆O 414.2168, Found: 415.2246 [M+H]⁺

-79Example 236 4-(3-butyl-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl)pyridin-2-amine

Starting from Préparation 6a following General procedure IX Example 236 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C_l6Hi9N₅ 281.1640, Found: 282.1710 [M+H]⁺

Example 237 4-[3-(2-cyclohexylethyl)-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl]pyridin2-amine

Starting from Préparation 6b following General procedure IX Example 237 was obtained. HRMS (TOF, ESI) m/z: Calculated for C20H25N5 335.2110, Found: 336.2184. [M+H]⁺

Example 238 4-[3-(cyclopropylmethyl)-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl]pyridin2-amine

Starting from Préparation 6c following General procedure IX Example 238 was obtained. HRMS (TOF, ESI) m/z: Calculated for Ci₆Hi₇N₅ 279.1484, Found: 280.1562 [M+H]⁺

Example 239 4-[3-(but-3-en-l-yl)-2-methyl-3/f-imidazo[4,5-6]pyridin-5-yl]pyridin-2amine

Starting from Préparation 6d following General procedure IX Example 239 was obtained. HRMS (IT-TOF, ESI) m/z: Calculated for C₁₆Hi₇N₅ 279.1484, Found: 280.1552 [M+H]⁺

Example 240 4-[3-(3,3-difluorocyclobutyl)-2-methyl-3//-imidazo[4,5-6]pyridin-5-yl]-6fluoropyridin-2-amine

Starting from Préparation 7a following General procedure X and using 6-amino-4-bromo2-fluoropyridine as the appropriate aryl halide Example 240 was obtained. HRMS (TOF, ESI) m/z: Calculated for C16H14F3N5 333.1201, Found: 334.1270 [M+H]⁺

Example 241 4-(3-cyclopropyl-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl)-3,6difluoropyridin-2-amine

Starting from Préparation 6e following General procedure X and using 6-amino-4-bromo2,5-difluoropyridine as the appropriate aryl halide Example 241 was obtained. HRMS (TOF, ESI) m/z: Calculated for C15H13F2N5 301.1139, Found: 302.1202 [M+H]⁺

Example 242 4-(3-cyclopropyl-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl)-3,5difluoropyridine-2,6-diamine

-80Starting from Préparation 6f following General procedure X and using 4-bromo-2,6diamino-3,5-difluoropyridine as the appropriate aryl halide Example 242 was obtained. HRMS (TOF, ESI) m/z: Calculated for C_I5H_l4F₂N₆ 316.1248, Found: 317.1310 [M+H]⁺

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 this assay, full-length human kinases from Cama Biosciences - DYRK1A (NM_001396, ref. 04-130; 2.0 ng/μΐ), DYRK1B (NM_004714, ref. 04-131; 1.2 ng/μΐ), CLK1 (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 (DYRK1A and DYRK1B) or 100 minutes (CLK1, CDK9 and GSK3p) at room température with ATP (Sigma A2383, 10 μΜ) and a //Light™-labeIIed 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 MgCl₂, 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 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 acceptor occurs, which will then émit light at 665 nm. The activity, and hence inhibition, of DYRKl A 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

I

-81 was conducted in assay buffer (pH 7.4), containing 15 mM Hepes; 20 mM NaCI; 1 mM EGTA; 10 mM MgC12; 0.02% Tween20 and 0.1 mg/ml Bovine-y-globulin. Test compounds of the invention were added in reaction buffer in a range of concentrations for 10 minutes at 30°C in the presence of 20 nM DYRK1A enzyme, 40 μΜ peptide substrate 5 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 measured at 590nm. The IC50 was calculated from the concentration-activity curve as the concentration of the test compound required for 50% inhibition of kinase activity. The 10 results are presented in Table 1.

EXAMPLE C: Cellular DYRK1A autophosphorvlation assay

On day 0, human U2-OS osteosarcoma cells were seeded in 12-well culture plates (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 15 units/ml penicillin, 50 μg/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 (Invitrogen) containing a sequence coding for full-length, wild-type human DYRK1A (NM 001396) with an HA tag, 0.3 % lipofectamine (Invitrogen 18324-020), and 0.6 % 20 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 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-HCl pH 7.4, 1% triton X-100, 1 mM 25 EGTA, 1 mM EDTA and protease (1% v/v; 539134; Calbiochem) and phosphatase (1% v/v; 524625; Calbiochem) inhibitor cocktails (50 μΙ lysis buffer/weil). The relative levels of phospho-Ser520-DYRKl A were assayed using either western blotting or the Mesoscale 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 30 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

-82blocked 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 DYRK1A antibody (Abnova H00001859; 0.5 pg/ml in 5% milk). Peroxidase-conjugated secondary antibodies were diluted into 5% milk and applied to membranes for 1 h 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 Bio-Rad GS-800 calibrated densitometer and quantitative analysis of western blots was performed using TotalLab software (Amersham). IC$o values for inhibition of phospho-Ser520-DYRKl A were calculated from dose-response curves plotting the ratio between phospho-Ser520-DYRKlA and total DYRK1A 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 μg/ml) for 1 hour with shaking at RT. Anti-phosphoSer520-DYRKlA antibody (Eurogentec SE6974-75; 2.3 - 3.0 mg/ml) and anti DYRK1A 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 gg/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-DYRKlA were calculated from dose-response curves. The results showed that the compounds of the invention are powerfiil inhibitors of cellular DYRK1A Ser520 autophosphorylation. The results are presented in Table 1.

EXAMPLE D: Pharmacodynamie assav in tumor xenografts for inhibition of DYRK1A autonhosphorvlation

For pharmacodynamies studies of inhibition of DYRK1A autophosphorylation, female SCID mice were injected subcutaneously with RS4;11 human acute lymphoblastic 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, 1% triton X-100, 1 mM EGTA, 1 mM EDTA and protease (1% v/v; 539134; Calbiochem)

-83and phosphatase (l% v/v; 524625; Calbiochem) inhibitor cocktails. The relative levels of phospho-Ser520-DYRKlA 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) 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 gg/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 phosphoSer520-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.

Compound	dose (mg/kg)	phospho-Ser520DYRK1A (% control at 2h)
Example 9	3	44
Example 154	3	28
Example 42	3	35
Example 53	3	49
Example 71	3	33
Example 101	3	25
Example 103	3	41
Example 106	9	46

EXAMPLE E: Efficacy studies in tumor xenografts

For anti-tumor efficacy studies, female nude balb/c nu/nu mice were injected subcutaneously with A2780 human ovarian carcinoma 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 75 mg/kg

-84once daily for 2 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.

-85Table 1: ICsn of Dvrkl/CIkl inhibitor

	IC₃₀ (μΜ) DyrklA TR-FRET assay	IC₃₀ (μΜ) DyrklA ADP assay	IC₃₀ (μΜ) Dyrkl B TR-FRET assay	IC₃₀^M)CLkl TR-FRET assay	IC₃₀ (μΜ) CDK9 TR-FRET assay	ΚΖ₃₀(μΜ) P-Ser520Dyrkl A -Cell assay
Example 1	0,013	0,010	0,004		0,314	0,080
Example 2	0,008	0,010	0,001		0,383	0,200
Example 3	0,020	0,020			2,573	0,230
Example 4	0,015	0,011			1,257	0,250
Example 5	0,006	0,020			6,555	1,000
Example 6	0,155	0,493	0,149		1,090
Example 7	0,070	0,079			2,380
Example 8	0,061	0,128
Example 9	0,011	0,007	0,006	0,021	2,149	0,090
Example 10	0,032	0,079	0,055		4,575
Example 11	0,004	0,011			3,449	0,170
Example 12	0,002	0,009	0,003			0,070
Example 13	0,012	0,035	0,019		>10
Example 14	0,002	0,008	0,001	0,016	1,946	0,050
Example 15	0,004	0,011	0,008		0,470	0,110
Example 16	0,153	0,367
Example 17	0,006	0,011				0,063
Example 18	0,002	0,013				0,108
Example 19	0,003	0,012	0,003		1,952	0,226
Example 20	0,016	0,032	0,016		2,921
Example 21	0,015	0,053			12,479
Example 22	0,069	0,364
Example 23	0,002	0,006	0,008	0,012	0,570	0,017
Example 24	0,005	0,008	0,015		3,528
Example 25	0,007	0,010	0,006		1,837	0,228
Example 26	0,004	0,007	0,006		1,823
Example 27	0,015	0,056	0,005		>10
Example 28	0,002	0,006	0,003	0,025	5,700	0,028

	ICso (μΜ) DyrklA TR-FRET assays	IC50 (μΜ) DyrklA ADP assays	ΐε₅₀(μΜ) DyrklB TR-FRET assays	IC₅₀^M)Clkl TR-FRET assays	Κ3₅₀(μΜ) CDK9 TR-FRET assays	Ι€ιο(μΜ) P-Ser520Dyrkl A -Cell assay
Example 29	0,004	0,011	0,011		3,435	0,057
Example 30	0,017	0,018	0,125		3,568
Example 31	0,009	0,010	0,002		1,776	0,070
Example 32	0,095	0,037
Example 33	0,045	0,018
Example 34	0,030	0,010	0,015		1,396
Example 35	0,012	0,008
Example 37	0,052	0,027
Example 38	0,028	0,008
Example 39	0,245	0,045
Example 40	0,154	0,187
Example 41	0,029	0,011	0,011		2,708	0,131
Example 42	0,012	0,008	0,010	0,053	2,938	0,045
Example 43	0,116	0,109
Example 44	0,019	0,011				0,023
Example 45	0,177	0,055
Example 46	0,056	0,035
Example 47	0,003	0,025	0,046		0,728
Example 48	0,116	0,056
Example 49	0,003	0,011	0,017	0,017	0,979	0,130
Example 50	0,029	0,057			1,992
Example 51	0,006	0,007	0,001	0,029	4,372	0,038
Example 52	0,006	0,006	0,008
Example 53	0,006	0,009	0,004	0,020	1,312	0,063
Example 54	0,003	0,006	0,003			0,023
Example 55	0,002	0,024	0,021			0,160
Example 56	0,009	0,015			0,357
Example 57	0,026	0,085	0,005		>10
Example 58	0,003	0,013	0,013		>10	0,080
Example 59	0,002	0,021	0,003		>10

	IC₅₀ (μΜ) Dyrkl A TR-FRET assays	IC50 (μΜ) Dyrkl A ADP assays	IC₃₀ (μΜ) Dyrkl B TR-FRET assays	IC₃₀^M)Clkl TR-FRET assays	IC_S0^M)CDK9 TR-FRET assays	IC₃₀(pM) P-Ser520Dyrkl A -Cell assay
Example 60	0,149	0,510
Example 61	0,002	0,009	0,004		>10	0,155
Example 62	0,166	0,781
Example 63	0,003	0,008	0,007		>10	0,024
Example 64	0,009	0,026	0,030		>10
Example 65	0,001	0,006	0,005	0,018	>10	0,022
Example 66	0,005	0,009	0,012		0,365	0,072
Example 67	0,104	0,903
Example 68	0,029	0,193	0,132		>10
Example 69	0,002	0,007
Example 70		0,013
Example 71	0,006	0,006	0,006	0,016	1,407	0,047
Example 72	0,010	0,015	0,014	0,090	>10	0,184
Example 73	0,004	0,009	0,008	0,019	4,660	0,065
Example 74	0,006	0,014	0,010	0,021	0,476	0,092
Example 75	0,003	0,012	0,006	0,019	0,843	0,035
Example 76		0,040
Example 77		0,008				0,077
Example 78		0,025		0,018		0,133
Example 79		0,021		0,014		0,068
Example 80		0,043
Example 81		0,021		0,015		0,094
Example 82		0,096
Example 83		0,007				0,037
Example 84		0,019				0,113
Example 85		0,016				0,143
Example 86		0,019				0,151
Example 87		0,017
Example 88		0,012				0,103
Example 89	0,004	0,014	0,009	0,024	1,464	0,068
Example 90		0,015		0,016		0,129

	IC₅₀ (μΜ) Dyrkl A TR-FRET assays	IC₅o (μΜ) Dyrkl A ADP assays	IC₅₀ (μΜ) Dyrkl B TR-FRET assays	IC50 (μΜ) Clkl TR-FRET assays	IC_5O^M)CDK9 TR-FRET assays	ICjo (μΜ) P-Ser520DyrklA -Cell assay
Example 91	0,004	0,013	0,008	0,016	2,916	0,062
Example 92	0,002	0,006	0,007	0,017	0,564	0,058
Example 93		0,007				0,107
Example 94	0,003	0,005	0,007	0,016	1,078	0,017
Example 9S	0,003	0,012	0,011	0,029	1,798	0,021
Example 96	0,004	0,011	0,010	0,020	3,094	0,075
Example 97		0,015		0,021		0,097
Example 98	0,004	0,007	0,009	0,015		0,019
Example 99		0,016				0,104
Example 100		0,006		0,014		0,006
Example 101	0,003	0,006	0,007	0,016	1,256	0,006
Example 102		0,017
Example 103	0,006	0,006	0,005	0,015	0,666	0,014
Example 104		0,045
Example 105		0,092
Example 106	0,008	0,012	0,006	0,019	>3	0,073
Example 107	0,008	0,012	0,007	0,037	>3	0,111
Example 108		0,017		0,026		0,109
Example 109	0,010	0,030	0,015	0,025	>3	0,220
Example 110		0,019		0,020		0,042
Example 111		0,012
Example 112	0,006	0,005	0,014	0,025	2,620	0,090
Example 113		0,010				0,243
Example 114	0,005	0,005	0,009	0,019		0,039
Example 115	0,003	0,013	0,006	0,028	5,692	0,034
Example 116		0,056				0,267
Example 117		0,006				0,075
Example 118		0,031
Example 119		0,004				0,105
Example 120		0,003				0,161
Example 121		0,008				0,041

	IC₅o (μΜ) Dyrkl A TR-FRET assays	IC₅o (μΜ) Dyrkl A ADP assays	IC50 (μΜ) Dyrkl B TR-FRET assays	ΙΟ₅₀(μΜ) Clkl TR-FRET assays	IC₅₀^M)CDK9 TR-FRET assays	ICoo(pM) P-Ser520Dyrkl A -Cell assay
Example 122		0,020				0,122
Example 123		0,010				0,082
Example 124		0,006				0,061
Example 125		0,022				0,151
Example 126		0,055				0,271
Example 127		0,015				0,089
Example 128		0,037				0,163
Example 129		0,037				0,130
Example 130		0,058
Example 131		0,016				0,045
Example 132		0,038				0,207
Example 133		0,015				0,074
Example 134		0,038				0,205
Example 135		0,016				0,098
Example 136		0,028				0,247
Example 137		0,048				0,197
Example 138		0,052				0,100
Example 139		0,005				0,012
Example 140		0,007				0,024
Example 141		0,010				0,191
Example 142		0,037
Example 143		0,013				0,037
Example 144	0,008	0,016	0,012	0,238	>3	0,128
Example 145		0,030		0,115		0,171
Example 146		0,089
Example 147		0,021
Example 148	0,002	0,007	0,006	0,016	1,244	0,100
Example 149	0,010	0,026	0,004		>10	0,330
Example 150	0,006	0,019	0,014		3,027	0,280
Example 151	0,004	0,013	0,008	0,019	2,871	0,170
Example 152	0,002	0,012	0,007		>10	0,220

	IC₅₀ (μΜ) DyrklA TR-FRET assays	Ιϋ₅ο(μΜ) DyrklA ADP assays	IC50 (μΜ) DyrklB TR-FRET assays	IC50 ^M)Clkl TR-FRET assays	IC₅₀ (μΜ) CDK9 TR-FRET assays	Ι€₃₀(μΜ) P-Ser520Dyrkl A -Cell assay
Example 153	0,001	0,010	0,003	0,016	1,019	0,035
Ex ample 154	0,004	0,007	0,002	0,023	3,386	0,020
Example 155	0,012	0,005
Example 156	0,013	0,017	0,016		0,554	0,151
Example 157	0,011	0,021	0,003	0,058	>10	0,153
Example 158	0,008	0,014	0,016
Example 159		0,043
Example 160	0,003	0,024	0,068			0,144
Example 161		0,020	0,005	0,218	>10	0,143
Example 162		0,056
Example 163		0,033
Example 164		0,032				0,152
Example 165	0,003	0,009	0,005	0,015		0,026
Example 166		0,085				0,250
Example 167		0,011				0,011
Example 168	0,002	0,011	0,006	0,015		0,032
Example 169		0,055
Example 170		0,035				0,131
Example 171		0,018				0,109
Example 172		0,007				0,092
Example 173		0,007				0,017
Example 174	0,016	0,074	0,013	0,083	>3
Example 175	0,007	0,020	0,016	0,040	>3	0,131
Example 176		0,093				0,223
Example 177	0,005	0,014	0,005	0,017	0,554	0,042
Example 178		0,176
Example 179		0,023				0,237
Example 180	0,005	0,013	0,010	0,016	0,467	0,044
Example 181		0,081
Example 182		0,026				0,175
Example 183		0,226

-9l -

	IC₅o(hM) Dyrkl A TR-FRET assays	IC50 (μΜ) Dyrkl A ADP assays	IC50 (μΜ) Dyrkl B TR-FRET assays	Ι€₅ο(μΜ) Clkl TR-FRET assays	ΙΟ₅₀(μΜ) CDK9 TR-FRET assays	ICjo (μΜ) P-Ser520Dyrkl A -Cell assay
Example 184		0,165
Example 185		0,041
Example 186		0,154
Example 187		0,082
Example 188		0,065				0,181
Example 189	0,007	0,013	0,007	0,017	0,339	0,026 [
Example 190		0,032				0,148
Example 191		0,200
Example 192		0,084
Example 193		0,028
Example 194		0,007				0,020
Example 195		0,013				0,106
Example 196		0,012				0,141
Example 197		0,007				0,054
Example 198		0,025		0,017		0,092
Example 199	0,003	0,012	0,007	0,016	1,102	0,053
Example 200	0,005	0,018	0,010	0,020	1,523	0,069
Example 201		0,021
Example 202		0,023		0,018		0,180
Example 203		0,017		0,016		0,148
Example 204		0,041
Example 205		0,030
Example 206	0,005	0,017	0,007	0,028	>3	0,094
Example 207		0,026		0,021		0,120
Example 208		0,016				0,155
Example 209		0,025
Example 210	0,003	0,008	0,006	0,018	1,005	0,047
Example 211		0,049
Example 212	0,003	0,007	0,040	0,017	>10	0,083
Example 213		0,069
Example 214		0,072

	IC₅o (μΜ) Dyrkl A TR-FRET assays	ICso (μΜ) Dyrkl A ADP assays	ICso (μΜ) Dyrkl B TR-FRET assays	ICjo^MJClkl TR-FRET assays	IC₅₀^M)CDK9 TR-FRET assays	IC₃o(pM) P-Ser520Dyrkl A -Cell assay
Example 215		0,066
Example 216		0,029
Example 217	0,006	0,010	0,008		0,881	0,089
Example 218		0,057
Example 219		0,040
Example 220	0,003	0,011	0,013	0,019	0,724	0,075
Example 221	0,027	0,008	0,012	0,016	0,317	0,043
Example 222	0,018	0,023	0,031	0,062	>3	0,244
Example 223		0,009		0,020		0,097
Example 224		0,009		0,020		0,057
Example 225		0,012		0,021
Example 226	0,005	0,013	0,010	0,023	0,713	0,148
Example 227		0,010		0,042		0,262
Example 228	0,004	0,010	0,012
Example 229	0,061	0,081
Example 230	0,221	0,928
Example 231	0,011	0,046	0,003		>10
Example 233	0,224	0,303
Example 234	0,090	0,236
Example 235	0,013	0,207	0,091		>10
Example 236	0,013	0,023	0,018
Example 237	0,005	0,045	0,005		0,718
Example 238	0,009	0,050	0,020
Example 239		0,068
Example 240		0,016				0,153
Example 241		0,098
Example 242		0,154

-93EXAMPLE F: Pharmaceutical composition: Tablets

1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 242 5g

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

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

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

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

Silica.................................................................................................................... 1g

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

Claims

1. Compound of formula (I):

(I) ♦ Ri represents a cyano group, a halogen atom, or a linear or branched (Ci-Ce)alkyl group optionally substituted by from one to three halogen atoms, ♦ R₂ represents a hydrogen, a linear or branched (Ci-Côjalkyl group, a linear or branched (C₂-Cg)alkenyl group, a linear or branched (C₂-C6)alkynyl group, Cyi, -(Ci-C6)alkylene-[O]_n-Cyi group, -(Ci-C6)alkenylene-[O]_n-Cyi group, -(Ci-CUalkylene-NR-Cyi group, -(Ci-Côjalkylene-S-Cyi group, -(Co-C6)alkylene-Cy₂-Cyi group, or -Cy₂-(Ci-C6)alkylene-Cyi group, it being understood that the alkyl and alkylene moieties defined hereinbefore may be linear or branched, ♦ R represents a hydrogen or a linear or branched (Ci-Ce)alkyl group, ♦ n is an integer equals to 0 or 1, ♦ R₃ represents a hydrogen atom, a halogen atom, -NR^R^ ,-NH-(Co-C6)alkylene-Cy₃₁-NH-CO-(Co-C₆)alkylene-Cy₃, -NH-CO-(C₀-C₆)alkylene-O-Cy₃, ♦ R4 and R5, each independently of the others, represent a hydrogen or a halogen atom, ♦ R^ and R^’, each independently of the others, represent a hydrogen or a linear or branched (Ci-Ce)alkyl group, ♦ Cyi, Cy₂ and Cy₃, independently of one another, represent a cycloalkyl group, a

-95heterocycloalkyl group, an aryl or an heteroaryl group, it being understood that:

- 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 fosed, 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 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 to be substituted by from 1 to 4 groups selected from linear or branched (Ci-Cejalkyl, linear or branched (C2-Ce)alkenyl group, linear or branched (C2-Cô)alkynyl group, linear or branched (Ci-Ce)alkoxy, linear or branched (Ci-Cejalkyl-S-, hydroxy, oxo (or TV-oxide where appropriate), nitro, cyano, -C(O)-OR’, -C(O)-R’, -O-C(O)-R’, -C(O)-NR’R”, -NR’-C(O)-R”, -NR’R”, linear or branched (Ci-Cejpolyhaloalkyl, difluoromethoxy, trifluoromethoxy, or halogen, it being understood that R’ and R” independently of one another represent a hydrogen atom or a substituted linear or branched (Ci-Ce)alkyl group, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

2. Compound of formula (I) according to claim 1, wherein R] represents a methyl or a cyano group.

-96X Compound of formula (I) according to claim 1 or 2, wherein Rj and R5 each represent a hydrogen atom.

4, Compound of formula (I) according to one of claims 1 to 3, wherein R₃ represents a NH₂ group.

5 5» Compound of formula (I) according to one of claims 1 to 3, wherein R₃ represents a hydrogen atom.

i* Compound of formula (I) according to one of claims 1 to 5, wherein R₂ represents a hydrogen, a linear or branched (Ci-Ce)alkyl group, a linear or branched (C₂-Cô)alkenyl group, a linear or branched (C₂-Cô)alkynyl group, -(Ci-Cô)alkylene-O-Cyi group, 10 -(Ci-C6)alkenylene-[O]_n-Cyi group, -(Ci-Ce)alkylene-NR-Cyi group, -(Ci-Céjalkylene-S-Cyi group, -(Co-Ce)alkylene-Cy₂-Cyi group, or -Cy₂-(C₂-Cô)alkylene-Cyi group, it being understood that the alkyl and alkylene moieties defined hereinbefore may be linear or branched.

L Compound of formula (I) according to one of claims 1 to 5, wherein R₂ represents 15 Cyj, a -(Ci-Cô)alkylene-Cy] group, -(Co-C6)alkylene-Cy₂-Cyj group, or -Cy₂-(CiCô)alkylene-Cyi group.

2» Compound of formula (I) according to claim 7, wherein R₂ represents:

- a cycloalkyl group,

- or a -(Ci-Côjalkylene-cycloalkyl or a -(Ci-Cô)alkylene-phenyl group,

20 - or a -cycloalkylene-phenyl group or a -cycloalkylene-(Ci-C6)alkylene-phenyl group, wherein the cycloalkyl, cycloalkylene and phenyl groups so defined can be optionally substituted according to the définitions mentioned previously.

2» Compound of formula (I) according to one of claims 1 to 5, wherein R₂ represents a 25 linear or branched (Cj-Cejalkyl group, wherein the alkyl group so defined can be optionally substituted according to the définitions of formula (I).

]

-97LL Compound of formula (I) according to one of daims 1 to 5, wherein R₂ represents a -(Ci-Côjalkylene-O-Cyj group.

IL Compound of formula (I) according to claim 10, wherein R₂ represents a -(Cj-Côjalkylene-O-pyridinyl group, wherein the pyridinyl group so defined can be optionally substituted according to the définitions of formula (I).

IL Compound of formula (I) according to claim 1, selected from the following group:

- 4-[2-methyl-3-(3-phenylcyclobutyl)-3?ï-imidazo[4,5-6]pyridin-5-yl]pyridine-2,6diamine,

- 4-(3-(3,3-difluorocyclobutyl)-2-methyl-3/7-imidazo[4,5-/>]pyridin-5-yl]pyridine2,6-diamine,

- 4-(3-{2-[(6-fluoropyridin-2-yl)oxy]ethyl}-2-methyl-3/7-imidazo[4,5-ô]pyridin-5yl)pyridine-2,6-diamine,

- 4 {3-[( l/?,2/?)-2-benzylcyclopropyl]-2-methyl-3//-imidazo[4,5-/?]pyridin-5yl} pyridine-2,6-diamine,

- 4-[3-(3-fluorocyclobutyl)-2-methyl-3J/-imidazo[4,5-à]pyridin-5-yl]pyridine-2,6diamine,

- 4-(3-hexyl-2-methyl-3H-imidazo[4,5-h]pyridin-5-yl)pyridine-2,6-diamine,

- 4-(3-cyclobutyl-2-methyl-3/7-imidazo[4,5-6]pyridin-5-yl)pyridine-2,6-diamine,

- 4-(3-(2-{[6-(difluoromethyl)pyridin-2-yl]oxy}ethyl)-2-methyl-3/7-imidazo[4,5Z>]pyridin-5-yl]pyridine-2,6-diamine,

- 4-[3-(5-methoxy-2,3-dihydro-17/-inden-2-yl)-2-methyl-3H-imidazo[4,5-ô]pyridin5-yl]pyridine-2,6-diamine,

- 4-(3-ethyl-2-methyl-3H-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine,

- 4-[2-methyl-3-(2- {[6-(trifluoromethyl)pyridin-2-yl]oxy) ethyl)-3//-imidazo[4,5ô]pyridin-5-yl]pyridine-2,6-diamine,

- 4-{3-[2-(2-methoxycyclohexyl)ethyl]-2-methyl-3//-imidazo[4,5-ô]pyridin-5y 1} pyridine-2,6-diamine,

- 4-(2-methyl-3-pentyl-3//-imidazo[4,5-6]pyridin-5-yl)pyridine-2,6-diamine,

- 4-(3-cyclohexyl-2-methyl-3//-imidazo[4,5-à]pyridin-5-yl)pyridine-2,6-diamine,

- 4-{2-methyl-3-[3-(methylsulfanyl)propyl]-3H-imidazo(4,5-h]pyridin-5yl ) pyridine-2,6-diamine,

-98- 4-{3-[(1Λ,25)-2-benzylcyclopropyl]-2-methyl-3/7-imidazo[4,5-ô]pyridin-5yl} pyridine-2,6-diamine,

- 4-{2-methyl-3-[2-(2-methylphenyl)ethyl]-3/7-imidazo[4,5-ô]pyridin-5-yl}pyridine2,6-diamine,

5 - 4-(3- {2-[(6-chloropyridin-2-yl)oxy]ethyl} -2-methyl-3/Z-imidazo[4,5-ô]pyridin-5yl)pyridine-2,6-diamine,

- 4-(3-{(27?)-2-[(6-fluoropyridin-2-yl)oxy]propyl}-2-methyl-3Z/-imidazo[4,5ô]pyridin-5-yl)pyridine-2,6-diamine,

- 4-[2-methyl-3-(2,2,2-trifluoroethyl)-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine-2,610 diamine,

- 3-cyclopentyl-5-(2,6-diaminopyridin-4-yl)-3Z7-imidazo[4,5-à]pyridine-2carbonitrile,

- 4-(3-cyclopropyl-2-methyl-3//-imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically 15 acceptable acid or base.

IX Compound of formula (I) according to claim 1 which is 4-(3-ethyl-2-methyl-3//imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine.

14. Compound of formula (I) according to claim 1 which is 4-(2-methyl-3-pentyl-3//imidazo[4,5-ô]pyridin-5-yl)pyridine-2,6-diamine.

20 15. Compound of formula (I) according to claim 1 which is 4-{2-methyl-3-[2-(2methylphenyl)ethyl]-3/7-imidazo[4,5-b]pyridin-5-yl}pyridine-2,6-diamine.

16. Compound of formula (I) according to claim 1 which is 4-[2-methyl-3-(2,2,2trifluoroethyl)-3//-imidazo[4,5-ô]pyridin-5-yl]pyridine-2,6-diamine.

IL Compound of formula (I) which is 4-(3-cyclopropyl-2-methyl-37/-imidazo[4,525 6]pyridin-5-yl)pyridine-2,6-diamine.

-99Process 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):

(Π)

5 wherein A represents a halogen atom, or a linear or branched (Ci-Ce)alkyl group optionally substituted by from one to three halogen atoms, X represent a halogen atom, and R₂ is as defined in formula (I), which compound of formula (II) is subjected to coupling with a compound of formula (III):

10 wherein:

- Rbi and Rb₂ represent a hydrogen, a linear or branched (Ci-Ce) alkyl group, or Rbi and Rb₂ form with the oxygen atoms carrying them an optionally methylated ring,

- Rb3 represents a hydrogen or group NH₂,

- R| and R5 are as defined in formula (I),

15 to yield compound of formula (IV):

- ιοο A

wherein A represents a halogen atom, or a linear or branched (Ci-Ce)alkyl group optionally substituted by from one to three halogen atoms, Rb3 represents a hydrogen or group NH₂, and R₂, R4 and R5 are as defined in formula (I),

5 which compound of formula (IV):

- may be reacted with Et₄NCN when A represents a halogen to yield the compounds of formula (I) wherein R|=-CN, or

- may be subjected to an aromatic nucleophilic substitution when R₂ represents a linear or branched HO-(C]-C6)alkylene group, and/or

10 - may be subjected to an acylation in the presence of an acid dérivative, 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 15 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.

- 101 121 Process for the préparation of compounds of formula (I) according to claim 1, which process is characterised in that there is used as starting material the compound of formula (ΙΓ):

5 wherein A’ represents a linear or branched (Ci-Cejalkyl group optionally substituted by from one to three halogen atoms, and X represents a halogen atom, which compound of formula (ΙΓ) is subjected to coupling with a compound of formula (ΠΙ):

10 wherein:

- R_Bi and Rb2 represent a hydrogen, a linear or branched (Ci-Cg) alkyl group, or Rbi and Rb2 form with the oxygen atoms carrying them an optionally methylated ring,

- Rb3 represents a hydrogen or group NH₂,

- Ri and R5 are as defined in formula (I),

15 to yield compound of formula (IV’):

- 102A'

wherein:

- A’ represents a linear or branched (Cj-C6)alkyi group optionally substituted by from one to three halogen atoms,

5 - R_B3 represents a hydrogen or group NH₂,

- R4 and R5 are as defined in formula (I), which compound of formula (IV’) is :

A) either subjected to a nucleophilic substitution in the presence of a compound of formula R₂-NH₂, wherein R₂ is as defined in formula (I) to yield the compound of

10 formula (V’) :

103 wherein:

- Rb3 represents a hydrogen or group NH₂,

5 - R₂, R4 and R5 are as defined in formula (I), which compound of formula (V’) is submitted to an intramolecular reaction (ring closure) in acidic medium, to yield the compound of formula (I),

A'

10 wherein:

- R is a linear or branched (Ci-Ce)alkyl group, an optionally substituted aryl, or a linear or branched polyhalogenated (Ci-Ce)alkyl group,

- A’ represents a linear or branched (Ci-Ce)alkyl group optionally substituted by from one to three halogen atoms,

15 - Rb3 represents a hydrogen or group NH₂,

- R4 and R5 are as defined in formula (I),

- 104 which compound of formula (VI’) is further subjected to a nucleophilic substitution in the presence of a compound of formula R2-NH2, wherein R2 is as defined in formula (I), to yield the compound of formula (Vif) :

A'

wherein:

- Rbj represents a hydrogen or group NH₂,

- R2, R4 and Rs are as defined in formula (I), which compound of formula (VU’) is submitted to an intramolecular organometallic coupling reaction, to yield the compound of formula (I) wherein the définition of Rj is limited to the one of A’, 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 synthesis may be protected and then deprotected according to the requirements of synthesis.

- 105-

21 Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17, or an addition sait thereof with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients.

2L Pharmaceutical composition according to claim 20 for use in the treatment of cancer, neurodegenerative disorders or metabolic disorders.

22. Pharmaceutical composition according to claim 21, 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.

23. Pharmaceutical composition according to claim 21, wherein the neurodegenerative disorders are selected from Alzheimer’s, Parkinson’s and Huntington’s diseases, Down’s syndrome, mental retardation and motor defects.

24. Use of a pharmaceutical composition according to claim 20 in the manufacture of a médicament intended for the treatment of cancer, neurodegenerative disorders or metabolic disorders.

25. Use according to claim 24, 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.

26. Use according to claim 24, wherein the neurodegenerative disorders are selected from Alzheimer’s, Parkinson’s and Huntington’s diseases, Down’s syndrome, mental retardation and motor defects.

27. Compound of formula (I) according to one of claims 1 to 17, or an addition sait thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancer, neurodegenerative disorders or metabolic disorders.

- 106 21 Use of a compound of formula (I) according to one of claims 1 to 17, 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.

5 21 Combination of a compound of formula (I) according to any one of claims 1 to 17 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.

21 Pharmaceutical composition comprising a combination according to claim 29 in 10 combination with one or more pharmaceutically acceptable excipients.

IL Combination according to claim 29 for use in the treatment of cancer.

i

32* Use of a combination according to claim 29 in the manufacture of a médicament for use in the treatment of cancer.

32* Compound of formula (I) according to any one of claims 1 to 17 for use in in the 15 treatment of cancer necessitating radiotherapy.