PYRIDINE AND PYRAZINE DERIVATIVES AS PROTEIN KINASE MODULATORS

WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 PYRIDINE AND PYRAZINE DERIVATIVES AS PROTEIN KINASE MODULATORS BACKGROUND This application claims priority to U.S. provisional application Serial No. 61/273,154, filed July 30, 2009, and U.S. provisional application Serial No. 61/357,720, filed June 23, 2010, the contents of which are incorporated herein by reference in their entirety. [0021 The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is protein kinases. Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. (Hardie, G. and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.: 1995). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost ail kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596; Knighton et al., Science 1991, 253,407-414; Hiles et al., Cell 1992, 70, 419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al., EMBO J. 1994, 13, 2352-2361). 10041 Many diseases are associated with abnormal cellular responses triggered by the protein kinase-mediated events described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, viral diseases, and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents. [0051 The cyclin-dependent kinase (CDK) complexes are a class of kinases that are targets of interest. These complexes comprise at least a catalytic (the CDK itself) and a regulatory (cyclin) subunit. Some of the more important complexes for cell cycle regulation WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 include cyclin A (CDK 1-also known as cdc2, and CDK2), cyclin B l-B3 (CDK1) and cyclin DlD3 (CDK2, CDK4, CDK5, CDK6), cyclin E (CDK2). Each of these complexes is involved in a particular phase of the cell cycle. Additionally, CDKs 7, 8, and 9 are implicated in the regulation of transcription. The activity of CDKs is regulated post4ranslationally, by transitory associations with other proteins, and by alterations of their intracellular localization. Tumor development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anti-cancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for, e.g., cyctin A/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cytotoxic and cytostatic drugs. While inhibition of cell cycle-related CDKs is clearly relevant in, e.g., oncology applications, inhibition of RNA polymerase-regulating CDKs may also be highly relevant in cancer indications. The CDKs have been shown to participate in cell cycle progression and cellular transcription, and loss of growth control is linked to abnormal cell proliferation in disease (see e.g., Malumbres and Barbacid, Nat. Rev. Cancer 200 l, 1:222). Increased activity or temporally abnormal activation ofcyclin-dependent kinases has been shown to result in the development of human tumors (Sherr C. J., Science 1996, 274 : 1672-1677). Indeed, human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators (Cordon-Cardo C., Am. J. Pari/701. 1995; 147: 545-560; Karp J. E. and Broder S., Nat. Med. 1995; l: 309-320; Hall M. et al., Adv. Cancer Res. 1996; 68: 671o8). 10081 Naturally occurring protein inhibitors of CDKs such as p16 and p27 cause growth inhibition in vitro in lung cancer cell lines (Kamb A., Curr. Top. MicrobioI. Immunol. 1998; 227: 139-148). 1009] CDKs 7 and 9 seem to play key roles in transcription initiation and elongation, respectively (see, e.g., Peterlin and Price. Cell 23: 297-305, 2006, Shapiro. J. Clin. Oncot. 24: 1770-83, 2006;). Inhibition of CDK9 has been linked to direct induction ofapoptosis in tumor cells of hematopoetic lineages through down-regulation of transcription of antiapoptotic proteins such as Moll (Chao, S.-H. et al. J. Biol. Chem. 2000;275:28345-28348; Chao, S.-H. et al. J. Biol. Chem. 200t;276:31793-31799; Lam et. al. Genome Biology 2: 0041.1-11, 2001; WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Chen et al. Blood 2005;106:2513; MacCallurn et al. Cancer Res. 2005;65:5399; and Alvi et al. Blood 2005;105:4484). In solid tumor cells, transcriptional inhibition by downregulation of CDK9 activity synergizes with inhibition of cell cycle CDKs, for example CDK1 and 2, to induce apoptosis (Cal, D.-P., Cancer Res 2006, 66:9270. Inhibition of transcription through CDK9 or CDK7 may have selective non-proliferative effect on the tumor cell types that are dependent on the transcription of mRNAs with short hall lives, for example Cyclin D l in Mantle Cell Lymphoma. Some transcription factors such as Myc and NF-kB selectively recruit CDK9 to their promoters, and tumors dependent on activation of these signaling pathways may be sensitive to CDK9 inhibition. [00101 Small molecule CDK inhibitors may also be used in the treatment of cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders that are due to aberrant cell proliferation. Vascular smooth muscle proliferation and intimal hyperplasia following balloon angioplasty are inhibited by over-expression of the cyclindependent kinase inhibitor protein. Moreover, the puñne CDK2 inhibitor CVT-313 (Ki = nM) resulted in greater than 80% inhibition of neointima formation in rats. CDK inhibitors can be used to treat diseases caused by a variety of infectious agents, including fungi, protozoan parasites such as Plasmodium falciparum, and DNA and RNA viruses. For example, cyclin-dependent kinases are required for viral replication following infection by herpes simplex virus (HSV) (Schang L. M. et al., J. Virol. 1998; 72: 5626) and CDK homologs are known to play essential roles in yeast. [00121 Inhibition of CDK9/cyclin T function was recently linked to prevention of H1V replication and the discovery of new CDK biology thus continues to open up new therapeutic indications for CDK inhibitors (Sausville, E. A. Trends Mole. Med. 2002, 8, $32- $37). 10013] CDKs are important in neutrophil-mediated inflammation and CDK ìnhibitors promote the resolution of inflammation in animal models. (Rossi, A.G. et al, Nature Med. 2006, 12:1056). Thus CDK inhibitors, including CDK9 inhibitors, may act as anti-inflammatory agents. [00141 Selective CDK inhibitors can be used to ameliorate the effects of various autoimmune disorders. The chronic inflammatory disease rheumatoid arthritis is characterized by synovial tissue hyperplasia; inhibition of synovial tissue proliferation should minimize WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 inflammation and prevent joint destruction. In a rat model of arthritis, joint swelling was substantially inhibited by treatment with an adenovirus expressing a CDK inhibitor protein p 16. CDK inhibitors are effective against other disorders of cell proliferation including psoriasis (characterized by keratinocyte hyperproliferation), glomerulonephritis, chronic inflammation, and lupus. Certain CDK inhibitors are useful as chemoprotective agents through their ability to inhibit cell cycle progression of normal untransformed cells (Chen, et al. J. Natl. Cancer Institute, 2000; 92: 1999-2008). Pro-treatment of a cancer patient with a CDK inhibitor prior to the use of cytotoxic agents can reduce the side effects commonly associated with chemotherapy. Normal proliferating tissues are protected from the cytotoxic effects by the action of the selective CDK inhibitor. Accordingly, there is a great need to develop inhibitors of protein kinases, such as CDKI, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as combinations thereof. Summary of the Invention There remains a need for new treatments and therapies for protein kinaseassociated disorders. There is also a need for compounds useful in the treatment or prevention or amelioration of one or more symptoms of cancer, inflammation, cardiac hypertrophy, and HIV. Furthermore, there is a need for methods for modulating the activity of protein kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, and combinations thereof, using the compounds provided herein. In one aspect, the invention provides a compound of Formula I: Rsy" "'R1 A3-.Ç Ai A2 AÇ L R2 R3 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 or a pharmaceutically acceptable salt thereof, wherein: [OOlSl [00191 [oo2ol A1 is N or CRó; A2 is N, N(O) or CR7 ; A3 is N or CRs; A4 is selected from a bond, SO2 , NRg, or O; L is selected from a bond, optionally substituted C1 _4 alkyl, C 6 cycloalkyl, C»6 heterocycloatkyl, or C2 alkenyl; R, is X-R16 ; [00231 X is a bond, or Ci-4 alkyl and; R16 is selected from the group consisting of C1 -6 alkyl, C36 branched alkyl, Cascycloalkyl, heterocycloalkyl, C 8 -partially unsaturated cycloalkyl, aryl, and heteroaryl; wherein Rt6 is substituted with one to three groups independently selected from halogen, hydrogen, C1 _6 alkyl, Ci.6 haloalkyl, C3 .6 branched alkyl, C3 .6 branched haloalkyl, OH, Ci. 6alkoxy, R22 -ORI2 , S(O)0 .2 R12 , R22 -S(O)0 .2 Rt2 . S(O)2 NRt3 R14 , R22 -S(O)2 NR13 RI4 , C(O)OR12 , R22 - C(O)OR|2, C(O)Ri9 , R22 -C(O)R19 , O-CI-3 alkyl, OC L-3 haloalkyl, OC(O)RIg, R22 -OC(O)RI9 , C(O)NRI3RI4, R22 -C(O)NRI3 R14 , NRisS(O)2 R12 , R22 -NRL5 S(O)2 RI2 , NR17 Ris, R22 -NRI7 R18 , NRtsC(O)R19, R22 -NRIsC(O)RIg, NRisC(O)OCH2 Ph, R22 -NR15 C(O)OCH2 Ph, NR15 C(O)ORI2 , R22-NRisC(O)ORi2,NRLsC(O)NRI3RI4, and R22 -NR15 C(O)NRi3 RL4 ; RI7 and RIs are each, independently, selected from the group consisting of hydrogen, hydroxyl, Ci_6 alkyl, Ci.6 haloalkyl, C3 _6 branched alkyl, C3 -6 cycloalkyl, Rzz-ORL2 . R2 zS(O)0-2RI2, R22 -S(O)2 NRI3 RI4 , R22 -C(O)ORI2 , R22 -C(O)Rt9 , R22 -OC(O)RI9 , R22 -C(O)NR13 RI4 , R22-NR15S(O)2Ri2, R22 -NR23 R24 , R22 -NRIsC(O)R 9 , R22 -NRisC(O)OCH2 Ph, R22 -NRisC(O)OR12 , Rn-NRIsC(O)NRI3RI4, cycloalkyl, heterocycloalkyl and heteroaryl; alternatively, Ri7 and Ris along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ñng wherein the carbon atoms of said ring are optionally substituted with R20 , and the nitrogen atoms of said ring are optionally substituted with R2 ; [00271 RI9 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; [00281 R20 is selected from the group consisting of C1 -6 alkyl or Ci-6 haloatkyl; WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 R21 is selected from the group consisting of C1 .6 alkyl, C1 _6 haloatkyl, C(O)RI2 , C(O)ORI2, S(O)2 RI2 ; Rn is selected from the group consisting of C1 -6 alkyl, C1 _6 haloalkyl, C»6 branched alkyl, C3 _6 branched haloalkyl; R23 and R24 are each, independently, selected from the group consisting of hydrogen, C1 .6 alkyl, C1 _6 haloalkyt, C3 -6 branched alkyl, C3 -6 branched haloalkyl; R2 is selected from the group consisting of optionally substituted C1 -6 alkyl, optionally substituted C3 -6 branched alkyl, optionally substituted C3 - cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R4 , Rs, and R6 are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C1 -4 alkyl, C1 _4 haloalkyl, C2 -4 alkenyl, C2 -4 alkynyl, amino, NRt0R11, and alkoxy; R3 , R7 and R8 are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, alkyl, hatoalkyl, alkenyl, alkynyl, alkoxy, NR10 R11 , C(O)RI2, C(O)OR12 , C(O)NRt3 R14 , S(O)0 .2 R12 , S(O)0 -2 NRI3 RI4 , and optionally substituted C3 _4 cyctoalkyl; R9 is selected from the group consisting of hydrogen, C1 -4 alkyl, alkoxy, C(O)R12 , C(O)OR15, C(O)NR13 R14 , S(O)0 -2 R12 , S(O)0 -2 NR13 RI4 , optionally substituted C3 -4 cycloalkyl, and optionally substituted heterocycloalkyl; R10 and R11 are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, C(O)RI2 , C(O)OR12 , C(O)NRI3 R14 , 5(O)0 -2 R12 , and S(O)0 _ 2NRI3R 4; alternatively, Ri0 and R1 l along with the nitrogen atom to which they are attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or a non-aromatic heterocyclic ring; RI2 and R15 are each, individually, selected from the group consisting of hydrogen, alkyl, branched alkyl, haloalkyl, branched haloalkyl, (CH2 )0 _3 -cycloalkyl, (CH2 )0 -3 - heterocycloalkyl, (CH2 )04 - aryl, and heteroaryl; R13 and RI4 are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyt, branched alkyl, haloalkyl, branched haloalkyt, alkoxy, cycloalkyl or heterocycloalkyl; and alternatively, R13 and RI4 along with the nitrogen atom to which they are WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or non-aromatic heterocyclic ring. !0039] One preferred embodiment of the present invention provides a compound of Formula I wherein, A1 is N; A2 is N; and A3 is CRs. Another aspect of the present invention provides a compound of Formula I wherein A1 is CR6 , A2 is CR7 , and A3 is CR8 . Yet another preferred embodimentt provides a compound of Formula I wherein, A1 is N; A2 is CRT; and A3 is CRs. A further preferred embodiment of the preceding aspects of the present invention provides a compound of Formula I wherein, R8 is selected from halogen, hydrogen, CN, CF3 , OC1.3-alkyl, and C1.3-alkyl, with CI, F, and methyl being the preferred Rs substituents, and CI being the particularly preferred ILs substituent. Other preferred embodiment of the present invention provides a compound of Formula I wherein, R1 is X-RI6 ; X is a bond, or Ci.2 alkyl; RI6 is selected from the group consisting of C1 _2 -alkyl, C4 .6 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; wherein Ri6 is substituted with one to three groups independently selected from halogen, hydrogen, C1.3alkyt, C3 _6 branched alkyl, OH, C1 _2 alkoxy, R22 -ORu, S(O)1 .2 R12 , C(O)ORI2, R22 -C(O)OR|2 , C(O)RIg, R22 -OC(O)RIg, C(O)NR13 R14 , NR15 S(O)2 R12 , NR17 R18 , R22-NRITRIs, NR15 C(O)R19 , R22 -NR15 C(O)R19 , and NRIsC(O)OCH2 Ph. Particularly preferred R16 substituents are selected from the group consisting ofC 2 -alkyt, cyclopentyl, cyclohexyl, piperidine, piperazine, morpholine, pyridine, pyrrolidine, cyclohexenyl, and tetrahydro-2Hpyran; wherein R16 is substituted with one to three groups selected from amino, hydroxyl, NHCH2-phenyl, CH2 -amino, COO-t-butyl, H, methoxy, NH-SO2 -ethyl, CH2 -NHSO2 -ethyl, SO2 - ethyl, t-butyl, methyl, CH2 -COOH, CO-NHCH3 , CON(CH3 )2 , NHC(CH3 )-CH2 -SO2 -CH3 , NHCOO-CH2-phenyl, hydroxyl-methyl, CH2 -NH-CH3 , CH2 -NH-ethyl, NH-CH2 -CH2 -methoxy, CH2 - NH-CO-CH3, NH-CH2 -CH2 OH, NH-CO-CH2 -N(CH3 )» NH-CO-methylpyrrolidine, NH-CH2 - C(CH3)-dioxolane, NH-CO-pyfidyl, NH-ethyl, pyrrolidine, CH2 -NH-CO-pyñdyt, NHtetrahydropyran, COCH2 -N(CH3 )2 , NH-CH2 -C(CH3 )-dimethyldioxolane, tetrahydropyran, COmethylpyrrolidine, CH2 -methylpipeñdine, NH-CO-CH3 , NH-SO2 -CH3 , NH-CH(CH2 -OCH3 )2 , NH-CH2-tetrahydrofuran, NH-CH2 -0xetane, NH-tetrahydropyran, NH-CH2 -dioxane, N(CH3 )- CH2CH2-OCH3, CH(OH)-CH2 -amino, NH-CH2 CH2 -OCF3 , NHCH2 -OCH3 , NH-CH2 -CH(CF3 )- OCH3, NH-CH(CH3 )-CH2 -OH, F, NH-oxetane, CH2 -CH2 -OCH3 , CH2 -OCH3 , CH2 - tetrahydropyran, CH2 -methylpiperizine, NH2 -CH2 -CH(OH)-CF3 , piperidine, CH2 -pyrrotidine, NH-CH(CH3)CH2OCH3, NH-tetrahydrofuran, (CH2 )3 -NH2 , hydroxyethyl, propyl, CH2 -pyridyl, WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 CH2-piperidine, morpholine, NH-chloropyrimidine, NH-CH2 CH2 -SO2 -methyl, (CH3 )3 -N(CH3 )2 , piperizine, HN ° LO HN /L.o 0, and CH2 -morpholine. Another preferred embodiment of the present invention provides a compound of Formula I wherein, R3 is selected from H, methyl, cyano, chloro, CONH2 , amino, cyclopropyl, ethyl, and fluoro; R4 is selected from halogen, methyl, hydrogen, and halo-methyl; 1% is H; R7 is selected from H, COOH, CI, F, CONH2 , CN, and CF3 ; Rs is CI; R17 and R18 are each, independently, selected from the group consisting of hydrogen, Ci4 alkyl, C t_4 haloalkyl, C3 . 6branched alkyl, R22 -OR12 . R22 -S(O)2 R12 , R22 -NRIsS(O)2 RI2 , heterocycloalkyl or heteroaryl; alternatively, Ri7 and RI8 along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein said ring carbon atoms are optionally substituted with R20 , and the ring nitrogen atoms are optionally substituted with R21 ; 100411 RI9 is selected from Ci.3 -alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R20 represents the group C1.3alkyl; and Rn is selection from the group consisting of C1 _4 alkyl, and C3 .6 branched alkyl. Further preferred are compounds of Formula I wherein, A4 is selected from NR9 , O, and a bond; L is selected from a bond, C1 .4 -alkyl, and cyclopropyl; R2 is selected from the group consisting of C3 -7 cycloalkyl, a rive to seven membered heterocycloalkyl, phenyl, and pyridyl, wherein each said R2 group is substituted with one, two, or three substituents independently selected from hydrogen, cyano, CO-NH2, halogen, methoxy, dihalo-methoxy, trihalo-methoxy, trihalo alkyl, C1_3-alkyl, and hydroxy; and R9 represents methyl, hydrogen, or ethyl. Provided in a particularly preferred embodiment are compounds of Formula I, wherein, Aa is CR6 ; A2 is CR7 ; A3 is CR8 ; A4 is selected from NR9 , O, and a bond; L is a bond, C1-2 alkyl, or C3 -4 -cycloalkyl; Ri is X-RI6 ; X is a bond, or Ca.2 alkyl; R16 is selected from the group consisting of C 2 -alkyl, cyclopentyl, cyclohexyl, pipeddine, piperazine, morpholine, pyridine, pyrrolidine, cyclohexenyl, and tetrahydro-2H-pyran; wherein R16 is substituted with WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 one to three groups independently selected from amino, hydroxyl, NHCH2 -phenyl, CH2 -amino, COO-t-butyl, H, methoxy, NH-SO2 -ethyl, CH2 -NHSO2 -ethyl, SO2 -ethyl, t-butyl, methyl, CH2 - COOH, CO-NHCH3 , CON(CH3 )2 , NHCH2 -CH2 -SO2 -CH3 , NH-COO-CH2 -phenyl, hydroxymethyl, CH2 -NH-CH3 , CH2 -NH-ethyl, NH-CH2 -CH2 -methoxy, CH2 -NH-CO-CH3 , NH-CH2 - CH2OH, NH-CO-CH2 -N(CH3 )2 . NH-CO-methylpyrrolidine, NH-CO-pyridyl, NH-ethyl, pyrrolidine, CH2 -NH-CO-pyridyl, COCH2 -N(CH3 )2 , tetrahydropyran, CO-methytpyrrolidine, CH2-methylpipeñdine, NH-CO-CH3 , NH-SO2 -CH3 , NH-CH2 -tetrahydrofuran, NH-CH2 - dioxane, N(CH3 )-CH2 CH2 -OCH3 , CH(OH)-CH2 -amino, NH-CH2 CH2 -OCF3 , NH(CH3 )-CH2 - OCH3, NH-CH2 -CH(CF3 )-OCH3 , F, NH-oxetane, CH2 -CH2 -OCH3 , CH2 -OCH3 , CH2 - tetrahydropyran, CH2 -methylpiperizine, NH2 -CH2 -CH(OH)-CF3 , piperidine, CH2 -pyrrolidine, NH-CH(CH3)CH2OCH3, NH-tetrahydrofuran, (CH2 )3 -NH2 , hydroxyethyl, propyl, CH2 -pyridyl, CH2-piperidine, morpholine, NH-chloropyrimidine, NH-CH2 CH2 -SO2 -methyl, (CH3 )3 -N(CH3 )2 , pipeñzine, CH2 -morpholine, NH-CH2 -C(CH3 )-dioxolane, NH-tetrahydropyran, NH-CH2 - C(CH3)-dimethyldioxolane, NH-CH(CH2 -OCH3 )2 , NH-CH2 -0xetane, NH-tetrahydropyran, N(CH3)-CH2CH2-OCH3, NH-CH(CH3 )-CH2 -OH, HN 0 HN o [00431 and NH-CH(CH3 )-CH2 -OH; 10044] R2 is selected from the group consisting ofcyclohexyl, 1,3-dioxane, pyridinyl, phenyl, tetrahydropyranyl, cycloheptyl, 1,4-dioxane, morpholinyl, alkyl substituted dioxane, tetrahydrofuranyl, dioxepane, piperidinyl, and /Is°2 , wherein each said R2 group is substituted with one, two, or three substituents independently selected from CI, Br, F, methoxy, hydroxy-methyl, hydrogen, carboxamide, cyano, dihalo-methoxy, trihalo-methoxy, trifluoro-methyl, hydroxyl, and methyl; and [00461 Rz, is chlore, hydrogen, trifluoro-methyl, fluoro, or promo; Rs, and R6 are each independently hydrogen; WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 cyclopropyl; lOOSOl lOO5H [00521 R3 is selected from hydrogen, fluoro, cyano, CO-NH2 , chloro, amino, methyl, and R7 is selected from H, trifluoro-methyl, COOH, CO-NH2 , and cyano; R8 represents Ci; and R9 is selected from the group consisting of H, ethyl, and methyl. Provided in a specifically preferred embodiment of the present invention is a compound of Formula I selected from: 10053] N2'-(trans-4-aminocyclohexyl)-5'-chloro-3,5-difluoro-N6-((tetrahydro-2H-pyran4-yl)methyl)-2,4'-bipyridine-2',6-diamine; N2'- (trans-4-aminoc yctohexyl)-5'-fluoro-N6- (3-fluorobenzyl)-2,4'-bipyridine-2',6- [00S4l diamine; [oossl 3,5'-dichloro-N2'-(trans-4-(((R)-2,2-dimethyl1,3-dioxolan-4y )methy )amin cyc hexy )-N6-((tetrahydr -2H-pyran-4-y )methy )-2 4'-bipyridine-2' 6diamine; [00561 5'-chloro-N6-((tetrahydro-2H-pyran-4-yl)dideuteromethyl)-N2'-(trans 100571 -4-(((S)-tetrahydrofuran-2-yl)methyl)aminocyc lohexyl)-2,4'-bipyridine-2',6-diamine; [00581 5'-chloro-5-fluoro-N2'-(trans-4-(2-(methylsulfonyl)ethylamino)cyclohexyl)-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; 100591 5'-chloro-5-fluoro-N2'-(trans-4-(oxetan-2-yl-methylami no)c yclohexyl)-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; [00601 3,5'-dichloro-N2'-(trans-4-((R)- 1 -methoxypropan-2-yt-amino)cyclohexyl)-N6- (((S)-tetrahydro-2H-pyran-3-yt)methyl)-2,4'-bipyridine-2',6-diamine; [00611 3,5'-dichloro-N2'-(trans-4-((R)- 1 -methoxypropan-2-yt-amino)cyclohexyl)-N6- (((R)-tetrahydro-2H-pyran-3-yl)methyl)-2,4'-bipyridine-2',6-diamine; 100621 4-((5'-chloro-2'-(trans-4-((R)- l-methoxypropan-2-yl-amino)cyctohexytamino)- 2,4'-bipyridin-6-yl-amino)methyl)tetrahydro-2 H-pyran-4-carbonitñle; [00631 N2'-(trans-4-aminocyclohexyl)-5'-chloro-5-fluoro-N6-(3-fluorobenzyl)-2,4'- bipyridine-2',6-diamine; [00641 2'-(trans-4-aminocyctohexytamino)-5'-chtoro-6-(3-fluorobenzylamino)-2,4'- bipyridine-5-carbonitrile; WO 2011/012661 CA 02767066 2011-12-30 Il PCT/EP2010/060984 [00651 N2'-(trans-4-aminocyclohexyl)-3-chloro-5'-fluoro-N6-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine; 5'-chloro-N6-(3-fluorobenzyl)-N2'- (( 1R,3S)-3- ((methylamino)methyl)cyclopentyl)-2,4'-bipyridine-2',6-diamine; [00671 3,5'-dichloro-N2'-(trans-4-((R)- l -methoxypropan-2-yl-amino)cyclohexyl)-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; 5'-chloro-3-fluoro-N2'-(trans-4-((R)-l-methoxypropan-2-yl-amino)cyclohexyl)- N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; [00691 5'-chloro-5-fluoro-N2'-(trans-4-((R)-l-methoxypropan-2-yl-amíno)cyclohexyl)- N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; [00701 5'-chloro-N6-((2,2-dimethyltetrahydro-2H-pymn-4-yl)methyl)-N2'-(tmns-4-((R)- l -methoxypropan-2-yl-amino)cyclohexyl)-2,4'-bipyridine-2',6-diamine; [00711 5'-chloro-N6-(((S)-2,2-dímethyltetrahydro-2H-pymn-4-yl)methyl)-N2'-(trans-4- ((R)- l-metho xypropan-2-yl-amino)cyclohexyl)-2,4'-bipyñdine-2',6-diamine; [00721 5'-chloro-5-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4-(( 1,1 - di x tetrahydr -2H-thi pyran-4-yl)methyl)amin y l hexy )-2 4'-bipyridine-2 6-diamine; 5'-chloro-5-fl uoro-N2'-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'-bipyñdine2',6-diamine; [00751 2',6-diamine; N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-((5-fluoropyridin-3-yl)methyl)-2,4'- bipyridine-2',6-diamine; trans-4-(5'-chloro-6-(3,5-difluorobenzylamino)-2,4'-bipyridin-2'-ylamino)cyclohexanol; (R)-5'- h r -N6-(3-flu r benzy )-N2'-(2-(piperidin-3-y )ethy )-2 4'-bipyridine2',6-diamine; N2'-(trans-4-amin cyc hexy )-5'-ch r -N6-(3,5-diflu r benzy )-2 4 -bipyridineN2'-(trans-4-aminocyclohexyl)-3,5'-dichloro-N6-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine; WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100801 N2'-(trans-4-aminocyclohexyl)-3,5'-dichloro-N6-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine; 100811 3,5'-dichloro-N2'-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro2H-pyran-4-yl) methyl)-2,4'-bipyñdine-2',6-diamine; [00821 2-(trans-4-(3,5'-dichloro-6-((tetrahydro-2H-pyran-4-yl)methyl)amino-2,4'- bipyridin-2'-yl-amino)cyclohexylamino)ethanol; 100831 trans-N 1-(5-chloro-4-(6-(((R)-tetrahydro-2H-pyran-3-yl)methyl)aminopyrazin-2yl)pyridin-2-yl)cyclohexane-l,4-diamine; 100841 3,5'-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4-(((R)- tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4'-bipyridine-2',6-diamine; 1008Sl 3,5'-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4-(((S)- tetrahydrofuran-2 -yl) met hyl)aminoc ycl ohexyl)-2,4'-bipyri dine-T, 6diamine; 3,5'-dichloro-N2'-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; 100871 5'-c hloro-N 6-((tetrahydro-2 H-pyran-4-yl)methyl)-N2'-(trans-4-(((R)- tetrahydrofuran-2 -yl)methyl)aminocyelohexyl)-2, 4'-bipyridine-2',6-diamine; 100881 5'-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4-(((S)- tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4'-bipyridine-2',6-diamine; N2'-(trans-4-aminocyclohexyl)-5'-chtoro-3-fluoro-N6-((tetrahydro-2H-pyran-4yl) methyl) -2,4'-bipyri dine-2', 6-diamine; 5'-chloro-3-fluoro-N2'-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; [00911 N2'-(trans-4-aminocyclohexyl)-3-bromo-5'-chloro-N6-((tetrahydro-2 H-pyran-4yl) methyl) -2,4'-bipyrid ine-2', 6-diamine; [00921 3-bromo-5'-chloro-N2'-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6- ((tetrahydro -2H -pyran-4-yl)methyl) -2,4'-bipyridi ne-2',6-diamine; 100931 trans-4-(3, Y-die hloro-6 -((2,2-d i methyltetrahydro-2 H-pyran-4-yl)methyl)amino2,4'-bipyridin-2'-yl-amino)cyclohexanol; 10094] (2 S)-3-(trans-4-(3,5'-dichloro-6 -((2,2-di methyltetrahydro-2 H -pyran-4yl ) methyl)amino -2,4'-bipyri di n-2'- yl -amino)cyclo hexyl amino)- t, t, t -tri fiuoropropan-2 -o 1; WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 (2R) -3 -(trans -4- (3,5 '-dichloro -6 -((2,2 -dimethyltetrahydro-2 H -pyran-4 - yl)methyl)amino-2,4'-bipyridin-2'-yl-amino)cyclohexylamino)- 1,1,1 -tñfluoropropan-2-ol; 3,5'-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4-(2- (tñfluoromethoxy)ethylamino)cyclohexyl)-2,4'-bipyridíne-2',6-diamine; N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(((R)-2,2-dimethyltetrahydro-2Hpyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(((S)-2,2-dimethyltetrahydro-2Hpyran-4-yl) methyl) -2,4'-bipyñd ine-2', 6-diamine; N2'-(trans-4-ammocyclohexyl)-3,5,5'-tdchloro-N6-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridìne-2',6-diamine; N2'-(trans-4-aminocyclohexyl)-5'-chloro-5-fluoro-N6-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine; N2'-(trans-4-ammocyclohexyl)-5'-chloro-N6-((4-methyltetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine; N2'-(trans-4-aminocyclohexyl)-5'-chloro-5-fluoro-N6-((4-methyltetrahydro-2 Ipyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; N2'- (trans-4-aminocyclo hexyl)-5'-chloro-N6-((4-fluorotetrahydro-2 H-pyran-4yl)methyl)-2,4'-bipyddine-2',6-diamine; trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-ylamino)cyclohexanol; 5'-chloro-N2'-(trans-4-(dimethylamino)cyclohexyl)-N6-(3-fluorobenzyl)-2,4'- bipyridine-2',6-diamine; 5'-chloro-N6-(3-fluorobenzyl)-N2'-(trans-4-(2-methoxyethylamino)cyclohexyl)- 2,4'-bipyridine-2',6-diamine; 2-(trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-ylamino)cyclohexylamino)ethanol; 5'-chloro-N6-(3,5-difluorobenzyi)-N2'-(trans-4-(2methoxyethylamino)cyclohexyl)-2,4'-bipyñdine-2',6-diamine; 5'-chloro-N6-(3-fluorobenzyl)-N2'-(trans-4-((2methoxyethyl)(methyl)amino)cyclohexyl)-2,4'-bipyridine-2',6-diamine; WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(((2R,6S)-2,6-dimethyltetrahydro2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine; 100111] ((5'-chloro-5-fluoro-2'-(trans-4-(2-methoxyethylamino)cyclohexylamino)-2,4'- bipyñdin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile; 100112] ((2'-(trans-4-arninocyclohexylamino)-5'-chloro-5-fluoro-2,4'-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitñle; 100113] ((5 - h or -5-fluoro-2'-(trans-4-(pr pylamino) y hexy amin )-2,4' bipyridin 6yl-arnino)methyl)tetrahydro-2H-pyran-4-carbonitrile; 1001141 ((5'-chloro-2'-(trans-4-(dipmpylamino)cyclohexylamino)-5-fluoro-2,4'-bipyñdin6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile; 1001151 ((5'-chloro5-fluoro-2'-(trans-4-((R)- 1 -methoxypro pan-2-ylamin ) y hexy amin )-2 4'-bipyridin-6-y -amin )methy )tetrahydr -2H-pyran-4arb nitrile; 1001161 • ((5'-chloro-2'-(trans-4-((2-methyl1,3-dioxolan-2y )methy )amin y hexy amin )-2 4 -bipyridin-6-y -amin )methy )tetrahydr -2H-pyran-4 carbonitrile; 100117] (4-((5'-ehloro-2'-(trans-4- ((R)- l-methoxypropan-2-yl-amino)cyclo hexylamino)- 2,4'-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-yl)methanol; and 5'-chloro-5-fluoro-N6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4- ( 1,1-dioxotetrahydrothio phen-3-yl-amino)cyclohexyl)-2,4'-bipyridine-2',6-diamine. Yet another preferred embodiment of the present invention provides a compound of Formula I selected from: trans-N l-(4-(3-chloro-6-((tetmhydro-2H-pyran-4-yl)methyl)amìnopyrazin-2yl)pyridin-2-yl)cyclohexane1,4-diamine; trans-N l-(5-chloro-4-(3-chloro-6-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane1,4-diamine; trans-4-(5-chloro-4-(5-chloro-6-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazin-2-yl)pyñdin-2-yl-amino)cyclohexanol; trans-Nl -(5-chloro-4-(5-chloro-6-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-l,4-diamine; 100124] trans-4-(5-chloro-4-(6-(((S)-tetrahydro-2H-pyran-3-yl)methyl)aminopyrazin-2yl)pyñdin-2-yl-amino)cyclohexanol; WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100125] trans-4-(5-chloro-4-(6-(((R)-tetrahydro-2H-pyran-3-yl)methyl)aminopyrazin-2yl)pyridin-2-yl-amino)iyclohexanol; |00126] trans-N l-(5-chloro-4-(6-(((S)-tetrahydro-2H-pyran-3-yl)methyl)aminopyrazin-2yl)pyridin-2-yl)cyclohexane-1,4-diamine; 100127] trans-N l-(5-chloro-4-(6-(((R)-tetrahydro-2H-pyran-3-yl)methyl)aminopyrazin-2yl)pyridin-2yl)cyclohexane1,4-diamine; trans-N l-(5-chloro-4-(6-(methyl((tetrahydro-2H-pyran-4yl)methyl)amino)pyrazin-2-yl)pyridin-2-yl)cyclohexane1,4-diamine; [001291 trans-N l-(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2yl)pyridin-2-yl)-N4-(2-methoxyethyl)cyclohexane1,4-diamine, [001301 trans-4-(5-chloro-4-(6-((tetrahydro-2H-pyran-3-yl)methyl)aminopyrazin-2yl)pyridin-2-yl-amino)cyclohexanol; 10013 ll trans-4-(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2yl)pyridin-2-yl-amino)cyclohexanol; and 1001321 trans-N 1 -(5-chloro-4-(6-(3-fl uorobenzylamino)pyrazin-2-yl)pyridin-2yl)cyclohexane1,4-diamine. Another aspect of the present invention provides a compound of Formula I, or pharmaceutically acceptable sait or solvate thereof, for use in therapy. Yet another aspect of the present invention provides a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a disease or condition mediated by CDK9. Yet another aspect of the present invention provides a method of treating a disease or condition mediated by CDK9 comprising administration to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable sait thereof. Provided in yet another aspect of the present invention is a compound of Formula I for use in a method of treating a disease or condition mediated by CDK9 is selected from cancer, cardiac hypotrophy, HIV and inflammatory diseases. [001361 Another aspect of the present invention provides a method of treating a cancer selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoetic system, genitourinary tract, WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal, and pancreatic cancer. !00137] Yet another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formuls 1, r a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carder, diluent or excipient. 100138] In another aspect, the invention provides a method of regulating, modulating, or inhibiting protein kinase activity which comprises contacting a protein kinase with a compound of the invention. In one embodiment, the protein kinase is selected from the group consisting of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, or any combination thereof. In another embodiment, the protein kinase is selected from the group consisting of CDK l, CDK2 and CDK9, or any combination thereof. In still another embodiment, the protein kinase is in a cell culture. In yet another embodiment, the protein kinase is in a mammal. In another aspect, the invention provides a method of treating a protein kinaseassociated disorder comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention such that the protein kinase-associated disorder is treated. In one embodiment, the protein kinase is selected from the group consisting ofCDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9. In one embodiment, the protein kinase-associated disorder is cancer. In still another embodiment, the cancer is selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoetic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancer. In one embodiment, the protein kinase-associated disorder is inflammation. In another embodiment, the inflammation is related to rheumatoid arthritis, lupus, type l diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, chronic inflammation, and organ transplant rejections. In another embodiment, the protein kinase-associated disorder is a viral infection. In one embodiment, the viral infection is associated with the HIV virus, human papilloma virus, herpes virus, poxyirus virus, Epstein-Barr virus, Sindbis virus, or adenovirus. In still another embodiment, the protein kinase-associated disorder is cardiac hypertrophy. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 In another aspect, the invention provides a method of treating cancer comprising administering to a subject in need thereofa pharmaceutically acceptable amount of a compound of the invention such that the cancer is treated. In one embodiment, the cancer is selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoetic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancer. [001451 In another aspect, the invention provides a method of treating inflammation comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the inflammation is treated, wherein the compound is a compound of the invention. In one embodiment, the inflammation is related to rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, chronic inflammation, and organ transplant rejections. [001461 In another aspect, the invention provides a method of treating cardiac hypertrophy compñsing administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the cardiac hypertrophy is treated, wherein the compound is a compound of the invention. In another aspect, the invention provides a method of treating a viral infection comprising administering to a subject in need thereofa pharmaceutically acceptable amount of a compound such that the viral infection is treated, wherein the compound is a compound of the invention. In one embodiment, the viral infection is associated with the HIV virus, human papilloma virus, herpes virus, poxyirus virus, Epstein-Ban" virus, Sindbis virus, or adenovirus. In one embodiment, the subject to be treated by the compounds of the invention is a mammal. In another embodiment, the mammal is a human. In another aspect, the compounds of the invention is administered, simultaneously or sequentially, with an antiinflammatory, antiproliferative, chemotherapeutic agent, immunosuppressant, anti-cancer, cytotoxic agent or kinase inhibitor or salt thereof. In one embodiment, the compound, or sait thereof, is administered, simultaneously or sequentially, with one or more ofa PTK inhibitor, cyclospoñn A, CTLA4-Ig, antibodies selected from anti-ICAM3, anti-IL-2 receptor, anti-CD45RB, anti-CD2, anti-CD3, anti-CD4, anti-CDS0, anti-CD86, and monoclonal antibody OKT3, CVT-313, agents blocking the interaction between CD40 and gp39, WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 fusion proteins constructed from CD40 and gp39, inhibitors ofNF-kappa B function, nonsteroidal antiinflammatory drugs, steroids, gold compounds, FK506, mycophenolate mofetil, cytotoxic drugs, TNF-a inhibitors, anti-TNF antibodies or soluble TNF receptor, rapamycin, leflunimide, cyclooxygenase-2 inhibitors, paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine, epothilone, vindesine, leurosine, or derivatives thereof. in another aspect, the invention provides a packaged protein kinaseassociated disorder treatment, comprising a protein kinase-modulating compound of the Formula I or Formula II, packaged with instructions for using an effective amount of the protein kinasemodulating compound to treat a protein kinase-associated disorder. In certain embodiments, the compound of the present invention is further characteñzed as a modulator of a protein kinase, including, but not limited to, protein kinases selected from the group consisting of abl, ATK, Bcr-abl, Blk, Brk, Btk, c-fms, e-kit, c-met, c-src, CDK, cRaft, CSFIIL CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, les, FGFRI, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, fit-t, Fps, Frk, Fyn, GSK, Gst-Flkl, Hck, Her-2, Her-4, IGF1R, INS-R, Jak, JNK, KDR, Lck, Lyn, MEK, p38, panHER, PDGFR, PLK, PKC, PYK2, Raf, Rho, ros, SRC, TRK, TYK2, UL97, VEGFR, Yes, Zap70, Aurora-A, GSK3-alpha, HIPKI, HIPK2, HIP3, IRAI, JNKI, JNK2, JNK3, TRKB, CAMKII, CK1, CK2, RAF, GSK3Beta, MAPK1, MKK4, MKK7, MST2, NEK2, AAK 1, PKCalpha, PKD, RIPK2 and ROCK-Il. (I think we should consider whether to include such an expansive list. May be restrict to those that are identified in the expanded cell plate assay?) In a preferred embodiment, the protein kinase is selected from the group consisting ofCDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 and any combination thereof, as well as any other CDK, as well as any CDK not yet identified. In a particularly preferred embodiment, the protein kinase is selected from the group consisting of CDKI, CDK2 and CDK9. In a particularly preferred embodiment, the protein kinase is selected from the group consisting of CDK9. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100153] In a particular embodiment, CDK combinations of interest include CDK4 and CDK9; CDKI, CDK2 and CDK9; CDK9 and CDK7; CDK9 and CDKI; CDK9 and CDK2; CDK4, CDK6 and CDK9; CDKI, CDK2, CDK3, CDK4, CDK6 and CDK9. 100154] In other embodiments, the compounds of the present invention are used for the treatment of protein kinase-associated disorders. As used herein, the term "protein kinase-associated disorder" includes disorders and states (e.g., a disease state) that are associated with the activity of a protein kinase, e.g., the CDKs, e.g., CDKI, CDK2 and/or CDK9. Nonlimiting examples of protein kinase-associated disorders include abnormal cell proliferation (including protein kinase-associated cancers), viral infections, fungal infections, autoimmune diseases and neurodegenerative disorders. 100155] Non-limiting examples ofprotein-kinase associated disorders include proliferative diseases, such as viral infections, auto-immune diseases, fungat disease, cancer, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, chronic inflammation, neurodegenerative disorders, such as Alzheimer's disease, and post-surgical stenosis and restenosis. Protein kinase-associated diseases also include diseases related to abnormal cell proliferation, including, but not limited to, cancers of the breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary passages, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenocarcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, and leukemia. Additional non-limiting examples of protein kinase-associated cancers include carcinomas, hematopoietic tumors of lymphoid lineage, hematopoietic tumors ofmyeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Protein kinase-associated disorders include diseases associated with apoptosis, including, but not limited to, cancer, viral infections, autoimmune diseases and neurodegenerative disorders. Non-limiting examples ofprotein-kinase associated disorders include viral infections in a patient in need thereof, wherein the viral infections include, but are not limited to, HIV, human papilloma virus, herpes virus, poxyirus, Epstein-Barr virus, Sindbis virus and adenovirus. 100159] Non-limiting examples of protein-kinase associated disorders include tumor angiogenesis and metastasis. Non-limiting examples of protein-kinase associated disorders also include vascular smooth muscle proliferation associated with atherosclerosis, postsurgical vascular stenosis and restenosis, and endometriosis. Further non-limiting examples of protein-kinase associated disorders include those associated with infectious agents, including yeast, fungi, protozoan parasites such as Plasitiodium falciparum, and DNA and RNA viruses. 100161] In another embodiment, the compound of the present invention is further characterized as a modulator of a combination of protein kìnases, e.g., the CDKs, e.g., CDK 1, CDK2 and/or CDK9. In certain embodiments, a compound of the present invention is used for protein kinase-associated diseases, and/or as an inhibitor of any one or more protein kinases. It is envisioned that a use can be a treatment of inhibiting one or more isoforms of protein kinases. The compounds of the invention are inhibitors of cyclin-dependent kinase enzymes. Without being bound by theory, inhibition of the CDK4/cyclin D1 complex blocks phosphorylation of the Rb/inactive E2F complex, thereby preventing release of activated E2F and ultimately blocking E2F-dependent DNA transcription. This has the effect of inducing GI cell cycle arrest. In particular, the CDK4 pathway has been shown to have tumor-specific deregulation and cytotoxic effects. Accordingly, the ability to inhibit the activity of combinations of CDKs will be of beneficial therapeutic use. 100163] Furthermore, the cell's ability to respond and survive chemotherapeutic assault may depend on rapid changes in transcñption or on activation of pathways which are highly sensitive to CDK9/cyclinTl (PTEF-b) activity. CDK9 inhibition may sensitize cells to TNFalpha or TRAIL stimulation by inhibition of NF-kB, or may block growth of cells by WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 reducing myc-dependent gene expression. CDK9 inhibition may also sensitize cells to genotoxic chemotherapies, HDAC inhibition, or other signal transduction based therapies. As such, the compounds of the invention can lead to depletion of antiapoptotic proteins, which can directly induce apoptosis or sensitize to other apoptotic stimuli, such as cell cycle inhibition, DNA or microtubule damage or signal transduction inhibition. Depletion of anti-apoptotic proteins by the compounds of the invention may directly induce apoptosis or sensitize to other apoptotic stimuli, such as cell cycle inhibition, DNA or microtubule damage or signal transduction inhibition. The compounds of the invention can be effective in combination with chemotherapy, DNA damage arresting agents, or other cell cycle arresting agents. The compounds of the invention can also be effective for use in chemotherapy-resistant cells. The present invention includes treatment of one or more symptoms of cancer, inflammation, cardiac hypertrophy, and HIV infection, as well as protein kinase-associated disorders as described above, but the invention is not intended to be limited to the manner by which the compound performs its intended function of treatment of a disease. The present invention includes treatment of diseases described herein in any manner that allows treatment to occur, e.g., cancer, inflammation, cardiac hypertrophy, and HIV infection. In certain embodiments, the invention provides a pharmaceutical composition of arty of the compounds of the present invention. In a related embodiment, the invention provides a pharmaceutical composition of any of the compounds of the present invention and a pharmaceutically acceptable carder or excipient of any of these compounds. In certain embodiments, the invention includes the compounds as novel chemical entities. In one embodiment, the invention includes a packaged protein kinaseassociated disorder treatment. The packaged treatment includes a compound of the invention packaged with instructions for using an effective amount of the compound of the invention for an intended use. [00169| The compounds of the present invention are suitable as active agents in pharmaceutical compositions that are efficacious particularly for treating protein kinaseassociated disorders, e.g., cancer, inflammation, cardiac hypertrophy, and HIV infection. The pharmaceutical composition in various embodiments has a pharmaceutically effective amount of the present active agent along with other pharmaceutically acceptable excipients, carriers, fillers, WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 diluents and the like. The phrase, "pharmaceutically effective amount" as used herein indicates an amount necessary to administer to a host, or to a cell, issue, or organ of a host, to achieve a therapeutic result, especially the regulating, modulating, or inhibiting protein kinase activity, e.g., inhibition of the activity of a protein kinase, or treatment of cancer, inflammation, cardiac hypertrophy, and HIV infection. [001701 In other embodiments, the present invention provides a method for inhibiting the activity of a protein kinase. The method includes contacting a cell with any of the compounds of the present invention. In a related embodiment, the method further provides that the compound is present in an amount effective to selectively inhibit the activity of a protein kinase. In other embodiments, the present invention provides a use of any of the compounds of the invention for manufacture of a medicament to treat cancer, inflammation, cardiac hypertrophy, and HIV infection in a subject. [001721 In other embodiments, the invention provides a method of manufacture of a medicament, including formulating any of the compounds of the present invention for treatment of a subject. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS The term "treat," "treated," "treating" or "treatment" includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. In certain embodiments, the treatment comprises the induction of a protein kinase-associated disorder, followed by the activation of the compound of the invention, which would in tum diminish or alleviate at least one symptom associated or caused by the protein kinase-associated disorder being treated. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder. The term "use" includes any one or more of the following embodiments of the invention, respectively: the use in the treatment of protein kinase-associated disorders; the use for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, e.g., in the manufacture of a medicament; methods of use of compounds of the invention in the treatment of these diseases; pharmaceutical preparations having compounds of the invention for the treatment of these diseases; and compounds of the invention for use in the WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 treatment of these diseases; as appropriate and expedient, if not stated otherwise. In particular, diseases to be treated and are thus preferred for use of a compound of the present invention are selected from cancer, inflammation, cardiac hypertrophy, and HIV infection, as well as those diseases that depend on the activity of protein kinases. The term "use" further includes embodiments of compositions herein which bind to a protein kinase sufficiently to serve as tracers or labels, so that when coupled to a fluor or tag, or made radioactive, can be used as a research reagent or as a diagnostic or an imaging agent. The term "subject" is intended to include organisms, e.g., prokaryotes and eukaryotes, which are capable of suffering from or afflicted with a disease, disorder or condition associated with the activity of a protein kinase. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic nonhuman animals. In certain embodiments, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancer, inflammation, cardiac hypertrophy, and HIV infection, and other diseases or conditions described herein (e.g., a protein kinase-associated disorder). In another embodiment, the subject is a cell. 1001761 The language "protein kinase-modulating compound," "modulator of protein kinase" or "protein kinase inhibitor" refers to compounds that modulate, e.g., inhibit, or otherwise alter, the activity of a protein kinase. Examples of protein kinase-modulating compounds include compounds of the invention, i.e., Formula I and Formula II, as well as the compounds of Table A, Table B, and Table C (including pharmaceutically acceptable salts thereof, as well as enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof). Additionally, a method of the invention includes administering to a subject an effective amount of a protein kinase-modulating compound of the invention, e.g., protein kinasemodulating compounds of Formula I and Formula II, as well as Table A, Table B, and Table C (including pharmaceutically acceptable salts thereof, as well as enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof). Where linking groups are specified by their conventional chemical formula herein, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2 0is intended to include -OCH2 - for this purpose only. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a fully saturated straight-chain (linear; unbranched) or branched chain, or a combination thereof, having the number of carbon atoms specified, if designated (i.e. C j-C10 means one to ten carbons). Examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, see-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-oetyl, and the like. If no size is designated, the alkyl groups mentioned herein contain 1-10 carbon atoms, typically 1-8 carbon atoms, and often 1-6 or 1-4 carbon atoms, and preferably 1-2 carbon atoms, lfthe alkyl group is a branched alkyl group, and the number of carbon atoms is not mentioned, the branched alkyl group will consist of 3-8 carbon atoms, typically about 3-6 carbon atoms, and particularly 3-4 carbon atoms. The term "alkenyl" refers to unsaturated aliphatic groups including straight-chain (linear; unbranched), branched-chain groups, and combinations thereof, having the number of carbon atoms specified, if designated, which contain at least one double bond (-C=C- ). Ail double bonds may be independently either (E) or (Z) geometry, as welt as mixtures thereof. Examples ofatkenyl groups include, but are not limited to, -CH2 -CH=CH-CH3 ; -CH=CH-CH=CH2 and-CH2 -CH=CH-CH(CH3 )-CH2 -CH3 . If no size is specified, the atkenyl groups discussed herein contain 2-6 carbon atoms. [001811 The term "alkynyl" refers to unsaturated aliphatic groups including straight-chain (linear; unbranched), branched-chain groups, and combinations thereof, having the number of carbon atoms specified, if designated, which contain at least one carbon-carbon triple bond (-C=C-). Examples ofalkynyl groups include, but are not limited to, -CH2 -C-=C-CH3 ; -C C-C CH and-CH2 -C-C-CH(CH3 )-CH2 -CH3 . If no size is specified, the alkynyl groups discussed herein contain 2-6 carbon atoms. 100182] Alkynyl and alkenyl groups can contain more than one unsaturated bond, or a mixture of double and triple bonds, and can be otherwise substituted as described for alkyl groups. [001831 The terms "alkoxy," "alkenytoxy," and "alkynytoxy" refer to -O-alkyl, -Or-alkenyl, and -Or-alkynyl, respectively. The term "cycloalkyl" by itself or in combination with other terms, represents, unless otherwise stated, cyclic versions ofalkyl, alkenyl, or alkynyl, or mixtures thereof. Additionally, cyeloalkyl may contain fused rings, but excludes fused aryl and heteroaryl WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 groups, and cycloalkyl groups can be substituted unless specifically described as unsubstituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, l-cyclohexenyl, 3-cyclohexenyl, cyclohexynyl, cyclohexynyl, cyclohexadienyl, cyclopentadienyl, cyclopentenyl, cycloheptyl, norbomyl, and the like. if no ring size is specified, the cycloalkyl groups described herein contain 3-8 ring members, or 3-6 ring members. [001851 The term "heterocyclic" or "heterocycloaklyl" or "heterocyclyl," by itself or in combination with other terms, represents a cycloalkyl radical containing at least one annular carbon atom and at least one annular heteroatom selected from the group consisting of O, N, P, Si and S, preferably from N, O and S, wherein the ring is not aromatic but can contain unsaturations. The nitrogen and sulfur atoms in a heterocyclic group may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized. In many embodiments, the annular heteroatoms are selected from N, O and S. The heterocyclic groups discussed herein, if not otherwise specified, contain 3-10 ring members, and at least one ring member is a heteroatom selected from N, O and S; commonly not more than three of these heteroatoms are included in a heterocyclic group, and generally not more than two of these heteroatoms are present in a single ring of the heterocyclic group. The heterocyclic group can be fused to an additional carboclic, heterocyclic, or aryl ring. A heterocyclic group can be attached to the remainder of the molecule at an annular carbon or annular heteroatom, and the heterocyclic groups can be substituted as described for alkyl groups. Additionally, heterocyclic may contain fused rings, but excludes fused systems containing a heteroaryl group as part of the fused ring system. Examples of heterocyclic groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), l-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, 1,2,3,4tetrahydropyridyl, dihydroindole (indoline), tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, l -piperazinyl, 2-piperazinyl, and the like. [001861 As with other moieties described herein, heterocycloalkyl moieties can be unsubstituted, or substituted with various substituents known in the art, e.g., hydroxy, halo, oxo (C=O), alkylimino (RN=, wherein R is a loweralkyl or loweralkoxy group), amino, alkylamino, dialkylamino, acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or haloalkyl. Non-limiting examples of substituted heterocycloalkyl groups include the following, where each moiety may be attached to the parent molecule at any available valence: WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 O O and OH Also included within heterocyclic are pipeñdine, morpholine, thiomorpholine, piperazine, pyrrolidine, tetrahydrofuran, oxetane, oxepane, oxirane, tetrahydrothiofuran, thiepane, thiirane, and optionally substituted versions of each of these. The terms "cycloalkyloxy" and "heterocycloalkyloxy" refer to -O-cycloalkyl and -O-heterocycloalkyl groups, respectively (e.g., cyclopropoxy, 2-piperidinyloxy, and the like). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100189] The term "aryl" means, unless otherwise stated, an aromatic hydrocarbon group which can be a single ring or multiple rings (e.g., from 1 to 3 rings) which are fused together. Aryl may contain fused rings, wherein one or more of the rings is optionally cycloalkyt, but not including heterocyclic or heteroaromatic rings; a fused system containing at least one heteroaromatic ring is described as a heteroaryl group, and a phenyl ring fused to a heterocyclic ring is described herein as a heterocyclic group. An aryl group will include a fused ring system wherein a phenyl ring is fused to a cyctoalkyl ring. Examples ofaryl groups include, but are not limited to, phenyt, l-naphthyl, tetrahydro-naphthalene, dihydro-I H-indene, 2-naphthyt, tetrahydronaphthyl and the like. 1001901 The term "heteroaryl" as used herein refers to groups comprising a single ring or two or three fused rings, where at least one of the rings is an aromatic ring that contain from one to four heteroatoms selected from N, O, and S as ring members (i.e., it contains at least one heteroaromatic ring), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. A heteroaryl group can be attached to the remainder of the molecule through an annular carbon or annular heteroatom, and it can be attached through any ring of the heteroaryl moiety, if that moiety is bicyclic or tricyclic. Heteroaryl may contain fused rings, wherein one or more of the rings is optionally cycloalkyl or heterocycloalkyl or aryl, provided at least one of the rings is a heteroaromatic ring. Non-limiting examples ofheteroaryt groups are t-pyrrotyl, 2-pyrrolyt, 3-pyrrolyl, 3-pyrazolyt, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazotyl, 2-phenyt-4-oxazolyl, 5-oxazotyl, 3-isoxazolyl, 4-isoxazolyl, 5isoxazotyl, 2-thiazolyt, 4-thiazolyt, 5-thiazotyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3pyridyl, 4-pyridyl, 2-pyñmidyl, 4-pyrimidyl, 5-benzothiazolyt, purinyl, 2-benzimidazolyl, 5indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxatinyl, 5-quinoxatinyt, 3-quinotyl, and 6-quinolyl. Substituents for each of the above noted aryt and heteroaryl ring systems are selected from the group of acceptable substituents described below. Aryl and/or heteroaryl groups commonly contain up to four substituents per ring (0-4), and sometimes contain 0-3 or 0-2 substituents. The terms "aryloxy" and "heteroarytoxy" refer to aryt and heteroaryl groups, respectively, attached to the remainder of the molecule via an oxygen linker (-O-). The term "arylalkyl" or "aralkyl" designates an alkyt-tinked aryl group, where the alkyt portion is attached to the parent structure and the aryt is attached to the atkyl WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 portion of the arylalkyl moiety. Examples are benzyl, phenethyl, and the like. "Heteroarylalkyl" or "heteroaralkyl" designates a heteroaryl moiety attached to the parent structure via an alkyl residue. Examples include fumnylmethyl, pyridinylmethyl, pyrimidinylethyl, and the like. Aralkyl and heteroaralkyl also include substituents in which at least one carbon atom of the alkyl group is present in the alkyl group and wherein another carbon of the alkyl group has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridylmethoxy, 3-(lnaphthyloxy)propyl, and the like). The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and perhaloalkyl. For example, the term "halo(C1 -C4 )alkyl" is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The prefix "perhalo" refers to the respective group wherein ail available valences are replaced by halo groups. For example "perhaloalkyl" includes -CC13 , -CF3 , -CC12 CF3 , and the like. The terms "perfluoroalkyl" and "perchloroalkyl"are a subsets of perhaloalkyl wherein all available valences are replaced by fluoro and chloro groups, respectively. Non limiting examples of perfluoroalkyl include -CF3 and -CF2 CF3 . Non limiting examples of perchloroalkyl include -CC13 and -CC12 CCI3 . [001941 "Amino" refers herein to the group -NH2 or -NRR', where R and R' are each independently selected from hydrogen or an alkyl (e.g, lower alkyl). The term "arylamino" refers herein to the group -NRR' where R is aryl and R' is hydrogen, alkyl, or an aryl. The term "aralkylamino" refers herein to the group -NRR' where R is an aralkyl and R' is hydrogen, an alkyl, an aryl, or an aralkyl. "Substituted amino" refers to an amino wherein at least one of R and R' is not H, i.e., the amino has at least one substituent group on it. The term alkylamino refers to -alkyl-NRR' where R and R' are each independently selected from hydrogen or an alkyl (e.g, lower alkyl). The term "aminocarbonyl" refers heoein to the group -C(O)-NH2 , i.e., it is attached to the base structure through the carbonyl carbon atom. "Substituted aminocarbonyl" refers herein to the group -C(O)-NRR' where R is alkyl and R' is hydrogen or an alkyl. The term "arylaminocarbonyl" refers herein to the group -C(O)-NRR' where R is an aryl and R' is WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 hydrogen, alkyl or aryl. "Aralkylaminocarbonyr' refers herein to the group -C(O)-NRR' where R is aralkyl and R' is hydrogen, aikyl, aryi, or aralkyl. "Aminosulfonyi" refers herein to the group -S(O)2 -NH2 . "Substituted aminosulfonyl" refers herein to the group -S(O)2 -NRR' where R is alkyl and R' is hydrogen or an alkyl. The term "aralkylaminosulfonlyaryl" refers herein to the group -aryl-S(O)2 -NH-aralkyl. "Carbonyl" refers to the divalent group -C(O)-. The term "sulfonyl" refers herein to the group -SO2 -. "Alkylsulfonyi" refers to a substituted sulfonyl of the structure -SO2 R in which R is alkyl. Alkylsulfonyl groups employed in compounds of the present invention are typically loweralkylsulfonyl groups having from 1 to 6 carbon atoms in R. Thus, exemplary alkylsulfonyl groups employed in compounds of the present invention include, for example, methylsulfonyl (i.e., where R is methyl), ethyisulfonyl (i.e., where R is ethyl), propylsulfonyl (i.e., where R is propyl), and the like. The term "arylsulfonyl" refers herein to the group -SO2 -aryl. The term "aralkylsulfonyl" refers herein to the group -SO2 -aralkyl. The term "sulfonamido" refers herein to -SO2 NH2 , or to -SO2 NRR' if substituted. Unless otherwise stated, each radical/moiety described herein (e.g., "alkyl," "cycloaikyl," "heterocycloalkyl, .... aryl," "heteroaryl," "alkoxy," etc.) is meant to include both substituted and unsubstituted forms. "Optionally substituted" as used herein indicates that the particular group or groups being described may have no non-hydrogen substituents (i.e., it can be unsubstituted), or the group or groups may have one or more non-hydrogen substituents. If not otherwise specified, the total number of such substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Typically, a group will contain up to three (0-3) substituents. Where an optional substituent is attached via a double bond, such as a carbonyl oxygen (=O), the group takes up two available valences on the group being substituted, so the total number of substituents that may be included is reduced according to the number of available valences. Suitable substituent groups include, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio, suifonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, suifonamido, carboxyl, formyl, loweralkyl, loweralkoxy, loweralkoxyaikyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyi, carbonylamino, heteroaryicarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl, alkylamino, WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 alkylsulfonyl, aralkylamino, alkylcarbonylamino, carbonyl, piperidinyl, morpholinyl, pyrrolidinyl and the like. Deuterium, when introduced into a compound at levels at least 5x above natural abundance, can also be considered a substituent for purposes of describing the compounds herein. Note that because deuterium is an isotope of hydrogen that does not substantially change the shape of the molecule, deuterium is exempt from the typical numerical limitations placed on numbers of substituent: deuterium (D) can be included in place of hydrogen (H) in addition to other substituents and should not be counted in the numerical limitations that apply to other substituents. A substituent group can itself be substituted by the same groups described herein for the corresponding type of structure. The group substituted onto the substituted group can be carboxyl, halo, nitro, amino, cyano, hydroxyl, loweralkyl, loweralkenyl, loweralkynyl, loweralkoxy, aminocarbonyl, -SR, thioamido, -SO3 H, -SO2 R, N-methylpyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, 4-chloropyrimidinyl, pyrindinyl, tetrahydropyranyl (or heterocycloalkyl, heteroaryl?) or cycloalkyl, where R is typically hydrogen or loweralkyl. When the substituted substituent includes a straight chain group, the substituent tan occur either within the chain (e.g., 2-hydroxypropyl, 2-aminobutyl, and the like) or at the chain terminus (e.g., 2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted substituents can be straight chain, branched or cyclic arrangements of covalently bonded carbon or heteroatoms (N, O or S). The term "cycloalkyl" may be used herein to describe a carbocyclic nonaromatic group that is connected via a ring carbon atom, and "cycloalkylalkyl" may be used to describe a earbocyclic non-aromatic group that is connected to the molecule through an alkyl linker. Similarly, "heterocyclyl" may be used to describe a non-aromatic cyclic group that contains at least one heteroatom as a ring member and that is connected to the molecule via a ring atom, which may be C or N; and "heterocyclylalkyl" may be used to describe such a group that is connected to another molecule through a linker. The sizes and substituents that are suitable for the cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups are the same as those described above for alkyl groups. As used herein, these terms also include rings that contain a double bond or two, as long as the ring is not aromatic. [002041 As used herein, "isomer" includes ail stereoisomers of the compounds referred to in the formulas herein, including enantiomers, diastereomers, as well as ail WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 conformers, rotamers, and tautomers, unless otherwise indicated. The invention includes ait enantiomers of any chiral compound disclosed, in either substantially pure levorotatory or dextrorotatory form, or in a racemic mixture, or in any ratio of enantiomers. For compounds disclosed as an (R)-enantiomer, the invention also includes the (S)-enantiomer; for compounds disclosed as the (S)-enantiomer, the invention also includes the (R)-enantiomer. The invention includes any diastereomers of the compounds referred to in the above formulas in diastereomeñcally pure form and in the form of mixtures in ail ratios. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers, conformers, rotamers, and tautomers of the compound depicted. For example, a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of enantiomers, including racemic mixtures; and a compound containing two chírat carbons is intended to embrace all enantiomers and diastereomers (including (R,R), (S,S), (R,S), and (R,S) isomers). In ail uses of the compounds of the formulas disclosed herein, the invention also includes use of any or all of the stereochemical, enantiomeric, diastereomeric, conformational, rotomeric, tautomeric, solvate, hydrate, polymorphic, crystalline form, non-crystalline form, sait, pharmaceutically acceptable salt, metabolite and prodrug variations of the compounds as described. 1o02071 hydrogen. The term "heteroatom" includes atoms of any element other than carbon or Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. Additionally, the phrase "any combination thereof" implies that any number of the listed functional groups and molecules may be combined to create a larger molecular architecture. For example, the terms "phenyl," "carbonyl" (or "=O"), "-O-, .... -OH," and Ci-6 (i.e., -CH3 and -CH2 CH2 CH2 -) can be combined to form a 3-methoxy-4-propoxybenzoic acid substituent. It is to be understood that when combining functional groups and molecules to create a larger molecular architecture, hydrogens can be removed or added, as required to satisfy the valence of each atom. The description of the disclosure herein should be construed in congruity with the laws and principals of chemical bonding. For example, it may be necessary to remove a hydrogen atom in order accommodate a substitutent at any given location. Furthermore, it is to WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 be understood that definitions of the variables (i.e., "R groups"), as well as the bond locations of the generic formulae of the invention (e.g., formulas I or I1), will be consistent with the laws of chemical bonding known in the art. It is also to be understood that ail of the compounds of the invention described above will further include bonds between adjacent atoms and/or hydrogens as required to satisfy the valence of each atom. That is, bonds and/or hydrogen atoms are added to provide the following number of total bonds to each of the following types of atoms: carbon: four bonds; nitrogen: three bonds; oxygen: two bonds; and sulfur: two-six bonds. As used herein, "isomer" includes ail stereoisomers of the compounds referred to in the formulas herein, including enantiomers, diastereomers, as well as ail conformers, rotamers, and tautomers, unless otherwise indicated. The invention includes ail enantiomers of any chiral compound disclosed, in either substantially pure levorotatory or dextrorotatory form, or in a racemic mixture, or in any ratio of enantiomers. For compounds disclosed as an (R)-enantiomer, the invention also includes the (S)-enantiomer; for compounds disclosed as the (S)-enantiomer, the invention also includes the (R)-enantiomer. The invention includes any diastereomers of the compounds referred to in the above formulas in diastereomerically pure form and in the form of mixtures in ail ratios. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace ail possible stereoisomers, conformers, rotamers, and tautomers of the compound depicted. For example, a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace ail enantiomers and diastereomers (including (R,R), (S,S), (R,A), and (R,Sí) isomers). In ail uses of the compounds of the formulas disclosed herein, the invention also includes use of any or all of the stereochemical, enantiomeric, diastereomeñc, conformational, rotomeric, tautomeric, solvate, hydrate, polymorphic, crystalline form, non-crystalline form, sait, pharmaceutically acceptable salt, metabolite and prodrug variations of the compounds as described. It will also be noted that the substituents of some of the compounds of this invention include isomeric cyclic structures. It is to be understood accordingly that constitutional isomers of particular substituents are included within the scope of this invention, WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 unless indicated otherwise. For example, the term "tetrazole" includes tetrazole, 2H-tetrazole, 3H-tetrazole, 4H-tetrazole and 5H-tetrazole. Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms (i.e., solvates). Compounds of the invention may also include hydrated forms (i.e., hydrates). In general, the solvated and hydrated forms are equivalent to unsolvated forms for purposes of biological utility and are encompassed within the scope of the present invention. The invention also includes ail polymorphs, including crystalline and non-crystalline forms. In general, ail physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. 100215] The present invention includes ail sait forms of the compounds described herein, as well as methods of using such salts. The invention also includes ail non-sait forms of any salt of a compound named herein, as well as other salts of any sait of a compound named herein. In one embodiment, the salts of the compounds comprise pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" are those salts which retain the biological activity of the free compounds and which can be administered as drugs or pharmaceuticals to humans and/or animals. The desired sait of a basic functional group of a compound may be prepared by methods known to those of skill in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitñc acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, hippuñc, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. The desired sait of an acidic functional group of a compound can be prepared by methods known to those of skill in the art by treating the compound with a base. Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N'- dibenzylethylenediamine, and tñethylamine salts. Pharmaceutically acceptable metabolites and prodrugs of the compounds referred to in the formulas herein are also embraced by the invention. The term "pharmaceutically WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, PRO-DRUGS AS NOVEL DELIVERY SYSTEMS, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., BIOREVERSIBLE CARRIERS IN DRUG DESIGN, American Pharmaceutical Association and Pergamon Press, 1987. Pharmaceutically acceptable esters of the compounds referred to in the formulas herein are also embraced by the invention. As used herein, the term "pharmaceutically acceptable ester" refers to esters, which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The invention further provides deuterated versions of the above-described compounds. As used herein, "deuterated version" refers to a compound in which at least one hydrogen atom is enriched in the isotope deuterium beyond the natural rate of deuterium occurrence. Typically, the hydrogen atom is enriched to be at least 50% deuterium, frequently at least 75% deuterium, and preferably at least about 90% deuterium. Optionally, more than one hydrogen atom can be replaced by deuterium. For example, a methyl group can be deuterated by replacement of one hydrogen with deuterium (i.e., it can be --CH2 D), or it can have ail three hydrogen atoms replaced with deuterium (i.e., it can be -CD3 ). In each case, D signifies that at least 50% of the corresponding H is present as deuterium. [002191 A substantially pure compound means that the compound is present with no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the total amount of compound as impurity and!or in a different form. For instance, substantially pure S,S compound means that no more than 15% or no more than 10% or no more WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 than 5% or no more than 3% or no more than 1% of the total R,R; S,R; and R,S forms are present. As used herein, "therapeutically effective amount" indicates an amount that results in a desired pharmacological and/or physiological effect for the condition. The effect may be prophylactic in terms of completely or partially preventing a condition or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for the condition and/or adverse effect attributable to the condition. Therapeutically effective amounts of the compounds of the invention generally include any amount sufficient to detectably inhibit Raf activity by any of the assays described herein, by other Rafkinase activity assays known to those having ordinary skill in the art or by detecting an inhibition or alleviation of symptoms of cancer. [002211 As used herein, the term "pharmaceutically acceptable carrier," and cognates thereof, refers to adjuvants, binders, diluents, etc. known to the skilled artisan that are suitable for administration to an individual (e.g., a mammal or non-mammal). Combinations of two or more carders are also contemplated in the present invention. The pharmaceutically acceptable cartier(s) and any additional components, as described herein, should be eompatiblë for use in the intended route of administration (e.g., oral, parenteral) for a particular dosage form. Such suitability will be easily recognized by the skilled artisan, particularly in view of the teaching provided herein. Pharmaceutical compositions described herein include at least one pharmaceutically acceptable cartier or excipient; preferably, such compositions include at least one carrier or excipient other than or in addition to water. [002221 As used herein, the term "pharmaceutical agent" or "additional pharmaceutical agent," and cognates of these terms, are intended to refer to active agents other than the claimed compounds of the invention, for example, drugs, which are administered to elicit a therapeutic effect. The pharmaceutical agent(s) may be directed to a therapeutic effect related to the condition that a claimed compound is intended to treat or prevent (e.g., conditions mediated by Raf kinase, including, but not limited to those conditions described herein (e.g., cancer)) or, the pharmaceutical agent may be intended to treat or prevent a symptom of the underlying condition (e.g., tumor growth, hemorrhage, ulceration, pain, enlarged lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, paraneoplastie phenomena, thrombosis, etc.) or to further reduce the appearance or severity of side effects of administering a claimed compound. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 When used with respect to methods of treatment/prevention and the use of the compounds and formulations thereof described herein, an individual "in need thereof" may be an individual who has been diagnosed with or previously treated for the condition to be treated. With respect to prevention, the individual in need thereof may also be an individual who is at risk for a condition (e.g., a family history of the condition, life-style factors indicative of risk for the condition, etc.). Typically, when a step ofadministeñng a compound of the invention is disclosed herein, the invention further contemplates a step of identifying an individual or subject in need of the particular treatment to be administered or having the particular condition to be treated. [002241 In some embodiments, the individual is a mammal, including, but not limited to, bovine, horse, feline, rabbit, canine, rodent, or primate. In some embodiments, the mammal is a palmate. In some embodiments, the primate is a human. In some embodiments, the individual is human, including adults, children and premature infants. In some embodiments, the individual is a non-mammal. In some variations, the primate is a non-human primate such as chimpanzees and other apes and monkey species. In some embodiments, the mammal is a farm animal such as cattle, horses, sheep, goats, and swine; pets such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "individual" does not denote a particular age or sex. In some variations, the individual has been identified as having one or more of the conditions described herein. Identification of the conditions as described herein by a skilled physician is routine in the art (e.g., via blood tests, X-rays, CT scans, endoscopy, biopsy, etc.) and may also be suspected by the individual or others, for example, due to tumor growth, hemorrhage, ulceration, pain, enlarged lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, paraneoplastic phenomena, thrombosis, etc. In some embodiments, the individual has further been identified as having a cancer that expresses a mutated Rat', such as a mutated B-Raf. In some embodiments, the individual has been identified as susceptible to one or more of the conditions as described herein. The susceptibility of an individual may be based on any one or more of a number of risk factors and/or diagnostic approaches appreciated by the WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 skilled artisan, including, but not limited to, genetic profiling, family history, medical history (e.g., appearance of related conditions), lifestyle or habits. As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural forms, unless the context clearly dictates otherwise. [002281 Unless defined otherwise or clearly indicated by context, ail technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General Synthetic Methods [002291 The compounds disclosed herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions, suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein. 1002311 Furthermore, the compounds disclosed herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomerenriched mixtures. Ail such stereoisomers (and enriched mixtures) are included within the scope of the embodiments, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents wellknown in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 The starting mateñals for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), EmkaChemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 199 l), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). [002331 The various starting materials, intermediates, and compounds of the embodiments may be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds may be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. Compounds of the embodiments may generally be prepared using a number of methods familiar to one of skill in the art, and may generally be made in accordance with the following reaction Schemes 1 and 2, which are described in detail in the Examples below. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 EXAMPLES Referring to the examples that follow, compounds of the embodiments were synthesized using the methods described herein, or other methods known to one skilled in the art. |00236] The compounds and/or intermediates were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2695 Separation Module (Milford, MA). The analytical columns were reversed phase Phenomenex Luna C18 5 4.6 x 50 mm, from Alltech (Deerfield, IL). A gradient elution was used (flow 2.5 mL/min), typically starting with 5 % acetonitrile/95 % water and progressing to % acetonitrile over a period of 10 minutes. Ail solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, MI), or Fisher Scientific (Pittsburgh, PA). In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel I B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques. Mass spectrometric analysis was performed on LCMS instruments: Waters System (Acuity UPLC and a Micromass ZQ mass spectrometer; Column: Acuity HSS C 18 1.8micron, 2.1 x 50 mm; gradient: 5-95 % acetonitrile in water with 0.05 % TFA over a 1.8 min period ; flow rate 1.2 mL/min; molecular weight range 200-1500; cone Voltage 20 V; column temperature 50 °C). Ail masses were reported as those of the protonated parent ions. GCMS analysis is performed on a Hewlett Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; injector volume: 1 IL; initial column temperature: 50 °C; final column temperature: 250 oC; ramp time: 20 minutes; gas flow rate: 1 mL/min; column: 5 % phenyl methyl siloxane, Model No. HP 190915-443, dimensions: 30.0 m x 25 m x 0.25 m). Nuclear magnetic resonance (NMR) analysis was performed on some of the compounds with a Varian 300 MHz NMR (Palo Alto, CA) or Varian 400 MHz MR NMR (Pato Alto, CA). The spectral reference was either TMS or the known chemical shitt of the WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 solvent. Some compound samples were run at elevated temperatures (e.g., 75 oC) to promote increased sample solubility. The purity of some of the compounds is assessed by elemental analysis (Desert Analytics, Tucson, AZ). |00242] Melting points are determined on a Laboratory Devices Mel-Temp apparatus (Holliston, MA). 100243] Preparative separations are carried out using a Combiflash Rf system (Teledyne lsco, Lincoln, NE) with RediSep silica gel cartridges (Teledyne lsco, Lincoln, NE) or SiliaSep silica gel cartridges (Siticycle Inc., Quebec City, Canada) or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a Waters 2767 Sample Manager, C-18 reversed phase column, 30X50 mm, flow 75 mL/min. Typical solvents employed for the Combiflash Rf system and flash column chromatography are dichloromethane, methanol, ethyl acetate, hexane, heptane, acetone, aqueous ammonia (or ammonium hydroxide), and triethyl amine. Typical solvents employed for the reverse phase HPLC are varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid. The examples below as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings. 1oo2481 1oo249] 1oo25o1 Abbreviations ACN: Acetonitrile BINAP: 2,2'-bis(diphenytphosphino)- l,l'-binapthyl DCM: Dichloromethane DIEA: diisopropylethylamine DIPEA: N,N-diisopropylethylamine DME: 1,2-dimethoxyethane DMF: N,N-dimethyl formamide DMSO dimethyl sulfoxide DPPF 1, l'-bis(diphenylphosphino) ferrocene eq equivalent EtOAc ethyl acetate WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 [002581 [002591 [002601 100263] [002641 EtOH ethanol HATU 2-(7-aza1H-benzotriazole1 - yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate HPLC high performance liquid chromatography MCPBA meta-chloroperoxybenzoic acid MeOH methanol NBS N-bromosuccinimide NMP N-methyl-2-pyrrotidone Rt rentention time THF tetrahydrofuran Synthetic Examples Compounds of the present invention can be synthesized by the schemes outlined b [002681 Scheme la. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 A3.,.Ç. A1 = A3.,.Ç. A1 X BR2 Il X A2 A4L "R2 R3 III Suzuki cross-coupling BR2= LB(OH)2 H H NH2R1' R5 YN<'T'N'RI' further R 5"[í NN'R1 j. A3 A1 functionalization A3 A1 SNAR R4 ' "I N R4N L. A2, L'R2 2 I A R2 R3 R3 V ri Rs Ií'N T-'LG A3 -':-Ai R4 AÇL-R2 R3 IV 100269] As shown in Scheme la, synthesis can start with a functionalized pyridine or pyrimidine I wherein LG is a leaving group such as F, CI, OTf, and the like. X can be a functional group like CI, Br, I or OTf. Compound I can be converted into boronic acid or boronic ester II by: 1002701 1) PdCl2 (dppf) DCM adduct, potassium acetate, bis(pinacolato)diboron heating from 30 - 120 °C in solvents such as THF, DMF, DME, DMA, toluene and dioxane; and 2) In a solvent such as THF or diethylether, anion halogen exchange by addition of nBuLi or LDA followed by quenching the anion with triisopropyl borate. Upon hydrolysis a moronic acid can be obtained. Suzuki cross-coupling reaction between compound II and pyridine or pyrazine III then gives bi-heteroaryl intermediate IV. The SNAR reaction between IV and a functionalized amine NH2 RI' under basic condition (DIEA, TEA, lutidine, pyridine) in a solvent such as DMF, THF, DMSO, NMP, dioxane with heating (30-130 °C) can give compound V. When Ri' is not identical to R1 , further functional munipulation is needed to obtain VI. When RI' is identical to R1, compound V will be the same as compound VI. Alternatively, VI can be obtained by WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 following Scheme lb. In which the Suzuki cross-coupling step is carried out between I and Vil. Boronic acid or ester VII is synthesized from III in the same fashion as described above. Scheme lb. Rs"-[í Nì/LG X A3"ÇA1 Rs',.IíN<-,,Ç" LG R41ìI ._ Re [' RÇ X l_ A3 zA, A2" ÆL'R2 A2 A,í LR2 Suzuki R4 ìììì cross-coupling N R3 R3 A2 . III Vil Ra BR2= --B(OH)2 IV H H NH2R1, Rs' í NK N" RI' further R '{í NKy'N" RI functionalization = Aa i=- A1 A3 .,-: A1 SNAR R'4 î NI R4 î ì A2A L'R2 A2Æ L'R2 R3 R3 v Vi ,L. R2 Another altemative route is illustrated in Scheme 2. As described in Scheme la, boronic ester or acid, X, can be prepared from aminopyridine or aminopyrimidine IX. Suzuki cross-coupling reaction between compound X and pyridine or pyrazine XI then can give the biheteroaryl intermediate XII. The SNAR reaction between XII and functionalized amine HA4 LR2 under basic condition (DIEA, TEA, lutidine, pyridine) in a solvent such as DMF, THF, DMSO, NMP, dioxane with heating (30-130 °C) can give compound V. When Ri' is not identical to R1 , further functional manipulation will be needed to obtain VI. When Ri' is identical with R1 , compound V wilt be the same as compound VII. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Scheme 2 H R5yN TIN'RI, AGAIN X H R5yN N'RI, AGAIN BR2 IX HA4LR2 j, SNAR X BR2= B(OH)2 X A2" LG R3 Xl Suzuki cross-coupling H RsyN T..'N-R1, A3 A1 A2"T -"LG R3 XII H H R5"]íN /N'RI' further Rs']íN /N'R1 A3 / A1 functionalization A3 / A1 2.Ç" "-A4 L'R2 2.Ç" --AÇ L-R2 R3 R3 VI V 100274] Compounds of the present invention, listed in Table 1, were prepared by following the specific procedures outlined below. The procedures include synthesis of intermeidates and using these intermediates to make compounds of Formula I. Synthesis of intermediates [002761 Synthesis of 6-bromo-N-(3-fluorobenzyl) pyridin-2-amine (Intermediate A) Br A WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100277] A solution of 2,6-dibromopyridine (7.1 g, 30.0 mmol) in NMP (16 mL) was mixed with a mixture of (3-fluorophenyl)methanamine (4.13 g, 33.0 mmol) and Huenig's Base (5.76 mL, 33.0 retool). The resulting mixture was stirred under argon at 115-120 °C for about 168 hr. The mixture was then cooled to ambient temperature and diluted with EtOAc (250 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2x), water (2x), brine (lx), dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude material. The crude material was puñfied by column chromatography [SiO2 , 120 g, ElOAc/hexane = 0/100 to 20/80] providing 6-bromo-N-(3-fluorobenzy!) pyridin-2-amine (7.11 g) as an off-white solid. LCMS (m/z): 281.1/283.1 [M+H]+; Retention time = 1.03 min. [00278[ Synthesis of 5'-chloro2'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6-ami ne (Intermediate B) B A mixture of6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (A, 2.0 g, 7.11 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (2.0 g, 11.4 mmol), PdClffdppf).CH2 Cl2 adduct (0.465 g, 0.569 retool), DME (27 mL) and 2M aqueous Na2 CO2 (9.25 mL, 18.50 mmol) was stirred at about 100 °C for 3 hr. After cooling to ambient temperature, the mixture was diluted with EtOAc (25 mL) and MeOH (20 mL), filtered, and concentrated in vacuo to yield a crude material. The crude material was purified by column chromatography [silica gel, 120g, EtOAcihexane = 0/100 to 20/80] providing 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)-2,4'- bipyridin-6-amine (1.26 g) as an off-white solid. LCMS (m/z): 332.2 [M+H]+; Retention time = 0.92 rein. Synthesis of 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (Intermediate C) WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 C 100281] A mixture of 2-bromo-6-fluoropyridine (750 mg, 4.26 mmol) in DMSO (3 mL) was mixed with (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (775 mg, 5.11 mmol) and NEt3 (1.426 mL, 10.23 mmol). The resulting mixture was heated at about 110 °C for 18 hr. The mixture was cooled to ambient temperature and diluted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a resulting residue. The resulting residue was puñfied by column chromatography [SiO2 , 40 g, EtOAc/heptane = 0/100 to 30/70]. Pure fractions were combined and concentrated in vacuo providing 6-bromo-N-((tetrahydro-2Hpyran-4-yl)methyl)pyridin-2-amine (B 1,940 mg) as a white solid. LCMS (m/z): 271.0/272.9 [M+H]+; Retention time = 0.8t min. 100282] Synthesis of 5'-chloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine (Intermediate D) F D A mixture of 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (C, 271 mg, 1 mmol), 5-chloro-2-fiuoropyridin-4-ylboronic acid (351 mg, 2.000 mmol), PdCl2(dppf).CH2C12 adduct (82 mg, 0.100 mmol) in DME (4.5 mL) and 2M Na2 CO3 (318 mg, 3.00 mmol) was heated in a sealed tube at about 103 °C for about 2 hr. The mixture tehn was coooled to ambient temperature, diluted with EtOAc (-25 mL) and MeOH (-5 mL), filtered, and WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 concentrated in vacuo to yield a resulting residue. The resulting residue was purified by column chromatography [SiO2 , 12 g, EtOAc/heptane = 10/90 to 50/50]. Fractions were combined and concentrated in vacuo providing 5'-chloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine (260 mg) as a yellow thick oil. LCMS (m/z): 322.1/323.9 [M+H]+; Retention time = 0.60 min. Synthesis of 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2amine (E) and 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (Intermediate F) Bi Br H E F 100285] A solution of6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (C, 1000 mg, 3.69 mmol) in chloroform (15 mL) was diluted with l-chloropyrrolidine-2,5-dione (NCS, 492 mg, 3.69 mmol). The mixture then was heated in a sealed tube at about 33 °C for about 16 hr, followed by heating the reaction mixture for about 24 hr at about 37 °C, and then for an additional 5 days at about 43 °C. The reaction mixture then was cooled to ambient temperature, diluted with IN aqueous sodium hydroxide solution and DCM. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting resulting residue was purified by column chromatography [ISCO, SiO2, 80g, EtOAc/heptane = 5/95 2 min, 5/95 to 30/70 2-15 min, to 35/65 15-18 min, then 35%]. Fractions were combined and concentrated in vacuo yielding 6-bromo-3-chloro-N-((tetrahydro2H-pyran-4-yl)methyl)pyridin-2-amine (F, 453 mg), and 6-bromo-5-chloro-N-((tetrahydro-2Hpyran-4-yl)methyl)pyridin-2-amine (E, -500 mg). (F): LCMS (m/z): 305.0 [M+H]+; Retention time = 1.01 rein. (E): LCMS (m/z): 305.0 [M+H]+; Retention time = 0.96 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 [002861 Synthesis of 3,5'-dichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine (Intermediate G) CI'x N G [002871 A mixture of 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2amine (E, 300 mg, 0.982 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (344 mg, 1.963 mmol), PdCI2(dppt).CH2C12 adduct (80 mg, 0.098 mmol) in DME (4.5 mL) and 2M aqueous sodium carbonate (4.5 mL, 4.50 mmol) was heated in a sealed tube at about 103 °C for about 16 hr. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (-100 mL) and saturated aqueous sodium carbonate solution. The organic layer was separated, washed with saturated aqueous sodium carbonate solution (2x), dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting resulting residue was purified by column chromatography [ISCO, SIO2, 25g, EtOAc/heptane = 0/100 to 25/751. Fractions were combined and concentrated in vacuo providing 3,5'-dichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridin6-amine (140 mg) as a light brown liquid. LCMS (m/z): 356.1 [M+H]+; Retention time : 0.96 min. [002881 Synthesis of 5,5'-dichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine (Intermediate H) N F c,N c', H H WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 A mixture of 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2amine (F, 200 mg, 0.654 mmol), 5-chloro-2-fluoropyñdin-4-ylboronic acid (230 mg, 1.309 mmol), PdC12(dppf).CH2Cl2 adduct (53.4 mg, 0.065 mmol) in DME (3 mL) and 2M aqueous sodium carbonate (3 mL, 6.00 mmol) was heated in a sealed tube at about 103 °C for 16 hr. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (-100 mL) and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution (2x), dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting resulting residue was purified by column chromatography [ISCO, SiO2, 25 g, EtOAc/heptane - 0/100 to 30/70]. Fractions were combined and concentrated in vacuo providing 5,5'-dichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)- 2,4'-bipyridin-6-amine (130 mg) as a nearly colorless liquid. LCMS (m/z): 356.1 [M+H]+; Retention time = 1.10 min. 100290] Synthesis of 5'-chloro-2', 5-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine (Intermediate I) CIr. F I F H 100291] 2-amine Step 1. Preparation of 3,6-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyt)pyridin- A mixture of 2,3,6-tñfluoropyddine (3 g, 22.54 mmol), (tetrahydro-2H-pyran-4yt)methanamine (3.89 g, 33.8 mmol) and triethylamine (7.86 mL, 56.4 mmol) in NMP (60 mL) was heated at about 70 °C for about 1 hr. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (-100 mL), brine (-50 mL) and water (-50 mL). The separated organic layer was washed with brine (1 x), 0.3N aqueous HCI (2x), saturated aqueous NaHCO3 solution (Ix), brine (Ix), dried over Na2 SO4 , filtered offand concentrated in vacuo providing WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 crude 3,6-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyt)pyridin-2-amine, which was directly used in the next reaction without further purification. Yield: 3.5 g. LCMS (m/z): 229.1 [M+H]+; Retention time = 0.79 min. Step 2. Preparation of 3-fluoro-6-methoxy-N-((tetrahydro-2H-pyran-4yl)methyl)p yridin-2-amine 100294] To a solution of 3,6-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyt)pyridin-2amine (5 g, 21.91 mmol) in MeOH (35 mL) was added sodium methoxide (25 wt.% in MeOH, 15.03 mL, 65.7 mmot). The resulting mixture was heated in a steel bomb at about 135 °C for -18 hr. The mixture then was cooled to ambient temperature and concentrated in vacuo. The resulting resulting residue was taken up in water (-250 mL) yielding a precipitate, which was collected by filteration, and then washed with water. The solid then was dissolved in toluene (10 mL)/DCM (10 mL), decanted from the dark brownish film and concentrated in vacuo. The resulting resulting residue was dried in high vacuo providing crude 3-fluoro-6-methoxy-N- ((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a nearly colorless oil, which was direetty used in the next reaction without further purification. Yield: 4.96 g. LCMS (m/z): 241.1 [M+H]+; Retention time = 0.87 min. 1002951 Step 3. Preparation of 5-fluoro-6-((tetrahydro-2H-pyran-4yt)methyl)aminopyridin-2-ot 1002961 To a solution of 3-fluoro-6-methoxy-N-((tetrahydro-2H-pyran-4yt)methyl)pyridin-2-amine 1002971 (4.6 g, 19.14 mmot) in acetonitrile (50 mL)was added sodium iodide (20.09 g, 134 mmol) and TMS-ehloride (17.13 mL, 134 mmol). The resulting mixture was stirred at about °C for 20 hr. The reaction mixture was cooled to ambient temperature and then diluted with EtOAe (80 mL) and water (40 mL). The diluted mixture was stirred vigorously for about 30 min. The organic layer was separated and washed with 0.1N aqueous HC1 solution. The combined aqueous layers were carefully neutralized (pli -7) with solid NaHCO3 solution and extracted with EtOAc (Ix 100 mL) and DCM (2x 50mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried over Na2 SO4 , filtered off and concentrated WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 in vacuo. The resulting resulting residue was purified by column chromatography [SiO2 , 80 g, EtOAc/heptane = 10/90 for 2 min, EtOAc/heptane = 10/90 to 100/0 over 23 rein, then EtOAc/heptane = 100/0] providing 5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyridin2-ol as a highly viscous oil which turned to purple upon standing at room temperature. Yield: 780 mg. LCMS (m/z): 227.1 [M+H]+; Retention time = 0.42 min. Step 4. Preparation of 5-fluoro-6-((tetrahydro-2H-pyran-4yl)methyl)aminopyridin-2-yl trifluommethanesul fonate 100299] A solution of 5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-ol (500 mg, 2.210 mmol) and triethylamine (0.462 mL, 3.31 mmol) in DCM (20 mL) was gradually diluted at about 0°C with tñfluoromethanesulfonic anhydride (1.120 mL, 6.63 mmol). The resulting mixture was stirred for about 2 hr at 0 °C and carefully mixed with ice-cooled saturated aqueous NaHCO3 solution. The aqueous layer was separated, and extracted with DCM (2x). The combined organic layers were dried over Na2 SO4 , filtered off and concentrated in vacuo. The resulting resulting residue was purified by column chromatography [SiO2 , 40 g, 30 min, EtOAc/heptane = 5/95 to 40/60] providing 5-fluoro-6-((tetrahydro-2H-pyran-4yl)methyl)aminopyridin-2-yl trifluoromethanesulfonate as a colorless oil. Yield: 743 mg. LCMS (m/z): 359.0 [M+H]+; Retention time = 1.02 min. 100300] Step 5. Preparation of 5'-chlom-2',5-difluoro-N-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridin-6-amine [003011 A mixture of 5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-yl trifluoromethanesulfonate (712 mg, 1.987 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (697 mg, 3.97 mmol), PdCl2 (dppf).CH2 C12 adduct (162 mg, 0.199 mmol) in DME (8 mL) and 2 M aqueous Na2 CO3 solution (2.6 mL, 1.987 mmol) in a sealed tube was heated at 95 °C for 3 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc (-100 mL) and saturated aqueous NaHCO3 solution. The separated organic layer was washed with saturated aqueous NaHCO3 (2x), dried over Na2 SO4 , filtered off and concentrated in vacuo. The resulting resulting residue was purified by column chromatography [SiO2 , 40 g, EtOAc/heptane = 0/100 to 25/75 over 20 min] providing 5'-chloro-2',5-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 bipyridin-6-amine as a white solid. Yield: 570 mg. LCMS (m/z): 340.1 [M+H]+; Retention time -- 0.99 min. 100302] Synthesis of (R/S)-5'-chloro-N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)- 2'-fluoro-2,4'-bipyridin-6-amine (Intermediate J) J [003031 H Step 1. Preparation of tert-butyl 6-bromopyridin-2-ylcarbamate To a solution of 6-bromopyridin-2-amine (3 g, 17.34 mmol), triethytamine (3.14 mL, 22.54 mmol) and DMAP (0.424 g, 3.47 mmol) in DCM (24 mL) was added slowly a solution of BOC-anhyddde (4.83 mL, 20.81 mmol) in DCM (6 mL). The reaction mixture was stirred at ambient temperature for -24 hr. The mixture was diluted with water, brine and EtOAc. The separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting resulting residue was purified by column chromatography providing tert-butyl 6-bromopyñdin-2-ylcarbamate as a white solid. Yield: 1.67 g. LCMS (m/z): 274.9 [M+H]+; Retention time = 0.95 min. [003051 Step 2: Preparation of 0US)-(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4methylbenzenesulfonate To a solution of(2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol (1 g, 6.93 mmol) in DCM (5 mL) and pyridine (5 mL, 61.8 mmol) was addedpara-toluenesutfonyl chloride (1.586 g, 8.32 mmol) and DMAP (0.042 g, 0.347 mmol). The mixture was stirred for 18 hr at ambient temperature. The reaction mixture was concentrated in vacuo and the resulting resulting residue was diluted with water and DCM. The separated organic layer was washed with 0.2N aqueous HCI (Ix), lN aqueous HC1 (2x), brine, dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting resulting residue was purified by column WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 chromatography [SiO2 , 40 g, EtOAc/hexane = 0/100 to 50/50; 25 min] providing (R/S)-(2,2dimethyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Yield: 2.05 g. LCMS (m/z): 299.1 [M+H]+; Retention time = 0.96 min. [003071 Step 3: Preparation of (R/S)-tert-butyl 6-bromopyridin-2-yl((2,2dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate [003081 To a mixture oftert-butyl 6-bromopyridin-2-ylcarbamate (686 mg, 2.51 mmol), K2CO3 (347 mg, 2.51 mmol), (2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4methylbenzenesulfonate (750 mg, 2.51 mmol) in DMF (10 mL) was added carefully Nail (60 wt.%, 141 mg, 3.52 mmol) in portions [Caution: gas development!]. The resulting mixture was stirred at about 45 °C for 4 hr. The mixture was warmed to ambient temperature and was diluted with EtOAc (-50 mL) and saturated aqueous NaHCO» The organic layer was separated, washed with saturated aqueous NaHCO3 solution (Ix), dried over Na2 SO4 , filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 40 g, 25 min, EtOAc/heptane = 0/100 to 25/75 over 25 min] providing (R/S)-tert-butyl 6-bromopyridin-2yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate as highly viscous, colorless oil. Yield: 723 mg. LCMS (m/z): 344.9 {loss oftert Bu-group}/(399.0).[M+H]+; Retention time = 1.22 min. [003091 Step 4: Preparation of(R/S)-tert-butyl 5'-chloro-2'-fluoro-2,4'-bipyridin-6yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate [003101 A mixture oftert-butyl 6-bromopyridin-2-yl((2,2-dimethyltetrahydro-2H-pyran-4yl)methyl)carbamate (710 mg, 1.778 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid, PdCl2(dppf).CH2Cl2 adduct (145 mg, 0.178 mmol) in DME (7 mL) and 2M aqueous Na2 CO3 solution (2.3 mL, 1.778 mmol) was heated in a sealed tube at about 98 °C for 2 hr. The mixture was cooled to ambient temperature and diluted with EtOAc @100 mL) and saturated aqueous NaI-ICO3 solution. The separated organic layer was washed with saturated aqueous NaHCO3 (2x), dried over Na2 SO4 , filtered offand concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 40 g, 25 min, EtOAc/heptane = 0/100 to 25/75 over WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 min] providing (R/S)-tert-butyl 5'-chloro-2'-fluoro-2,4'-bipyridin-6-yl((2,2dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate as a highly viscous, colorless oil. Yield: 605 mg. LCMS (m/z): 394.1 {loss oftert Bu-group}/450.2 [M+H]+; Retention time = 1.24 min. Step 5. Preparation of(R/S)-5'-chloro-N-((2,2-dimethyltetrahydro-2H-pyran-4yl)methyl)-2'-fluoro-2,4'-bipyridin-6-amine 100312] To a solution oftert-butyl 5'-chloro-2'-fluoro-2,4'-bipyridin-6-yl((2,2dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (950 mg, 2.111 mmol) in methanol (5 mL) was added 4M HCl/dioxane (15 mL, 494 mmol). The resulting mixture was stirred for -45 min at ambient temperature. The mixture then was concentrated in vacuo and the resulting resulting residue was dissolved in EtOAc (-50 mL) and saturated aqueous NaHCO3 solution (-50 mL). The separated organic layer was washed with saturated aqueous NaHCO3 solution (Ix), brine (Ix), dried over Na2 SO4 , filtered off and concentrated in vacuo providing crude (R/S)-5'-chloroN-((2 2-dimethy tetrahydr -2H-pyran-4-y )methy )-2'-flu r -2 4'-bipyñdin-6-amine as a colorless oil, which was directly used in the next reaction without further purification. Yield: 740 mg. LCMS (m/z): 350.1 [M+H]+; Retention time = 0.69 min. Synthesis of 5'-chloro-2',3,6-trifluoro-2,4'-bipyridine (Intermediate K) K 100314] Step 1. Preparation of 3,6-difluoro-2-methoxypyridine 100315] 2,3,6-Trifluoropyridine (17.91 ml, 188 mmol) was dissolved in anhydrous MeOH (300 ml) and the resulting mixture was placed under argon. This mixture then was treated with a 25wt% methanolic solution of sodium methoxide (43.0 ml, 188 mmol). The resulting mixture WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 was then heated at about 65° C for 2 hr. The reaction mixture was cooled to ambient temperature, and concentrated in vacuo to yield a residue whihc then was mixed with brine (200 mL), and extracted with Et20 (3 x 200 ml). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give 21.5 g (79% yield) of crude 3,6-difluoro-2methoxypyridine as a white solid which was carried on to the next step without purification. 100316] Step 2. Preparation of3,6-difluoro-2-hydroxypyridine To 3,6-difluoro-2-methoxypyridine (21.5 g, 148 mmol) in acetonitrile (250 ml) was added sodium iodide (66.6 g, 445 mmol) and chlorotrimethylsilane (56.8 ml, 445 mmol). The resulting mixture was heated at 80-85 °C for 2.5 hr. The mixture was cooled to ambient temperature and diluted with EtOAc (300 mL) and water (300 mL) and vigorously stirred for another hr. The layers were separated, and the aqueous phase was extracted with additional ethyl acetate (200 mL). The combined organic layers were washed sequentially with 0.6 N aqueous HCI (250 mL) and brine (250 mL) and concentrated in vacuo to yield a slurry. The slurry was filtered and rinsed three times with cold acetonitrile to yield 10.8 g of desired product as a white solid. The filtrate was concentrated and purified by flash chromatography over silica gel (heptanes:ethyl acetate gradient) to give an additional 4.2 g (77% yield combined) of 3,6difluoro-2-hydroxypyridine as a white solid. LCMS (m/z): 132.0 [M+H]+; retention time = 0.47 min. Step 3. Preparation of 3,6-difluoropyridin-2-yl tñfluoromethanesulfonate 100319] An ice water bath-cooled solution of 3,6-difluoro-2-hydroxypyridine (10.75 g, 82 mmol) and triethylamine (22.86 ml, 164 mmol) in DCM (550 ml) was mixed with a solution of trifluoromethanesulfonic anhydride (16.63 ml, 98 mmol) in DCM (100 ml) over 20 min. The resulting mixture then was stirred for 2 hr at 0 °C, with the progress of the reaction followed by TLC (2:1 heptanes:ethyl acetate). The reaction mixture was quenched with saturated aqueous NaHCO3 solution (200 mL). The separated aqueous layer was extracted with DCM (2x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel (EtOAc/heptane WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 gradient) to give 16.3 g (76% yield) of 3,6-difluoropyridin-2-yl triftuoromethanesutfonate as a yellow oil. [003201 Step 4. Preparation of 5'-chloro-2',3,6-trifluoro-2,4'-bipyridine A mixture of3,6-difluoropyridin-2-yt trifluoromethanesulfonate (3.50 g, 13.30 mmol) and 5-chloro-2-fluoropyñdine-4-boronic acid (3.27 g, 18.62 mmol) in THF (27 ml) was degassed by bubbling Argon gas for 10 min. Aqueous sodium carbonate (13.30 ml, 26.6 mmol) and PdCl2 (dppf).CH2 C12 adduct (0.652 g, 0.798 mmot)were added, and the mixture was degassed for an additional 5 min. The resulting reaction mixture was stirred at about 100 °C for 2 hr in a sealed vessel. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and water. The separated organic layer was dried over Na2 SO4 , filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel (heptanes/ethyt acetate gradient) to yield 2.78 g (85% yield) of 5'-chloro-2',3,6-trifluoro-2,4'-bipyridine as a crystalline solid. LCMS (m/z): 244.9 [M+H]+; retention time = 0.86 min. Synthesis of 5'-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4yt)methyl)-2'-fluoro-2,4'-bipyridin-6-amine (Intermediate L) Cl I N.« F H Step 1. Preparation of (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one 1003241 A solution of 2,6-dimethyl-4H-pyran-4-one (2g, 16. l mmol) in 20ml ethanol was stirred over 10% Pd/C (0.2g) under hydrogen (15 psi) for 16 hours at ambient temperature. TLC showed two spots; one was desired product and second one was side product in a 1 : 1 ratio. GCMS M+ 128 for product, and M+ 130 for side product. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Suspension was filtered off, and the filtrate was concentrated to remove solvent to give 2.3g crude product which contained -30% of the side product. The resulting oily residue was treated with 2.3g Dess-Martin pedodinane in 15ml DCM at ambient temperature for 16 hours. GCMS showed oxidation was complete, desired product formation was confirmed by GCMS at M+ 128. -3ml NaS2CO3 was added to the suspension and the resulting mixture was stirred for l hour at ambient temperature, then 20ml saturated sodium bicarbonate solution was added to, and new mixture was stirred for another hour. The organic phase was separated, washed with water, brine, dried and filtered through celite. Th filtrate was concentrated and resulting residue was purified by ISCO eluting with 10% ethyl acetate in heptane to yield 600 mg of the desired product. GCMS: M=t28. HNMR: 1.5ppm (6H), 2.3ppm (4H), 3.75ppm (2H). [003261 2H-pyran Step 2. Preparation of (2R,6S,E)-4-(methoxymethylene)-2,6-dimethyltetrahydro100327] To a suspension of (methoxymethyl)triphenyl phosphine chloride (1.5g, 4.45 mmol) in 8ml THF at -10°C, was added dropwise 4.45ml 1.0M/THF solution of sodium bis(trimethylsilyl) amide. The resulting reaction mixture was stirred for 1 hour, followed by addition of a solution of (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (380mg, 2.96 mmol) in 2ml THF. The resulting mixture was warmed to ambient temperature and stirred for an additional 3 hours. GCMS showed formation of desired product at M+156, as mojor component. The reaction mixture was quenched with 15ml water, and was extracted with diethyl ether (2x30ml). The combined organic phase was washed with brine, dried and concentrated. The resulting residue was purified by ISCO eluting with t 0% ethyl acetate in heptane to yield 240 mg of the desired product as a colorless oil, GCMS showed M=156. HNMR: 5.9ppm (1H), 3.45ppm (3H), 3.25ppm (2H), 2.45ppm (tri), 1.85ppm (IH), 1.6ppm (1H), 1.38ppm (IH), 1.1 ppm (6H). Step 3. Preparation of (2R,6S)-2,6-dimethyitetrahydm-2H-pyran-4-carbaldehyde 100329] A mixture of (2R,6S,E)-4-(methoxymethylene)-2,6-dimethyltetrahydro-2H-pyran (240mg, 1.53 mmol) and 88% formic acid (1.5ml, 34.4 mmol) in water was heated in an oil bath WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 under Argon to about 90°C for 1 hour. GCMS indicated that reaction was complete under the condition. The reaction mixture was cooled in an ice bath, neutralised with 6N NaOH to a pli=6, and extracted with diethyl ether. The organic phase were dried and concentrated to dryness to yield 120 mg of the desired product as yellow colored oil. GCMS M= 142. HNMR showed 9.51 ppm (s, 1H, CHO). Step 4. Preparation of 6-bromo-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4yl) methyl) pyridin-2-amine The mixture of (2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-carbaldehyde (120mg, 0.84 mmol) and 6-bromo-2-aminopyridine (219mg, 1.26 mmol) in 5ml DCM was stirred at ambient temperature for about 40 min. To this solution was added sodium triacetoxy borohydride (268mg, 1.26 mmol), followed by the addition of 0.01ml acetic acid. The resulting solution was stirred at ambient temperature for about 40 hours. The reaction mixture was concentrated in vacuo to yield a residue was diluted with ethyl acetate, washed with sodium bicarbonate, brine, dried, concentrated. The resulting resulting residue was purified by ISCO eluting with 10% to 20% ethyl acetate in heptane to yield 110 mg of the desired product as colorless oil. LCMS (m/z): 299/301 (MH+), retention time = 1.01 min. Step 5. Preparation of 5'-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4yl)methyl)-2'-fluoro-2,4'-bipyridin-6-amine A mixture of 6-bromo-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4yl)methyl) pyñdin-2-amine (110 mg, 0.36 mmol), 5-chloro-2-fluoro-pyridine-4-boronic acid (193 mg, 1.10 mmol), 0.55 ml 2.0M saturated sodium carbonate aqueous solution in 2 ml DME was purged with Argon for 3 min, PdCl2 (dppf)CH2 Cl2 (30 mg, 0.037 mmol) was added to this purged. The resulting mixture was heated at about 95°C in an oil bath for 3.5 hours. Formation of the desired product was confirmed by LCMS: MH+ 350, 0.70 min. The preceding reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. The resulting residue was purified by ISCO eluting with 10% ethyl acetate in WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 heptane to give 90mg desired product as colorless oil. LCMS (m/z): 350 (MH+), retention time = 0.70 min. Synthesis of 5'-chloro-N6-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine (Intermediate M) ff,. N N H2 ,<o M 100335] A mixture of 5'-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4yl)methyl)-2'-fluoro-2,4'-bipyridin-6-amine (60mg, 0.17 mmol), and 3.0ml 28% ammonium hydroxide aqueous solution was heated at about 130°C in an oil bath for 17 hours. Formation of compound M was Reaction confirmed by LCMS/LC data. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, and brine, dried over sodium sulfate and concentrated to yield 50 mg of the desired product. LCMS (m/z): 347 (MH+), retention time = 0.53 min. [003361 Synthesis of 3-bromo-5'-chlom-2'-fluoro-N-((te rahydro-2H-pyran-4yl)methyl)- 2,4'-bipyridin-6-amine (Intermediate N) 1ì iF N WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1003371 A mixture of 5'-chloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyñdin-6-amine (516 mg, 1.60 mmol) and N-bromosuccinimide (286 mg, 1.60 mmol) in acetonitñle (12 mL) was stirred at 90° C for 3 hr in a sealed vessel. Volatiles were removed under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate and brine. The organic phase was dñed (Na2SO4), filtered, and concentrated. The crude material was purified by column chromatography over silica gel (heptanes/ethyl acetate gradient) to yield 608 mg of the desired product. LCMS (m/z): 402.0 [M+H]+; Retention time = 1.03 min. [01B381 Synthesis of intermediate (4-methoxytetrahydro-2H-pyran-4-yl) methyl 4methylbenzenesulfonate (Intermediate O) Step 1. Synthesis of 1,6-dioxaspiro[2.5]octane 100340] To a clear solution oftrimethylsulfonium iodide (3.27 g, 16 mmol) in 20 ml of DMSO was added dìhydro-2H-pyran-4(3H)-one (l.0g, 10 mmol) with stirring. To this mixture, under nitrogen, was then slowly added KOtBu (1.68g, 15 mmol) in 15 ml of DMSO. The resulting solution was then stirred overnight at ambient temperature. Water (50ml) was slowly added to the mixture, and the resulting mixture was extracted with diethyl ether (3x20ml). The ether layers were combined, dried and concentrated in vacuo to yield 650 mg of the crude product. 1H NMR (300 MHz, CHLOROFORM-d) ì5 ppm 1.44 - 1.62 (m, 2 H) 1.76 - 1.98 (m, 2 H) 2.70 (s, 2 H) 3.70 -3.98 (m, 4 H). IOO341] Step 2. Synthesis of(4-methoxytetrahydro-2H-pyran-4-yl) methanol [003421 To a solution of 1,6-dioxaspiro[2.5]octane (600 mg, 5.26mmol) in methanol (10 ml) at 0 °C (ice-water) under nitrogen was added camphorsulfonic acid (50 mg, 0.21 mmol) and WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 the resulting mixture was stirred at about 0 °C for 2 hours. The mixture was concentrated in vacuo and the crude residue was used in the next step without purification. The desired product was obtained as a light yellow oil (707 mg). [00343! Step 3. To a solution of (4-methoxytetrahydro-2H-pyran-4-yl) methanol (300 mg, 2.05 mmol) in pyridine (4 ml) at ambient temperature was added toluenesulfonic chloñde (430 mg, 2.25 mmol) and the resulting mixture was stirred overnight at about 25 °C. The stirred mixture was concentrated and the solid residue was dissolved in DCM and purified by silica gel chromatography using a 12 g column, eluting with 0-30% ethyl acetate in heptane to yield the desired compound "O" as a light yellow solid (360 mg).tH NMR (300 MHz, CHLOROFORMd) 6 ppm t.45 - 1.63 (m, 2H) 1.6t - 1.79 (m, 2 H) 2.46 (s, 3 H), 3.16 (s, 3 H) 3.53 - 3.75 (m, 4 H) 3.93 (s, 2 H), 7.36 (d, J = 8.20 Hz, 2 H) 7.81 (d, J = 8.20 Hz, 2 H). [003441 Synthesis oftert-butyl 6-bromo-5-chloropyridin-2-yl((4-methoxytetrahydro-2Hpyran-4-yl)methyl)carbamate (Intermediate P) ',r To a stirred solution of tert-butyl 6-bromo-5-chloropyddin-2-ylcarbamate (140 mg, 0.455 mmol) in DMF (2 ml) under nitrogen was added Nail (60%, 30 mg, 0.774 mmol). The resulting mixture was stirred at ambient temperature for one hour. A solution of (4methoxytetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (intermediate O, 164 mg, 0.546 mmol) in DMF (1.5ml) was then added to the preceding mixture. The resulting mixture was then stirred overnight at about 85 °C. The stirred mixture was diluted with 30 ml of ethyl acetate, washed with water (20 ml x3) and dried. After concentration the resulting residue was purified by silica gel chromatography using a 12g column, eluting with 5-20% ethyl acetate in hexane to yield the desired compound "P" as a viscous oil (92 mg), which solidified upon standing overnight. LCMS (m/z): 437.0 [M+H]+; Retention time = 1.158 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Synthesis of (1-methoxycyclohexyl)methyl 4-methylbenzenesulfonate (Intermediate Q) [003471 This compound was synthesized from cyclohexanone following the procedure described for (4-methoxytetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (Intermediate O). [003481 LCMS (m/z): 299.2 [M+H]+; Retention time = 1.055 min. Synthesis of 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate R) [003501 NC NH2 Step 1. Synthesis ofdihydro-2H-pyran-4,4(3H)-dicarbonitrile [003511 A mixture ofmalononitrile (0.991 g, 15 mmol), l-bromo-2-(2bromoethoxy)ethane (3.83 g, 16.50 mmol) and DBU (4.97 ml, 33.0 mmol) in DMF (6 ml) was heated at about 85 °C for 3 hours, and then cooled to ambient temperature. The mixture was concentrated in vacuo, the resulting residue was diluted with ethyl acetate, washed three times with water and dried overnight under high vacuum to yield the desired produoE as a light brown solid (1.65 g). GC-MS: 136 [Ml; Retention time = 5.76 rein. 1H NMR (300 MHz, CHLOROFORM-d) ì5 ppm 2.14-2.32 (m, 4 H) 3.77-3.96 (m, 4 H). [003521 Step 2. A mixture of dihydro-2H-pyran-4,4(3H)-dicarbonitrile (450 mg, 3.31 mmol)<autotext key="0BD391A6'' name="'' index="l'' field="Reactants'' type= " fiel d" length="34"/> and Sodium borohydride (375 mg, 9.92 mmol)<autotext key="0BD391A7" name="[Reactants]" index="2'' field="Reactants'' type="field'' length="38"/> WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 in EtOH ( 15 ml)<autotext key="0BD391A8" name="" index='' 1" field='' Solvents" type="field" length=" 12"/ was stirred at ambient temperature for about 4 hours. The mixture was concentrated and the resulting residue was diluted with ethyl acetate, washed with water and dried. Concentration in vacuo afforded 388 mg of the crude product which was used directly in the next step. LCMS (m/z): 141.0 [M+H]+; Retention time = 0.18 min. [003531 Synthesis of 4-((6-bromopyridin-2-yl-amino)methyl)telrahydro-2H-pyran-4carbonitrile (Intermediate S) If H [003541 To 2-bromo-6-fluoropyddine (400 mg, 2.273 mmol) in DMSO (4 ml) at ambient temperature was sequentially added 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate R, 382 mg, 2.73 mmol) and triethylamine (0.792 ml, 5.6g mmol). The resulting light brown mixture was heated at 110 "C in a sealed glass bomb for 18 hours. The reaction mixture then was cooled to ambient temperature, reaction mixture diluted with EtOAc, washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 890 mg of a light brown liquid. The crude material was purified by silica gel chromatography using a 12g column, eluting with 5%-20% ethyl acetate in hexane to afford 410 mg (60.9 %) of the desired product "S". LCMS (m/z): 297.9 [M+H]+; Retention time = 0.823 min. 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm: 1.67-1.96 ( m, 4H),, 3.59-3.78 (m, 4H), 3.98 (m, 2H),4.82 (t, J=6.65Hz, IH), 6.39 (d, J=8.22,1H), 6.72-6.84 ( m, IH), 7.16-7.33 (m, 1H). Synthesis of 5'-chloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5- (trifluoromethyl)-2,4'-bipyridin-6-amine (Intermediate T) and 5'-chloro-2'-fluoro-N-((tetrahydro2H-pyran-4-yl)methyl)-3-(trifluoromethyl)-2,4'-bipyridin-6-amine (Intermediate U). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 CF3 H T 1003561 Step 1. Synthesis of 6-chloro-N-((tetmhydro-2H-pyran-4-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine and 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3- (trifluoromethyl)pyridin-2-amine H CF3 H [003571 To a solution of 2,6-dichloro-3-(trifiuoromethyl)pyridine (320 mg, 1.482 retool) in DMSO (l.5ml) at ambient temperature was added (tetrahydro-2H-pyran-4-yl)methanamine (188 mg, 1.630 retool) and triethylamine (0.207 ml, 1.482 retool). The resulting light brown mixture was heated at about 120 °C in a sealed glass bomb for about 18 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (20mL), washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 502 mg of a light brown crude liquid, which was purified by column chromatography ( 5 to 50% ethyl acetate in heptane)to yield the desired products. [003581 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(tñfiuoromethyl)pyridin-2amine: 340 mg, 78 %: LCMS (m/z): 295.2 [M+H]+; Retention time = 0.971 rein; and 6-chloroN-((tetrahydro-2H-pyran-4-yl)methyl)-3-(trif[uoromethyl)pyddin-2-amine: 80 mg, 18 %. LCMS (m/z): 295. l [M+H]+; Retention time = 1.033 rein. Step 2a. A mixture of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3- (tñfluoromethyl)pyridin-2-amine(100 mg, 0.339 retool), 5-chloro-2-fluoropyridin-4-ylboronic acid (89 mg, 0.509 mmol), PdC%(dppf).CH2 Cl2 adduct (27.7 mg, 0.034 mmol), DME (1.5 mL) and 2M aqueous Na2 CO2 (0.5 mL, 1 retool) was stirred in a sealed glass vessel at about 100 °C WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 for about 3 hours. After cooling to ambient temperature the mixture was diluted with EtOAc (25 mL) and MeOH (20 mL), filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography [silica gel, 12g, EtOAc/hexane = 5/100 to 50/50] to yield 5'-chl r -2'- u r -N-((tetrahydr -2H-pyran-4-y )methy )-5-(tri u r methy1)-2 4'-bipyddin-6amine (Intermediate T, 102 mg,, 77 % ). LCMS (m/z): 390.2 [M+H]+; Retention time = 1.12 min. Step 2b. Intermediate U was synthesized following the procedure described f r5'-chl r -2'- u r -N-((tetrahydr -2H-pyran-4-y )methyl)-5-(t u r methy )-2 4'-bipy din6-amine LCMS (m/z): 390.2 [M+H]+; Retention time = 1.01 min. [003621 Synthesis of 3,5'-dichloro-N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2'- fluoro-2,4'-bipyñdin-6-amine (Intermediate V) F CI N V H L,.«õ Step 1. 6-Bromo-2-aminopyridine (15 g, 87 mmol) and TEA (13.3 mL, mmol) were dissolved in 173 mL ofDCM. BOC-anhydride (20.8 g, 95 mmol) was then dissolved in 100 mL of DCM and added over l 0 min using a syringe pump. The reaction mixture was stirred at ambient temperature for 72 hr. The solvents were evaporated and the resulting residue was purified by silica gel chromatography (heptane:EtOAc 1:0 to 7:3) to give the product as a colorless solid (23.0 g, 97%). LCMS (m/z): 272.8/274.8 (M+H), retention time = 0.97 min. Step 2. tert-Butyl 6-bromopyridin-2-ylcarbamate (23.0 g, 84 mmol) was mixed with acetonitrile, (CH3 CN, 281 mL), and NCS (11.24 g, 84 mmol). The reaction mixture WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 mixture was heated at about 85°C for 3 hours, and an additional 5.5 g of NCS was then added. Heating was continued at about 85oC for an additional 3 hours, followed by addition of 5.5 g of NCS. Ail starting materials were consumed after about 1 hour. Brine (50 mL) was added and acetonitrile was evaporated under vacuum. The residual aqueous solution was extracted three times with EtOAc. Ail EtOAc layers were combined, dried over Na2SO4, filtered through a fritted filter and concentrated under vacuum. The resulting residue was purified on silica gel, eluting with 3% EtOAc in heptane to afford the product as a colorless solid (14.6 g, 56.3%). LCMS (m/z): 306.9/308.9/310.9 (M+H), retention time = 1.14 rein. 100365] Step 3. A solution oftert-Butyl 6-bromo-5-chloropyridin-2-ylcarbamate (2.32 g, 7.54 mmol) in DMF (25 mL) was mixed with sodium hydride (60% dispersion in minerai oil, 513 mg, 12.8 mmol), and the resulting mixture reaction mixture was stirred for 30 minutes at ambient temperature. (2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (3.15 g, 10.56 mmol), dissolved in 5 mL DMF, was then added and the resulting mixture was stirred at about 25 °C for 3 hours. The reaction mixture mixture was partitioned between water and EtOAc. The layers were separated and the EtOAe layer was washed twice with water. The EtOAc layer was then dried over sodium sulfate, filtered through a fritted filter and concentrated under vacuum. The resulting residue was purified using silica gel chromatography (0 to 30% EtOAc in heptane) to yield the product as a colorless solid (2.16 g, 66%). LCMS (m/z): 432.9/434.9/436.9 (M+H), retention time = 1.28 min. 100366] Step 4. A mixture oftert-butyl 6-bromo-5-chloropyridin-2-yl((2,2dimethyltetrahydro-2H-pyran-4-yl)methyI)carbamate (1.86 g, 4.29 mmol), 5-chloro-2fluoropyridin-4-ylboronic acid (1.50 g, 8.58 mmol), PdC12(dppf)*DCM adduct (350 mg, 0.429 mmol), DME (15.6 mL) and 2 M aqueous sodium carbonate solution (5.4 mL) were combined in a glass bomb. The bomb was sealed and heated at about 98°C for 2 hours. The reaction mixture mixture was cooled to ambient temperature and then diluted with EtOAc. The diluted mixture was washed three times with saturated aqueous NaHCO3 solution, dried over sodium sulfate, filtered through a fritted filter and concentrated under vacuum. Purification was done using silica gel chromatography (15% EtOAc in heptane) to yield the product as a colorless solid (1.5 g, 72%). LCMS (m/z): 484.2/486.1 (M+H), retention time = 1.33 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1003671 Step 5. tert-Butyt 3,5'-dichloro-2'-fluoro-2,4'-bipyridin-6-yl((2,2dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (8 mg, 0.017 mmol), DCM (1 mL) and TFA (0.1 mL, 1.3 mmol) were combined in a 4 mL screw cap vial. The vial was capped and the reaction mixture mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated under vacuum and the residual material was converted to the free base using sodium bicarbonate. (5.8 mg, 91%). LCMS (m/z): 3484.2/386.l/388.2 (M+H), retention time = 1.07 min. Synthesis of 2,3-difluoropyridin-4-ylboronic acid (Intermediate W) }(OH)2 W 100369] A mixture of THF and hexanes (6mL, 1:1 v:v), and diisopropyl amine (0.681 mL, 4.78 mmol) was cooled to -78 °C. BuLi (2.5 M in hexanes, 2.00 mL, 5.00 mmol) was added to the cooled mixture, followed by addition of 2,3-difluoropyridine after about 15 minutes. The mixture was stirred for 1 hour at -78 °C before being transferred to a 3 mL THF solution of triisopropyl borate (1.11 mL, 4.78 mmol) at -78 °C via a cannula. The resulting solution was stirred at -78 °C for I hour, slowly warmed up to ambient temperature and then quenched with 2 M NaOH solution (20 mL). The two layers were separated and the aqueous phase was washed once with ether. The aqueous phase was then acidified with HC1 to pli 5 and extracted three times with EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated to yield the product as a light yellow solid, which was used in the next step without purification. LCMS (m/z): 159.9 (M+H), retention time = 0.35 min. Synthesis of trans-N I -( 1,3-dimethoxypropan-2-yl)cyclohexane1,4-diamine (Intermediate X) WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 I O ",,N O-.. H X Step 1. To Nail (0.366 g, 9.16 mmol) in THF (12 mL) at 0 °C was added 1,3dimethoxy-2-propanol (1 g, 8.32 mmol) in THF (8 mL) solution. The mixture was warmed to ambient temperature and stirred for 0.5 hour. To this was added tosyl chloride (1.587 g, 8.32 mmol) in one portion. The resulting white cloudy mixture then was stirred at ambient temperature for 16 hours. LC/MS showed complete conversion to 1,3-dimethoxypropan-2-yl 4methylbenzenesulfonate. The reaction mixture mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo to yield 2 g of a colorless oil. The crude mixture was purified by Analogie system (silica gel column 80 g, gradient: 0 min, 100%n-heptane; 5-12 min, 20% EtOAc in Heptane; 12-15 min. 30% EtOAc in Heptane and hold until 30 min). The pure fractions were combined and concentrated in vacuo to yield 1.25 g of the tosylate product 1,3dimethoxypropan-2-yl 4-methylbenzenesulfonate as a colorless oil, which solidified upon standing. 100372] Step 2. To the tosylate obtained in Step 1 (0.8g, 2.92 mmol) in DMSO (8 ml) was added 1,4-trans-cyclohexane diamine (0.999 g, 8.75 mmol). The reslting brown mixture was heated in a capped vial to about 95 °C, with stirring, for 2 hours. The reaction mixture mixture was poured into 10% HCI in water (10 mL) at 0 °C (ice cubes in HCI) and extracted with DCM (lx20 mL). The aqueous (light pink) was basified with 6N NaOH to a pli >12 and extracted with DCM (2x20mL). The organic extracts were combined, dried with sodium sulfate and concentrated in vacuo to yield compound "X" as a purple liquid. LC/MS showed containing desired product (M+1=217, Rt=-0.32min, no UV absorption at 214nm wavelength). This was used in the next step without further purification. 1003731 Synthesis of 4-((5'-chloro-2',5-difluoro-2,4'-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate AA) WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 ;N F H 100374] Step 1: pyran-4-carbonitrile F Synthesis of 4-((3,6-difluoropyridin-2-yl-amino)methyl)tetrahydro-2HCN H æ0 To 2,3,6-Trifluoropyridine (0.6g, 4.5 mmol) in DMSO (5 ml) at room temperature was added 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate R, 1.01g, 7.23 mmol) and Iríethylamine (1.57 ml, 11.24 mmol) sequentially. The light brown mixture was heated at 105 °C in a sealed glass bomb for 18 hours. After cooled to room temperature the reaction mixture was extracted with EtOAc (40 ml), washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to give a light brown liquid. This crude material was purified by silica gel chromatography using a 12 g column, eluting with 5%- 20% ethyl acetate in hexane to afford 550 mg (48.2 % yield) of the desired product. LCMS (m/z): 254.1 [M+H]+; retention time = 0.743 min. 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.69 - 1.95 (m, 4 H) 3.60 - 3.82 (m, 4 H) 4.00 (ddd, J=12.13, 4.30, 1.96 Hz, 2 H) 5.02 (br. S., 1 H) 6.12 (td, J=5.58, 2.54 Hz, 1 H) 7.19-7.33 (m, 1 H). [00376| Step 2: Synthesis of 4-((6-(benzyloxy)-3-fluoropyridin-2-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 CN H F æO [003771 Benzyl alcohol (352 mg, 3.26 mmol) was dissolved in anhydrous DMF (2 ml) and placed under argon. This was then treated with a 60% dispersion in oil of SODIUM HYDRIDE (78.7 mg, 3.26 mmol). This resultant suspension was then stirred at room temperature for min. At this time it was treated with a solution of 4-((3,6-difluoropyridin-2ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (275 mg, 1.09 mmol) dissolved in anhydrous DMF (2 ml). Once the addition was complete the reaction was stirred at 90°C for hours. The reaction was allowed to cool to room temperature. It was then poured into brine (20 ml). This was extracted with EtOAc (3 x 15 ml). The combined extracts were washed with H2 0 (3 x l0 ml) followed by bñne (1 x l0 ml). The organic layer was dñed (-Na2 SO4 ), filtered, and the solvent removed in vacuo to give the crude material which was purified using the ISCO and a 12 g SiO2 column. Eluted using 100 hexanes to 30 EtOAc / 70 hexanes over 20 min. 245 mg (66% yield) of the desired product was obtained as a viscous liquid. LCMS (m/z): 342.1 [M+H]+; retention time = 1.017 min. Step 3: Synthesis of 4-((3-fluoro-6-hydroxypyridin-2-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrite A mixture of 4-((6-(benzyloxy)-3-fluoropyridin-2-ylamino)methyl)tetrahydro2H-pyran-4-carbonit61e (200 mg, 0.586 mmol), AMMONIUM FORMATE (111.3 mg, 1.758 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 mmol) and Pd-C (10%, wet, 25mg) in methanol (4 ml) was stirred at 70 °C for 45 min and cooled. The mixture was then filtered to remove Pd-C and inorganics, the filterate was then concentrated and dried further via high vacumm to afford 141 mg ( 96% yield) of the crude product as a light pink solid. LCMS (m/z): 252.1 [M+H]+; retention time = 0.540 min. [003801 Step 4: Synthesis 6-((4-cyanotetrahydro-2H-pyran-4-yl) methyl)-amino-5fluoropyridin-2-yl trifluo romethanesulfonate FF9 TIl O F H I Ó To a solution of 5-fluoro-6-((4-cyano-tetrahydro-2H-pyran-4yl)methyl)aminopyridin-2-ol (141 mg, 0.562 mmol) and TEA (0.782 ml, 5.60 mmol) in DCM (6 ml) was added trifluoromethanesulfonic anhydride (0.142 ml, 0.842 mmol) slowly at 0 °C. The mixture was stirred for 2 hours at 0 °C and one hour at room temperature and poured carefully into ice-cooled saturated aqueous NaHCO3 solution. The separated aqueous layer was extracted with DCM (2xl 0ml). The combined organic layers were dñed over Na2 SO«, filtered off and concentrated in vacuo. The residue was purified by column chromatography [ISCO, SiO2 , 12g, min, EtOAc/heptane = 5/95 for 2 min, then EtOAc/heptane = 5/95 to 40/60 for 2min-17min]. Pure fractions were combined and concentrated in vacuo to give a colorless oil (200 mg, 0.522 mmol, 93 % yield) as the desired product. LCMS (m/z): 384.0 [M+H]+; Rt = 0.946 min. Step 5: Synthesis of 4-((5 '-chloro-2',5-difluoro-2,4'-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate AA) A mixture of 5-fluoro-6-((4-cyano-tetrahydro-2H-pyran-4-yl)methylamino) WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 pyridin-2-yt trifluoromethanesulfonate (200 mg, 0.522 mmol), 5-chtoro-2fluoropyridin-4-ylboronic acid (183.2 mg, 1.044 mmot), PdCl2 (dppf)-CH2 Cl2 adduct (85.1 mg, 0.104 mmol), and SODIUM CARBONATE (221.6 mg, 2.08 mmol, in 1 ml of water) in DME (3 ml) was de-gassed and heated at 110 °C for 20 min in a sealed microwave vial, cooled. The upper layer of mixture was separated, the bottom one was extracted with ethyl acetates, the organic layers were combined and concentrated to afford the crude product, which was purified by ISCO ( 10 to 50% ethyl acetate in heptane, 20 rein)to afford 150 mg ( 79% yield)of the desired product was an off-white solid. LCMS (m/z): 365.1 [M+H]+; retention time = 0.929 min. Synthesis of 4-((5'-chloro-2'-fluoro-2,4'-bipyridin-6-yt-amino)methyt)tetrahydro2H-pyran-4-carbonitrile (Intermediate AB) H 1003861 A mixture of4-((6-bromopyridin-2-yl-amino)methyl)tetrahydro-2H-pyran-4carbonitrile ( Intermediate S, 410 mg, 1.384 mmol), 5-chloro-2-fluoropyridin-4-ytboronic acid (362.2mg, 2.07 mmol), PdCl2 (dppf).CH2 Cl2 adduct (113 mg, 0.14 retool), DME (5 MI) and 2 M aqueous Na2 CO (1.75 MI, 3.5 mmol) was sealed and stirred at 110 °C for 20 min using microwave reactor. After cooling to room temperature the mixture was extracted with EtOAc (35 MI), filtered and concentrated in vacuo. The crude mateñal was purified by column chromatography [silica gel, 24g, EtOAc/hexane = 5/100 to 50/50] to provide 4-((5'-chloro-2'- fluoro-2,4'-bipyridin-6-ylamino)methyt)tetrahydro-2H-pyran-4-carbonitrile (360 mg, 75 % yield). LCMS (m/z): 347 [M+H]+; retention time = 0.8t4 rein. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 [003871 Synthesis of 5'-chloro-2'-fluoro-N-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)- 2,4'-bipyridin-6-amine (intermediate AC) H [003881 Step 1" Synthesis oftert-butyl 6-bromopyridin-2-yl((4-methoxytetrahydro-2Hpyran-4-yl)methyl) carbamate [003891 To a solution of tert-butyl 6-bromo-pyridin-2-ylcarbamate (136mg, 0.50mmol) in DMF (2ml) under nitrogen was added Nail (60%, 40mg, 1.0 mmol) under stirring. The resultant mixture was stirred at room temperature for one hour. A solution of(4-methoxytetrahydro-2Hpyran-4-yl)methyl 4-methylbenzenesulfonate (Intermediate O, 152 mg, 0.506mmol) in DMF (1.5ml) was then added. The resulting mixture was then stirred at 85 °C for about 18 hours. The mixture was diluted with 30 ml of ethyl acetate, washed with water (20 ml x3) and dried with sodium sulfate. After concentration the residue was purified by silica gel chromatography using a 12g column, eluting with 5-20% ethyl acetate in hexane to give the desired title compound as a viscous oil (92 mg, 46% yield), which solidified upon standing overnight. LCMS (m/z): 403.1 [M+H]+; Rt = 1.026 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100390] Step 2: Synthesis of tert-butyl 5'-chloro-2'-fluoro-2,4'-bipyridin-6-yl((4methoxytetrahydro-2H-pyran-4-yl) methyl)carbamate 100391] A mixture oftert-butyl 6-bromo-pyridin-2-yl((4-methoxytetrahydro-2H-pyran-4yl)methyl)carbamate (50 mg, 0.125 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (43.7mg, 0.249 mmol), PdCl2 (dppf).CH2 C12 adduct (l 5.2 mg, 0.019 mmol), DME (1.5 MI) and 2M aqueous Na2 CO2 (0.25 MI, 0.5 mmol) was sealed and stirred at 100 °C for 3 hours. After cooling to room temperature the mixture was diluted with EtOAc (15 Ml), filtered and concentrated in vacuo. The crude material was purified by column chromatography [silica gel, 12g, EtOAc/hexane = 5/100 to 50/50] to provide tert-butyl 5'-chloro-2'-fluoro-2,4'-bipyridin-6yl((4-methoxytetrahydro-2H-pyran-4-yl)methyl)carbamate (32 mg, 57 % yield). LCMS (m/z): 452.2 [M+H]+; retention time = 1.068 min. Step 3: Synthesis of 5'-chloro-2'-fluoro-N-(O-methoxytetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridin-6-amine (Intermediate AC) 100393] A solution of tea-butyl 5'-chloro-2'-fluoro-2,4'-bipyridin-6-yl((4methoxytetrahydro-2H-pyran-4-yl)methyl)carbamate (32 mg, 0.071 mmol) and TRIFLUOROACETIC ACID (0.982 ml, 12.75 mmol) in DCM (2ml) was stirred at room temperature for 40 min. The mixture was then concentrated to afford 22 mg of the crude material which was used in the next step without purification. LCMS (m/z): 352.2 [M+H]+; Rt = 0.634 min. Example I a (Compound 1) N2'-(trans-4-amin cyc hexy )-5'-ch r -N6-(3u r benzy )-2 4 -bipyridine-2 6-diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H ""NH2 Step 1. Preparation oftrans-Nl-(5-chloro-4-iodopyñdin-2-yl)cyclohexane1,4-diamine 100394] A mixture of 5-chloro-2-fluoro-4-iodopyridine (1000 mg, 3.88 mmol), DMSO (7 ml), and trans-cyclohexane-1,4-diamine (2661 mg, 23.31 mmol) reaction mixture was stirred at about 85 °C for 2 hours, followed by LCMS. The crude reaction mixture mixture then was mixed with 5 ml DMSO, filtered and purified by prep LC. After lyapholization, 1.17 grams of the title compound was obtained as a TFA sait. LCMS (m/z): 352.1 (MH+), retention time = 0.50 min. [003951 Step 2. Preparation of trans-Nl-(5'-chloro-6-fluoro-2,4'-bipyridin-2'- yl)cyclohexane1,4-diamine A mixture of trans-N 1 - (5-chloro-4-iodopyridin-2-yl)cyclohexane1,4-diamine (from step 1 above, 300 mg, 0.853 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyridine (285 mg, 1.280 mmol), PdC12(dppf).CH2Cl2 adduct (84 mg, 0.102 mmol), DME (4 ml), Ethanol (1 ml), and 2M sodium carbonate (1.706 ml, 3.41 retool) reaction mixture was stirred at about 90 °C until done by LCMS. The reaction mixture mixture was cooled, then diluted with 25 ml of ethyl acetate and 10 ml of methanol, filtered, and concentrated to yield a crude solid. The crude solid was dissolved in DMSO, filtered and purified by prep LC. After lyapholization, 200 mg of the title compound was obtained as a TFA sait. LCMS (m/z): 321.0 (MH+), retention time = 0.48 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100397] Step 3. Preparation of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(3fluorobenzyl)-2,4'-bipyñdine-2',6-diamine 100398] To trans-N 1-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane1,4-diamine (from Step 2 above, 200 mg, 0.623 mmol) was added DMSO (2 ml) and (3fluorophenyl)methanamine (351 mg, 2.81 mmol). The crude reaction mixture mixture was stirred at 115 °C until done, as indicated by LCMS. The excess amine was removed under reduced pressure. The resulting crude rsidue was dissolved in 2 ml of DMSO, filtered, puñlíed by prep LC and lyphilized to yield a TFA sait. The TFA sait was free-based using 200 ml of ethyl acetate and washed with saturated sodium bicarbonate 35 ml (Ix), water (2x), saturated brine (Ix), dried over sodium sulfate, filtered and concentrated to yield a solid. The solid was dissolved in (1 : 1 ACN/water), filtered, and lyapholized to yield 80 mg of the title compound as free-base. LCMS (m/z): 426.1 (MH+), retention time = 0.61 min.; 1H NMR (300 MHz, METHANOL-d4, 25 °C) 1.21 - 1.40 (m, 4 H) 1.89 - 2.00 (m, 2 H) 2.07 (d, J=10.56 Hz, 2 H) 2.69 - 2.79 (m, 1 H) 3.55 - 3.64 (m, 1 H) 4.57 (s, 2 H) 6.53 (d, J=8.61 Hz, 1 H) 6.59 (s, 1 H) 6.80 (d, J=7.04 Hz, 1 H) 6.90 - 6.97 (m, 1 H) 7.09 (d, J=10.17 Hz, 1 H) 7.14 - 7.20 (m, 1 H) 7.25 - 7.34 (m, 1 H) 7.48 (t, J=7.83 Hz, 1 H) 7.93 (s, 1 H) Example lb (Compound 1) N2'-(transs-4-aminoc yclohexyl)-5'-chloro-N6-(3-fluorobenzy 1)-2, 4'-bipyri dine -2',6-diamine H ""NH2 Step 1. Preparation of 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 [004001 A mixture of 2,6-dibromopyridine (7.1 g, 30.0 mmol), NMP (16 ml), (3fluorophenyl)methanamine (4.13 g, 33.0 mmol) and Hunig's Base (5.76 ml, 33.0 mmol) was flushed with argon. The crude reaction mixture mixture was stirred at 115-120 °C for about 168 hours. LC/MS was used to monitor the reaction. The crude mixture was then cooled to room temperature, and then diluted with 250 ml of ethyl acetate, washed with saturated sodium bicarbonate (2x), water (2x), saturated, sait solution (Ix), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography using a 120 g column, eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to yield, 7.11 grams of the titled compound as a free base, which was used in the next step without further purification. LCMS (m/z): 281.1/283.1 (MH+), retention time = 1.03 min. [004011 amine Step 2. Preparation of 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6- A mixture of 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (2.0 g, 7.11 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (1.996 g, 11.38 mmol), PdC12 (dppf).CH2 Cl2 adduct (0.465 g, 0.569 mmol), DME (27 ml), and 2M sodium carbonate (9.25 ml, 18.50 mmol) reaction mixture was stirred at aboutl00 °C for 3 hours. The crude mixture was cooled to room temperature, diluted with 25 ml ethyl acetate and 20 ml methanol, filtered and concentrated to yield crude residue.. The crude residue was purified by silica gel chromatography using a 120 g column, eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, to yield 1.259 grams of titled compound as free base, which was used in the next step without further purification. LCMS (m/z): 332.2 (MH+), retention time = 0.92 min. Step 3. Preparation of N2'-(trans-4-aminocyclohexyt)-5'-chloro-N6-(3fluorobenzyl)-2,4'-bipyridine-2',6-diamine A mixture of 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6-amine (725 mg, 2.185 mmol) was added DMSO (7 ml), trans-cyclohexane-l,4-diamine (1996 mg, t7.48 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 mmol) and TEA (0.609 ml, 4.37 mmol) was stirred at about 100 °C for 20 hours. The reaction was monitored by LC/MS. The crude reaction mixture mixture was cooled to room temperature, diluted with 3 mi DMSO, filtered, and purified by prep HPLC. (there is a general HPLC conditions in the general experimental session).The fractions were concentrated, mixed with 500 ml ethyl acetate, and basified with saturated sodium bicarbonate t20 ml. The ethyl acetate layer was separated, and the basic water layer was extracted with 300 ml ethyl acetate. The ethyl acetate layers were combined and washed with water (3x), saturated sait solution(Ix), dñed with sodium sulfate, filtered and concentrated to yield a solid. The solid was dissolved in (1:1 ACN/ water) filtered and lyapholized to yield 755 mg of the title compound as free-base. LCMS (m/z): 426.3 (MH+), retention time = 0.59 rein.; IH NMR (300 MHz, METHANOL-d4, 25 °C) 6 ppm 1.10 - 1.43 (m, 4 H) 1.90 (d, J=12.01 Hz, 2 H) 2.01 (d, J=12.01 Hz, 2 H) 2.70 - 2.84 (m, l H) 3.47 - 3.60 (m, l H) 4.48 (s, 2 H) 6.44 (d, J=8.50 Hz, I H) 6.51 (s, 1 H) 6.71 (d, J=7.33 Hz, 1 H) 6.79 - 6.91 (m, 1 H) 7.00 (d, J=9.96 Hz, 1 H) 7.05 - 7.13 (m, 1 H) 7.15 - 7.27 (m, 1 H) 7.40 (t, J=7.77 Hz, 1 H) 7.85 (s, l H) Example 2 (Compound 2) N2 -(transs-4-aminocyclohexyl)-N6-(cyclohexylmethyl)-2,4 -bipyridine-2,6-diamine H ""NH2 H Step 1. Preparation of trans-N l-(4-bromopyridin-2-yl)cyclohexane1,4-diamine A mixture of4-bromo-2-chloropyridine (1500 mg, 7.79 mmol), DMSO (15 ml), and trans-cyclohexane-1,4-diamine (4450 mg, 39.0 mmol)was stirred at 100 °C until the formation of the product, as indicated by LCMS. The reaction mixtuoe was cooled to room WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 temperature, filtered and purified by prep LC, and lyapholized to yield 393mg of the title compound as a TFA salt. LCMS (m/z): 270.2/272.2 (MH+), retention time = 0.31 min. Step 2. Preparation oftrans-Nl-(6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane1,4-diamine 1004061 A mixture of trans-N 1-(4-bromopyridin-2-yl)cyclohexane1,4-diamine ( 102 mg, 0.377 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyñdine (80 mg, 0.359 mmol), PdC12(dppf).CH2 C12 adduct (29.3 mg, 0.036 mmol), DME (2 ml), Ethanol (0.2 ml), and 2M sodium carbonate (0.717 ml, 1.435 mmol) reaction mixture was stirred at about 85 °C until completion, as indicated by LCMS. The crude mixture was cooled to room temperature, diluted with 5 ml of ethyl acetate and 2 ml of methanol, filtered and concentrated to yield a crude solid. The solid was dissolved in DMSO, refiltered, purified by prep LC, and lyapholized to yield 64 mg of the title compound as its TFA sait. LCMS (m/z): 287.2 (MH+), retention time = 0.43 min. Step 3. Preparation of N2'-(transs-4-aminocyclohexyl)-N6-(cyclohexylmethyl)-2,4'-bipyridine2',6-diamine A mixture oftranss-Nl-(6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-l,4-diamine (15 mg, 0.052 mmol), DMSO (0.4 ml), and cyclohexylmethanamine (59.3 mg, 0.524 mmol) was heated at at about 105 °C for about 24 hours, or until the product pormation was completed, as indicated by LCMS. The excess amine was removed under reduced pressure to yield a residue. The residue was mixed with 0.5 ml of DMSO, filtered and purified by prep LC. After lyphilization, 11.3 mg of the title compound was obtained as a TFA sait. LCMS (m/z): 380.3 (MH+), retention time = 0.61 min. IH NMR (400 MHz, METHANOL-d4, 45 °C) 6 ppm 0.97 - 1.11 (m, 2 H) 1.17 - 1.36 (m, 3 H) 1.49 - 1.72 (m, 6 H) 1.71 - 1.80 (m, 2 H) 1.84 (d, J=12.91 Hz, 2 H) 2.11 - 2.28 (m, 4 H) 3.t3 - 3.25 (m, 1 H) 3.28 (d, 2 H, App.) 3.65 - 3.75 (m, 1 H) 6.65 (d, J=8.61 Hz, 1 H) 7.16 (d, J=7.43 Hz, 1 H) 7.43 - 7.48 (m, 1 H) 7.52 (t, J=7.83 Hz, 1 H) 7.64 (s, 1 H) 7.85 (d, J=7.04 Hz, 1 H) Example 3 (Compound 3) WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 tra.s-N 1 -(5 -chloro-4-(6-(cyclohexylmethylamino)pyridin-2-yl)pyrimidin-2-yl)cyclohexane1,4diamine H ""NH2 H Step 1. Preparation of 2,5-dichloro-4-(6-fluoropyridin-2-yl)pyñmidine 100408] A mixture of 2,4,5-trichloropyrimidine (49.3 mg, 0.269 mmol), 2-fluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyñdine (50 mg, 0.224 mmol), PdCl2 (dppf).CH2 Cl2 adduct (18.31 mg, 0.022 mmol), DME (0.7 ml), and 2M sodium carbonate (0.247 ml, 0.493 retool) reaction mixturewas stirred at about 80 °C until the reaction mixture was complete, as indicated by LCMS. The reaction mixture mixture was cooled, diluted with 5 ml of ethyl acetate and 1 ml of methanol, filteoed and concentrated to yield a crude solid. The crude material was purified by silica gel chromatography using a 12g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, to yield 39.5 mg of titled compound as a free base. LCMS (m/z): 244.0 (MH+), retention time = 0.89 min. Step 2. Preparation of trans-Nl-(5-chloro-4-(6-fluoropyridin-2-yl)pyrimidin-2-yl)cyclohexane1,4-diamine 100409] A mixture of2,5-dichloro-4-(6-fluoropyridin-2-yl)pyrimidine (37 mg, 0.152 mmol), DMSO (1.5 ml) and transs-cyclohexane-1,4-diamine (87 mg, 0.758 mmol)reaction mixturewas stirred at about 75 °C for about 2 hours.. The reaction mixture was cooled, filter and purified by prep LC, and then lyapholized to yield 39.5 mg of the title compound as a TFA salt. LCMS (m/z): 322.2(MH+), retention time = 0.59 rein. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 3. Preparation of trans-N l-(5-chloro-4-(6-(cyclohexylmethylamino)pyridin-2-yl)pyrimidin2-yl)cycl ohexane1,4 -diamine 100410] A mixture oftrans-Nl-(5-chloro-4-(6-fluoropyridin-2-yl)pyrimidin-2yl)cyclohexane-1,4-diamine (12 mg, 0.037 mmol), cyclohexylmethanamine (42.2 mg, 0.373 mmol), and DMSO (0.35 ml) was stirred at about 105 °C for about 24 hours. The excess cyclohexylmethanamine was removed under vacuum to yield a residue. The residue was mixed with 0.5 ml DMSO, filtered, purified by prep HPLC and then lyapholized to yield 9.4 mg of the title compound as a TFA sait. LCMS (m/z): 415.3 (MH+), retention time = 0.67 min.; 1H NMR (400 MHz, METHANOL-d4, 45 °C) 6 ppm 0.89 - 1.07 (m, 2 H) 1.10 - 1.30 (m, 3 H) 1.30 - 1.54 (m, 4 H) 1.55 - 1.65 (m, 2 H) 1.69 (d, J=12.91 Hz, 2 H) 1.76 (d, J=t2.91 Hz, 2 H) 1.96 - 2.14 (m, 4 H) 2.98 - 3.10 (m, 1 H) 3.18 (d, J=6.65 Hz, 2 H) 3.71 - 3.82 (m, 1 H) 7.03 (d, J=9.00 Hz, t H) 7.49 (br. s., 1 H) 7.83 (t, J=8.22 Hz, 1 H) 8.35 (s, 1 H) Example 4 (Compound 4) (N2'-(trans-4-(amin methy )cyc hexy )-5'-ch r -N6-( 3u r benzy )-2 4'-bipyridine-2 6diamine H cI N ",,/NH2 Stepl. Preparation oftert-butyl (trans-4-(5-chloro-4-iodopyridin-2-ylamino)c yclohexyl)methylcarbamate 1004111 A mixture of 5-chloro-2-fluoro-4-iodopyridine (517 mg, 2.008 mmol), tert-butyl (trans-4-aminocyclohexyl)methylcarbamate (550 mg, 2.410 mmol), DMSO (2 ml) and TEA (0.336 ml, 2.410 mmol) reaction mixturewas stirred at about 95 °C for about 26 hours. The crude reaction mixture mixture was cooled to room temperature, mixed with 125 ml ethyl acetate, washed with saturated sodium bicarbonate (2x), water (3x), saturated sait solution (Ix), WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 dried sodium sulfate, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography using a 40g column, eluting from 0%-35% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, yielding 656 mg of titled compound as free base. LCMS (m/z): 466.1(MH+), retention time = 0.93 min. Step 2. Preparation oftert-butyl (trans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-ylamino)cyclohexyl)methytcarbamate [004121 A mixture oftert-butyl (trans-4-(5-chloro-4-iodopyridin-2-ylamino)cyclohexyl)methytcarbamate (510 mg, 1.095 mmot), 2-fluoro-6-(4,4,5,5-tetramethyl1,3,2-dioxaborotan-2-yl)pyridine (440 mg, 1.971 mmol), PdCl2 (dppf).CH2 Ct2 adduct (89 mg, 0.109 mmol), DME (7.5 ml), and 2M sodium carbonate (2.464 ml, 4.93 mmot) reaction mixturewas stirred at about 100 °C for about 2 hours. The reaction mixture mixture was cooled to room temperature, mixed with 20 ml ethyl acetate, filtered and concentrated to yield a crude solid. The crude solid was purified by silica gel chromatography using 40g column, eluting from 0%-45% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, yielding 396 mg of titled compound as a free base. LCMS (m/z): 435.2(MH+), retention time = 0.85 min.. Step 3. Preparation of N-(trans-4-(aminomethyl)cyclohexyl)-5'-chloro-6-fluoro-2,4'-bipyridin2'-amine A mixture oftert-butyl (trans-4-(5'-chlom-6-fluoro-2,4'-bipyridin-2'-ylamino)cyclohexyl)methylcarbamate (390 mg, 0.897 mmol), 4M HC1 in Dioxane (5604 tl, 22.42 mmol) reaction mixturewas stirred at ambient temperature for 1 hr. The crude reaction mixture mixture was concentrated, and then dried under high vacuum to a constant mass giving 335 mg of the title compound as a HCL sait. LCMS (m/z): 335.1 (MH+), retention time --- 0.51 min. Step 4. Preparation of N2'-(trans-4-(aminomethyl)cyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)- 2,4'-bipyridine-2',6-diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100413| A mixture of N-(trans-4-(aminomethyl)cyclohexyl)-5'-chloro-6-fluoro-2,4'- bipyridin-2'-amine (15 mg, 0.045 mmol), DMSO (0.35 ml), TEA (0.012 ml, 0.090 mmol) and (3-fluorophenyl)methanamine (50.5 mg, 0.403 mmol) reaction mixturewas flushed with argon and then stirred at about 105 °C for about 40 hours. The excess (3-fluorophenyl)methanamine was removed under reduced pressure to yield a crude material, which was mixed with 0.5 mlDMSO, filtered, purified by prep LC, and then lyapholized to yield 11.2 mg of the title compound, as a TFA sait. LCMS (m/z): 440.2(MH+), retention time = 0.62 min. 1H NMR (300 MHz, METHANOL-d4, 25 °C) 6 ppm 1.11 - 1.28 (m, 2 H) 1.28 - 1.47 (m, 2 H) 1.67 (ddd, J=10.92, 7.40, 3.66 Hz, 1 H) 1.92 (d, J=l 1.72 Hz, 2 H) 2.14 (d, J=10.55 Hz, 2 H) 2.83 (d, J=6.74 Hz, 2 H) 3.57 - 3.69 (m, 1 H) 4.63 (s, 2 H) 6.84 (d, J=8.79 Hz, 1 H) 6.90 (s, 1 H) 6.94 (d, J=7.03 Hz, 1 H) 6.96 - 7.03 (m, 1 H) 7.10 (d, J=9.96 Hz, 1 H) 7.18 (d, J=7.62 Hz, 1 H) 7.29 - 7.39 (m, 1 H) 7.697.77 (m, 1 H)8.0t (s, 1 H) Example 5 (Compound 5) (5'-ch r -N6-(3-flu r benzy )-N2'-(piperidin-4-y )-2 4'-bipyridine-2' 6-diamine H Step 1. Preparation oftert-butyl 4-(5-chloro-4-iodopyridin-2-yl-amino)piperidine1-carboxylate A mixture of 5-chloro-2-fluoro-4-iodopyridine (517 mg, 2.008 mmot), tert-butyt 4-aminopiperidine-l-carboxylate (603 mg, 3.01 mmol), DMSO (2 ml) and TEA (0.420 ml, 3.01 mmol) oeaction mixturewas stirred at 90 °C for 18 hours. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (2x), water (3x), saturated sait solution (1 x), dried sodium sulfate, filtered and concentrated to yield a crude material, which was purified by silica gel chromatography using a 40g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 concentrated to constant mass, giving 585 mg of the title compound as free base. LCMS (m/z): 438. I (MH+), retention time = 1.00 min. Step 2. Preparation oftert-butyl 4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)piperidine1 - carboxylate A mixture of tert-butyl 4-(5-chloro-4-iodopyridin-2-yl-amino)piperidine1- carboxylate (468 mg, 1.069 retool), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyddine (429 mg, 1.925 retool), PdC12 (dppf).CH2 Cl2 adduct (87 mg, 0.107 retool), DME (7.5 ml), and 2M sodium carbonate (2.406 ml, 4.81 retool) reaction mixture was stirred at 100 °C for 2 hr. The reaction mixture mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, filtered and concentrated to yield a crude material. The crude material was puñfied by silica gel chromatography using a 40g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 360 mg of the title compound as free base. LCMS (m/z): 407.2 (MH+), retention time = 0.85 rein. Step 3. Preparation oftert-butyl 4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-ylamino)piperidine1 -carboxylate A mixture of tert-butyl 4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-ylamino)piperidine-l-carboxylate (200 mg, 0.492 mmol), DMSO (2 ml), TEA (0.137 ml, 0.983 mmol) and (3-fluorophenyl)methanamine (554 mg, 4.42 mmol) reaction mixture was flushed with argon and stirred at 100 °C for 40 hr, as the reaction mixture progress was followed by LCMS. The reaction mixture was cooled to room tempoerature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (2x), water (3), saturated sait solution (Ix), dried over sodium sulfate, filtered and concentrated to yield a crude material, which was was purified by silica gel chromatography using a 12g column, eluting from 0%-35% ethyl acetate with hexane. The desired fractions were collected and concentrated to constant mass, giving 225 mg of the title compound as a free base. LCMS (m/z): 5t2.3 (MH+), retention time = 0.91 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 4. Preparation of 5'-chloro-N6-(3-fluorobenzyl)-N2'-(piperidin-4-yl)-2,4'-bipyridine-2',6diamine A mixture oftert-butyl 4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-ylamino)piperidine-l-carboxylate (220 mg, 0.430 mmol), HCI 4M in Dioxane (7 mL, 28.0 mmol) was stirred at ambient temperature for 1 hr. The solvent was evaporated under reduced pressure to yield a solid which was furthe dried under high vaccum to yield 250mg of the title compound as a HCI sait. A portion of the title compound was purified by prep LC, and then lyapholized to yield 19.0 mg of the title compound as a TFA sait.. LCMS (m/z): 412.2 (MH+), retention time = 0.60 min.; IH NMR (300 MHz, METHANOL-d4, 25 °C ) 15 ppm 1.66 - 1.83 (m, 2 H) 2.25 (dd, J=14.21, 3.08 Hz, 2 H) 3.08 - 3.21 (m, 2 H) 3.36 - 3.51 (m, 2 H) 3.96 - 4.12 (m, 1 H) 4.65 (s, 2 H) 6.74 (s, 1 H) 6.91 (s, 1 H) 6.94 (s, 1 H) 6.98 - 7.06 (m, 1 H) 7.12 (d, J=9.96 Hz, 1 H) 7.19 (d, J=7.62 Hz, 1 H) 7.31 - 7.43 (m, 1 H) 7.77 - 7.85 (m, 1 H) 8.09 (s, 1 H) Example 6 (Compound 6) 5'-ch r -N2'-( -(ethy su f ny )piperidin-4-y )-N6-(3u r benzy )-2 4'-bipyridine-2' 6 diamine H O Preparation of 5'-chloro-N2'-(1-(ethylsulfonyl)piperidin-4-yl)-N6-(3-fluoro benzyl)-2,4'- bipyridine-2',6-diamine [004181 A mixture of 5'-chloro-N6-(3-fluorobenzyl)-N2'-(piperidin-4-yl)-2,4'-bipyridine2',6-diamine (Example 6,16 mg, 0.039 mmol), dichloromethane (0.5 ml), and TEA (0.022 ml, 0.155 mmol) was cooled to 0 °C. This cooled mixture was then diluted with a solution of 0.03 ml of dichlormethane with ethanesulfonyl chloride (6.99 mg, 0.054 mmol). The reaction mixture then was warmed to ambient temperature and stirred for 1 hour, followed by LCMS. The WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 reaction mixture solvent was removed under reduced pressure, to yield a residue which was dissolved in 0.75 ml DMSO, filtered, purified by prep LC and then lyapholized to yield 9.9 mg of the title compound, as a TFA sait. LCMS (m/z): 504.2 (MH+), retention time = 0.77 min.; tri NMR (300 MHz, METHANOL-d4, 25 °C) ì5 ppm t.32 (t, J=7.33 Hz, 3 H) 1.47 - 1.67 (m, 2 H) 2.08 (d, J=10.84 Hz, 2 H) 2.96 - 3.12 (m, 4 H) 3.75 (d, J=12.89 Hz, 2 H) 3.80 - 3.92 (m, l H) 4.65 (s, 2 H) 6.83 (s, t H) 6.92 (d, J=9.08 Hz, 1 H) 6.95 (d, J=7.62 Hz, 1 H) 7.01 (t, J=8.64 Hz, 1 H) 7.11 (d, J=9.96 Hz, 1 H)7.19 (d, J=7.62 Hz, 1 H) 7.30-7.41 (m, 1 H) 7.75 -7.85 (m, 1 H) 8.06 (s, 1 H) Example 7 (Compound 7) N-( trans-4-( 5'-ch r -6-( 3u r benzy amin )-2 4'-bipyri din-2'-y -amin )c yc hexy )-2- (dimethytamino)aeetamide Preparation of N-(trans-4-(5'-chtoro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-ylarnino)cyclohexyl)-2-(dimethytamino)acetamide A mixture of 2-(dimethylamino)acetic acid (6.05 mg, 0.059 mmol), NMP (0.5 ml), Huenig's Base (0.023 ml, 0.132 mmot), and HATU (24.55 mg, 0.065 mmol) was stirred at ambient temperature for 5 minutes, folowed by addition of N2'-(trans-4-aminocyclohexyl)-5'- chloro-N6-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine (Example 1) (12.5 mg, 0.029 mmol). The resulting mixture was stirred at ambient temperature for 4 hours. The crude reaction mixture mixture was diluted with 0.25 ml of DMSO, filtered, purified by prep LC and then lyapholized to yield 6.8 mg of the title compound, as a TFA sait. LCMS (m/z): 511.3 (MH+), retention time = 0.62 min.; 1H NMR (300 MHz, METHANOL-d4, 25 °C) 6 ppm 1.32 - 1.53 (m, WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 4 H) 1.98 - 2.07 (m, 2 H) 2.07 - 2.18 (m, 2 H) 2.92 (s, 6 H) 3.60 - 3.68 (m, 1 H) 3.70 - 3.82 (m, 1 H) 3.90 (s, 2 H) 4.63 (s, 2 H) 6.83 (d, J=8.79 Hz, 1 H) 6.86 (s, 1 H) 6.93 (d, J=7.03 Hz, 1 H) 6.99 (s, 1 H) 7.10 (d, J=9.67 Hz, 1 H) 7.18 (d, J=7.62 Hz, 1 H) 7.28 - 7.40 (m, 1 H) 7.68 - 7.77 (m, 1 H) 8.01 (s, l H) Example 8 (Compound 8) trans 4-( 5'-ch r -6-(piperidin 4-y -amin )-2 4'-bipyridin-2 -y -amin )cyc hexan Step 1. Preparation of trans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexanol [004201 To 5-chloro-2-fiuoro-4-iodopyridine (600 mg, 2.331 mmol) was added DMSO (2.2 ml), trans-4-aminocyclohexanol (1074 mg, 9.32 mmol) and TEA (0.390 ml, 2.80 mmol). The resulting reaction mixture was stirred at 75 °C for 24 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (1 x), water (Ix), saturated salt solution (Ix), dried over sodium sulfate, filtered and concentrated to yield a crude material. The crude material was purified by silica gel chromatography using a 40g column eluting froml 5%-75% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 750 mg of the title compound as free base, which was used in the next step without further purification. LCMS (m/z): 353.0 (MH+), retention time = 0.56 min. Step 2. Preparation oftrans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)cyclohexanol 1004211 A mixture oftrans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexanol (575 mg, 1.631 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (655 mg, 2.94 mmol), PdCl2 (dppf).CH2 Cl2 adduct (133 mg, 0.163 mmol), DME (15 ml), and t 2M sodium WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 carbonate (4.48 ml, 8.97 mmol) reaction mixture was stirred at 95 °C for 2 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, 15 ml of methanol,, filtered and concentrated to yield a crude product. The crude was purified by silica gel chromatography using a 40g column, eluting from 35%-85% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 440 mg of titled compound as free base. LCMS (m/z): 322.2(MH+), retention time = 0.53 min. Step 3. Preparation of trans-4-(5'-chloro-6-(piperidin-4-yl-amino)-2,4'-bipyridin-2'-ylamino)eyclohexanol A mixture of trans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)cyctohexanot (15.5 mg, 0.048 mmol), DMSO (0.4 ml), and tea-butyl 4-aminopiperidine-l-carboxylate (48.2 mg, 0.241 mmol) reaction mixture was stirred at 105 °C for 40 hr. LCMS indicated formation of the intermediate tea-butyl 4-(5'-chloro-2'-(trans-4-hydroxyeyelohexylamino)-2,4'-bipyridin-6-ytamino)pipeñdine-l-carboxylate (LCMS (m/z): 502.4(MH+), retention time = 0.70 min.). The Boc protecting group was removed from the intermediate by adding HCL 6M aq (140 tl, 0.840 mmol) to the crude reaction mixture mixture, followed by stirring the mixture at 90 °C for minutes. The reaction mixture was cooled, 0.5 ml of DMSO was added, filtered and purified by prep LC. Lyapholization of the material yielded 9.8 mg of the title compound, as a TFA sait. LCMS (m/z): 402.3 (MH+), retention time = 0.41 min.; 1H NMR (300 MHz, METHANOL-d4, 25°C) 6 ppm 1.32 - 1.52 (m, 4 H) 1.71 - 1.87 (m, 2 H) 1.96 - 2.12 (m, 4 H) 2.27 (dd, J=14.21, 3.37 Hz, 2 H) 3.06 - 3.18 (m, 2 H) 3.39 - 3.50 (m, 2 H) 3.54 - 3.68 (m, 2 H) 4.05 - 4.17 (m, 1 H) 6.72 (d, J=8.50 Hz, 1 H) 6.90 (d, J=7.33 Hz, 1 H) 7.00 (s, 1 H) 7.56 - 7.64 (m, I H) 8.01 (s, I H) Example 9 (Compound 9) N-(trans-4-(amin methy )cyc hexy )-5'-eh r -6-(3u r benzy xy)-2 4'-bipyridin-2'-amine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 1. Preparation of 2-bromo-6-(3-fiuorobenzyloxy)pyridine To 2-bromo-6-fluoropyridine (176 mg, 1.000 mmol) was added DMF (1.5 ml) and (3-fluorophenyl)methanol (139 mg, 1.100 mmol) and cesium carbonate (391 mg, 1.200 mmol), and the resulting mixture reaction mixture was stirred at 95 °C for 6 hr, as the progress of the reaction mixture was followed by LCMS. The reaction mixture mixturre was cooled to room temperature, diluted wiht 120 mi of ethyl acetate, washed with saturated sodium bicarbonate (lx), water (lx), saturated salt solution (lx), dried over sodium sulfate, filtered and concentrated to yield a crude product which was purified by silica gel chromatography using a12g column eluting from 0%-20% ethyl acetate with hexane. The desioed fractions were combined and concentrated to constant mass, giving 156 mg of the title compound as a free base. LCMS (m/z): 282.0/284.0 (MH+), retention time = l. 19 min. Step 2. Preparation of 5'-chloro-2'-fluoro-6-(3-fluorobenzyloxy)-2,4'-bipyridine 100424] A mixture of 2-bromo-6-(3-fluorobenzyloxy)pyridine (145 mg, 0.514 mmol), 5-chloro-2-fluoropyridin-4-ytboronic acid (144 mg, 0.822 mmol), PalladiumTetrakis (71.3 mg, 0.062 mmol), DME (3 ml), and t 2M sodium carbonate (1.028 ml, 2.056 mmol) was reaction mixture was stirred at 100 °C for 3 hr, followed by LCMS. The reaction mixture was cooled, diluted wiht 10 ml of ethyl acetate, filtered and concentrated to yield a crude product, which was purified by silica gel chromatography using a 12g column eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 100 mg of titled compound as a free base. LCMS (m/z): 333.1 (MH+), retention time = 1.26 min. WO 2011/012661 CA 02767066 2011-12-30 9O PCT/EP2010/060984 Step 3. Preparation of N-(trans-4-(aminomethyl)cyclohexyl)-5'-chloro-6-(3-fluorobenzyloxy)- 2,4'-bipyridin-2'-amine To 5'-chloro-2'-fluoro-6-(3-fluorobenzyloxy)-2,4'-bipyridine (30 mg, 0.090 mmol) was added DMSO (0.8 ml), TEA (0.025 ml, 0.180 mmol), and tea-butyl (trans-4aminocyclohexyl)methylcarbamate (41.2 mg, 0.180 retool). The reaction mixture was flushed with argon and stirred at 100-105 °C for 40 hr. Formation of the intermediate product tert-butyl (trans-4-(5'-chloro-6-(3-fluorobenzyloxy)-2,4'-bipyridin-2'-ylamino)cyclohexyl)methylcarbamatewas indicated by LCMS. (LCMS (m/z): 541.4 0VIH+), retention time = 1.05 min.). The solvent DMSO was removed under reduce pressure. The Boc group was removed from the intermediate by adding 4M HC1 in Dioxane (1.5 ml, 6.00 mmol), followed with stirring at ambient temperature for 90 minutes. The solvent was removed under reduced pressure. The crude product was dissolved in 1.0 ml of DMSO with 0.075 ml of water, filtered and purified by prep LC. After lyphilization, 28.3 mg of the title compound was obtained as a TFA sait. LCMS (m/z): 441.3(MH+), retention time = 0.76 min.; 1H NMR (300 MHz, METHANOL-d4, 25°C) 6 ppm 1.12 - 1.29 (m, 2 H) 1.29 - 1.47 (m, 2 H) 1.60 - 1.76 (m, J=14.76, 7.51, 3.66, 3.66 Hz, 1 H) 1.92 (d, J=12.60 Hz, 2 H) 2.16 (d, J--10.55 Hz, 2 H) 2.84 (d, J=6.74 Hz, 2H) 3.58 - 3.71 (m, 1 H) 5.43 (s, 2 H) 6.92 - 6.99 (m, 2 H) 6.99 - 7.08 (m, 1 H) 7.18 (d, J=9.67 Hz, 1 H) 7.25 (d, J=7.62 Hz, 1 H) 7.30 - 7.42 (m, 2 H) 7.83 (t, J=7.77 Hz, 1 H) 8.01 (s, 1 H) Example 10 (Compound 10) trans-N -benzy -N4-(4-( 6-(3-flu r benzy amin )pyrazin-2-y )pyridin-2-y )cyc hexane4- diamine H N N« A çx H v WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 1. Preparation of 6-chloro-N-(3-fluorobenzyl)pyrazin-2-amine: To 2,6-dichloropyrazine (175 mg, 1.175 mmol) was added DMSO (1.5 ml), TEA (0.196 ml, 1.410 mmol) and (3fluorophenyl)methanamine (368 mg, 2.94 mmol)l. The reaction mixture then was stirred at 90 °C until completion as indicated by LCMS, about 1 hour. To the reaction mixture was added 3 ml of DMSO, filtered and the residue was purified by prep LC. Airer lyphilization, 160 mg of the title compound was obtained as a TFA. LCMS (m/z): 238.1 (MH+), retention time = 0.96 min. Step 2. Preparation of N-(3-fluorobenzyl)-6-(2-fluoropyridin-4-yl)pyrazin-2-amine: To 6chloro-N-(3-fluorobenzyl)pyrazin-2-amine (140 mg, 0.589 mmol) was added 2-fluoropyridin-4ylboronic acid (125 mg, 0.884 mmol), PalladiumTetrakis (82 mg, 0.071 mmol), DME (3.3 ml), and 2M sodium carbonate (1.031 ml, 2.062 mmol). The resulting reaction mixture was stirred at 110 °C until completion as indicated by LCMS, about 3 hours. The reaction mixture was cooled to room temperature, diluted wiht 20 ml of ethyl acetate, filtered and concentrated to yield a crude solid. The solid was dissolved in DMSO, filtered and purified by prep LC. After lyphilization, 72 mg of the title compound was botained as a TFA sait,. LCMS (m/z): 299.1 (MH+), retention time = 0.89 min. Step 3. Preparation of trans-N 1-(4-(6-(3-fluorobenzylamino)pyrazin-2-yl)pyridin-2yl)cyclohexane1,4-diamine: [004261 To N-(3-fluorobenzyl)-6-(2-fluoropyñdin-4-yl)pyrazin-2-amine (30 mg, 0.101 mmol) was added DMSO (0.6 ml) and trans-cyclohexane-l,4-diamine (115 mg, 1.006 mmol). The reaction mixture then was stirred at 105 °C until completion as indicated by LCMS, about hours. To the crude reaction mixture, after cooling to room temperature mixture was added 0.75 ml of DMSO, the resulting mixture filtered and purified by prep LC. Atter lyphilization, 34 mg of the title compound was obtained as a TFA sait. LCMS (m/z): 393.2 (MH+), retention time = 0.54 min. Step 4. Preparation of trans-Nl-benzyl-N4-(4-(6-(3-fluorobenzylamino) pyrazin-2-yl)pyridin-2yl)cyclohexane1,4-diamine: 1004271 To trans-Nl-(4-(6-(3-fluorobenzyl amino)pyrazin-2-yl)pyridin-2-yl)cyclohexane1,4-diamine (19 mg, 0.048 mmol) was added NMP (0.6 ml), acetic acid (0.042 ml, 0.726 mmol) WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 and benzaldehyde (10.27 mg, 0.097 mmol). The resulting reaction mixture was stirred overnight at ambient temperature. To the srirred reaction mixture was added sodium tñacetoxyborohydride (41.0 mg, 0.194 retool) and the resulting mixture was stirred overnihgt (24 hours) at ambient temperature. To the reaction mixture mixture then was added additional sodium triacetoxyborohydñde (21.0 mg, 0.099 retool) and the resulting mixture was stirred for an additonal 2 more hours. To the crude mixture then was added 0.8 ml of DMSO, filtered and purified by prep LC. After lyphilization, 7.0 mg of the title compound was obtained as a TFA sait. LCMS (m/z): 483.2 (Mid+), retention time = 0.65 rein.; 1H NMR (300 MHz, METHANOL-d4, 25°C) 6 ppm 1.35 - 1.51 (m, 2 H) 1.51 - 1.69 (m, 2 H) 2.04 - 2.36 (m, 4 H) 3.08 - 3.18 (m, l H) 3.56 - 3.70 (m, 1 H) 4.16 (s, 2 H) 4.60 (s, 2 H) 6.82 - 6.93 (m, l H) 7.03 (d, J=9.67 Hz, 1 H) 7.11 (d, J=7.62 Hz, 1 H) 7.19 - 7.29 (m, 1 H) 7.32 (d, J=6.74 Hz, 1 H) 7.35 - 7.46 (m, 5 H) 7.54 (s, 1 H) 7.80 (d, J:6.74 Hz, 1 H) 7.97 (s, 1 H) 8.25 (s, 1 H) Example 11 (Compound 11) N2 (tra s 4-amin cyc hexy )-N6-(3u r benzyl)-4-(tri u r methyl)-2 4'-bipyridine 2' 6 diamine H ",NH2 Step 1. Preparation of 6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyi)pyñdin-2-amine: To 2,6-dichloro-4-(trifluoromethyl)pyridine (250 mg, 1.157 mmol) was added DMSO (2 ml), TEA (0.194 ml, 1.389 retool), and (3-fluorophenyi)methanamine (290 mg, 2.315 mmol). The reaction mixture was stirred at 90 °C until completion as indicated by LCMS, about 1 hour. To the crude reaction mixture was added 1.5 mi of DMSO, filtered and purified by prep LC. After lyphilization, 158 mg of the title compound was obtained as a TFA sait. LCMS (m/z): 305.1 (MH+), rt=- 1.21 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 2. Preparation of 2'-fluoro-N-(3-fluorobenzyt)-4-(trifluoromethyl)-2,4'-bipyridin-6-amine: [004291 To 6-chlom-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyñdin-2-amine (70 mg, 0.230 mmol) was added 2-fluoropyridin-4-ylboronic acid (58.3 mg, 0.414 mmol), PdCl2(dppf).CH2Cl2 adduct (22.52 mg, 0.028 mmot), DME (1.2 ml), and 2M sodium carbonate (0.460 ml, 0.919 mmol). The resulting reaction mixture was stirred at 105 °C until completion as indicated by LCMS, about 6 hours. The reaction mixture was cooled, 15 mi of ethyl acetate and 5 ml of methanol was added, filtered and concentrated to yield a crude solid. The solid was purified by prep LC. The product was free-based using 200 ml of ethyl acetate and washed with saturated sodium bicarbonate (Ix), water (2x), saturated sait solution (Ix), dried sodium sulfate, filtered and concentrated to a constant mass, yielding 35 mg of titled compound as free base. LCMS (m/z): 366.2 (MH+), retention time = t.20 min. Step 3. preparation of N2'-(trans-4-aminocyctohexyl)-N6-(3-fluorobenzyl)-4-(trifluoromethyl)- 2,4'-bipyridine-2',6-diamine: To 2'-fluom-N-(3-fluorobenzyt)-4-(tñfluoromethyl)-2,4'-bipyridin-6-amine (34 mg, 0.093 mmol) was added DMSO (1.7ml) and trans-cyctohexane-l,4-diamine (159 mg, t.396 mmol). The resulting reaction mixture was stirred at 105 °C until completion as indicated by LCMS, about 40 hours. To the crude reaction mixture was added 0.75 ml of DMSO, filtered and purified by prep LC. After lyphilization, 28. t mg of the title compound was obtained as a TFA sait. LCMS (m/z): 460.3 (MH+), retention time = 0.72 min.; 1H NMR (300 MHz, METHANOL-d4, 25°C) ì5 ppm 1.40 - 1.72 (m, 4 H) 2.18 (t, J=13.77 Hz, 4 H) 3.11 - 3.24 (m, ]H) 3.62 - 3.76 (m, 1 H) 4.72 (s, 2 H) 6.95 (s, 1 H) 7.12 (d, J=9.96 Hz, 1 H) 7.17 - 7.24 (m, 1 H) 7.27 - 7.37 (m, 1 H) 7.40 (s, 1 H) 7.42 - 7.48 (m, 1 H) 7.69 (s, 1 H) 7.87 (d, J=6.74 Hz, 1 H) Example 12 (Compound t 2) N2 -( tr ans-4-amin cy c hexy )- 5 -ch r - 5u r -N6-( 3u r be nzy )- 2 4 -bipyridine2 6diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 1. Preparation of 3,6-difluoro-N-(3-fluorobenzyl)pyridine-2-amine: 2,3,6-trifluoropyridine (1.07 mL, 1.5 g, 11.27 mmol), 3-fluorobenzylamine (3.18 mL, 3.53 g, 28.2 mmol), and triethylamine (4.71 mL, 3.42 g, 33.8 mmol) were dissolved inNMP (39 mL) to form a mixture This mixture reaction mixturewas stirred at 100°C for 1 hr. The reaction mixture was then extracted with EtOAc (3 x 75 mL). The combined extracts were washed with H2 0 (4 x 75 mL) followed by brine (1 x 75 mL). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 100 hexanes to 30 EtOAc / 70 hexanes yielded 2.63 g (98%)of 3,6-difluoro-N-(3-fluorobenzyl)pyridine-2-amine. LCMS (m/z): 239.1 (MH+), retention time = 1.01 min. [004321 Step 2. Preparation of 3-fluoro-N-(3-fluorobenzyl)-6-methoxypyridin-2-amine: 3,6-difluoro-N-(3-fluorobenzyl)pyridine-2-amine (0.5209 g, 2.19 mmol), was dissolved in anhydrous MeOH ( 6.6 mL) and placed under argon. This mixture then was treated with sodium methoxide (0.500 mL, 0.473 g, 2.19 mmol, 25% in MeOH) by slow addition. The resulting mixture was then heated in the microwave at 150°C for four 30 min. The reaction mixture was then poured into brine (25 mL). This mixture was extracted with EtOAc (3 x 25 mL), the combined extracts were washed with brine (1 x 25 mL) and dried (Na2 SO4 ). After filtration the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 100 hexanes to 25 EtOAc / 75 hexanes afforded 0.3408 g (62%) of 3-fluoro-N-(3-fluorobenzyl)-6-methoxypyridin-2-amine. LCMS (m/z): 251.1 (MH+), retention time = 1.07 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 3. Preparation of5-fluoro-6-(3-fluorobenzylamino)pyridine-2-oh 3-fluoroN-(3-fluorobenzyl)-6-methoxypyridin-2-amine (0.100 g, 0.400 mmol) was dissolved in anhydrous CH3 CN (I .6 mL). This mixture was treated with sodium iodide (0.301 g, 2.01 mmol) followed by trímethylsilylchloride (0.257 mL, 0.218 g, 2.01 mmol). The resulting reaction eaction mixturewas then heated at reflux for 2 hr. The reaction mixture was then treated with MeOH (1 ml), and the resulting mixture was stirred at ambient temperature for 2 hr, and then concentrated in vacuo. The resulting residue was dissolved in EtOAc (25 ml) and partitioned with H2 0 (25 ml). The H2 0 layer was extracted with EtOAc (2 x 25 ml). The organic layers were combined and washed with brine (1 x 25 ml). The organic layer was dried (Na2 SO4 ), filtered, and the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 10 EtOAc / 90 hexanes to 60 EtOAc / 40 hexanes gave 0.060 g (64%) of5-fluoro-6-(3-fluorobenzylamino)pyridine-2-ol. LCMS (m!z): 237.2 (MH+), retention time = 0.74 min. Step 4. Preparation of 5-fluoro-6-(3-fluorobenzylamino)pyridine-2-yl tñfluoromethanesutfonate 100434] 5-fluoro-6-(3-fluorobenzylamino)pyridine-2-ol (0.060 g, 0.254 mmol) was dissolved in anhydrous CH2 C12 (2.0 mL) and placed under argon. The solution was cooled to 0°C in an ice bath. It was then treated with triethylamine (0.096 mL, 0.070 g, 0.691 mmol) followed by dropwise addition oftrifluoromethanesulfonic anhydride (0.058 mL, 0.096 g, 0.340 mmol). Once the addition was complete, the reaction mixture was stirred at 0°C for 2 hr. The reaction mixture was then poured into saturated NaHCOa (25 mL). This mixture was extracted with EtOAc (2 x 25 mL). The combined extracts were washed with brine (1 x 25 mL), dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 5 EtOAc / 95 hexanes to 60 EtOAc / hexanes yielded 0.081 g (87%) of 5-fluoro-6-(3-fluorobenzylamino)pyridine-2-yl trifluoromethanesulfonate. LCMS (m/z): 369.1 (MH+), retention time = t. 15 min. Step 5. Preparation of 5'-chloro-2',5-difluoro-N-(3-fiuorobenzyl)-2,4'-bipyridin-6-amine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 5-fluoro-6-(3-fluorobenzylamino)pyridine-2-yl trifluoromethanesulfonate (0.0811 g, 0.220 retool), 5-chloro-2-fluoropyridin-4-ylboronic acid (0.116 g, 0.661mmol), and sodium carbonate (0.286 mL, 0.573 retool, 2M in H2 0) were dissolved in DME (2 mL). The solution was then degassed by sparging with argon for 5 rein. It was then treated with PdCl2 (dppf) CH2CI2 adduct (0.036 g, 0.044 mmol). The reaction mixture was then heated in the microwave at 120°C for 10 min. The reaction mixture was then filtered through a pad of Celite. The filtrate was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 5 EtOAc / 95 hexanes to 60 EtOAc / 40 hexanes yielded 0.044 g (57%) of 5'-chloro-2',5-difluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6-amine. LCMS (m/z): 350.0 (MH+), retention time = 1.16 rein. Step 6. Preparation of N2'-(trans-4-aminocyclohexyl)-5'-chloro-5-fluoro-N6-(3-fluorobenzyl)- 2,4'-bipyridine-2',6-diamine 5'-chloro-2',5-difluom-N-(3-fluorobenzyl)-2,4'-bipyridin-6-amine (0.022 g, 0.063 mmol) was dissolved in anhydrous DMSO (0.93 mL) and charged to a microwave vial, and then treated with trans-cyclohexane-l,4-diamine (0.072 g, 0.629 mmol). The reaction mixture then was heated at 100°C for 18 hr. The material was purified by preparative reverse-phase HPLC to yield 0.0151 g (44%) of NZ-(trans-4-aminocyclohexyl)-5'-ehlom-5-fluoro-N6-(3-fluorobenzyl)- 2,4'-bipyñdine-2',6-diamine as the TFA sait. LCMS (m/z): 444.2 (MH+), retention time = 0.7 rein. Example 13 (Compound 13) 2'-(( I r, 4r)-4-am n cyc hexy amin )-5'- h r -6-(3-flu r benzy amin )-2 4 -bipyridine-5carbonitrile WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H r..: N Step 1. Preparation of 6-chloro-2-(3-fluorobenzylamino)nicotinonitrile 2,6-dichloronicotinonitfile (0.500 g, 2.89 mmol), (4-fluorophenyl)methanamine (0.816 mL, 0.904 g, 7.23 mmol), and tfiethylamine (1.21 mL, 0.877 g, 8.67 mmol) were ail mixed in NMP (10 mL). The resulting solution then was heated at 50°(2 for t8 hr. The reaction mixture was then poured in H2 0 (25 mL), and extracted with EtOAc (3 x 25 mL). The combined extracts were washed with H2 0 (4 x 25 mL), and brine (1 x 25 mL). The organic layer was separated and dried (Na2 SO4 ), filtered, and the solvent removed in vacuo. The resulting residue was purified using silica gel column chromatography. Etution using 1 EtOAc / 3 hexanes to 3 EtOAc / 1 hexanes afforded 0.6024 g (80%) of 6-chloro-2-(3fluorobenzytamino)nicotinonitrile. LCMS (m/z): 350.0 (MH+), retention time - 0.96 min. IH NMR (300 MHz, CDC13 ) 6 4.58(d, J=5.86 Hz, 2 H) 5.48 (br. s., 1 H) 6.30 (d, J=8.50 Hz, 1 H) 6.96 - 7.06 (m, 2 H) 7.10 (d, J=7.62 Hz, t H) 7.28 - 7.38 (m, l H) 7.58 (d, J=8.79 Hz, 1 H). Step 2. Preparation of 5'-chloro-2'-fluoro-6-(3-fluorobenzylamino)-2,4'-bipyridine-5-carbonitrile [004381 6-chloro-2-(3-fluorobenzytarnino)nicotinonitrile (0.602 g, 2.30 mmol), 5-chloro2-fluoropyridin-4-ylboronic acid (1.21 g, 6.91 mmol), and sodium carbonate (2.99 mL, 5.99 mmol, 2M in H2 0) were dissolved in DME (10.5 mL). The resulting solution was then degassed by sparging with argon for 5 min. It was then treated with PdCt2 (dppf) CH2 C12 adduct (0.376 g, 0.460 mmol). The resulting reaction mixture was heated in the microwave at 120°t2 for 10 min. It was then filtered through a pad of Cetite. The filtrate was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 5 EtOAc / 95 hexanes to 50 EtOAc / 50 hexanes yielded 0.2689 g (33%) of 5'-chloro-2'-fluoro-6-(3WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 fluorobenzylamino)-2,4'-bipyridine-5-carbonitrile. LCMS (m/z): 357.2 (MH+), retention time = 1.02 min. Step 3. Preparation of 2'-((1r, 4r)-4-amonocyclohexylamino)-5'-chtoro-6-(3fluorobenzylamino)-2,4'-bipyridine-5-carbonitrile [004391 5'-chloro-2'-fluoro-6-(3-fluorobenzytamino)-2,4'-bipyridine-5-carbonitrile (0.2689 g, 0.754 mmol) was dissolved in anhydrous DMSO (l 1.0 mL) and charged to a microwave vial. This mixture was treated with trans-cyclohexane-l,4-diamine (0.861 g, 7.54 mmol), and the reaction mixture was then heated at 100°C for 5 hr. The reaction mixture mixture was cooled to ambient temperature, and the material was purified by preparative reversephase HPLC and freebased to yield 0.253 9 g (75%) of 2'-((1 r, 4r)-4-amonocyclohexylamino)-5'- chloro-6-(3-fluorobenzylamino)-2,4'-bipyddine-5-carbonitrile. LCMS (m/z): 451.2 (MH+), retention time = 0.67 min. Example 14 (Compound 14) 2'-((t r, 4r)-4-amin cy hexy amin )-5'-ch r -6-(3-flu r benzy amin )-2 4'-bipyridine-5carboxamide H N N« Step 1. Preparation of 2'-((t r, 4r)-4-aminocyclohexylamino)-5'-chloro-6-(3-fluorobenzylamino)- 2,4'-bipyridine-5-carboxamide 2'-(( t r, 4r)-4-amonocyclohexyl amino)-5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridine-5carbonitrite (0.028 g, 0.055 mmol) was dissolved in DMSO (0.5 mL), and the solution was WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 cooled to 0°C in an ice bath. The cooled solution was treated with potassium carbonate (0.0011 g, 0.0078 mmol) followed by hydrogen peroxide (0.007 mL, 0.0069 mmol). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 2 hr. More of the reagents in the same amounts were added and the reaction mixture was heated to 50°C for 16 hr. This procedure was repeated and the reaction mixture was heated at 65°C for an additional 4 hr. The reaction mixture was diluted with brine (10 mL), extracted with EtOAc (3 x 10 mL), the combined extracts were washed with brine (1 x l0 mL) and dried (Na2 SO4 ), filtered and concentrated in vacuo. The material was purified by preparative reverse-phase HPLC to afford 0.0042 g (13%) of 2'-((1 r, 4r)-4-aminocyclohexylamino)-5 '-chloro-6-(3-fluorobenzylamino)- 2,4'-bipyridine-5-carboxamide as the TFA sait. LCMS (m/z): 469. l (MH+), retention time = 0.56 min. Example 15 (Compound 15) 2 -( tr asses-amin c y c he x y amin )- 5 -ch r 6-( 3 u r benzy amine )- 2 4 '-b ip yri dine-4carbonitrile H "'NH2 NC Step 1. Preparation of 2-chloro-6-(3-fluorobenzylamino)isonicotinonitrile To a scintillation vial containing 2,6-dichloroisonicotinonitrile (500 mg, 2.89 mmol) was added NMP (6 ml) and (3-fluorophenyl)methanamine (868 mg, 6.94 mmol). The homogenous reaction mixture was capped and heated to 110 °C in a oil bath for 1 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3 , H2 0 and sat NaC1. The organic layer was dried Na2 SO4 , filtered and concentrated.The crude residue was purified by column chromatography on silica gel (0-20%EtOAc/Hexane) to give 2-chloro-6-(3WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 fluorobenzylamino)isonicotinonitrile (750 mg, 95%). LCMS (m/z): 262.0 (MH+), retention time = 1.03 min. Step 2. Preparation of 5'-chloro-2'-fluoro-6-(3-fluorobenzylamino)-2,4'-bipyridine-4-carbonitrile To a degassed suspension of 2-chloro-6-(3-fluorobenzylamino) isonicotinonitrile (150 mg, 0.573 mmol) and 5-chloro-2-fluoropyridin-4-ylboronic acid (151 mg, 0.860 mmol) in DME (5 ml) was added Na2 CO3 (1.433 ml, 2M, 2.87 mmol) and Pd(Ph3 P)4 (66.2 mg, 0.057 mmol). The reaction mixture was capped and heated to 110 °C in an oil bath for 2 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3 , and then sat NaC1. The organic layer was dñed over Na2SO4, filtered and concentrated. The resulting residue was purified purified by column chromatography on silica gel (0-20%EtOAc/Hexane) to give 5'- chloro-2'-fluoro-6-(3-fluorobenzylamino)-2,4'-bipyridine-4-carbonitrile (95 mg, 47%). LCMS (m/z): 357.0 (MH+), retention time = 1.09 min Step 3. Preparation of 2'-(trans-4-arrfinocyclohexylamino)-5'-chloro-6-(3-fluorobenzylamino)- 2,4'-bipyridine-4-carbonitrile [004421 To a scintillation vial containing 5'-chloro-2'-fluoro-6-(3-fluorobenzylamino)-2,4'- bipyñdine-4-carbonitrile (72 mg, 0.202 mmol) was added DMSO (3 ml) and trans-cyclohexane1,4-diamine (230 mg, 2.018 mmol). The homogenous yellow reaction mixture was capped and heated to 105 °C in a oil bath for 3 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3 , sat NaCI. The organic layer was dried Na2 SO4 , filtered and concentrated.The crude solid was puñfied by Prep HPLC and the collected fractions were combined and diluted with EtOAc and neutralized with sat NaHCO3 and then sat NaC1. The organic layer was dried over Na2 SO4 , filtered and concentrated to afford 2'-(trans-4-aminocyclohexylamino)-5'-chloro6-(3-fluorobenzylamino)-2,4'-bipyridine-4-carbonitñle (73 mg, 80%). LCMS (m/z): 451.2 (MH+), retention time = 0.70 min. IH NMR (400 MHz, METHANOL-d4) d ppm 1.34 - 1.48 (m, 2 H) 1.50 - 1.64 (m, 2 H) 2.06 - 2.22 (m, 4 H) 3.08 - 3.20 (m, 1 H) 3.63 - 3.74 (m, 1 H) 4.61 (s, 2 H) 6.81 (s, 1 H) 6.87 (s, 1 H) 6.91 - 6.99 (m, 1 H) 7.02 (s, 1H) 7.04 - 7.10 (m, 1 H) 7.12 - 7.18 (m, 1 H) 7.25 - 7.36 (m, 1 H) 8.00 (s, 1 H). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Examples 16 and 17 (Compounds 16 and 17) 2 (tra s-4-amin cyc hexy amin )-5'-ch r -6-(3u r benzy amin )-2 4 -bipyridine-4carboxamide & 2'-(trans-4-aminocyclohexylamino)-5'-chloro-6-(3-fluorobenzylamino)-2,4'- bipyñdine-4-carboxylic acid H íN.>. N,,. I o .y o.ç H Step 4. Preparation of 2'-(trans-4-aminocyclohexylamino)-5'-chloro-6-(3fluorobenzylamino)-2,4'-bipyñdine-4-carboxamide: To a scintillation vial containing 2'-(trans-4amin y hexy amin )-5 - h r -6-(3-f u r benzy amin )-2 4'-bipyridine-4arb nitri e (11 mg, 0.024 mmol) and K2 CO3 (33.7 mg, 0.244 mmol) at 0 °C was added DMSO (1 ml) and H2 02 (10.68 lxl, 0.122 mmol). The reaction mixture was capped and stirred at 0 °C for 10 min and rt for 10 min. The reaction mixture was diluted with EtOAc and washed with H2 0, sat NaCI. The organic layer was dried over Na2 SO4 , filtered and concentrated. The crude oil/solid was purified by reverse phase preparative HPLC to yield a TFA sait of 2'-(trans-4-aminocyclohexylamino)-5'- chloro-6-(3-fluorobenzylamino)-2,4'-bipyridine-4-carboxamide (3.5 mg, 25% ), LCMS (m/z): 469.2 (MI-I+), retention time = 0.56 min and 2'-(trans-4-aminocyclohexylamino)-5'-chloro-6-(3fluorobenzylamino)-2,4'-bipyridine-4-carboxylic acid (3.2 mg, 22%), LCMS (m/z): 470.2 (MH+), retention time = 0.61 rein. Example 18 (Compound 18) h r -N2 -(trans-4 (dimethy amin )cyc hexy1)-N6-(3u r benzy )-2 4'-bip yridine-2 6diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H |00444] Step 1. Preparation of 5'-chloro-N2'-(trans-4-(dimethylamino)cyclohexyl)-N6-(3fluorobenzyl)-2,4'-bipyridine-2',6-diamine: To a scintillation vial containing N2'-(trans-4aminocyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine (7 mg, 0.016 retool) and formaldehyde (6.12 III, 0.082 mmol) was added MeOH (0.3 ml) and Pd/C (5.25 mg, 4.93 lamol). The reaction mixture was stirred under hydrogen at room temperature for 16 hours. The reaction mixture mixture was filtered over celite and concentrated. The crude solid was purified by reverse phase preparative HPLC to yield 5'-chloro-N2'-(trans-4- (dimethylamino)cyclohexyl)-N6-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine (2.0 mg, 24%). LCMS (m/z): 454.2 (MH+), retention time = 0.61 min. as a TFA salt after lypholyzing. Example 19 (Compound 19) 2-( trans-4-( 5'-chloro-6-( 3fluorobenzylamino )-2,4 '-bip yridin-2'-yl-amino ) cyclohexylamino)ethanol H I.,: N H [004451 Step 1. Preparation ofN2'-(tra,s-4-(2-(tert-butyldimethylsilyloxy) ethylamino) cyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'-bipyñdine-2',6-diamine: To a scintillation vial containing N2'-(trans-4-amin cyc hexy )- 5 - h r -N6-(3-flu r benzy )-2 4'-bipy dine-2 6diamine (17 mg, 0.040 mmol) and K2 CO3 (22.06 mg, 0.t60 mmol) was added DMF (0.3 ml) and WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 (2-bromoethoxy)(tert-butyl)dimethylsilane (9.55 mg, 0.040 mmol). The reaction mixture was capped and heated to 75 °C for 7hr. The reaction mixture was diluted with DCM and washed with I-I2 0, sat NaCI. The organic layer was dried over Na2 SO4 , filtered and concentrated. The crude solid was purified by reverse phase preparative HPLC. Collected fractions were combined, neutralized with Saturated NaHCO3 and extracted with EtOAc. The organic layer was dñed over Na2SO4, filtered, concentrated and used directly in next step. LCMS (m/z): 584.3 (MH+), retention time = 0.87 min. [004461 Step 2. Preparation of 2-(trans-4-(5'-chlom-6-(3-fluorobenzylamino)-2,4'- bipyridin-2'-yl-amino) cyclohexylamino)ethanol: To a scintillation vial containing N2'-(trans-4- (2-(tert-butyldimethylsilyloxy) ethylamino) cyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'- bipyridine-2',6-diamine (from step 1) was added THF (0.300 ml) and TBAF (0.160 mi, 0.319 mmol). The homogenous reaction mixture was capped, and stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and purified by reverse phase preparative HPLC to yield 2-(trans-4-( 5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyddin-2'-yl-amino) cyclohexylamino)ethanol (2.2 mg, 9%). LCMS (m/z): 470.3 (MI-i+), retention time = 0.58 min as a TFA sait atter lypholyzing. IH NMR (400 MHz, METHANOL-d4) 6 ppm 1.31 - 1.46 (m, 2 H) 1.51 - 1.67 (m, 1 H) 2.21 (d, J=10.56 Hz, 2H) 3.11 - 3.20 (m, 2 H) 3.66 - 3.77 (m, 1 H) 3.77 - 3.83 (m, 1 H) 4.62 (s, 1 H) 6.74 (s, 1 H) 6.78 - 6.84 (m, IH) 6.87 - 6.92 (m, 1 H) 6.96 - 7.03 (m, 1 H) 7.08 - 7.14 (m, 1 H)7.15-7.21 (m, 1 H)7.31 -7.38(m, 1 H) 7.687.76 (m, 1H)8.02(s, 1 H). Examp!ç20 (Compound 20) 5'-chloro-N6-(3-fluorobenzyl)-N2'-(trans-4-(2-(methylsulfonyl) ethylamino) cyctohexyl)-2,4'- bipyridine-2',6-diamine H WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step l. Preparation of 2-(methylsulfonyl)ethyl methanesulfonate: To a roundbottom flask containing 2-(methylsulfonyl)ethanol (400 mg, 3.22 retool) at 0 °C was added DCM (10 ml) and triethylamine (4.91 BI, 0.035 mmol), followed by dropwise addition ofmesyl chloride (2.96 mg, 0.026 mmol). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 2 hr. The reaction mixture was diluted with DCM and washed with sat NaHCO3 and then sat NaCI. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified via ISCO(0-60% EtOAc/Hexane) to yield 2- (methylsulfonyl)ethyl methanesulfonate (400 mg, 61%). LCMS (m/z): 203.0 (MH÷), retention time = 0.37 min. Step 2. Preparation of 5'-chloro-N6-(3-fluombenzyl)-N2'-(trans-4-(2- (methylsulfonyl)ethylamino) cyclohexyl)-2,4'-bipyridine-2',6-diamine: To a scintillation vial containing N2'-(trans-4-amin cyc hexy )-5 - h r -N6-(3-f u r benzy )-2 4 -bipyridine-2' 6diamine (10 mg, 0.023 mmol) and K2CO3 (8 mg, 0.058 mmol) was added DMSO (0.5 ml) and 2-(methylsulfonyl)ethyl methanesulfonate (30 mg). The reaction mixture was capped and heated to 120 °C in an oil bath for 4 hr. The resulting solution was purified by by reverse phase preparative HPLC to yield 5'-chloro-N6-(3-fluorobenzyl)-N2'-(trans-4-(2- (methylsulfonyl)ethylamino)cyclohexyl)-2,4'-bipyridine-2',6-diamine (3.7 mg, 24%). LCMS (m/z): 532.2 (MH+), retention time = 0.62 min as a TFA sait after lypholyzing. Example 21 (Compound 21) 5'-ch r -N6-( 3u r benzy )-N2'-( trans-4-(methy amin )cyc hexyl)-2 4 '-bipyridine-2 6diamine H CI WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step l. Preparation of (1 s,4s)-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'- bipyridin-2'-yl-amino)cyclohexyl methanesulfonate: To a round-bottom flask containing (l s,4s)- 4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino)cyclohexanol (obtained following example 2) (85 mg, 0.199 mmol) at 0 °C was added DCM (2 ml) and tdethylamine (0.042 ml, 0.299 mmol), followed by dropwise addition of Mesyl Chloride (0.020 ml, 0.259 mmol). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 2 hr. The reaction mixture was diluted with DCM and washed with sat NaHCO3 , and then sat NaCl. The organic layer was dried over Na2 SO4 , filtered and concentrated to yield (ls,4s)-4-(5'- chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino) cyclohexyl methanesulfonate (90 mg, 90 % yield), LCMS (m/z): 505.3 (MH+), retention time = 0.77 min. The resulting residue was used in next step without further purification. Step 2. Preparation of 5'-chloro-N6-(3-fluorobenzyl)-N2'-(trans-4-(methylamino) cyclohexyl)- 2,4'-bipyridine-2',6-diamine: 100450] To a scintillation vial containing (I s,4s)-4-(5'-chloro-6-(3-fluorobenzylamino)- 2,4'-bipyridin-2'-yl-amino)cyclohexyl methanesulfonate (20 mg, 0.040 mmol) was added MeOH (1 ml) and methyl amine (0.594 ml, 2M, 1.188 mmol). The reaction mixture was capped and heated to 70 °C in a oil bath for 16 hr. Solvent was evaporated and recharge the vial with 0.6 ml 30% methyl amine in ethanol. After heating at 70 °C for another 6 hr, the reaction mixture was concentrated and purified by reverse phase preparative HPLC to yield 5'-chloro-N6-(3- u r benzy )-N2'-(trans-4-(methy amin )cy hexy )-2 4'-bipyridine-2' 6-diarr ne (6.5 mg, 0.015 mmol, 37.3 %), LCMS (m/z): 440.3 (MH÷), retention time = 0.61 min and 5'-chloro-N2'- (cyclohex-3-enyl)-N6-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine (3.5 mg, 22%)LCMS (m/z): 409.2 (MI-l+), retention time = 0.82 min. IH NMR (400 MHz, METHANOL-d4) 6 ppm 1.32 - 1.46 (m, 2 H) 1.47 - 1.62 (m, 2 H) 2.20 (d, J=l 1.35 Hz, 4H) 3.01 - 3.11 (m, 1 H) 3.67 - 3.78 (m, 1 H) 4.64 (s, 2 H) 6.81 (s, 1 H) 6.88 - 6.97 (m, 3 H) 6.97 - 7.05 (m, 1H) 7.08 - 7.14 (m, 1 H) 7.16 - 7.22 (m, 1 H) 7.31 - 7.41 (m, 1 H) 7.75 - 7.83 (m, 1 H) 8.05 (s, 1 H). Example 22 (Compound 22) WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 ch r -N6-(3u r benzy )-N2'-(tra s-4-((methy amin )methy ) y hexy )-2 4'-bipyridine2',6-diamine H I N..< Ne/"-.. Step 1. Preparation of (trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-ylamino) cyclohexyl)methyl methanesulfonate: 1004511 To a round-bottom flask containing (trans-4-(5'-chloro-6-(3-fluorobenzylamino)- 2,4'-bipyridin-2'-yl-amino)cyclohexyl) methanol (obtained following example 2) (102 mg, 0.231 mmol) at 0 °C was added DCM (2 ml) and triethylamine (0.048 ml, 0.347 mmol), followed by dropwise addition of Mesyl Chloride (0.023 ml, 0.301 mmol). The ice bath was removed and the reaction mixture was stirred at rt for 2 hr. The reaction mixture was diluted with DCM and washed with sat NaI-ICO3 and then sat NaCI. The organic layer was dried over Na2 SO4 , filtered and concentrated to yield (trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-ylamino)cyclohexyl)methyl methanesulfonate (110mg, 92 % yield), LCMS (m/z): 519.2 (MH+), retention time = 0.80 min. The resulting residue was used in next step without further purification. [004521 Step 2. Preparation of 5'-chloro-N6-(3-fluorobenzyl)-N2'-(trans-4-((methylamino) methyl)cyclohexyl)-2,4'-bipyridine-2',6-diamine: To a scintillation vial containing (trans-4-(5'- chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino)cyclohexyl) methyl methanesulfonate (15 mg, 0.029 retool) was added MeOH (1 ml) and a solution of methyl amine (0.144 ml, 0.289 mmol) in MeOH. The reaction mixture was capped and heated to 70 °C in a oil bath for 16 hr. The resulting solution was concentrated and purified by reverse phase preparative HPLC to yield 5'-chloro-N6-(3-fluorobenzyl)-N2'-(trans-4-((methylamino) methyl)cyclohexyl)-2,4'-bipyñdineWO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 2',6-diamine (8.6 mg, 52%), LCMS (m/z): 454.2 (MH+), retention time = 0.64 min as a TFA salt after lypholyzing. IH NMR (400 MHz, METHANOL-d4) ì5 ppm 1.15 - 1.29 (m, 2 H) t.29 - 1.42 (m, 2 H) 1.67 - 1.80 (m, 1 H) 1.86 - 1.96 (m, 2 H) 2.09 - 2.21 (m, 2 H) 2.71 (s, 3 H) 2.90 (d, J=7.04 Hz, 2 H) 3.58 - 3.70 (m, 1 H) 4.63 (s, 2H) 6.88 (s, 2 H) 6.94 (d, J=7.43 Hz, I H) 6.96 - 7.03 (m, 1 H) 7.07 - 7.13 (m, 1 H) 7.15 - 7.21 (m, 1 H) 7.29 -7.39 (m, 1 H) 7.69 - 7.78 (m, I H) 8.01 (s, 1 H). Example 23 (Compound 23) -ch r -N6-(3,5-di u r benzy )-N2'-(trans-4-(pyrr idin- -y )cyc hexy )-2 4'-bipyridine-2' 6diamine H o, F Step 1. Preparation of 5'-chloro-N6-(3,5-difluorobenzyl)-N2'-(trans-4-(pyrrolidinl-yl)cyclohexyl)-2,4'-bipyridine-2',6-diamine : To a scintillation vial containing N2'-(trans-4aminocyclohexyl)-5'-chloro-N6-(3,5-difluorobenzyl)-2,4'-bipyñdine-2',6-diamine ( 12.3 mg, 0.028 mmol) (obtained following example 2) and K2 CO3 (15.32 mg, 0.111 mmol) was added DMSO (0.5 ml) and 1,4-dibromobutane (5.98 mg, 0.028 mmol). The reaction mixture was capped and heated at 60 °C for 7 hr. The reaction mixture was diluted with DCM and washed with H2 0, sat NaCI. The organic layer was dried over Na:SO4 , filtered and concentrated. The crude solid was purified by reverse phase preparative HPLC to yield 5'-chloro-N6-(3,5difluorobenzyl)-N2'-(trans-4-(pyrrolidin1-yl)cyclohexyl)-2,4'-bipyridine-2',6-diamine (7.8 mg, 46.0 %), LCMS (m/z): 498.3 (MH+), retention time = 0.65 min as a TFA salt after lypholyzing. IH NMR (400 MHz, METHANOL-d4) 6 ppm 1.26 - 1.40 (m, 2 H) 1.48 - 1.62 (m, 2 H) 1.85 - WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1.98 (m, 2 H)1.99 - 2.24 (m, 7 H) 2.99 - 3.14 (m, 4 H) 3.51 - 3.68 (m, 3 H) 4.54 (s, 2 H) 6.69 - 6.80 (m, 3 H) 6.81 - 6.90 (m, 3 H) 7.60 - 7.69 (m, 1 H) 7.94 (s, 1 H). Example 24 (Compounds 256 + 257) N2 -trans-4 amin eyc hexy )-5'-ch r -N6-(((R) 2 2-dimethy tetrahydr -2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine and N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(((S)- 2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine H "N H2 Step 1: Preparation of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(((R/S)-2,2dimethyltetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine 100454] A mixture of (R/S)-5'-chloro-N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)- 2'-fluoro-2,4'-bipyridin-6-amine (35 mg, 0.100 mmol), trans-cyclohexane-l,4-diamine (91 mg, 0.800 mmol), DIPEA (20.25 mg, 0.200 mmol) in DMSO (0.35 mL) was heated at 109 °C for 16 hr. The mixture was diluted with DMSO, filtered through a syringe filter and purified by HPLC to give N2'- (trans-4-aminocyelohexyl)-5'-chloro-N6 -(((R/S)-2,2dimethyltetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine as its trifluoroaeetic acid salt. Yield: 29 mg. LCMS (m/z): 444.2 [M+H]+; Retention time = 0.51 min. N2'-(trans-4-amin cyc hexy )-5'-ch r -N6-(((R)-2 2-dimethy tetrahydr -2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine and N2'-(trans-4-aminocyelohexyl)-5'-ehloro-N6-(((S)- 2,2-dimethyltetrahydro-2H-pymn-4-yl)methyl)-2,4'-bipyridine-2',6-diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1004551 N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(((R/S)-2,2-dimethyltetrahydro-2Hpyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine trifluoroacetic acid sait was dissolved in MeOH (2 mL) and filtered through VariPure(TM)IPE [500 mg per 6 mL tube; 0.9 mmol (nominal); part no.: PL3540-C603VP], eluted with MeOH (6 mL) and concentrated in vacuo providing N2'- (trans-4-amin ye hexy )-5'- h r -N6-(((R/S)-2 2-dimethy tetrahydr -2H-pyran-4-y )methy )- 2,4'-bipyñdine-2',6-diamine as a colorless oil. Yield: 20 mg. The enantiomers were resolved by chiral HPLC [Chiralpak AD column 21 x 50 mm, 20mie; 20 mg/2 mL EtOH; heptane/IPA; 85:15 (v:v); 20 mL/min, 330 psi]. Fraction 1: White solid. Yield: 7.2 mg. Retention time: 10.4 min. [Chiralpak AD-H, column 4.6 x 100 mm, 5 mic; 20 mg/2 mL EtOH; heptane/IPA; 85:15 (v:v); 1 mL/min]. H NMR (400 MHz, METHANOL-d4 ) 5 1.07 - 1.18 (m, 2 H) 1.20 (s, 3 H) 1.21 (s, 3 H) 1.23 - 1.41 (m, 4 H) 1.65 - 1.74 (m, 2 H) 1.90 - 1.99 (m, 2 H) 2.09 (m, 3 H) 2.71 (br. s., 1 H) 3.19 (d, J=6.65 Hz, 2 H) 3.57 - 3.67 (m, 1 H) 3.67 - 3.74 (m, 2 H) 6.52 (d, 1 H) 6.61 (s, 1 H) 6.71 (d, 1 H) 7.42 - 7.50 (m, 1 H) 7.94 (s, 1 H). 100456| Fraction 2: White solid. Yield: 6.6 mg. Retention time: 17.4 min. [Chiralpak AD-H, column 4.6 x 100 mm, 5 mie; 20 mg/2 mL EtOH; heptane/IPA; 85:15 (v:v); ! mL/min]JH NMR (400 MHz, METHANOL-d4 ) õ 1.06 - 1.18 (m, 2 H) 1.20 (s, 3 H) 1.21 (s, 3 H) 1.24 - 1.42 (m, 4 H) 1.63 - 1.74 (m, 2 H) 1.91 - 2.01 (m, 2 H) 2.04 - 2.!9 (m, 3 H) 2.75 (br. s., 1 H) 3.19 (d, J=7.04 Hz, 2 H) 3.57 - 3.66 (m, 1 H) 3.66 - 3.74 (m, 2 H) 6.52 (d, 1 H) 6.61 (s, 1 H) 6.72 (d, 1 H) 7.43 - 7.50 (m, 1 H) 7.94 (s, 1 H). Absolute stereochemistry of compounds in Fraction 1 and Fraction 2 is not determined. Example 25 (Compound 269) N2 -(trans-4-aminocyclohexyl)-5 -chloro-5-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4 - bipyridine-2',6-diamine H I.< N WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 A mixture of 5'-chloro-2',5-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine (30 mg, 0.088 mmol) and trans-cyclohexane-l,4-diamine (81 mg, 0.706 mmol) in DMSO (0.3 mL) under argon in a sealed tube was heated at 103 °C for 18 hr. The mixture was allowed to cool to ambient temperature. The mixture was diluted with DMSO and filtered through a syringe filter. Purification by HPLC provided N2'-(trans-4-aminocyclohexyl)- 5'- h r -5-f u r -N6-((tetrahydr -2H-pyran-4-y )methy )-2 4'-bipyridine-2' 6-diamine as its trifluoroacetic acid sait. Yield: 22.3 mg. LCMS (m/z): 434.1 [M+H]+; Retention time = 0.57 min. 1004581 1H NMR (400 MHz, METHANOL-d4 ) 6 1.22 (dd, J=12.91, 4.30 Hz, 2 H) 1.31 - 1.65 (m, 6 H) 1.87 (ddd, J=l 1.05, 7.34, 3.91 Hz, 1 H) 2.07 (dd, 4 H) 3.00 -3.13 (m, 1 H) 3.24 - 3.34 (m, 4 H) 3.50 - 3.64 (m, 1 H) 3.84 (dd, J=ll.15, 2.93 Hz, 2 H) 6.79 (dd, t H) 6.93 (s, 1 H) 7.20 (dd, 1 H) 7.93 (s, t H). Example 26 (Compound 155) Ethyl 2-(trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-ylamino) cyclohexylamino)oxazole-4-carboxylate H A mixture of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'- bipyridine-2',6-diamine (25 mg, 0.059 mmol), ethyl 2-chlorooxazole-4-carboxylate (12.88 mg, 0.073 mmol), triethylamine (0.04t mL, 0.293 mmol) in dioxane (1 mL) was heated at 80 °C for -20 hr. The mixture was concentrated in vacuo. The resulting residue was dissolved in DMSO and purified by HPLC providing ethyl 2-(trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'- bipyridin-2'-yl-amino)cyclohexylamino)oxazole-4-carboxylate as its trifluoroacetic acid sait. Yield: 7.1 mg. LCMS (m/z): 565.2 [M+H]+; Retention time = 0.85 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 27 (Compound 156) 5'- h r -N2'-(trans-4-(6h ropyrimidin-4-y -amin ) yc hexy )-N6-(3u r benzy )-2 4'- bipyridine-2',6-diamine H ìJ H 100460] A mixture of N2'-(trans-4-aminoeyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'- bipyridine-2',6-diamine (25 mg, 0.059 retool), 4,6-diehloropyrimidine (l 0.93 mg, 0.073 retool), triethylamine (0.020 mL, 0.147 mmol) in dioxane (l mL) was heated at 80 °C for - 16 hr. The mixture was concentrated in vacuo. The resulting residue was dissolved in DMSO and purified by HPLC providing 5'-chloro-N2'-(trans-4-(6-chloropyñmidin-4-yl-amino)cyclohexyl)-N6-(3fluorobenzyl)-2,4'-bipyridine-2',6-diamine as its trifluoroacetic acid salt. Yield: 18 mg. LCMS (m/z): 538. l [M+H]+; Retention time = 0.82 rein. Examole 28 (Compound 266) [004611 N2'-(trans-4-aminoeyelohexyl)-3,5,5'-trichloro-N6-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine H I N.,>. NÆ ../',. c, H 6 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 1: Preparation of6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2amine To a solution of 2-bromo-6-fluoropyridine (3 g, 17.05 mmol) in DMSO (8 mL) was added (tetrahydro-2H-pyran-4-yl)methanamine (3.10 g, 20.46 mmol) and tñethylamine (5.68 mL, 40.9 mmol). The mixture was heated at 110 °C for 18 hr. The mixture was allowed to cool to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution (lx), water (Ix), brine (lx), dried over Na2 SO4 , filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel providing 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a white solid. Yield: 4.24 g. LCMS (m/z): 270.9/273.0 [M+H]+; Retention time -- 0.78 min. Step 2: Preparation of 6-bromo-3,5-dichloro-N-((tetrahydro-2H-pyran-4yl)methyl)pyridin-2-amine [004651 Step 2a: To a solution of 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyñdin2-amine (20 g, 74 mmol) in acetonitñle (240 mL) was added NCS (9.85 g, 74 mmol). The mixture was heated to 80 °C for 3 hr. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The resulting residue was diluted with brine (200 mL) and extracted with EtOAc (3x 200 mL). The combined organic layers were concentrated in vacuo. The resulting residue was purified by column chromatography [SIO2 , EtOAc/heptane = 0/100 to 50/50] providing 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2amine (12 g) and a mixture of 6-bromo-3,5-dichloro-N-((tetrahydro-2H-pyran-4yl)methyl)p yñdin-2-amine/6-bromo-3 -chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyñdin-2amine (5 g, ratio -2:3). Step 2b: To a solution of a mixture of 6-bromo-3,5-dichloro-N-((tetrahydro-2Hpyran-4-yl)methyl)pyridin-2-amine/6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4yl)methyl)pyñdin-2-amine (4.5g, ratio -2:3) in acetonitrile (40 mL) was added NCS (1.250 g, 9.36 mmol). The mixture was heated to 80 °C for 50 min. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 120 g, EtOAc/heptane] providing 6-bromo-3,5-dichloro-N-((tetrahydro2H-pyran-4-yl)methyl)pyridin-2-amine as white solid. Yield: 2.25 g. LCMS (m/z): 340.9 [M+H]+; Retention time = 1.11 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 3: Preparation of 3,5,5'-trichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridin-6-amine A mixture of 6-bromo-3,5-dichloro-N-((tetrahydro-2H-pyran-4yl)methyl)pyridin-2-amine (1 g, 2.94 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (0.774 g, 4.41 mmol), PdCl2 (dppf).CH2 Cl2 adduct (0.240 g, 0.294 mmol) in DME (12 mL) and 2M aqueous Na2 CO3 solution (4 mL, 2.94 mmol) in a sealed tube was heated at 90 °C for 2 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc (-100 mL) and saturated aqueous NaHCO3 . The separated organic layer was washed with saturated aqueous NaHCO3 (2x), brine, dried over NazSO4 , filtered off and concentrated in vacuo. The resulting residue was puñfied by column chromatography ISiO2 , 80 g, EtOAc/heptane = 0/100 to 30/70 over 25 min] providing 3,5,5'-trichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine as a colorless liquid. Yield: 510 mg. LCMS (m/z): 391.9 [M+H]+; Retention time = 1.14 min. 100469] Step 4: Preparation of N2'-(trans-4-aminocyclohexyl)-3,5,5'-trichloro-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine 100470] A mixture of 3,5,5'-trichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine (35 mg, 0.090 mmol)and trans-cyclohexane-1,4-diamine (10.23 mg, 0.090 mmol) in DMSO (0.3 mL) under argon in a sealed tube was heated at 100 °C for 18 hr. The mixture was allowed to cool to ambient temperature. The mixture was diluted with DMSO, filtered through a syringe filter. Purification by HPLC provided N2'-(trans-4-aminocyclohexyl)- 3 5 5'-trich r -N6-((tetrahydr -2H-pyran-4-yl)methy )-2 4'-bipyridine-2' 6-diamine as its trifluoroacetic acid salt. Yield: 38 mg. LCMS (m/z): 486.0 [M+H]+; Retention time = 0.70 min. H NMR (400 MHz, METHANOL-d4 ) 6 1.28 (dd, J= 13. l 1, 4.11 Hz, 2 H) 1.341.48 (m, 2 H) 1.491.69 (m, 4 H) 1.85-2.01 (m, 1 H) 2.10 (d,J=12.13 Hz, 2 H) 2.152.26 (m, 2 H) 3.07 - 3.20 (m, t H) 3.31 - 3.40 (m, 4 H) 3.65 - 3.75 (m, 1 H) 3.91 (dd, J=l 1.35, 2.74 Hz, 2 H) 6.59 (s, l H) 7.69 (s, l H) 8.02 (s, 1 H). Example 29 (Compound 311) WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 N2 -(trans-4-amin cyc hexy )-5'- h r -N6-((4-methy tetrahydr -2H-pyran-4-y )methy )-2 4'- bipyridine-2',6-diamine [004721 Step 1: Preparation of 4-methyltetrahydro-2H-pymn-4-carbonitrile (following reference: WO2005/058860) To a solution oftetrahydro-2H-pyran-4-carbonitrile (2 g, 18.00 mmol) in THF (10 mL) at 0 - 5 °C was slowly added LHMDS (21.59 mL, 21.59 mmol). The mixture was stirred for 1.5 hr 0 °C. Iodomethane (3.37 mL, 54.0 mmol) was added slowly and stirring was continued for 30 min at -4) °C and -2 hr at ambient temperature. The mixture was cooled to 0 °C and carefully diluted with IN aqueous HC1 (30 mL) and EtOAc (5 mL) and concemrated. The resulting residue was taken up in diethylether and the separated organic layer was washed with brine, dried over Na2 SO4 , filtered off and concentrated in vacuo providing crude 4methyltetrahydro-2H-pyran-4-carbonitrile as an orange oil, which was directly used in the next reaction without further purification. Yield: 1.8 g. LCMS (m/z): 126.1 [M+H]+; Retention time -- 0.44 min. [004741 Step 2: Preparation of (4-methyltetrahydro-2H-pyran-4-yl)methanamine To a solution of 4-methyltetrahydro-2H-pyran-4-carbonitrile (1.8 g, 14.38 mmol) in THF (30 mL) was added carefully IM LAH!THF (21.57 mL, 21.57 mmol) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C, allowed to warm to ambient temperature and stirred for -3 hours at ambient temperature. To the reaction mixture was carefully added water (0.9 mL), 1N aqueous NaOH (2.7 mL) and water (0.9 mL) [Caution: gas development!]. The WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 mixture was vigorously stirred for 30 min. The precipitate was filtered offand rinsed with THF. The solution was concentrated in vacuo providing crude (4-methyltetrahydro-2H-pyran-4yl)methanamine as a yellowish solid, which was directly used in the next step without further purification. Yield: 1.54 g. LCMS (m/z): 130. l [M+H]+; Retention time = 0.21 rein. Step 3: Preparation of 6-bromo-N-((4-methyltetrahydro-2H-pyran-4yl)methyl)p yridin-2-amine To a solution of 2-bromo-6-fluoropyridine (619 mg, 3.52 retool) in DMSO (3 mL) was added (4-methyltetrahydro-2H-pyran-4-yl)methanamine (500 mg, 3.87 mmol) and tñethylamine (498 mg, 4.93 mmol). The mixture was heated at 110 °C for 18 hr. The mixture was allowed to cool to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution (1 x), water (1 x), brine (Ix), dried over Na2 SO«, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography_[SiO2, 24 g, EtOAc/heptane = 0/100 2 min, 0/100 to 40/60 2-25 min] providing 6-bromo-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a white solid. Yield: 750 mg. LCMS (m/z): 285.0/287.0 [M+H]+; Retention time = 0.88 min. Step 4: Preparation of 5'-chloro-2'-fluoro-N-((4-methyltetrahydro-2H-pyran-4yl)methyl)- 2,4'-bipyridin-6-amine 1004791 A mixture of 6-bromo-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2amine (750 mg, 2.63 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (830 mg, 4.73 mmol), PdCl:(dpptì)-CH2Cl2Adduct (215 mg, 0.263 mmol) in DME (12 mL) and 2M aqueous Na2 CO3 (4 mL, 8.00 mmol) in a sealed tube was heated at 103 °C for 4 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc (-50 mL) and saturated aqueous NaHCO3 solution. The separated organic layer was washed with saturated aqueous NaHCO3 solution (2x), dried over Na2 SO4 , filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SIO2 , 40 g, 20 min, EtOAc/heptane = 0/100 for 2 min, then EtOAc/heptane = 5/95 to 50/50 over 18 min, then EtOAc/heptane = 50/50] providing 5'-chloro2'-fluoro-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridin-6-amine as a colorless oil. Yield: 691 mg. LCMS (m/z): 336.2 [M+H]+; Retention time = 0.66 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1004801 Step 5: Preparation of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-((4methyltetmhydm-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine 1004811 A mixture of 5'-chloro-2'-fluoro-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)- 2,4'-bipyridin-6-amine (50 mg, 0.149 mmol), trans-cyclohexane1,4-diamine (136 mg, 1.19 l mmol), DIPEA (30.1 mg, 0.298 mmol) in DMSO (0.5 mL) was heated at 107 °C for 16 hr. The mixture was diluted with EtOAc and saturated aqueous NaHCO3 solution. The separated aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over Na2SO4, filtered offand concentrated in vacuo. The resulting residue was dissolved in DMSO/water (1/1), filtered through a syringe filter and purified by HPLC providing N2'-(trans4-amin y hexy )-5 - h r -N6-((4-methy tetrahydr -2H-pyran-4-y )methy )-2 4'-bipyridine2',6-diamine as its trifluoroacetic acid sait. Yield: 59.5 mg. LCMS (m/z): 430.3 [M+H]+; Retention time = 0.48 min. [004821 H NMR (400 MHz, METHANOL-d4 ) 5 1.13 (s, 3 H) 1.33 - 1.49 (m, 4 H) 1.49 - 1.68 (m, 4 H) 2.06 - 2.23 (m, 4 H) 3.07 - 3.22 (m, 1 H) 3.37 (s, 2 H) 3.60 - 3.69 (m, 2 H) 3.70 - 3.80 (m, 3 H) 6.77 (s, 1 H) 6.90 (d, J=7.04 Hz, 1 H) 7.12 (d, J=9.00 Hz, 1 H) 7.81 - 7.91 (m, 1 H) 8.09 (s, 1 H). Example 30 (Compound 312) N2 -(trans-4-amin cyc hexy )-5'-ch r -5u r -N6-((4-methy tetrahydr -2H-pyran-4yl)methyl)-2,4'-bipyridine-2',64iamine F H 1004831 Step 1: Preparation of 3,6-difluoro-N-((4-methyltetrahydro-2H-pyran-4yl)methyl)pyridin-2-amine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100484] A mixture of 2,3,6-trifluoropyridine (858 mg, 6.45 mmol), (4-methyltetrahydro2H-pyran-4-yl)methanamine (1000 mg, 7.74 mmol) and triethylamine (2.158 mL, 15.48 mmol) inNMP (16 mL) was heated at 70 °C for 1 hr. The reaction mixture was allowed to ambient temperature and was diluted with EtOAc (N100 mL), brine (-50 mL) and water (-50 mL). The separated organic layer was washed with bñne (Ix), 0.3N aqueous HC1 (2x), saturated aqueous NaHCO3 solution (1 x), brine (1 x), dried over Na2 SO4 , filtered off and concentrated in vacuo to provide crude 3,6-difluoro-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a colorless oil, which was directly used in the next reaction without further purification. Yield: 1.4 g. LCMS (m/z): 243.1 [M+H]+; Retention time = 0.86 min. Step 2: Preparation of 3-fluoro-6-methoxy-N-((4-methyltetrahydro-2H-pyran-4yl)methyl)pyridin-2-amine 100486] To a solution of 3,6-difluoro-N-(O-methyltetrahydro-2H-pyran-4yl)methyl)pyridin-2-amine (1.4 g, 5.78 mmol) in MeOH (14 mL) was added sodium methoxide (25 wt.% in MeOH, 7 mL, 30.8 mmol). The mixture was heated in a steel bomb at 135 °C for 3days. The mixture was cooled to ambient temperature and concentrated in vacuo. The resulting residue was taken up in water (200 mL), and the resulting precipitate was filtered off and rinsed with water. The solid was dissolved in DCM. The organic solution was washed with brine, dried over Na2 SO4 , filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 80 g, 20 min, EtOAe/heptane = 0/100 for 2 min, then EtOAc/heptane = 5/95 to 25/75 over 23 min, EtOAc/heptane = 25/75] providing 3-fluoro-6methoxy-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as an off-white solid. Yield: 1.22 g. LCMS (m/z): 255.1 [M+H]+; Retention time = 0.89 min. Step 3: Preparation of 5-fluoro-6-((4-methyltetrahydro-2H-pyran-4yl)methyl)aminopyridin-2-ol To 3-fluoro-6-methoxy-N-((4-methyltetrahydro-2H-pyran-4-yl)methyt)pyñdin-2amine in aee onitrile (12 mL) was added sodium iodide (4.24 g, 28.3 mmol) and slowly TMS-C1 (3.62 mL, 28.3 mmol). The mixture was heated to reflux (oil bath: 83 °C) for 4 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc and saturated aqueous WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 NaHCO3 solution. The mixture was vigorously stirred for 15 min and acidified with 0.5N aqueous NaHSO4 solution and stirring was continued for 5 min. The mixture was neutralized with saturated aqueous NaHCO3 solution. The separated aqueous phase was extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , g, 25 min, EtOAc/heptane = 5/95 for 2 min, 5/95 to 50/50 over 18 min, then 50/50] providing 5fluoro-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-ol as colorless highly viscous oil. Yield: 420 mg. LCMS (m/z): 241.1 [M+H]+; Retention time = 0.55 min. Step 4: Preparation of 5-fluoro-6-((4-methyltetrahydro-2H-pyran-4yl)methyt)aminopyñdin-2-yl trifluoromethanesulfonate [004901 To a solution of 5-fluoro-6-((4-methyltetrahydro-2H-pyran-4yl)methyl)aminopyridin-2-ol (420 mg, 1.748 mmot) and triethytamine (0.731 mL, 5.24 mmol) in DCM (t6 mL) was added trifluoromethanesutfonic anhydride (0.443 mL, 2.62 mmol) slowly at 0 °C. The mixture was stirred for 2 hr at 0 °C and poured carefully into ice-cooled saturated aqueous NaHCO» solution. The separated aqueous layer was extracted with DCM (2x). The combined organic layers were dried over Na2 SO4 , filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 24 g, EtOAc/heptane = 5/95 for 2 min, then EtOAc/heptane = 5/95 to 40/60 over 13 min, then EtOAc/heptane = 40/60] providing 5-fluoro-6-((4-methyltetrahydro-2H-pyran-4-yt)methyl)aminopyridin-2-yl tfifluoromethanesulfonate as colorless oil. Yield: 600 mg. Step 5: Preparation of 5'-chloro-2',5-difluoro-N-((4-methyltetrahydro-2H-pyran4-yl) methyt)-2,4'-bipyridin-6-amine [004921 A mixture of 5-fluoro-6-((4-methyttetrahydro-2H-pyran-4yl)methyl)aminopyridin-2-yl trifluoromethanesulfonate (600 mg, 1.611 mmot), 5-chloro-2fluoropyridin-4-ylboronic acid (565 mg, 3.22 mmol), PdC12 (dppf)-CH2 C12 adduct (132 mg, 0.161 mmol) in DME (8 mL) and 2M aqueous Na2 CO3 (3 mL, 6.00 mmol) in a sealed tube was heated at 102 °C for 10 hr. The mixture was cooled to ambient temperature and was diluted with EtOAc (-t00 mL) and saturated aqueous NaHCO3 solution. The separated organic layer was WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 washed with saturated aqueous NaHCO3 solution (2x), dried over Na2 SO4 , filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , g, EtOAc/heptane = 0/100 for 3 min, EtOAc/heptane = 0/100 to 30/70 over 17 min, then EtOAc/heptane = 30/70] providing 5'-chloro-2',5-difluoro-N-((4-methyltetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridin-6-amine as a colorless oil. Yield: 490 mg. LCMS (m/z): 354.2 [M+H]+; Retention time -- 1.05 nain. 100493] Step 6: Preparation of N2'-(trans-4-aminocyclohexyl)-5'-chloro-5-fluoro-N6-((4methyltetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine 100494] A mixture of 5'-chloro-2',5-difluoro-N-((4-methyltetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridin-6-amine (50 mg, 0.141 retool), trans-cyclo hexane1,4-diamine (129 mg, 1.131 mmol), DIPEA (28.6 mg, 0.283 retool) in DMSO (0.5 mL) was heated at 107 °C for 16 hr. The mixture was diluted with EtOAc and saturated aqueous NaHCO3 solution. The separated aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over Na2 SO4 , filtered offand concentrated in vacuo. The resulting residue was dissolved in DMSO/water (1/1), filtered through a syringe filter and purified by HPLC providing N2'- (trans-4-amin cy hexy1)-5'- h r -5u r -N6-((4-methy tetrahydr -2H-pyran-4-y )methyl)- 2,4'-bipyridine-2',6-diamine as its trifluoroacetic acid salt. Yield: 61.3 mg. LCMS (m/z): 448.2 [M+H]+; Retention time = 0.62 min. 100495] JH NMR (400 MHz, METHANOL-d4 ) 6 1.06 (s, 3 H) 1.28 - 1.54 (m, 4 H) 1.54 - 1.65 (m, 4 H) 2.06 - 2.25 (m, 4 H) 3.09 - 3.22 (m, 1 H) 3.49 (s, 2 H) 3.57 - 3.72 (m, 3 H) 3.72 - 3.81 (m, 2 H) 6.86 (dd, 1 H) 6.92 (s, 1 H) 7.31 (dd, 1 H) 7.99 (s, 1 H) Example 31 (Compound 313) N2 -(trans-4-amin cyc hexy )-5 -ch r -N6-((4u r tetrahydr -2H-pyran-4-y )methy )-2 4 - bipyridine-2',6-diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H N ì].,,NH2 Step 1" Preparation of 4-fluorotetrahydro-2H-pyran-4-carbaldehyde (as described in WO2009/011836) Step la: To a solution of DIPEA (6.12 mL, 35.0 mmol) in DCM (80 mL) was added trimethylsilyl trifluoromethanesulfonate (7.79 g, 35.0 mmol) followed by a solution of tetrahydro-2H-pyran-4-carbaldehyde (2 g, 17.52 mmol) in DCM (80 mL) at 0 °C. Upon completion of the addition, the reaction mixture was allowed to stir at ambient temperature for 2 hr. The mixture was concentrated in vacuo and the resulting residue was treated with hexane (200 mL). The precipitate was filtered off and the solution was concentrated in vacuo providing crude trimethylsilyl ether, which was directly used in the next step without further purification. Step 1 b: To a solution of crude trimethylsilyl ether in DCM (100 mL) was added dropwise a solution of N-fluorobenzenesulfonimide (5.53 g, 17.52 mmol), dissolved in DCM (50 mL), at 0 °C. The mixture was stirred for 3 hr at ambient temperature and the crude solution of 4-fluorotetrahydro-2H-pyran-4-carbaldehyde was directly used in the next reaction. Step 2: Preparation of 6-bromo-N-((4-fluorotetrahydro-2H-pyran-4yl) methyl)pyri din-2 -ami ne 100500] To 6-bromopyridin-2-amine (3.03 g, 17.50 mmol) was added the crude solution of 4-fluorotetrahydro-2H-pyran-4-carbaldehyde in DCM. To the mixture was added acetic acid (1.002 mL, 17.50 mmol) and sodium triacetoxyborohydride (5.56 g, 26.3 mmol) in portions. The mixture was stirred for 2 hr at ambient temperature. The mixture was diluted carefully with saturated aqueous NaHCO3 solution. The separated aqueous layer was extracted with DCM (Ix). The combined organic layers were washed with water (Ix), saturated aqueous NaHCO3 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 solution (lx) and concentrated in vacuo. The solid resulting residue was dissolved in DCM (100 mL) and 3M aqueous HCI (60 mL). The separated organic layer was extracted with 3M aqueous HCI (3x 20 mL). The combined acidic layers were washed with DCM (lx). Solid NaHCO3 was added carefully to the acidic solution [Caution: gas development[] until pli>-8. The aqueous mixture was extracted with DCM (2x) and EtOAc (2x). The combined organic layers were concentrated in vacuo. The resulting residue was dissolved in EtOAc. The solution was washed with 0.3M aqueous HCI, and brine, dried over Na2 SO4 , filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 40 g, EtOAc/heptane = 5/95 for 3 min, then EtOAc/heptane = 5/95 to 30/70 over 15 min, then EtOAc/heptane -- 30/70] providing 6-bromo-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a white solid. Yield: 1.82 g. LCMS (m/z): 288.9/291.0 [M+H]+; Retention time = 0.84 min. Step 3: Preparation of 5'-chloro-2'-fluoro-N-((4-fluorotetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridin-6-amine [005021 A mixture of 6-bromo-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)pyridin-2amine (1 g, 3.46 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (1.092 g, 6.23 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.282 g, 0.346 mmol) in DME (13 mL) and 2M aqueous Na2 CO3 (5.19 mL, 10.38 mmol) in a sealed tube was heated at 100 °C for 2 hr. The mixture was cooled to ambient temperature and was diluted with EtOAc (-50 mL) and saturated aqueous NaHCO» The separated organic layer was washed with saturated aqueous NaHCO3 (2x), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiOz, 80 g, EtOAc/heptane = 5/95 for 4 min, then EtOAciheptane = 5/95 to 50/50 over 18 min, then EtOAc/heptane = 50/50] providing 5'-chloro-2'-fluoro-N-((4fluorotetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridin-6-amine as a colorless oil. Yield: 1.00 g. LCMS (m/z): 340.1 [M+H]+; Retention time = 0.67 min. Step 4: Preparation of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-((4-fluorotetrahydro-2Hpyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine A mixture of 5'-chloro-2'-fluoro-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)- 2,4'-bipyridin-6-amine (75 mg, 0.221 mmol) and trans-cyclohexane-l,4-díamine (202 mg, 1.766 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 mmol) in DMSO (1 mL) under argon in a sealed tube was heated at 103 °C for 18 hr. The mixture was coo]ed to ambient temperature and diluted with EtOAc and water. The separated organic layer was washed with saturated aqueous NaHCO3 solution and concentrated in vacuo. The resulting residue was dissolved in DMSO/water (-2/1), filtered through a syringe filter. Purification by HPLC provided N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-((4fluorotetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine as its trifluoroacetic acid salt. The material was dissolved in MeOH (-3 mL), filtered through VariPure(TM)IPE [500 mg per 6 mL tube; 0.9 mmol (nominal); part no.: PL3540-C603VP], eluted with MeOH (15 mL) and concentrated in vacuo. The resulting residue was dissolved in acetonitrile/water (-3/1) and lyophilized providing N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-((4-fluorotetrahydro-2Hpyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine. Yield: 58 mg. LCMS (m/z): 434.2 [M+H]+; Retention time = 0.50 min. [005041 IH NMR (400 MHz, METHANOL-d4 ) 6l.32 (d, J=9.78 Hz, 4 H) 1.73 - 1.88 (m, 4 H) 1.91 - 1.99 (m, 2 H) 2.08 (d, J=9.78 Hz, 2 H) 2.67 - 2.78 (m, 1 H) 3.57 - 3.73 (m, H) 3.75 - 3.84 (m, 2 H) 6.60 (d, J=8.61 Hz, l H) 6.63 (s, 1 H) 6.78 (d, J=7.43 Hz, 1 H) 7.34 - 7.55 (m, 1 H) 7.94 (s, 1 H). Example 32 (Compound 152) 100505] N2'-((I S,3S,4S)-4-amino-3-methylcyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)- 2 4 -bipyridine-2' 6-diamine/N2'-(( R 3R 4R)-4-amin -3-methy cy hexy )-5'-ch r -N6-(3fluorobenzyl)-2,4'-bipyridine-2',6-diamine H "'N H2 Step 1 : Preparation of 4-(dibenzylamino)cyclohexanol WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1005071 To a mixture of4-aminocyclohexanol (3.51 g, 23.15 mmol) and K2 CO3 (12.80 g, 93 mmol) in acetonitrile (100 mL) was added benzylbromide (5.64 mL, 47.5 mmol) and the mixture was stirred at reflux for 17 hr. The crude mixture was concentrated in vacuo and the resulting residue was dissolved in water and EtOAc. The separated aqueous layer was extracted with EtOAc (2x -100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered off and concentrated in vacuo providing crude 4-(dibenzylamino)cyclohexanol as a viscous oil, which was directly used in the next step without further purification. Yield: 6.12 g. LCMS (m/z): 296.1 [M+H]+; Retention time = 0.59 min. Step 2: Preparation of 4-(dibenzylamino)cyclohexanone (following reference WO96/07657) To a solution of oxalylic acid (2.03 mL, 20.31 mmol) in DCM (80 mL) at -60 °C was added dropwise DMSO (3.46 mL, 48.8 mmol). After stirring for 5 min, a solution of 4- (dibenzylamino)cyclohexanol (6 g, 20.31 mmol) in DCM (40 mL) was added slowly. The mixture was stirred for 15 min and NE% (14.3 mL, 103 mmol) was added slowly. After stirring for 15 min the ice bath was removed and the mixture was stirred for additional 16 hr. The mixture was diluted with water (100 mL). The separated organic layer was washed with brine (1 x -75 mL), dried over Na SO4 , filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 120 g, EtOAc/hexane = 10/90 to 50/50] providing 4-(dibenzylamino)cyclohexanone as a white solid. Yield: 5.5 g. LCMS (m/z): 294.1 [M+H]+; Retention time = 0.58 min. Step 3: Preparation of (2S,4S)-4-(dibenzylamino)-2-methylcyclohexanone/(2R,4R)-4- (dibenzylamino)-2-methylcyclohexanone 1005091 A solution of 4-(dibenzylamino)cyclohexanone (4 g, 13.63 mmol) in THF (27 mL) was added to KHMDS/toluene (32.7 mL, 16.36 mmol) at ambient temperature. The mixture was stirred for 15 min at ambient temperature. Triethylborane (IM in THF, 17.72 mL, 17.72 mmol) was added dropwise and the mixture was allowed to stir an additional 30 min. lodomethane (1.6 mL, 25.7 mmol) was added and the mixture was stirred for 20 hr at ambient temperature. Aqueous 1M NaOH solution was added (-25 mL) and the mixture was vigorously stirred for 3 hr. The mixture was extracted with EtOAc (4x -100 mL) and the combined organic layers were washed with brine, dried over Na2 SO4 , filtered off, and concentrated in vacuo. The WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 resulting residue was purified by column chromatography [SiO2 , 125 g, EtOAc/hexane = 0/100 to 20/80]. Fractions were combined and and concentrated in vacuo providing (2S,4S)-4- (dibenzylamino)-2-methylcyclohexanone/(2R,4R)- 4-(dibenzylamino)-2-methylcyclohexanone as a highly viscous oil, which became partially a white solid. Yield: 3.1g. LCMS (m/z): 308.2[M+H]+; Retention time = 0.65 min (major isomer). Ratio major/minor isomer: -9:1. Step 4: Preparation of (1R,2S,4S)-4-(dibenzylamino)-2-methylcyclohexanol/(l S,2R,4R)-4- (dibenzylamino)-2methylcyclohexanol. [005101 To a solution of (2S,4S)-4-(dibenzylamino)-2-methylcyclohexanone/(2R,4R)-4- (dibenzylamino)-2-methylcyclohexanone (3.1 g, 10.08 mmol) in THF (55 mL) at -78 °C was added L-selectride (15.13 mL, 15.13 mmol) dropwise. After stirring for 5 min at -78 °C the mixture was allowed to warm up to 0 °C. Stirring was continued for 18 hr as the reaction mixture mixture was warmed from 0 °C to ambient temperature. The mixture was diluted carefully with IN aq NaOH (15 mL) and stirred vigorously for 3 hr. The mixture was extracted with EtOAc (3x MOO mL). The combined organic layers were washed with brine (MOO mL), dried over Na2 SO4 , filtered offand concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 120 g, EtOAc/hexane= 0/100 to 20/80 over-25 min; EtOAc/hexane = 20/80 to 40/60 over 5 rein] providing (1R,2S,4S)-4-(dibenzylamino)-2methylcyclohexanol/(1S,2R,4R)-4-(dibenzylamino)-2-methylcyclohexanol as a colorless liquid. Yield: 2.83 g. LCMS (m/z): 310.3 [M+H]+; Retention time = 0.66 min. Step 5: Preparation of (1 S,3S,4S)-4-azido-N,N-dibenzyl-3-methylcyclohexanamine/(1R,3R,4R)- 4-azido-N,N-dibenzyl-3-methylcyclohexanamine [005111 A mixture of DIAD (5.03 mL, 25.9 mmol) and triphenylphosphine (6.78 g, 25.9 mmol) in THF (35 mL) was allowed to form a sait. After 30 rein a solution of(1R,2S,4S)-4- (dibenzylamino)-2-methylcyclohexanol/(1S,2R,4R)-4-(dibenzylamino)-2-methylcyclohexanol (2 g, 6.46 mmol) and diphenyl phosphorazidate (2.507 mL, 11.63 mmol) in THF (25 mL) was added and the mixture was stirred for 20 hr at 55 °C. The mixture was cooled to ambient temperature and diluted with EtOAc and brine. The separated organic layer was dried over Na2SO4, filtered off and concentrated in vacuo providing crude (1S,3S,4S)-4-azido-N,NWO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 dibenzyl-3-methyleyclohexanamine/(1R,3R,4R)-4-azido-N,N-dibenzyl-3methyleyelohexanamine as orange oil, which was directly used in the next step without further purification. LCMS (m/z): 335.1 [M+H]+; Retention time = 0.81 rein. Step 6: Preparation of (1S,3S,4S)-N t,NI -dibenzyl-3-methyleyelohexanet ,4diamine/(1R,3R,4R)-N1 ,N t-dibenzyl-3-methylcyclohexanet ,4-diamine 1005121 To a solution of (t S,3S,4S)-4-azido-N,N-dibenzyl-3methylcyelohexanamine/(1R,3R,4R)-4-azido-N,N-dibenzyl-3-methyleyelohexanamine (2. t 74 g, 6.5 retool) in acetic acid (50 mL) was added slowly Zn-dust (0.638 g, 9.75 mmol). The mixture was stirred for 30 min at ambient temperature. Additional Zn-dust was added (150 mg) and stirring was continued for-t 5min. The mixture was diluted carefully with iN aqueous HCI and diethylether. The separated aqueous layer was extracted with diethylether (5x -100 mL). The aquous layer was partially lyophilized and concentrated to dryness in vacuo. The resulting residue was diluted with IN aqueous HC1 and concentration to dryness was repeated. Dilution with IN HCI and concentration was repeated. The resulting residue was dissolved in water/acetonitrile and lyophilized to provide crude (t S,3S,4S)-N 1 ,N t -dibenzyl-3methylcyelohexane1,4-diamine/( 1R,3R,4R)-N 1 ,N 1 -dibenzyl-3-methyleyclohexanet ,4-diamine as fluffy white solid. The crude material was directly used in the next step without further purification. Yield: 2.292 g. LCMS (m/z): 309.3 [M+H]+; Retention time = 0.50 rein. Step 7: Preparation oftert-butyl (tS,2S,4S)-4-(dibenzylamino)-2methylcyelohexylcarbamate/tert-butyl (t R,2R,4R)-4-(dibenzylamino)-2methylcyelohexylcarbamate 1005131 To (1 S,3 S,4S)-N t ,N 1-dibenzyl-3-methyleyclohexane1,4-diamine/(l R,3R,4R)- N I,N t-dibenzyl-3-methyleyelohexane-1,4-diamine (1.851 g, 6 mmol) in dioxane (200 mL) and saturated aqueous NaHCO3 solution (100 mL) was added BOC-anhydride (2.438 mL, 10.50 mmol), dissolved in dioxane (-5 mL). The resulting white suspension was stirred vigorously for t8 hr. The mixture was extracted with DCM (4x 300 mL) and EtOAe (Ix 100 mL). The combined organic layers were concentrated in vacuo. The resulting residue was dissolved in WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 EtOAc, washed with brine, dried over Na2 SO4 , filtered of and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 120 g, DCM/MeOH = 100/0 to 95/5]. Fractions containing product were combined, concentrated in vacuo providing tert-butyl (1S,2S,4S)-4-(dibenzylamino)-2-methylcyclohexylcarbamate/tert-butyl (1R,2R,4R)-4- (dibenzylamino)-2-methylcyclohexylcarbamate. Yield: 778 mg. LCMS (m/z): 409.2 [M+H]+; Retention time = 0.84 rein. Step 8: Preparation oftert-butyl (1S,2S,4S)-4-amino-2-methylcyclohexylcarbamate/tert-butyl (IR,2R,4R)-4-amino-2-methylcyclohexylcarbamate 100514] A mixture oftert-butyl (1S,2S,4S)-4-(dibenzylamino)-2methylcyclohexylcarbamate/tert-butyl (1R,2R,4R)-4-(dibenzylamino)-2methylcyclohexylcarbamate (750 mg, 1.836 mmol) and Pearlman's catalyst (290 mg, 2.73 mmol) in EtOH (35 mL) was hydrogenated in a steel bomb under H2 -atmosphere (pressure -75 psi) for 16 hr. The steel bomb was flushed with Argon, Celite and methanolwere added. The mixture was filtered and concentrated in vacuo. The white resulting residue was dissolved in acetonitrile/water (1 : 1) and lyophilized giving crude tert-butyl (1S,2S,4S)-4-amino-2methylcyclohexylearbamate/tert-butyl (1R,2R,4R)-4-amino-2-methylcyclohexylcarbamate, which was directly used in the next step without further purification. Yield: 412 mg. LCMS (m/z): 173.2/229.3 [M+H]+; Retention time = 0.54 min. 100515] Step 9: Preparation of N2'-((1S,3S,4S)-4-amino-3-methylcyclohexyl)-5'-chloroN6-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine/N2'-((1 R,3R,4R)-4-amino-3methylcyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine Step 9a: A mixture of Intermediate B (preparation of intermediate B is described in the intermediate session which is in front of the Examples) (25 mg, 0.075 mmol), tea-butyl (1S,2S,4S)-4-amino-2-methylcyclohexylcarbamate/tert-butyl (1R,2R,4R)-4-amino-2methylcyclohexylcarbamate (25.8 mg, 0.113 retool), triethylamine (28 lai, 0.201 retool) in DMSO (0.25 mL) was heated at 100 °C for 3days. The mixture was allowed to cool to ambient temperature and diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 solution (10 mL). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 The separated aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na2 SO4 , filtered off and concentrated in vacuo providing crude tel't-butyl (1 S,2S,4S)- 4-(5'-chl m-6-(3u r benzylamin )-2 4'-bipyridin-2'-yl-amin )-2 methylcyc hexylcarbamate/ tel't-butyl (t R,2R,4R)-4-(5'-cNoro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino)-2methylcyclohexylcarbamate, which was directly used in the next step without further purification. Step 9b: To a solution of crude tert-butyl (l S,2S,4S)-4-(5'-chloro-6-(3- u r benzy amin )-2 4'-bipy din-2'-y -amin )-2-methy cy hexy carbamate/tert-buty (1R,2R,4R)-4-(5'-chloro-6-(3-fluombenzylamino)-2,4'-bipyridin-2'-yl-amino)-2methylcyclohexylcarbamate was dissolved in MeOH (3 mL) was added 4M HCl/dioxane (9 mL, 36.0 mmol). The mixture was stirred for 1 hr and concentrated in vacuo. The resulting residue was dissolved in DMSO, filtered over a syringe filter and purified by HPLC providing N2'- (( 1 S,3 S,4S)-4-amino-3-methylcyclohexyl)- 5'-chloro-N6-(3-fluorobenzyl)-2,4'-bipyridine-2',6diamine/N2'-(( R 3R 4R)-4-amin -3-methy cyc hexy )-5'-ch r -N6-(3u r benzy )-2 4'- bipyridine-2',6-diamine as the trifluoroacetic acid sait. Yield: 28.1 mg. LCMS (m/z): 440.1 [M+H]+; Retention time = 0.62 min. Example 33 (Compound 224) 1005181 5-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)-3-((tetrahydro-2Hpyran-4-yl)methyl)aminopyrazine-2-carboxamide H "'NH2 Step 1. Preparation of 5-(5-chloro-2-fluoropyddin-4-yl)-3-((tetrahydro-2H-pyran4-yl)methyl)aminopyrazine-2-carboxamide: WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine (0.0342 g, 0.096 retool), CuCN (0.034 g, 0.383 retool), and dppf (0.085 g, 0.153 retool) were dissolved in dioxane (1.5 ml). The solution was then degassed by sparging with argon for 5 rein. It was then treated with Pd2 (dba)3 (0.035 g, 0.038 retool). The reaction mixture was then heated at 100°C for 5 hr. The reaction mixture was filtered through a pad of Celite then it was concentrated in vacuo to give 0.110 g of 5-(5-chloro-2-fluoropyridin-4yl)-3-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazine-2-carboxamíde. LCMS (m/z): 366 (Mit+), retention time = 0.89 min. [005211 Step 2. Preparation of 5-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4yl)-3-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazine-2-carboxamide: 5- (5-chloro-2-fluoropyridin-4-yl)-3-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazine-2-carboxamide (0.035 g, 0.096 retool) was dissolved in DMSO (2 ml). This was treated with 1,4-diaminocyclohexane (0.109 g, 0.957 mmol). The reaction mixture was then heated at 100°C for 4 hr. The material was purified by preparative reverse-phase HPLC to give 0.0053 g of 5-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)-3-((tetrahydro2H-pyran-4-yl)methyl)aminopyrazine-2-earboxamide as the TFA sait. LCMS (m/z): 460.1 (MH+), retention time = 0.54 rein. Example 34 (Compound 231) trans-N 1 -(5-chloro-4-(5-methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2yl)pyridin-2-yl)cyclohexane1,4-diamine H "'N H2 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 [005231 Step I. Preparation of 6-(5-chloro-2-fluoropyridin-4-yl)-3-methyl-N-(tetrahydro2H-pyran-4-yl-methyl)pyrazine-2-amine: [005241 3-chloro-6-(5-chloro-2-fluoropyñdin-4-yl)-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine (0.0275 g, 0.077 mmol), methylboronic acid (0.014 g, 0.231 mmol), and sodium carbonate (0.100 ml, 0.200 mmol, 2M aq solution) were dissolved in DME (1.0 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf).CH2Cl2 adduct (0.013 g, 0.015 mmol). The reaction mixture was then heated in the microwave at 105°C for 20 min. More of the above reagents in the same amounts were added to the reaction mixture and heating in the microwave was continued at 115°C for 20 min. The reaction mixture was allowed to cool to ambient temperature. It was then filtered through a pad of Celite. The filtrate was concentrated in vacuo to yield 0.0497 g of a mixture of 6-(5-chloro-2fluoropyridin-4-yl)-3-methyl-N-((tetrahydro-2H-pyran-4-yl)pyrazine-2-amine and 6-(2-fluoro-5methy py din-4-y )-3-methy -N-((tetrahydr -2H-pyran-4-y -methy )pyrazine 2-amine. [005251 Step 2. Preparation oftrans-Nl-(5-chloro-4-(5-methyl-6-((tetrahydro-2H-pyran4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclo hexane1,4-diamine: 100526] The mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-3-methyl-N-((tetrahydro-2Hpyran-4-yl)pyrazine-2-amine and 6-(2-fluoro-5-methylpyfidin-4-yl)-3-methyl-N-((tetrahydro2H-pyran-4-yl_methyl)pyrazine-2-amine (0.025 g, 0.074 mmol) and (0.023 g, 0.074 mmol) respectively was dissolved in DMSO (1 ml). This was treated with 1,4-diaminocyclohexane (0.085 g, 0.742 mmol). The reaction mixture was then heated at 100°C for 18 hr. The material was purified by preparative reverse-phase HPLC to give 0.0047 g of trans-N 1-(5-chloro-4-(5methy -6-((tetrahydr -2H-pyran-4-y )methy )amin pyrazin-2-y )pyridin-2-y ) y hexane1,4diamine as the TFA sait. LCMS (m/z): 431.2 (MH+), retention time = 0.49 min. Example 35 (Compound 240) trans-Nl-(5 ch r -4-(5-cy pr py 6-((tetrahydr -2H-pyran-4-y )methy )amin pyrazin-2yl)pyridin-2-yl)cyclohexane1,4-diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Step 1. Preparati n f6-(5-ch r -2u r pyridin-4-t )-3-cyc pr py -N-((tetrahydr -2H pyran4-yl)methyl)pyrazin-2-amine: 100527] 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine (0.0316 g, 0.088 mmol), potassium eyclopropyltrifluoroborate (0.026 g, 0.177 mmol), and potassium phosphate (0.113 g, 0.531 mmol) were dissolved in a mixture of toluene (1 ml) and H2 0 (0.170 ml). The solution was then degassed by sparging with argon for min. At this time it was treated with PdClz(dppf).CH2 Cl adduet (0.014 g, 0.018 mmol). The reaction mixture was then heated in the microwave at 115°O for 25 min. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to give 0.0445 g of the crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 20 EtOAc / 80 heptane to 70 EtOAc / 30 heptane gave 0.0271 g (84%) of 6-(5- h r -2 u r pyridin-4-t )-3y pr py -N-((tetrahydr -2H-pyran-4-y )methy )pyrazin-2amine. LCMS (m/z): 363.1 (MH+), retention time = 1.06 min. Step 2. Preparation oftrans-A?-(5-chloro-4-(5-eyclopropyl-6-((tetrahydro-2Hpyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)eyclohexane-l,4-diamine: [005291 6-(5-chloro-2-fluoropyridin-4-tl)-3-cyclopropyl-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine (0.0267 g, 0.074 mmol) was dissolved in DMSO (1 ml). This was treated with 1,4-diaminocyclohexane (0.084 g, 0.736 mmol). The reaction mixture was then heated at 100°C for 4 hr. Additional 1,4-diaminocyelohexane (0.084 g, 0.736 mmol) and triethylamine (0.0204 ml, 0.028 g, 0.294 mmol) were added. Heating at 100°C was continued for WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 17 hr. The reaction mixture was purified using prep HPLC. The material was purified by preparative reverse-phase HPLC to yield 0.0240 g of trans-NL(5-chloro-4-(5-cyclopropyl-6- ((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane1,4-diamine as the TFA sait. LCMS (m/z): 457.2 (MH+), retention time = 0.60 min. Example 36 (Compound 241) trans-NI -(5-chloro-4-(5-ethyl-6- ((tetrahydro-2H-pyran-4-yl)methyl)ami no pyrazin-2 -yl)pyridin-2 - yl)cyclohexane1,4-diamine H N.q N« A FH" o 1005301 Step 1. Preparation of 6-(5-chlom-2-fluoropyridin-4-yl)-3-ethyl-N-((tetrahydro2H-pyran-4-yl)methyl)pyrazine-2-amine: 100531] 3-chlom-6-(5-chlom-2-fluoropyñdin-4-yl)-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine (0.0347 g, 0.097 mmol), ethylboronic acid (0.014 g, 0.194 mmol), and sodium carbonate (0.126 ml g, 0.253 mmol, 2 M aq solution) were dissolved in DME (1 ml). The solution was then degassed by sparging with argon for 5 min. At this time it was treated with PdCl2 (dppf).CH2 Cl2 adduct (0.016 g, 0.019 mmol). The reaction mixture was then heated in the microwave at 115°C for 25 min. More ethylboronic acid (0.014 g, 0.194 mmol) and PdCl2 (dppf).CH2 Cl2 adduct (0.016 g, 0.019 mmol) were added. The reaction mixture was then heated in the microwave at 115°C for 25 min. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford 0.0709 g of crude product. The material was purified using the Isco with a 4 g SiO2 column. The resulting residue was subjected to silica gel column chromatography. Elution using 20 EtOAc / 80 heptane to EtOAc / 30 heptane gave 0.0049 g (14%) of 6-(5-chloro-2-fluoropyridin-4-yl)-3-ethyl-NWO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 ((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amine. LCMS (m/z): 351.1 (MH÷), retention time = 0.97 min. 100532] Step 2. Preparation of trans-N -(5-chloro-4-(5-ethyl-6-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-l,4-diamine: 1005331 6-(5-chloro-2-fluoropyridin-4-yl)-3-ethyl-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazine-2-amine (0.0053 g, 0.015 mmol) was dissolved in DMSO (1 ml). This was treated with 1,4-diaminocyclohexane (0.017 g, 0.151 mmol). The reaction mixture was then heated at 100°C for 4 hr. Additional 1,4-diaminocyclohexane (0.017 g, 0. t 51 mmol) and triethylamine (0.0084 ml, 0.012 g, 0.060 mmol) were added. Heating at 100°C was continued for 17 hr. The reaction mixture was purified using prep HPLC. The material was purified by preparative reverse-phase HPLC to give 0.0040 g oftrans-NL(5-chloro-4-(5-ethyl-6- ((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane1,4-diamine as the TFA sait. LCMS (m/z): 445.2 (MH+), retention time = 0.54 min. Example 37 (Compound 255) trans-N1 -(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)amino-3- (trifluoromethyl)pyrazin-2yl)pyridin-2-yl)cyclohexane1,4diamine H N Ne. C1i "]"N H2 Step 1. Preparation of 6-chloro-5-iodo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine: WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1005341 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (0.250 g, 1.098 mmol) was dissolved in a mixture of DMSO (4.30 ml) and H2 0 (0.105 ml). It was cooled to 0°C in an ice bath and was then treated with N-iodosuccinimide (0.247 g, 1.098 mmol) by portionwise addition. Once the addition was complete the reaction mixture was stirred at ambient temperature for 24 hr. Additional NIS (0.025 g, 0.111 mmol) was added. Stirring at ambient temperature was continued for 24 hr. The reaction mixture was diluted with H2 0 (50 ml). This was extracted with EtOAc (3 x 50 ml). The organic layers were combined and washed with brine (1 x 50 ml). The oranic layer was dried (Na2 SO4 ), filtered, and the solvent removed in vacuo to give 0.410 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 30 EtOAc / 70 heptane to 100 EtOAc gave 0.2144 g (55%) of 6chloro-5-iodo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine. LCMS (m/z): 353.9 (MH+), retention time = 0.92 min. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.37 (qd, 2 H) 1.59 (s, 2 H) 1.67 (d, J=-12.91 Hz, 2 H) 1.77 -1.94 (m, J=14.87, 7.63, 7.63, 3.52 Hz, I H) 3.25 (t, J--6.46 Hz, 2 H) 3.39 (td, J=l 1.74, 1.96 Hz, 2 H) 4.00 (dd, J=l 1.15, 3.72 Hz, 2 H) 4.80 (br. s., 1 H) 7.62 (s, 1 H). 100535] Step 2. Preparation of t-butyl-6-chloro-5-iodopyrazin-2-yl((tetrahydro-2H-pyran4-yl)methyl)carbamate: 6-chloro-5-iodo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (0.0801 g, 0.227 mmol) was dissolved in anhydrous DMF and placed under nitrogen. It was then treated with sodium hydride (0.0109 g, 0.272 mmol, 60% dispersion in mineral oil) followed by di-t-butyldicarbonate (0.099 g, 0.453 mmol). The reaction mixture was then stirred at 50°C for 24 hr. More Nail (0.0109 g, 0.072 mmol) and Boc2 0 (0.099 g, 0.453 mmol) were added. The reaction mixture was then heated at 70°C for 18 hr. The reaction mixture was cooled to ambient temperature, and then it was poured into brine (25 ml). This was extracted with EtOAc (3 x ml). The combined extracts were washed with H2 0 (3 x 25 ml) followed by brine (1 x 25 ml). The organic layer was dñed (Na2 SO4 ), filtered, and the solvent removed in vacuo to yield 0.0846 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 25 EtOAc / 75 heptane to 75 EtOAc / 25 heptane gave 0.0569 g (55%) oft-butyl6-chloro-5-iodopyrazin-2-yl((tetrahydro-2H-pyran-4-yl)methyl)carbamate. LCMS (m/z): 454.0 (MH+), retention time = 1.20 min. IH NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 - 1.46 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 (m, 4 H) 1.46 - 1.64 (m, 26 H) 1.81 - 2.02 (m, 2H) 3.26 - 3.42 (m, 3 H) 3.86 (d, J=7.04 Hz, 3 H) 3.96 (dd, J=l 1.54, 2.93 Hz, 3 H) 8.86 (s, 1 H). 1005361 Step 3. Preparation of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5- (trifluoromethyl)pyrazin-2-amine t-butyl-6-c hloro-5-iodopyrazin-2-yl((tetrahydro-2 H-pyran-4-yl)methyl)carbamate (0.0569 g, 0.125 mmol), methyl 2-chloro-2,2-difluoroacetate (0.047 ml, 0.063 g, 0.439 mmol), potassium fluoride (0.015 g, 0.251 mmol), and copper (I) iodide (0.100 g, 0.527 mmol) were dissovled in anhydrous DMF (0.80 ml) and placed under argon. The reaction mixture was then heated at 115°C for 17 hr. It was allowed to cool to ambient temperature. The reaction mixture was filtered through a pad of Celite. The filtrate was poured into brine (25 ml). This was extracted with EtOAc (3 x 25 ml). The combined extracts were washed with H2 0 (1 x 25 ml) followed by brine (1 x 25 ml). The organic layer was dried (Na2 SO4 ), filtered, and the solvent removed in vacuo to give 0.0401 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 25 EtOAc / 75 heptane to 100 EtOAc gave 0.0569 g (55%) of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(tfifluoromethyl)pyrazin-2amine. LCMS (m/z): 296.0 (MH ), retention time -- 0.93 min. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.39 (qd, J=12.33, 4.50 Hz, 2 H) 1.68 (d, J=l 1.35 Hz, 3 H)1.80 - 2.00 (m, J=14.87, 7.63, 7.63, 3.52 Hz, 1 H) 3.32 - 3.47 (m, 4 H) 4.01 (dd, J=l 1.35, 3.52 Hz, 2 H) 5.26 (br. s., 1 H) 7.76 (s, 1 H). Step 4. Preparation of 6-(5-chloro-2-fiuoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)- 5-(trifl uoromet hyl)pyrazin-2-amine 100538] 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrazin-2amine (0.020 g, 0.068 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (0.036 g, 0.203 mmol), and sodium carbonate (0.088 ml, 0.176 mmol, 2 M in H2 0) were dissolved in DME (0.70 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf) CH2 C12 adduct (0.011 g, 0.014 mmol). The reaction mixture was then heated in a microwave at 110°C for 25 min. Boronic acid (-0.036 g, 0.203 mmol) and PdCl2 (dpptì) CH2 C12 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 adduct ( 4).011 g, 0.014 mmol) were added. Heating in the microwave was continued at 110°C for 25 min. The reaction mixture was then filtered through a pad of Celite. The filtrate was then concentrated in vacuo to give 0.0759 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 25 EtOAc / 75 heptane to 100 EtOAc gave 0.0178 g (67%) of 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-5- (trifluoromethyl)pyrazin-2-amine. LCMS (m/z): 391.1 (MH+), retention time = 0.96 min. Step 5. Preparation oftrans-Ni-(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)amino-3- (trifluoromethyl)pyrazin-2-yl)pyridin-2-yt)cyclohexane-l,4-diamine [005391 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)- 5- (trifluoromethyl)pyrazin-2-amine (0.0178 g, 0.046 mmol) was dissolved in anhydrous DMSO (1.0 ml) and charged to a microwave vial. This was treated with trans-cyclohexane-1,4-diamine (0.052 g, 0.456 mmol). The reaction mixture was then heated at 100°C for 18 hr. The reaction mixture was allowed to cool to ambient temperature. The material was purified by preparative reverse-phase HPLC to give 0.0086 g (32%) of tmns-Nl-(5-chloro-4-(6-((tetrahydro-2H-pyran-4yl)methyl)amino-3-(trifluoromethyl)pyrazìn-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine as the TFA salt. LCMS (m/z): 485.3 (MH+), retention time -- 0.63 min. Example 38 (.Compound 260) N2'-(trans 4-amin cyc hexy )-3-ch r -5' u r -N6-((tetrahydr -2H-pyran-4-y )methy )-2 4 - bipyridine-2',6-diamine H ì N ì].,,NH2 Step 1. Preparation of 2,5-difluoropyridin-4-ylboronic acid WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 |005401 Diisopropylamine (1.74 ml, 1.24 g, 12.20 mmol) was dissolved in anhydrous THF (22 ml) and placed under argon. The solution was cooled to -20°C and then treated with nbutyllithium (7.66 ml, t2.25 mmol, t.6 M in hexanes) by slow addition over 10 min. The newly formed LDA (LDA -- lithium diisopropylamide, this acronyl should be listed in the general session) was then cooled to -78°C and treated with a solution of 2,5-difluoropyridine (1.05 ml, 1.33 g, 11.56 mmol) dissolved in anhydrous THF (3 ml) by slow addition over 30 min. Once the addition was complete the reaction mixture was allowed to stir at -78°C for 4 hr. At this time the reaction mixture was treated with a solution oftriisopropyl borate (5.90 ml, 4.78 g, 25.4 mmol) dissolved in anhydrous THF (8.6 ml) by dropwise addition. Once the addition was complete the reaction mixture was allowed to warm to ambient temperature then stired at ambient temperature for an additional hour. The reaction mixture was then quenched by adding 4% aq NaOH (34 ml). The layers were separated and the aqueous layer was cooled in an ice bath. It was then acidified to pli = 4 with 6N HC1 (- 10 ml) not letting the temperature go above 10°C. This was then extracted with EtOAe (3 x 50 ml). The extracts were then washed with brine (1 x 50 ml), dried (Na2 SO4 ), filtered, and the solvent removed in vacuo. The resulting residue was triturated with Et20 to give 0.8084 g (44%) of 2,5-difluoropyridin-4-ylboronic acid. Step 2. Preparation of 3-chloro-2',5'-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine 100541] 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (0.500 g, 1.64 mmol), 2,5-difluoropyridin-4-ylboronie acid (0.260 g, 1.64 mmol), and sodium carbonate (2.45 ml, 4.9t mmol, 2 M in H2 0) were dissolved in DME (7.36 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2 (dppf) CH2 C12 adduct (0.267 g, 0.327 mmol). The reaction mixture was then heated in the microwave at 105°C for min. More boronic acid (0.260 g, t.64 mmol) and PdCl2 (dppf) CH2 C12 adduct (0.267 g, 0.327 mmol), and }t2 0 (-2 ml) were added. Heating in the microwave was continued at 110°C for min. The reaction mixture was then filtered through a pad of Celite. The filtrate was then concentrated in vacuo to give 1.2090 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 10 EtOAc / 90 heptane to 80 EtOAc / heptane gave 0.3584 g (65%)of 3-chloro-2',5'-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)- WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 2,4'-bipyridin-6-amine. LCMS (m/z): 340.0 (MH÷), retention time = 0.90 min. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.37 (qd, 3 H) 1.60 (br. s., 2 H) 1.68 (d, J=-12.91 Hz, 3 H)1.84 (ddd, J=-I 1.15, 7.24, 4.30 Hz, 1 H) 3.21 (t, J=6.26 Hz, 2 H) 3.32 - 3.45 (m, 3 H) 4.00 (dd, J=-I 1.15, 3.72 Hz, 2 H) 4.74 (br. s., 1 H) 6.45 (d, ./--9.00 Hz, 1 H) 6.99 - 7.07 (m, 1 H) 7.51 (d, J=-8.61 Hz, 1 H) 8.12 (s, 1 H). Step 3. Preparation of N2'-(trans-4-aminocyclohexyl)-3-chloro-5'-fluoro-N6-((tetrahydro-2Hpyran-4-yl) methyl)-2,4'-bipyridine-2',6-diamine 1005421 3chloro-2',5'-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyddin-6amine (0.0509 g, 0.150 mmol) was dissolved in anhydrous DMSO (3.0 ml) and charged to a microwave vial. This was treated with trans-cyclohexane-1,4-diamine (0.171 g, 1.498 mmol). The reaction mixture was then heated at 100°C for 18 hr. More trans-cyclohexane-l,4-diamine (0.171 g, 1.498 mmol) was added and the reaction mixture was stirred at 120°C for 18 hr. The reaction mixture was allowed to cool to ambient temperature. The material was purified by preparative reverse-phase HPLC to give 0.2410 g (30%) of N2'-(trans-4-aminocyclohexyl)-3- h ro-5' f u r -N6-((tetrahydro-2H-pyran-4-y )methy )-2 4'-bipyridine-2' 6-diamine as the TFA sait. LCMS (m/z): 434.2 (MH+), retention time = 0.55 min. Example 39 (Compound 282) N2'-(trans-4-amin cyc hexy )-5 -ch r -3u r -N6-((tetrahydro 2H pyran-4 y )methy )-2,4'- bipyridine-2',6-diamine H I N NCI "'NH2 F N H WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step l. Preparation oftrans-Nl-(5'-chloro-3,6-difluoro-2,4'-bipyridin-2'- yl)cyclohexane1,4-diamine: To a solution of 5'-chloro-2',3,6-tñfluoro-2,4'-bipyfidine (95 mg, 0.388 mmol) in DMSO (2.5 mL) was added trans-1,4-diaminocyclohexane (177 mg, 1.55 mmol). The mixture was stirred at 90 °C for 2 hr. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2SO4), filtered, and concentrated to give 137 mg of crude trans-N 1-(5'-chloro-3,6-difluoro-2,4'-bipyddin-2'- yl)cyclohexane1,4-diamine which was used without further purification. LCMS (m/z): 339.0 (MH+), retention time = 0.54 min Step 2. Preparation of N2'-(trans-4-aminocyclohexyl)-5'-chloro-3-fluoro-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamin« To a solution oftrans-N l-(5'- chloro-3,6-difluoro-2,4'-bipyridin-2'-yl)cyclohexane-l,4-diamine (79 mg, 0.388 mmol) in DMSO (1.5 ml) was added 4-aminomethyltetmhydropyran (161 mg, 1.40 mmol). The mixture was irradiated by microwave at 180 °C for 1 hr in a sealed microwave vial. The crude reaction mixture was purified by reverse phase HPLC and lyophilized to give N2'-(trans-4aminocyclohexyl)-5'-chloro-3 -fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyfi dine2',6-diamine as its TFA salt. LCMS (m/z): 434.2 (Mid+), retention time = 0.57 min.; 1H NMR (400 MHz, DMSO-d6) 6 ppm 1.07 - 1.32 (m, 2 H) 1.32 - 1.49 (m, 1 H) 1.59 (d, J=12.91 Hz, l H) 1.68 - 1.83 (m, l H) 1.96 (dd, 2 H) 2.93 - 3.04 (m, 1 H) 3.06 (d, J--6.65 Hz, 1 H) 3.24 (t, J=10.76 Hz, 1 H) 3.54 - 3.70 (m, 1 H) 3.82 (dd, J=10.96, 2.74 Hz, 1 H) 6.53 (s, 1 H) 6.57 (dd, J=9.19, 2.93 Hz, 1 H) 7.41 (t, 1 H) 7.79 (d, J=3.91 Hz, 2 H) 8.04 (s, 1 H) WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 40 (Compound 283) 5'-chloro-3-flu oro-N2'-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran4-yl)methyl)-2,4'-bipyridine-2',6-diamine H C N= - " " %.ó [005461 Preparation of 5'-chloro-3-fluoro-N2'-(trans-4-(2meth xyethylamin )cycl hexyl)-N6-((tetrahydr -2H-pyran-4-y )methy )-2 4'-bipyridine-2' 6diamine: To a mixture of N2'-(trans-4-aminocyclohexyl)-5'-chloro-3-fluoro-N6-((tetrahydro-2Hpymn-4-yl)methyl)-2,4'-bipyridine-2',6-diamine trifluoroacetate (30 mg, 0.055 mmol) and sodium carbonate (23 mg, 0.22 mmol) in DMSO (0.75 ml) was added p-toluenesulfonic acid 2methoxyethyl ester (l 5 mg, 0.066 mmol). The mixture was stirred at 85 °C for 20 hr in a sealed microwave vial. The cooled reaction mixture was filtered. The filtrate was purified by reverse phase HPLC and lyophilized to give 5.0 mg of 5'-chloro-3-fluoro-N2'-(trans-4-(2meth xyethy amin )cycl hexyl)-N6-((tetrahydr -2H-pyran-4-yl)methyl)-2 4'-bipyridine-2' 6diamine as its TFA sait. LCMS (m/z): 492.2 (MH+), retention time = 0.57 min.; l H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.10 - 1.46 (m, 6 H) 1.64 - 1.74 (m, 2 H) 1.86 (hr. s., 2 H) 1.95 - 2.09 (m, 2 H) 2.09 - 2.26 (m, 2 H) 2.58 (hr. s., l H) 2.88 (t, J=5.09 Hz, 2 H) 3.17 (t, J=6.26 Hz, 2 H) 3.29 - 3.45 (m, 5 H) 3.53 (t, ./--5.09 Hz, 3 H) 4.00 (dd, J=-I 1.35, 3.52 Hz, 2 H) 4.34 - 4.47 (m, 1 H) 4.54 - 4.68 (m, l H) 6.35 - 6.48 (m, 2 H) 7.31 (t, J=-8.80 Hz, l H) 8.11 (s, 1 H). Example 41 (Compound 286) N2 (trans 4 amin cyc hexy )-3 br m -5 h r -N6-((tetrahydr -2H-pyran-4-y )methy )-2 4'- bipyñdine-2',6-diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Preparation of N2'-(trans-4-aminocyclohexyl)-3-bromo-5'-chloro-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine: To a solution of 3-bromo-5'- chloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyñdin-6-amine (100 mg, 0.250 mmol) in DMSO (1 mL) was added trans-l,4-diaminocyclohexane (114 mg, 0.998 mmol). The mixture was stirred at 110 °C for 19 hr. The crude reaction mixture was purified by reverse phase HPLC and lyophilized to give 51 mg of N2'-(trans-4-aminocyclohexyl)-3-bromo-5'- chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine as its TFA sait. LCMS (m/z): 494.2/496.1 (MH+), retention time = 0.61 min; 1H NMR (400 MHz, DMSO-d6) d ppm 1.06 - 1.31 (m, 4 H) 1.31 - 1.49 (m, 2 H) 1.49 - 1.64 (m, 2 H) 1.64 - 1.82 (m, 1 H) 1.85 - 2.11 (m, 4 H) 2.93 - 3.12 (m, 3 H) 3.22 (t, J=10.96 Hz, 2 H) 3.61 (t, J=10.76 Hz, 1 H) 3.81 (dd, J=l 1.35, 2.74 Hz, 2 H) 6.39 (s, 1 H) 6.48 (d, 1 H) 6.82 (br. s., 1 H) 6.94 (br. s., 1 H) 7.59 (d, J=9.00 Hz, 1 H) 7.78 (d, J=3.91 Hz, 2 H) 8.02 (s, 1 H) Example 42 (Compound 288) (R)-3-(trans-4-(5'-ch r -6-((tetrahydr -2H-pyran-4-y )methy )amin -2 4'-bipyridin-2'-y - amino)cyclohexylamino)- 1,1,1-trifluoropropan-2-ol H WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100548| Step 1. Preparation of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-((tetrahydro2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine: To a solution of 5'-chloro-2'-fluoro-N- ((tetrahydro-2 H-pyran-4-yl)methyl)-2,4'-bipyridin-6-amine (500 mg, 1.55 mmol) in DMSO (7 mL) was added trans1,4-diaminocyclohexane (710 mg, 6.22 mmol). The mixture was stirred at °C for 19 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dñed over sodium sulfate, filtered, and concentrated to give 600 mg of N2'-(trans-4-aminoeyclohexyl)-5'- chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine. LCMS (m/z): 416.1 (MH+), retention time = 0.48 min. [005491 Step 2. Preparation of(R)-3-(trans-4-(5'-chloro-6-((tetrahydro-2H-pyran-4yl)methyl)amino-2,4'-bipyridin-2'-yl-amino)cyclohexylamino)- 1,1, l-trifluoropropan-2-oh To a solution of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)- 2,4'-bipyridine-2',6-diamine (50 mg, 0.120 mmol) in 2-propanol (0.8 mL) was added (R)-(+)- 3,3,3-trifluoro-l,2-epoxypropane (10.4 uL, 0.120 mmol). The mixture was stirred at 60 °C for 17 hr. The reaction mixttLre was concentrated. The resulting residue was purified by reverse phase HPLC and lyophilized to give 63 mg of (R)-3-(trans-4-(5'-chloro-6-((tetrahydro-2H-pyranJ 4-yl)methyl)amino-2,4'-bipyridin-2'-yl-amino)cyclohexylamino)- 1,1,1 -trifluoropropan-2-ol as its TFA sait. LCMS (m/z): 528.3 (MH+), retention time = 0.53 min; IH NMR (400 MHz, DMSOd6) ô ppm 1.08 - 1.34 (m, 4 H) 1.36 - 1.56 (m, 2 H) 1.61 (d, J=12.52 Hz, 2 H) 1.70 - 1.90 (m, 1 H) 2.04 (d, J=-9.39 Hz, 3 H) 2.13 (d, J=-I 1.74 Hz, 1 H) 2.97 - 3.19 (m, 4 H) 3.24 (t, J=10.76 Hz, 3 H) 3.64 (d, J=-10.96 Hz, 1 H) 3.83 (dd, J=10.96, 2.74 Hz, 2 H) 4.36 - 4.50 (m, 2 H) 6.54 - 6.68 (m, 2 H) 6.70 (d, J=7.04 Hz, 0 H) 6.94 (br. s., 0 H) 7.23 (br. s., 0 H) 7.53 (br. s., 0 H) 8.04 (s, 0 H) 8.76 (br. s., 2 H) Example 43 (Compound 289) (S)-3-(trans-4-(3 5'-dich r -6-((tetrahydm 2H-pyran-4-y )methy )amin -2 4 -bipyridin-2'-y - amino)cyclohexylamino)- 1,1, l-trifluoropropan-2-ol WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H N Ni-_ Step I. Preparation of N2'-(trans-4-aminocyclohexyl)-3,5'-dichloro-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine: To a solution of 3,5'-diehloro2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridin-6-amine (500 mg, 1.40 mmol) in DMSO (8 mL) was added trans-l,4-diaminoeyclohexane (641 mg, 5.61 mmot). The mixture was stirred at 95 °C for 38 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (dichtoromethane/methanol gradient) to give 480 mg of N2'- (trans-4-amin cycl hexyl)-3 5'-dieh r -N6-((tetrahydr -2H-pyran-4-y )methy )-2 4'-bipyridine2',6-diamine. LCMS (m/z): 450.2 (MH+), retention time = 0.55 min. [005511 Step 2. Preparation of(S)-3-(trans-4-(3,5'-dichloro-6-((tetrahydro-2Hpyran-4yt)methyt)amino-2,4'-bipyridin-2'-yl-amino)cyctohexylamino)- t, 1,1-trifluoropropan-2-oh To a solution of N2'-(trans-4-amin yc hexy )-3 5'-dich r -N6-((tetrahydr -2H-pyran-4-y )methy )- 2,4'-bipyridine-2',6-diamine (54 mg, 0. t20 mmol) in 2-propanol (0.4 mL) was added (S)-(-)- 3,3,3-trifluoro-l,2-epoxypropane (10.4 uL, 0.120 mmol). The mixture was stirred at 70 °C for 2 hr. The reaction mixture was concentrated. The resulting residue was purified by reverse phase HPLC and tyophilized to give 32 mg of (S)-3-(trans-4-(3,5'-dichloro-6-((tetrahydro-2H-pyran-4yl)methyl)amino-2,4'-bipyridin-2'-yl-amino)cyelohexylamino)- I, I, 1 -trifluoropropan-2-ol as its TFA sait. LCMS (m/z): 562.3 (MH+), retention time = 0.70 min; IH NMR (400 MHz, DMSOd6) 6 ppm 1.0t - 1.33 (m, 4 H) 1.35 - 1.65 (m, 4 H) 1.64 - t.84 (m, I H) 1.93 -2.23 (m, 4 H) 2.94 - 3.18 (m, 4 H) 3.17 - 3.35 (m, 3 H) 3.53 - 3.69 (m, 1 H) 3.81 (dd, J=t 1.35, 2.74 Hz, 2 H)4.33 - 4.48 (m, t H) 6.38 (s, I H) 6.55 (d, t H) 6.82 (br. s., 1 H) 6.93 (br. s., 1 H) 7.23 (br. s., I H) 7.48 (d, IH) 8.02 (s, 1 H) 8.72 (br. s., 2 H) WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 44 (Compound 292) 3-br m 5 -ch r -N2 -(trans-4-(2-meth xyethy amin )cyc hexy )-N6-((tetrahydr -2H pyran4-yl)methyl)-2,4'-bipyridine-2',6-diamine H Preparation of 3-bromo-5'-chloro-N2'-(trans-4-(2meth xyethy amin ) yc hexy )-N6-((tetrahydr -2H-pyran-4-y )methy )-2 4 -bipyridine-2' 6diamine: To a mixture of N2'-(trans-4-aminocyclohexyl)-3-bromo-5'-chloro-N6-((tetrahydro2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine (30 mg, 0.061 mmol) and sodium carbonate (19 mg, 0.18 mmol) in DMSO (0.6 ml)was added p-toluenesulfonic acid 2-methoxyethyl ester (21 mg, 0.091 mmol). The mixture was stirred at 85 °C for 20 hr in a sealed microwave vial. The cooled reaction mixture was filtered. The filtrate was concentrated and the resulting residue was purified by reverse phase HPLC and lyophilized to give 3.8 mg of 3-bromo-5'-chloro-N2'- (trans-4-(2-meth xyethy amin ) y hexy )-N6-((tetrahydr -2H-pyran-4-y )methy )-2 4'- bipyridine-2',6-diamine as its TFA sait. LCMS (m/z): 554.1 (MH+), retention time = 0.61 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 45 (Compound 295) 3,5 -dichl r -N6-((tetrahydr -2H-pyran-4-yl)methyl)-N2'-(trans-4-((R)-3,3,3-tri u r -2methoxypropylamino)cyclohexyl)-2,4'-bipyddine-2',6-diamine H H Preparation of 3,5'-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4- ((R)-3 3 3-tri u r -2-meth xypr pylamin )cycl hexyl)-2 4'-bipyridine-2' 6-diamine: To a solution of 3 5 -di hl r -2 - u r -N ((tetrahydr -2H-pyran-4-yl)methyl)-2 4'-bipyridin 6-amine (36 mg, 0.10 mmol) in DMSO (0.4 mL)was added trans-Nl-((R)-3,3,3-trifluoro-2methoxypropyl)cyclohexane-l,4-diamine (48 mg, 0.20 retool) and 2,6-1utidine (0.023 mL, 0.20 retool). The mixture was stirred at 120 °C for 20 hr. The cooled reaction mixture was purified by reverse phase HPLC and lyophilized to give 11.4 mg of 3,5'-dichloro-N6-((tetrahydro-2Hpyran 4-yl)methy1)-N2 -(trans 4-((R) 3 3 3-tri u r -2-meth xypr py1amin )cycl hexyl) 2 4'- bipyridine-2',6-diamine as its TFA sait. LCMS (m/z): 576.2 (MH+), retention time = 0.68 rein. Example 46 (Compound 297) trans-4-(3 5 -dichl r -6-((2 2-dimethy tetrahydr -2H-pyran 4-y )methy )amin -2 4'-bipyridin-2 - yl-amino)cyclohexanol H IN hiA ï3.,,o. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Preparation of trans-4-(3,5'-dichloro-6-((2,2-dimethyltetrahydro-2H-pymn-4yl)methyl)amino-2,4'-bipyridin-2'-yl-amino)cyclohexanoh To a solution oftert-butyl 3,5'- dich r -2'- u r -2 4'-bipyridin-6-y ((2 2-dimethy tetrahydr -2H-pyran-4-y )methy )carbamate (30 mg, 0.062 mmol) in DMSO (0.4 mL) was added trans-4-aminocyclohexanol (36 mg, 0.31 mmol) and DIEA (0.022 mL, 0.12 mmol). The mixture was stirred at 135 °C for 3 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The resulting residue was re-dissolved in tfifluoroacetic acid (1 mL), stirred for 15 min at ambient temperature, and then concentrated under reduced pressure. The crude resulting residue was puñfied by reverse phase HPLC and lyophilized to give 23 mg of trans-4-(3,5'-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4yl)methyl)amino-2,4'-bipyridin-2'-yl-amino)cyclohexanol as its TFA sait. LCMS (m/z): 479.3 (MH+), retention time = 0.72 min; 1H NMR (400 MHz, DMSO-d6) 6 ppm 0.96 (d, J=l 2.91 Hz, 2 H) 1.08 (s, 6 H) 1.15 - 1.35 (m, 4 H) 1.54 (d, J=-12.91 Hz, 2 H) 1.71 - 2.10 (m, 5 H) 3.00 (d, J=-6.65 Hz, 2 H) 3.31 - 3.63 (m, 5 H) 6.47 (s, 1 H) 6.58 (d, 1 H) 7.50 (d, J=-9.00 Hz, 1 H) 8.05 (s, 1 H) Example 47 (Compound 298) (2S)-3-(trans-4-(3,5 -dich r -6-((2 2-dimethy tetrahydr -2H-pyran-4-y )methy )amin -2 4'- bipyridin-2'-yl-amino)cyclohexylamino)- 1,1,1 -trifluoropropan-2-o I H H 100555] Step 1. Preparation of N2'-(trans-4-aminocyclohexyl)-3,5'-dichloro-N6-((2,2dimethyltetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine: To a solution oftertbutyl 3,5'-dichloro-2'-fluoro-2,4'-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4yl)methyl)carbamate (40 mg, 0.083 mmol)in DMSO (0.4 mL) was added trans-1,4WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 diaminocyclohexane (47 mg, 0.41 mmol) and DIEA (0.029 mL, 0.17 mmol). The mixture was stirred at 120 °C for 2 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dñed over sodium sulfate, filtered, and concentrated. The resulting residue was re-dissolved in trifluoroacetic acid (1 mL), stirred for 15 min at ambient temperature, and then concentrated under reduced pressure. The resulting residue was taken up in DCM, washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered, and concentrated to give 39 mg of N2'- (trans-4-amin y hexy )-3 5'-di h r -N6-((2 2-dimethy tetrahydr -2H-pyran-4-y )methy )- 2,4'-bipyñdine-2',6-diamine. LCMS (m/z): 478.4 (MH+), retention time = 0.64 min. [005561 Step 2. Preparation of(S)-3-(trans-4-(3,5'-dichloro-6-((tetrahydro-2H-pyran-4yl)methyl)amino-2,4'-bipyridin-2'-yl-amino)eyclohexylamino)- l, l, 1 -trifluoropropan-2-oh To a solution of N2'-(trans-4-amin cycl hexyl)-3 5'-di hl r -N6-((2 2-d methyltetrahydr -2H-pyran4-yl)methyl)-2,4'-bipyridine-2',6-diamine (l 9 mg, 0.040 mmol) in 2-pmpanol (0.3 mL) was added (S)-(-)-3,3,3-trifluoro-l,2-epoxypropane (3.4 uL, 0.040 mmol). The mixture was stirred at °C for 2 hr. The reaction mixture was concentrated. The resulting residue was purified by reverse phase HPLC and lyophilized to give 9.1 mg of (2S)-3-(trans-4-(3,5'-dichloro-6-((2,2dimethyltetrahydr -2H-pyran-4-yl)methyl)amin -2 4'-bipy din-2'-yl-amin )cycl hexylamin )- 1, l, 1-trifluoropmpan-2-ol as its TFA salt. LCMS (m/z): 590.5 (MH+), retention time = 0.71 min; 1H NMR (400 MHz, DMSO-d6) 6 ppm 0.81 - 1.32 (m, 12 H) 1.33 - 1.66 (m, 4 H) 1.82 - 1.99 (m, 1 H) 1.99 -2.21 (m, 4 H) 2.89 - 3.04 (m, 2 H) 3.04 - 3.19 (fa, 2 H) 3.27 (d, J=2.35 Hz, 2 H) 4.40 (hr. s., l H) 6.38 (s, l H)6.55 (d, J=9.00 Hz, 1 H) 6.77 (hr. s., 1 H) 6.91 (hr. s., I H) 7.21 (br. s., 1 H) 7.48 (d, J--9.00 Hz, 1 H) 8.03 (s, 1H) Example 48 (Compound 301) 5'-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4-(2- (trifluoromethoxy)ethylamino)cyclohexyl)-2,4'-bipyridine-2',6-diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H N N. i- Preparation of 5'-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4-(2- (trifluoromethoxy)ethylamino)cyclohexyl)-2,4'-bipyridine-2',6-diamine: To a mixture of N2'- (trans 4 amin cycl hexyl)-5'-chl r -N6-((tetrahydr -2H-pyran-4-yl)methyl)-2 4'-bipyridine2',6-diamine (42 mg, 0. l 0 mmol) and triethylamine (0.028 mL, 0.20 mmol) in chloroform (0.4 ml) was added 2-(trifluoromethoxy)ethyl tdfluoromethanesulfonate (39 mg, 0. t 5 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC, and tyophilized to give 32 mg of 5'- chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4-(2- (trifluoromethoxy)ethylamíno)cyclohexyl)-2,4'-bipyddine-2',6-diamine as its TFA sait. LCMS (m/z): 528.4 (MH+), retention time = 0.53 min.; IH NMR (400 MHz, DMSO-d6) d ppm 1.09 - t.34 (m, 4 H) 1.35 - 1.54 (m, 2 H) 1.55 - 1.69 (m, 2 H) 1.73 - 1.89 (m, 1 H) t.94 - 2.17 (m, 4 H) 3.04 - 3.t5 (m, 1 H) 3.t4 - 3.20 (m, 2 H) 3.20 - 3.30 (m, 2 H) 3.30 - 3.47 (m, 2 H) 3.55 - 3.72 (m, l H) 3.84 (dd, 3"--11.15, 2.54 Hz, 2 H) 4.35 (t, 3"--4.70 Hz, 2 H) 6.65 (s, l H) 6.67 - 6.83 (m, 2 H) 7.05 (hr. s., 0 H) 7.46 - 7.68 (m, 0 H) 8.06 (s, 0 H) 8.82 (d, J=3.52 Hz, 2 H) Example 49 (Compound 302) 3,5'-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyt)-N2'-(trans-4-(2- (trifluoromethoxy)ethylamino)cyclohexyl)-2,4'-bipyridine-2',6-diamíne WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H H 1005591 Preparation of 3,5'-dichioro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4- (2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4'-bipyridine-2',6-diamine: To a mixture of N2'- (trans-4-am n eye hexy )-3 5'-dich r -N6-((tetrahydr -2H-pyran14-y )methy )-2 4'-bipyridine2',6-diamine (45 mg, 0.10 mmol) and triethylamine (0.028 mL, 0.20 mmol) in chloroform (0.4 ml) was added 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (39 mg, 0.15 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC, and lyophilized to give 29 mg of 3,5'- dichloro-N6-((tetrahydro-2 H-pyran-4-yl)methyl)-N2'-(trans-4-(2- (trifluoromethoxy)ethylamino)cyelohexyl)-2,4'-bipyfidine-2',6-diamine as its TFA sait. LCMS (m/z): 562.4 (MH+), retention time - 0.67 min.; 1H NMR (400 MHz, DMSO-d6) 6 ppm 1.07 - 1.32 (m, 4 H) 1.36 - 1.52 (m, 2 H) 1.58 (d, 3"--12.91 Hz, 2 H) 1.65 - 1.84 (m, 1 H) 2.07 (d, J=-10.56 Hz, 4 H) 2.99 - 3.17 (m, 3 H) 3.23 (t, 3"--10.76 Hz, 2 H) 3.35 (br. s., 2 H) 3.64 (br. s., 1 H) 3.72 - 3.89 (m, 2 H) 4.34 (t, J--4.89 Hz, 2 H) 6.32 - 6.47 (m, 1 H) 6.49 - 6.65 (m, 1 H) 6.67 - 7.10 (m, 2 H) 7.49 (d, J-=-9.00 Hz, 1 H) 8.03 (s, 1 H) 8.75 (d, J=3.91 Hz, 1 H) Example 50 (Compound 284) N2'-(trans-4-aminocyclohexyl)-5'-chloro-N 6-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4yl)methyl)-2,4 -bipyridine-2,6-diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H CI N N "NH2 1005601 The mixture of 5'-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4yl)methyl)-2'-fluoro-2,4'-bipyridin-6-amine L (30mg, 0.08 mmol), trans-l,4-cyclohexanediarnine (49mg, 0.43 mmol) and triethylamine (26mg, 0.25 mmol) in 1.Sml DMSO was heated in a reaction vessel at 110°C in an oil bath for 16h. Formation of desired product was confirmed by LC/MS. The reaction mixture solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. Crude compound was purified by HPLC to give desired product as TFA salt. LCMS (m/z): 444.2/446.2 (MH+), retention time = 0.54 min. Example 51 (Compound 285) -ch r -N6 (((2R 6 ) 2 6-dimethy tetrahydr -2H-pyran-4-yl)methyl)-N2'-(trans-4-(2methoxyethylamino)cyclohexyl)-2,4'-bipyridine-2',6-diamine H 100561| The mixture of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(((2R,6S)-2,6dimethyl tetrahydro-2H-pyran-4-yl) methyl-2,4'-bipyridine-2',6-diamine Compound 284 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 (20mg, 0.045 mmol), p-toluenesulfonic acid 2-methoxyethyl ester (14mg, 0.06 mmol) and sodium carbonate (9.6mg, 0.09 mmol) in I ml DMSO was heated in a reaction vessel at 105°C in an oil bath for 3h. Formation of desired product was confirmed by LCMS, MH+ 502/504, 0.58min, with -50% conversion. Mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated. Crude product was purified by HPLC to give desired product as TFA sait. LCMS (m/z): 502.2/504.2, retention time = 0.56 min. Example 52 (Compound 191) N2'-((I R 3R) 3 amin cyc penty )-5'-ch r -N6-(3-f u r benzy )-2 4 -bipyridine-2' 6-diamine 1005621 Step 1. Preparation of6-bromo-N-(3-fluorobenzyl)pyridin-2-amine: To 2,6dibromopyridine (7.1 g, 30.0 mmol) was added NMP (16 ml), (3-fluorophenyl)methanamine (4.13 g, 33.0 mmol) and Huenig's Base (5.76 ml, 33.0 mmol) flushed with argon. The crude reaction mixture was stirred at 115-120 °C for 168 hr, followed by LCMS. The crude mixture was cooled, 250 ml of ethyl acetate was added, washed with saturated sodium bicarbonate (2x), water (2x), saturated salt solution (1 x), dried sodium sulfate, filtered, concentrate. The crude was purified by silica gel chromatography using 120g column, eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 7.11 grams of the title compound as a free base used without further purification. LCMS (m/z): 281.1/283.1 (MH+), retention time = 1.03 min. amine: Step 2. Preparation of 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100564] To 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (2.0 g, 7.11 mmol) was added 5chloro-2-fluoropyrídin-4-ylboronic acid (1.996 g, 11.38 mmol), PdC12(dppf).CH2C12 adduct (0.465 g, 0.569 mmol), DME (27 ml) and last 2M sodium carbonate (9.25 ml, 18.50 mmol). The crude reaction was stirred at 100 °C for 3 hr, followed by LCMS. The crude mixture was cooled, ml of ethyl acetate and 20 ml of methanol was added, filtered and concentrated to provide a crude product. The crude was purified by silica gel chromatography using a 120g column, eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 1.259 grams of titled compound as free base use with out further purification. LCMS (m/z): 332.2 (MH+), retention time = 0.92 min. Step3. Preparation of (1S,3R)-3-(5'-chloro-6-(3-fluorobenzylamino)-2,4'- bipyridin-2'-yl-amino)cyclopentanoh To 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyñdin-6amine (75 mg, 0.226 mmol), was added (1S,3R)-3-aminocyclopentanol (68.6 mg, 0.678 mmol), NMP (0.75 ml) and triethylamine (0.158 ml, 1.130 mmol). The crude reaction mixture was stirred at 100 °C for 18 hr, and and the reaction progress followed by LCMS. The crude reaction mixture was cooled, filtered, and purified by prep LC. The product fractions were collected, mL of I M NaOH and 50 mL of EtOAc were added. The aqueous layer was removed, the organic layer was washed with 50 mL of saturated sait solution, dried over sodium sulfate, and reduced to constant mass. 28 mg of the desired compound was obtained. LCMS (m/z): 413.1 (MH+), retention time = 0.67 min.; IH NMR (400 MHz, CHLOROFORM-d, 25°C) 6 ppm 1.71 (d,J= 14.09 Hz, 1 H) 1.751.91 (m, 2 H) 1.97-2.05 (m, 1 H) 2.10-2.16 (m, 1 H) 2.61 (br. s., 1 H) 4.03 - 4.18 (m, 1 H) 4.39 (tt, J = 4.84, 2.59 Hz, 1 H) 4.55 (d, J = 5.09 Hz, 2 H) 5.19 (br. s., 2 H) 6.41 (d, J = 8.22 Hz, 1 H) 6.55 (s, 1 H) 6.90 - 7.02 (m, 2 H) 7.05 - 7.18 (m, 2 H) 7.24 - 7.34 (m, 1 H) 7.43 - 7.55 (m, 1 H) 8.07 (s, 1 H). [005661 Step 4. Preparation of N2'-((1R,3R)-3-aminocyclopentyl)-5'-chloro-N6-(3fluorobenzyl)-2,4'-bipyridine-2',6-diamine: To (1S,3R)-3-(5'-chloro-6-(3-fluorobenzylamino)- 2,4'-bipyñdin-2'-yl-amino)cyclopentanol (28 mg, 0.068 mmol) was added DCM (1 ml), diisopropyl ethylamine (0.030 ml, 0.170 mmol) then mesyl chloride (5.81 lai, 0.075 mmol), stirred at ambient temperature for 1 hr, and followed by LCMS. Another 3 uL of mesyl chloride was added and the reaction mixture was stirred an additional 30 minutes at ambient temperature. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 DCM was removed by rotary evaporation, and crude (1S,3R)-3-(5'-chloro-6-(3fiuorobenzylamino)-2,4'-bipyridin-2'-yl-amino)cyclopentyl LCMS (m/z): 491.2 (MH+), retention time = 0.76 min. was redissolved in 2 mL DMF. Sodium amide (8.82 mg, 0.136 mmol) and diisopropyl ethylamine (0.030 ml, 0.170 mmol) were added, and the reaction mixture was heated at 50 °C for 18 hours, at which point only N2'-((1R,3R)-3-azidocyclopentyl)-5'-ehloro-N6-(3fiuorobenzyl)-2,4'-bipyridine-2',6-diamine was observed by LCMS (m/z): 438.2 (MH+), retention time = 0.83 min. The resulting reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was removed, and the organic layer was washed with water (1 x) then saturated sait solution (1 x), dried over sodium sulfate, and reduced to constant mass. Crude N2'-(( 1 R,3 R)-3-azidocyelopentyl)-5'-chloro-N6-(3fluorobenzyl)-2,4'-bipyridine-2',6-diamine (20 mg, 0.046 mmol, LCMS (m/z): 438.2 (MH+), retention time = 0.83 min.) was dissolved in 1 mL of methanol, and 10% palladium on charcoal (4.86 mg, 0.046 mmol) was added under argon. H2 was bubbled through the solution while stirring for 1 hr at ambient temperature, and the reaction was followed by LCMS. The crude reaction mixture was filtered over celite washed with methanol, reduced, redissolved in DMSO, filtered and purified through prep LC. The resulting product fractions were combined, then 50 mL of I M NaOH and 50 mL of EtOAC were added. The aqueous layer was removed, the organic layer was washed with saturated salt solution, dried over sodium sulfate, and reduced to constant mass. 8 mg of the desired compound was obtained. LCMS (m/z): 412.1 (MH+), retention time = 0.58 min.; 1H NMR (300 MHz, CHLOROFORM-d, 25 °C) õ ppm 1.31 - 1.54 (m, 2 H) 1.71 - 1.86 (m, 4 H) 1.98 - 2.13 (m, 1 H) 2.20 - 2.35 (m, 1 H) 3.54 (qd, J=6.35, 6.15 Hz, 1 H) 4.14 (sxt, J=6.56 Hz, 1 H) 4.55 - 4.67 (m, 3 H)5.11 (t,J=5.86 Hz, 1 H)6.40 (d, J=-8.50 Hz, 1 H)6.56 (s, 1 H)6.88-7.02 (m, 1 H) 7.12 - 7.16 (m, 1 H) 7.29 - 7.34 (m, 1 H) 7.47 - 7.52 (m, 1 H) 8.09 (s, 1 H). Example 53 (Compound 205) (1 S,3R)-3-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino)-N,Ndimethylcyclopentanecarboxamide WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Step 1. Preparation of6-bromo-N-(3-fluorobenzyl)pyridin-2-amine: To 2,6dibromopyridine (7.1 g, 30.0 mmol) was added NMP (16 ml), (3-fluorophenyt)methanamìne (4. t3 g, 33.0 mmol) and Huenig's Base (5.76 ml, 33.0 mmol) fushed with argon. The crude reaction mixture was stirred at 115-120 °C for 168 hr, followed by LCMS. The crude mixture was cooled, 250 ml of ethyl acetate was added, washed with saturated sodium bicarbonate (2x), water (2x), saturated salt solution (Ix), dried sodium sulfate, filtered, concentrate. The crude was purified by silica gel chromatography using 120g column, eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 7.11 grams of the titled compound as a free base used without further purification. LCMS (m/z): 281.1/283.1 (MH+), retention time = 1.03 min. 1005681 Step 2. Preparation of 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6amine: To 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (2.0 g, 7.11 mmol) was added 5-chtoro2-fluoropyridin-4-ylboronic acid (t.996 g, 11.38 mmol), PdCi2(dppf).CH2Cl2 adduct (0.465 g, 0.569 mmol), DME (27 ml) and last 2M sodium carbonate (9.25 ml, t8.50 mmol). The crude reaction mixture was stirred at t00 °C for 3 hr, followed by LCMS. The crude mixture was cooled, 25 ml of ethyl acetate and 20 mi of methanol was added, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using a 120g column, etuting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 1.259 grams of title compound as free base use with out further purification. LCMS (m/z): 332.2 (MH+), retention time = 0.92 min. [005691 Step 3: Preparation of (1S,3R)-3-(5'-chloro-6-(3-fluorobenzytamino)-2,4'- bipyridin-2'-yl-amino)cyclopentanecarboxylic acid: To 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)- WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 2,4'-bipyridin-6-amine (100 mg, 0.301 mmol), was added (1S,3R)-3aminoiyilopentaneearboxylic acid (117 mg, 0.904 mmol), powdered potassium hydroxide (85 mg, 1.507 mmot) and dioxane (1 ml). The reaction mixture was stirred at 100 °C for 18 hr in a sealed vessel and followed by LCMS. The crude reaction mixture was partitioned between mL saturated ammonium chloride and 30 mL ethyl acetate. The organic layer was removed, dried over sodium sulfate, and reduced. This was redissolved in 1.5 mL DMSO, filtered, and purified through prep LC. The product fractions were combined and extracted with 50 mL ethyl acetate, which was dried over sodium sulfate, and concentrated to constant mass. t0 mg of the desired compound was obtained. LCMS (m/z): 441.2 (MH+), retention time = 0.68 min. 1H NMR (400 MHz, CHLOROFORM-d, 25 °C) 6 ppm 1.59 (m, 2 H) 1.83 (m, 2 H) 1.99 (m, 1 H) 2.72 (m, 1 H) 3.40 (br. s., 1 H) 3.78 (br. s., 1 H) 4.42 (br. s., 1 H) 5.48 (br. s., 1 H) 6.29 (d, J=8.22 Hz, 1 H) 6.50 (s, 1 H) 6.80 - 6.92 (m, 2 H) 6.95 - 7.10 (m, 2 H) 7.16 - 7.25 (m, 1 H) 7.38 (t, J=8.02 Hz, 1 H)7.89 (s, 1 H). 100570] Step 4. Preparation of(l S,3R)-3-(5'-chloro-6-(3-fluorobenzylamino)-2,4'- bipyridin-2'-yt-amino)-N,N-dimethylcyelopentaneearboxamide: To (1S,3R)-3-(5'-chtoro-6-(3fluorobenzytamino)-2,4'-bipyridin-2'-yt-amino)cyelopentanecarboxylic acid U-31332-EXP080 (10 mg, 0.023 mmol), 2M dimethyl amine in THF (0.011 ml, 0.023 mmol), NI- ((ethylimino)methytene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (8.70 mg, 0.045 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (4.32 mg, 0.032 mmol) were added then dimethylformamide (1 ml) and diisopropyt ethylamine (0.016 ml, 0.091 mmol) were added, and the reaction mixture was stirred at ambient temperature for 18 hr and the progress followed by LCMS. The crude reaction mixture was filtered and purified by preparative LC. The product fractions were combined, 50 mL of 1M NaOH and 50 mL of ethyl acetate were added. The organic layer was removed, washed with 50 mL IM NaOH, 50 mL saturated sait solution, dried over sodium sulfate, and reduced to constant mass. 3 mg of the desired compound was obtained. LCMS (m/z): 468.1 (MH+), retention time = 0.72 min., IH NMR (300 MHz, CHLOROFORMd) 6 ppm 1.77 - 2.16 (m, 6 H) 2.96 (s, 3 H) 3.07 (s, 3 H) 3.10 - 3.25 (m, 1 H) 4.29 (m, 1 H) 4.56 (d, J=-5.27 Hz, 2 H) 5.12 (br. s., 1 H) 5.87 (br. s., 1 H) 6.38 (d, J----8.50 Hz, 1 H) 6.58 (s, 1 H) 6.91 - 7.01 (m, 1 H) 7.06 - 7.20 (m, 1 H) 7.26 - 7.37 (m, 2 H) 7.44 - 7.53 (m, 1 H) 8.09 (s, 1 H). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 54 (Compound 235) - h r -N6-(3u r benzy )-N2 -(( R 3 )-3-((methy ami )methy ) y penty )-2 4 - bipyridine-2',6-diamine H 100571] Step 1. Preparation of6-bromo-N-(3-fluorobenzyl)pyridin-2-amine: To 2,6dibromopyñdine (7.1 g, 30.0 mmol) was added NMP (16 ml), (3-fluorophenyl)methanamine (4.13 g, 33.0 mmol) and Huenig's Base (5.76 ml, 33.0 mmol) flushed with argon. The crude reaction mixture was stirred at 115-120 °C for 168 hr, followed by LCMS. The crude mixture was cooled, 250 ml of ethyl acetate was added, washed with saturated sodium bicarbonate (2x), water (2x), saturated sait solution (Ix), dried sodium sulfate, filtered, concentrate. The crude was purified by silica gel chromatography using 120g column, eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 7.11 grams of the titled compound as a free base used without further puñfication. LCMS (m/z): 281.1/283.1 (MH+), retention time = 1.03 min. 100572] Step 2. Preparation of 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6amine: To 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (2.0 g, 7.11 mmol) was added 5-chloro2-fluoropyridin-4-ylboronic acid (1.996 g, 11.38 mmol), PdCl2(dppf).CH2Cl2 adduct (0.465 g, 0.569 mmol), DME (27 ml), and 2M sodium carbonate (9.25 ml, 18.50 mmol). The crude reaction mixture was stirred at 100 °C for 3 hr, and the reaction progress followed by LCMS. The crude mixture was cooled, 25 ml of ethyl acetate and 20 ml of methanol were added, filtered and concentrated to yield a crude product. The crude was purified by silica gel chromatography using a 120g ISCO column, eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 1.259 grams of title compound as free base use with out further purification. LCMS (m/z): 332.2 (MH+), retention time = 0.92 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100573] Step 3. Preparation of (1R,4S)-tert-butyl 3-oxo-2-azabicyclo [2.2.1 ]heptane-2carboxylate: A mixture of (1S,4R)-2-azabicyclo [2.2.1 ]hept-5-en-3-one (2 g, 18.33 mmol) and 10% Pd/C (0.780 g, 0.733 mmol) in MeOH (100 ml) was stirred under atmospheric pressure of H2 at ambient temperature for 2 hr, and the reaction progress was followed by LCMS. Pd/C was filtered offover Celite and the filter cake was washed with MeOH. The combined organics were concentrated to afford crude (1R,4 S)-2-azabicyclo [2.2.1 ] heptan-3-one. LCMS (m/z): 112.1 (MH+), retention time = 0.30 min. The resulting resulting residue was redissolved in DCM (100 ml), to which di-tert-butyl dicarbonate (8.51 ml, 36.7 mmol)and DMAP (1.231 g, 10.08 mmol) were added and stirred at ambient temperature for 18 hr and the reaction progress was followed by LCMS. Solvent was removed, and the crude reaction mixture was purified through column chromatography, 10-40% EtOAc:Heptane. The desired fractions were concentrated to constant mass, yielding ( 1R,4S)-tert-butyl 3-oxo-2-azabicyclo [2.2.1 ]heptane-2-carboxylate (2.99 g, 14.15 mmol) of a white solid. LCMS (m/z): 156.2 (M-tBu), retention time = 0.75 min. 100574] Step 4. Preparation oftert-butyl (1R,3S)-3- (hydroxymethyl)cyclopentylcarbamate 1005751 (1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.99 g, 14.15 mmol) was dissolved in MeOH (40 ml) and cooled to 0 °C. Sodium Borohydride (1.071 g, 28.3 mmol) was added and the reaction was stirred at 0 °C for 1 hr, and the reaction progress was followed by LCMS. MeOH was removed and the resulting residue was partitioned between EtOAc (250 mL) and H20 (250 mL). The organic layer was washed with brine (250 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude mateñal was purified by column chromatography, 50-100% EtOAc in heptane to yield tert-butyl (IR,3S)-3- (hydroxymethyl)cyclopentylcarbamate (2.92 g, 13.56 mmol) as a white solid. LCMS (m/z): 160.2 (M - tBu), retention time = 0.65 min. 1005761 Step 5. Preparation of ((1S,3R)-3-aminocyclopentyl)methanoh Tert-butyl (1R,3S)-3-(hydroxymethyl)cyclopentylcarbamate (2.92 g, 13.56 mmol) was dispersed in H20 (50 ml) and refluxed at 100 °C for 18 hr, followed by LCMS. Water was removed by WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 azeotroping with toluene (50 mL x 3). Collected ((1S,3R)-3-aminocyclopentyl)methanol (1.92 g, 12.50 mmol) as a clear, viscous oil which was used without further purification. LCMS (m/z): 116.1 (MH+), retention time = 0.67 min. [005771 Step 6. Preparation of((l S,3R)-3-(5'-chloro-6-(3-fluorobenzylamino)-2,4'- bipyridin-2'-yl-amino)cyclopentyl)methanoh To 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)-2,4'- bipyridin-6-amine (100 mg, 0.301 mmol) was added DMSO (1 ml), ((IS,3R)-3aminocyclopentyl)methanol (104 mg, 0.903 mmol) and TEA (0.21 ml, 1.51 mmol). The crude mixture was stirred at 100 °C for 20 hours, followed by LCMS. The crude reaction mixture was cooled, was diluted with EtOAc (60 mL), washed H2 0 (60 mL x 2), brine (60 mL), dried over Na2SO4, and reduced. The crude was adsorbed onto silica gel, and purified by silica gel chromatography, 40-80% EtOAc/Heptane, 12g ISCO silica column, resulting in ((1 S,3R)-3-(5'- chloro-6-(3-fluorobenzylamino)-2,4'-bipyñdin-2'-yl-amino)cyclopentyt)methanol (101 mg, 0.237 mmol). LCMS (m/z): 427.1 (MH+). retention time = 0.69 min. [005781 Step 7. Preparation of ( 1 S,3 R)-3-(5'-chloro-6-(3-fluorobenzytamino)-2,4'- bipyridin-2'-yl-amino) cyclopentanecarbaldehyde [005791 In a flame-dried argon purged 20 mL conical flask, oxalyl chloride (0.025 ml, 0.281 mmol) was dissolved in DCM (0.5 ml) and cooled to -78 °C under argon. DMSO (0.030 ml, 0.422 mmol) was dissolved in DCM (0.5 ml) and added dropwise to the previous solution ( I don't see issues here). This was stirred for 30 min at -78 °C. ((1S,3R)-3-(5'-chloro-6-(3fluorobenzylamino)-2,4'-bipyñdin-2'-yl-amino)cyclopentyl)methanol (60 mg, 0.141 mmol) was dissolved in DCM (0.5 ml) and added dropwise to the reaction mixture. The resulting mixture was stirred for 60 min at -78 °C. TEA (0.078 ml, 0.562 mmol) was dissolved in DCM (0.5 ml) and added dropwise to the reaction mixture, after which the reaction mixture was allowed to stir and warm to ambient temp over 2 hr. The reaction mixture was diluted with EtOAc, washed with saturated NH4CI (30 mL x 3), H20 (30 mL), brine (30 mL), dried over Na2SO4 and reduced. The resulting resulting residue was used without further purification. LCMS (m/z): 425.2 (MH+), retention time = 0.72. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 8. Preparation of 5'-chloro-N6-(3-fluorobenzyl)-N2'-((1R,3S)-3- ((methyl amino)methyl)cyclopentyl)-2,4'-bi pyri dine-2',6-d iamine 100580] To (1S,3R)-3-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-ylamino)cyclopentanecarbaldehyde (20 mg, 0.047 mmol) was added methyl amine in THF (0.5 ml, 1.0 mmol) and DCM (0.5 mL). Acetic acid (2.69 tal, 0.047 mmol), and sodium tñacetoxyborohydride (t4.96 mg, 0.071 mmol) were added and stirred for 2 hr at ambient temperature, and the reaction progress was followed by LCMS. Solvents were removed, and the crude reaction mixture redissolved in 1.5 mL of DMSO, followed by purificatin using preperative HPLC. Product fractions were combined and lyophilized to affore 5'-chloro-N6-(3fluorobenzyl)-N2'-((1R,3 S)-3-((methylamino)methyl)cyclopentyl)-2,4'-bipyridine-2',6-diamine (2.5 mg, 0.006 mmol) as a TFA sait. LCMS (m/z): 440.2 (MH+), retention time -- 0.62 min. Example 56 (Compound 212) N-2'-(trans-4-amin eyc hexy )-5 -ch r -N6-((R)-6xaspir [2.5] ctan- -y )-2 4'-bipyridine2',6-diamine PI 1005811 Step 1: Preparation of (R)-6-bromo-N-(6-oxaspiro[2.5]octan1 -yl)pyridin-2amine: To a solution of 2, 6-dibromopyridine (200 mg, 0.84 mmot) in NMP (0.42 mL) was added (R)-6-oxaspiro[2.5]oetan-l-amine hydrochtoride (138 mg, 0.84 mmol) and potassium carbonate (350 mg, 2.53 mmol). The mixture was heated at 110 °C for 18 hr. The mixture was allowed to cool to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water, and brine and dried over sodium sulfate, filtered offand concentrated in vacuo. The resulting residue was purified by column WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 chromatography [SiO2 , 40 g, EtOAc/heptane = 0/100 to 30/70]. Pure fractions were combined and concentrated in vacuo giving 210 mg of titled compound. LCMS (m/z): 282.9/284.9 [M+H]+, retention time = 0.85 min. 1005821 Step 2. Preparation of (R)-5'-chloro-2'-fluoro-N-(6-oxaspiro[2.5]octan-l-yl)-2,4'- bipyridin-6-amine: 100583] A mixture of(R)-6-bromo-N-(6-oxaspiro[2.5]octan-l-yl)pyridin-2-amine (C, mg, 0.35 mmol), 5-chloro-2-fluompyridin-4-ylboronic acid (136 mg, 0.77 mmol), PdCl2(dppf).CH2Cl2 adduct (23 mg, 0.028 mmol) in DME (1 mL) and 2M Na2 CO3 (97 mg, 0.92 mmol) in a sealed tube was heated at 103 °C for 2 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc (-25 mL) and MeOH (-5 mL), filtered offand concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 12 g, EtOAc/heptane = 10/90 to 50/50]. Fractions were combined and concentrated in vacuo giving mg of titled compound. LCMS (m/z): 334.0/336.0 [M+H]+, retention time = 0.64 min. Step3. Preparation of N-2'-(trans-4-aminocyclohexyl)-5'-chlom-N6-((R)-6oxaspiro[2.5]octan1-yl)-2,4'-bipyridine-2',6-diamine: A mixture of(R)-5'-chloro-2'-fluoro-N-(6oxaspiro[2.5]octanl-yl)-2,4'-bipyridin-6-amine (15 mg, 0.045 mmol), trans-cyclohexane1,4diamine (10.3 mg, 0.090 mmol), in DMSO (0.2 mmol) in a sealed tube was heated at 110 °C for 18 hr. The mixture was allowed to cool to ambient temperature. To the reaction mixture was added 0.5 ml of DMSO, filtered and purified by prep LC. After lyophilisation, 5.0 mg of the titled compound as a TFA sait was obtained. LCMS (m/z): 428.3/430.3 (MH+), retention time - 0.46 min. Example 57 (Compound 230) N-(4-Amino-cyclohexyt)-5'-chloro-N-( 1,1 -di oxo-hexahydro1 -thiopyran-4-yl-methyl)- [2,4']bipyridinyl-6,2'-diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H O [005851 Step 1. Preparation of toluene-4-sulfonic acid 1,l-dioxo-hexahydrol-thiopyran4-yl-methyl ester: A solution of (l, l-Dioxo-hexahydro-l-thiopyran-4-yl)-methanol (500 mg, 3.04 mmol) in pyridine (10 mL) was added 4-methylbenzene-l-sulfonyl chloride (871 mg, 4.57 mmol). The mixture was stirred at ambient temperature for 18 hr. The mixture was diluted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water, and brine and dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 12 g, EtOAc/heptane = 0/100 to 30/70]. Pure fractions were combined and concentrated in vacuo giving 736 mg of title compound. LCMS (m/z): 319. l (MH+), retention time - 0.69 rein. [005861 Step 2. Preparation of (6-Bromo-pyridin-2-yl)-(l, 1-dioxo-hexahydro1 -thiopyran4-yl-methyl)-amine: A mixture of toluene-4-sulfonìc acid 1, l-dioxo-hexahydro-l-thiopyran-4-ylmethyl ester (736 mg, 2.31 mmol), 6-bromopyñdin-2-amine (400 mg, 2.312 mmol), potassium carbonate (639 mg, 4.62 mmol), sodium hydñde (111 mg, 4.62 mmol) in a sealed tube was heated at 68 °C for 18 hr. The mixture was allowed to cool to ambient. The mixture was diluted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water, and bñne and dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 12 g, EtOAc/heptane = 0/100 to 30/70]. Pure fractions were combined and concentrated in vacuo giving 240 mg of titled compound. LCMS (m/z): 318.8/320.9 (MH+), retention time = 0.71 min. Step 3. Preparation of (5'-Chloro-2'-fluoro-[2,4']bipyridinyl-6-yl)-(1,1 -dioxohexahydro1 -thiopyran-4-yl-methyl)-ami ne WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 A mixture of (6-bromo-pyridin-2-yt)-(1,1-dioxo-hexahydro-l-thiopyran-4-ylmethyl)-amine (238 mg, 0.746 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (261 mg, 1.491 mmol), adduct (48.7 mg, 0.060 mmol) in DME (2 mL) and 2M Na2 CO3 (205 mg, 1.938 mmol) in a sealed tube was heated at 103 °C for 2 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc (-25 mL) and MeOH (-5 mL), filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 12 g, EtOAc/heptane = 10/90 to 50/50]. Fractions were combined and concentrated in vacuo giving 150 mg of the title compound. LCMS (m/z): 370.0/372.0 (MH+); Retention time = 0.56 min. Step 4. Preparation of N-(4-amino-cyclohexyl)-5'-chloro-N-(l, 1 -dioxohexahydro1 -thiopyran-4-yl-methyl)-[2,4']bipyridinyl-6,2'-diamine: A mixture of (R)-5'-chloro2'-fluoro-N-(6-oxaspiro[2.5]octan-l-yl)-2,4'-bipyridin-6-amine (40 mg, 0.108 mmol), and transcyclohexane-l,4-diamine (124 mg, 1.082 mmol) in DMSO (0.4 mmol) was heated in a sealed tube at 100 °C for 4 hr. The mixture was allowed to cool to ambient temperature. To the cooled reaction mixture was added 0.5 ml of DMSO, filtered and purified by prep LC. After lyophilisation, 10.0 mg of the titled compound as a TFA sait was obtained. LCMS (m/z): 464.1/466.1 (MH+), retention time = 0.44 min. Example 58 (Compound 317) 5'-chloro-N6-(dide utero-(tetrahydro-2H-pyran-4-yl)methyl)-N2'-(tmns-4-(((S)-tetrahydrofuran2-yl) methyt)aminocyclohexyl)-2,4'-bipyridine-2',6-diamine H N" D H æO 100590] Stepl. Preparation ofdideutero-(tetrahydro-2H-pyran-4-yl)methanamine: To a solution of tetrahydro-2H-pyran-4-carbonitrile (800 mg, 7.20 mmol) in THF (20 mL) was added WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 aluminum(Ill) lithium deuteride at 0 °C. The mixture was stirred at 0 °C for 2 hr. To the stirred reaction mixture was sequentially added 300 uL of water, 900 tL of I N NaOH and 300 [aL of water. The mixture was filtered through a thin Iayer ofcelite to remove the solid. The filtrate was dried over sodium sulfate, filtered off and concentrated in vacuo giving 700 mg of titled compound. LCMS (m/z): 118.2 [M+H]+, retention time = 0.25 min. The crude product was used directly for next step. Step2. Preparation of 6-bromo-N-(dideutero(tetrahydro-2H-pyran-4yl)methyl)pyridin-2-amine: To a solution of 2, 6-dibromopyridine (1051 mg, 5.97 mmol) in DMSO (5 mL) was added dideutero(tetrahydro-2H-pyran-4-yl)methanamine (700 mg, 5.97 mmol) and diisopropylethylamine (926 mg, 7.17 mmol). The mixture was heated at 80 °C for 2 hr. The mixture was allowed to cool to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water, and brine and dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SIO2 , 40 g, EtOAc/heptane = 0/100 to 30/70]. Pure fractions were combined and concentrated in vacuo giving 780 mg of titled compound. LCMS (m/z): 272.9/274.9 [M+H]+, retention time = 0.77 min. 100592] Step3. Preparation of 5'-chloro-N-(dideutero(tetrahydro-2H-pyran-4-yl)methyl)- 2'-fluoro-2,4'-bipyridin-6-amine: A mixture of 6-bromo-N-(dideutero(tetrahydro-2H-pyran-4-yl)methyl)pyridin-2amine (500 mg, 1.83 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (642 mg, 3.66 mmol), PdCl2(dppf).CH2Cl2 adduct (120 mg, 0.146 mmol) in DME (1 mL) and 2M Na2 CO3 (2.38 ml, 4.76 mmol) was heated in a sealed tube at 80 °C for 48 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc (-25 mL) and MeOH (-5 mL), filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2 , 12 g, EtOAc/heptane = 10/90 to 50/50]. Fractions were combined and concentrated in vacuo giving 180 mg of titled compound. LCMS (m/z): 324.0/325.8 [M+H]+, retention time = 0.58 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1005941 Step4. Preparation of 5'-chloro-N6-(dideutero(tetrahydro-2H-pyran-4-yl)methyl)- N2'-(trans-4-(((S)-tetrahydrofuran-2yl)methyl)aminocyclohexyl)-2,4'-bipyridine-2',6-diamine: A mixture of 5'- h r -N-(dideuter (tetrahydr -2H-pyran-4-y )methy )-2'- u r -2 4'-bipyridin-6amine (30 mg, 0.093 mmol), trans-N l-(((S)-tetrahydrofuran-2-yl)methyl)cyclohexane-1,4diamine (60 mg, 0.30 mmol), in DMSO (0.4 mmol) was heated in a sealed tube at 110 °C for 68 hr. The mixture was allowed to cool to ambient temperature. To the reaction mixture mixture was added 0.5 ml of DMSO, filtered and purified by prep LC. After lyophilisation, 10.0 mg of the titled compound as a TFA sait was obtained. LCMS (m/z): 502.3/504.3 (MH+), retention time = 0.49 min. Example 59 (Compound 324) 1005951 5'-chloro-5-fluoro-N2'-(trans-4-(oxetan-2-yl-methylamino)cyelohexyl)-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine H IN N- /. 1005961 To a stirred solution of N2'-(trans-4-aminocyclohexyl)-5'-chloro-5-fluoro-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine (90 mg, 0.207 retool)) in DMSO (1.0 ml) was add potassium carbonate (71.7 mg, 0.518 mmol), followed by folllloowwoxetan-2-yl-methyl 4-methylbenzenesulfonate (151 mg, 0.622 mmol). The mixture was heated at 83 °C for 2h. The mixture was allowed to cool to ambient temperature, then diluted with water and then extracted with EtOAc (x3). The organics were combined then washed with water (x2), saturated brine (x2), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC and lyophilized to yield titled compound. LCMS (m/z): 504.4/506.5 (MH÷) retention time = 0.60 min as a TFA sait. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 60 (Compound 222) trans-4-(5-chl r -4-(5-ch r -6-((tetrahydr -2H-pyran-4-yl)methy )amin pyrazin-2-y )pyridin2-yl-amino)cyclohexanol H CI Step 1. Preparati n f6-br m -3h r -N-((tetrahydr -2H-pyran-4-y )methy )pyrazin-2-amine. To a scintillation vial containing 3,5-dibromo-2-chloropyrazine (l g, 3.67 mmol) and TEA (1.024 ml, 7.34 mmol) was added MeCN (5 ml) and (tetrahydro-2H-pyran-4yl)methanamine (0.557 g, 3.67 mmol). The homogenous reaction mixture was capped, and heated to 80 °C in a oil bath for 4 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and sequentially washed with sat NaHCO3 , and sat NaCl. The organic layer was dried Na2 SO4 , filtered and concentrated. The crude was purified by column chromatography on silica gel (20%EtOAc/Hexane) to yield 6-bromo-3-chtoro-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine (688 mg, 2.244 mmol, 61. t % yield), yield), LCMS (m/z): 308.0 (MI-I+), retention time = 0.94 min, and 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine (55 mg, 0.179 mmol, 4.89 % yield), LCMS (m/z): 308.0 (MH+), retention time = 0.91 min. Step 2. Preparation of 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro2H-pyran-4-yl)methyl)pyrazin-2-amine To a degassed suspension of 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine (358 mg, 1.168 mmol), Na2CO3 (1.518 ml, 3.04 mmol) and 5chloro-2-fluoropyridin-4-ylboronic acid (307 mg, 1.752 mmol) in DME (5 ml) was added PdC12(dppf).CH2C12 adduct (76 mg, 0.093 mmol). The reaction mixture was capped in a flask and heated to 100 °C for 4 hr an oil bath. The reaction mixture was diluted with EtOAc and WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 washed with }t2 0 saturated NaCI. The organic layer was dried Na2 SO4 , filtered and concentrated. The crude oil/solid was purified column chromatography on silica gel (30%EtOAc/Hexane) to yield 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2Hpyran-4-yl)methyl)pyrazin-2-amine (160 mg, 0.448 mmol, 38.4 % yield), LCMS (m/z): 357.0 (MH+), retention time = 1.02 min. Step 3. Preparation oftrans-4-(5-ehloro-4-(5-chloro-6-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazin-2-yl)pyridin-2-yl-amino)cyclohexanol :To a scintillation vial containing 3h r 6-(5h r -2u r pyridin-4 y )-N-((tetrahydr -2H-pyran 4-y )methy )pyrazin-2amine (20 mg, 0.056 mmol) was added DMSO (1 ml) andtrans-4-aminocyclohexanol (32.2 mg, 0.280 mmol). The reaction mixture was capped and heated to 120 °C in an oil bath for 3 hr. The reaction product was purified by reverse phase preparative HPLC to yield trans-4-(5-chloro-4- (5-chloro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-ylamino)cyclohexanol (2.2 mg, 4.86 Immole, 8.69 % yield), LCMS (m/z): 452.1 (Mil+), retention time = 0.76 min as a TFA sait after lypholyzing. IH NMR (400 MHz, METHANOL-d4) 6 ppm 1.17 - 1.26 (m, 4 H) 1.27 - 1.39 (m, 2 H) 1.58 (dd, J=13.11, 1.76 Hz, 2 H) 1.84 - 2.02 (m, 5 H) 3.30 (d, J=-7.04 Hz, 4 H) 3.43 - 3.61 (m, 2 H) 3.84 (dd, J=-I 1.35, 3.13 Hz, 2H) 6.58 (s, i H) 7.66 (s, 1 H)7.90 (s, 1 H). Example 61 (Compound 223) trans-N -(5-ch r -4-(3-ch r -6-((tetrahydr -2H-pyran-4-y )methy )amin pyrazin-2-y )pyridin2-yl)cyclohexane1,4-diamine H wNì N« CI f]'°' NH2 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 100601] Step 1. Preparation of 5-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydm2H-pyran-4-yl)methyl)pyrazin-2-amine. To a suspension of 6-bromo-5-chloro-N-((tetrahydro2H-pyran-4-yl)methyl)pyrazin-2-amine (20 mg, 0.065 mmol), Na2 CO3 (17.98 mg, 0.170 mmol)" and 5-chloro-2-fluompyridin-4-ylboronic acid (17.16 mg, 0.098 mmol) in DME (1 ml) was added PdCl2 (dppf).CH2 CI2 adduct (4.26 mg, 5.22 lamol). The reaction mixture was capped in a flask and heated to 100 °C for 4 hr an oil bath. The reaction mixture was diluted with EtOAc and washed with HzO sat NaC1. The organic layer was dñed Na2 SO4 , filtered and concentrated. The crude was purified by column chromatography on silica gel (50%EtOAc/Hexane) to yield 5- h r -6-(5h r -2u r pyridin-4-y )-N-((tetrahydr -2H-pyran-4-y )methy )pyrazin-2-amine (10 mg, 0.028 mmol, 42.9 % yield). LCMS (m/z): 357.0 (MH+), retention time = 0.95 min. [006021 Step 2. Preparatiuon oftrans-Nl-(5-chloro-4-(3-chloro-6-((tetrahydro-2H-pyran4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyctohexane-l,4-diamine. To a scintillation vial containing 5-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl) pyrazin-2-amine (10 mg, 0.028 mmol) and TEA (7.80 tl, 0.056 mmol) was added DMSO (1 ml) and trans-cyclohexane-1,4-diamine (32.0 mg, 0.280 mmol). The resulting homogenous reaction mixture was capped and heated to 100 °C in an oil bath for 3 hr. The reaction product was purified by reverse phase preparative HPLC to yield trans-Nl-(5-chloro-4-(3-chloro-6- ((tetrahydr -2H pyran 4 y )methy )amin pyrazin-2-y )py din-2-y )cy 1 hexane4-diamine (7.7 mg, 0.014 mmol, 48.6 % yield), LCMS (m/z): 451.1 (MI-I+), retention time - 0.63 min and a TFA sait after lyapholization. IH NMR (400 MHz, METHANOL-d4) 6 ppm 1.23 - 1.36 (m, 3 H) 1.36 - 1.49 (m, 2 H) 1.51 - 1.71 (m, 4 H), 1.80 - 1.94 (m, 1 H) 2.06 - 2.25 (m, 4 H) 3.08 - 3.19 (m, 1 H) 3.23 (d, J=6.65 Hz, 2 H) 3.33 - 3.43 (m, 2 H) 3.66 - 3.77 (m, 1 H) 3.92 (dd, J=l 1.35, 3.13 Hz, 2 H) 6.69 (s, 1 H) 7.76 (s, 1 H) 8.05 (s, 1 H). Example 62 (Compound 225) 3-chloro-6-(5-c hloro-2-(trans-4-(pyrmlidin1 -yl)cyclohexylamino)pyridin-4-yl)-N-((tetrahydro2H-pyran-4-yl)methyl)pyrazin-2-amine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 [006041 Step 1. Preparation of 3-chloro-6-(5-chlom-2-(trans-4-(pyrrotidin1 - yl)cyclohexylamino) pyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine: To a scintillation vial containing trans-N 1-(5-chloro-4-(5-chloro-6-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine (12 mg, 0.027 mmol) and K2CO3 (3.67 mg, 0.027 mmol) was added DMF (l ml) and 1,4-dibromobutane (3.15 tl, 0.027 mmol). The reaction mixture was capped and heated to 60 °C for 3 hr. The crude solution was concentrated and purified by reverse phase preparative HPLC to yield 3-chloro-6-(5-chloro-2- (trans-4-(pyrr lidin-l-yl)cycl hexylamin )pyridin-4-yl)-N-((tetrahydr -2H-pyran-4yl)methyl)pyrazin-2-amine (3.8 mg, 6.13 p.mol, 23.07 % yield), LCMS (m/z): 505.2 (MI/+), retention time = 0.64 min, and a TFA sait after lyapholization. . I H NMR (400 MHz, METHANOL-d4) 6 ppm 1.26 - 1.47 (m, 4 H) 1.56 - 1.73 (m, 4 H) 2.01 (m, 3 H) 2. l0 -2.32 (m, 6 H) 3.09 - 3.23 (m, 3 H) 3.36 - 3.44 (m, 4 H) 3.60 - 3.78 (m, 3 H) 3.89 - 3.98 (m, 2 H) 6.76 (s, l H) 7.76 (s, l H) 8.03 (s, l H). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 63 (Compound 226) 6-(2-(trans-4-aminocyclohexylamino)-5 -chloropyridin-4-yt)-N2- ((tetrahydro-2H-pyran-4yt)methyl)pyrazine-2,3-diamine 1006061 Step 1. Preparation of 6-bromo-N2-((tetrahydro-2H-pyran-4-yt)methyl)pyrazine2,3-diamine : To a scintillation vial containing 3,5-dibromopyrazin-2-amine (500 mg, 1.977 mmol) and TEA (0.551 ml, 3.95 mmol) was added MeCN (6 ml) and (tetrahydro-2H-pymn-4yl)methanamine (300 mg, 1.977 mmol). The homogenous reaction mixture mixture was capped and heated to 80 °C in a oil bath for 36 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and washed with sat NaHCO3 , sat NaCl. The organic layer was dñed Na2SO4, filtered and concentrated. The crude was purified by column chromatography on silica gel (30%EtOAe/Hexane) to yield 6-bromo-N2-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2,3diamine (351 mg, 1.222 mmol, 61.8 % yield). 100607] Step 2. Preparation of 6-(5-chloro-2-fluoropyridin-4-yl)-N2-((tetrahydro-2Hpyran-4-yl)methyl)pyrazine-2,3-diamine [006081 To a degassed suspension of 6-bromo-N2-((tetrahydro-2H-pyran-4yl)methyl)pyrazine-2,3-diamine (100 mg, 0.348 mmol), Na2 CO3 (96 mg, 0.905 mmol)" and 5chloro-2-fluoropyridin-4-ylboronic acid (92 mg, 0.522 mmol) in DME (3 ml) was added PdClz(dppf).CH2Cl2 adduet (22.75 mg, 0.028 mmol). The reaction mixture was capped in a flask and heated to 100 °C for 4 hr an oil bath. The reaction mixture was diluted with EtOAc and washed with 1-I2 0, sat NaCI. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by column chromatography on silica gel (100%EtOAe/Hexane) to yield WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 6-(5 h r -2u r py din-4-y )-N2-((tetrahydr 2H-pyran-4-y )methy )pyrazine-2 3-diamine (34 mg, 0.101 mmol, 28.9 % yield). ). LCMS (m/z): 338.2 (MH retention time = 0.65 min. 1006091 Step 3. Preparation of 6-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4yl)-N2-((tetrahydro-2H-pyran-4-yl)methyt)pyrazine-2,3-diamine : To a scintillation vial containing 6- (5-chloro-2-fluoropyridin-4-yl)-N2-((tetrahydro-2H-pyran-4-yl)methyt)pyrazine2,3-diamine (17 mg, 0.050 mmol) was added DMSO (1.3 ml) and trans-cyclohexane-l,4-diamine R2 (57.5 mg, 0.503 mmol). The homogenous reaction mixture was capped and heated to t00 °C in a oil bath for 16 hr. The reaction mixture was purified by reverse phase preparative HPLC to yield 6- (2-(trans-4-amin yc hexy amin )-5-ch r pyridin-4-y )-N2-((tetrahydr -2H-pyran-4yl)methyt)pyrazine-2,3-diamine (13.7 mg, 0.025 mmot, 49.9 % yield), LCMS (m/z): 432.1 (MH+), retention time = 0.41 min as a TFA sait after lyphotyzing. 1H NMR (400 MHz, METHANOL-d4) d ppm 1.30 - 1.50 (m, 4 H) 1.51 - 1.65 (m, 2 H) 1.69 - 1.78 (m, 2 H) 1.93 - 2.06 (m, 1 H) 2.07 - 2.24 (m, 4 H) 3.t0 - 3.19 (m, t H) 3.36 - 3.45 (m, 2 H) 3.48 (d, J=6.65 Hz, 2 H) 3.64 - 3.75 (m, 1 H) 3.96 (dd, J=-I 1.35, 3.t3 Hz, 2 H) 7.04 - 7.10 (m, t H) 7.64 (s, 1 H) 8.01 (s, l H). Example 64 (Compound 233) trans-N (5-ch m-4-(3-methy -6-((tetrahydr -2H-pyran-4-y )methy )amin pyrazin-2yt)pyridin-2-yl)cyclohexane1,4-diamine H Nì N« -I"- Step 1. Preparation of 6-(5-chloro-2fluoropyridin-4-yl)-5-methyl-N-((tetrahydro2H-pyran-4-yl)methyl)pyrazin-2-amine • To a degassed suspension of 5-chloro-6-(5-chloro-2fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (10 mg, 0.028 mmol), WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Na2CO3 (0.036 ml, 2 M, 0.072 mmol)" and methylboronic acid (5 mg, 0.084 mmol) in DME (1 ml) was added PdCl2(dppf).CH2C12 adduct (6 mg, 7.35 Ismol). The reaction was capped and heated to 105 °C for 4 hr an oil bath. The reaction was diluted with EtOAc and washed with H20, sat NaCI. The organic layer was dried Na2 SO4 , filtered and concentrated. The crude was purified by column chromatography on silica gel (50%EtOAciHexane) to yield 6-(5-chloro-2flu r pyridin-4-y )-5-methy -N-((tetrahydr -2H-pyran-4-y )methy )pyrazin-2-amine (7 mg, 0.021 mmol, 74.2 % yield). LCMS (m/z): 337.2 (MH ), retention time = 0.81 min. Step 2. Preparation of trans-N 1 -(5-chloro-4-(3-methyl-6-((tetrahydro-2H-pyran4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane1,4-diamine 100612] To a scintillation vial containing 6-(5-chloro-2-fluoropyridin-4-yl)-5-methyl-N- ((tetrahydro-2H-pyran-4-yl)methyl) pyrazin-2-amine (7 mg, 0.021 mmol) was added DMSO and trans-cyclohexane-l,4-diamine (23.73 mg, 0.208 mmol). The homogenous reaction mixture was capped and heated to 100 °C in an oil bath for 4 hr. The crude solution was purified by reverse phase preparative HPLC to yield trans-Nl-(5-chloro-4-(3-methyl-6-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazin-2-yl)pyridin-2 -y l)cyclohexane1,4-diamine ( 1.1 mg, 2.018 tmol, 9.71 % yield), LCMS (m/z): 431.2 (MH+), retention time = 0.47 min as a TFA sait after lypholyzing. Example 65. (Compound 316) 5'-ch r -N6 ((6,6-dimethy - 4-di xan-2-y )methy )-N2'-(trans-4-((R)- -meth xypr pan-2-y - amino)cyclohexyl)-2,4'-bipyridine-2',6-diamine H Step 1. Preparation of 1 -(allyloxy)-2-methylpropan-2-ol. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1006131 To allylic alcohol (57.4 mL, 844 mmol) at 0 °C was added Nail (60% in minerai oil, 2.43 g, 101 mmol). After 20 min 2,2-dimethyloxirane (15 mL, 169 retool) was added and the solution was refluxed ovemight. Saturated NH4 CI solution was added and extracted three times with ether. The organic layers were combined, dried over Na2 SO4 and concentrated to remove ether. The resulting residue was distilled (allylic alcohol was distilled first then the product was collected at 42 torr, bp 58-60 °C) to give the product as a colorless oil (12.3 g, 56%). IH NMR (400 MHz, CDC13) ì ppm 5.87-5.96 (IH, m), 5.26-5.31 (IH, m), 5.18-5.21 (IH, m), 4.03-4.05 (2H, m), 3.28 (2H, s), 2.31 (IH, br s), 1.23, (3H, s), 1.22 (3H, s). Step 2. Preparation of2-methyll-(oxiran-2-ylmethoxy)propan-2-ol. [006141 l-(Allyloxy)-2-methylpropan-2-ol (1.50 g, 11.5 retool) was dissolved in DCM (50 mL) and cooled to 0 "C. mCPBA (77% max, 9.94 g) was added. The suspension was stirred at 0 °C for 6.5 hr. and then saturated NaHCO3 solution (-20ml) and Na2 S2 03 solution (-20ml) were added. The resulting mixture was stirred at 0 °C for 15 min and the two layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were combined, dñed over Na2 SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 1:0 to 1:2) to give the product as a colorless oil (620 mg, 37%). IH NMR (400 MHz, CDC13) 6 ppm 3.64 (IH, ddd, J= 12.0, 5.2, 2.8 Hz), 3.24-3.29 (IH, m), 3.173.21 (IH, m), 3.11-3.14 (IH, m), 2.97-3.00 (IH, m), 2.88 (IH, br s), 2.60-2.64 (1H, m), 2.442.47 (IH, m), 1.02 (6H, s). Step 3. Preparation of (6,6-dimethyl1,4-dioxan-2-yl)methanol. [006151 2-methyl-l-(oxiran-2-ylmethoxy)propan-2-ol (620 mg, 4.24 mmol) and 10-CSA (300 mg, 1.29 mrnol) were dissolved in DCM (30 mL) and stirred at ambient temperature for 24 hr. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous phase was extracted four times with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 1:0 to 1:2) to give the desired product as a colorless oil (400 mg, 64%). Some starting material was recovered. IH NMR (400 MHz, CDC13) 6 ppm 3.90-3.96 (IH, m), 3.76 (1H, dd, J= 11.2, 2.8 Hz), 3.56 (1H, dd, J= 11.6, 4.0 Hz), 3.46-3.50 (2H, m), 3.29 (IH, t,J= 11.2 Hz), 3.24 (1H, dd, J= 11.6, 1.2 Hz), 2.69 (IH, br s), 1.35 (3H, s), 1.13 (3H, s). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 4. Preparation of (6,6-dimethyl-1,4-dioxan-2-yl)methyl methanesulfonate TEA (0.52 mL, 3.74 mmol) and (6,6-dimethyl-l,4-dioxan-2-yl)methanol (390 mg, 2.67 mmol) were dissolved in DCM (10 mL). Methanesulfonyl chloride (0.249 mL, 3.20 mmol) was slowly added at 0 °C. After the addition was completed the solution was warmed to ambient temperature and stirred for 1 hr. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over Na2 SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 4" 1 to 1: l) to give the product as a colorless oil (584 mg, 98%). 1H NMR (400 MHz, CDC13) 6 ppm 4.00-4.09 (3H, m), 3.74 (1H, dd, J= 11.2, 2.8 Hz), 3.42 (IH, d, J-- ll.6 Hz), 3.16-3.23 (2H, m), 2.99 (3H, s), 1.27 (3H, s), 1.05 (3H, s). Step 5. 6-bromo-N-((6,6-dimethyl-l,4-dioxan-2-yl)methyl)pyridin-2-amine 6-Bromopyridin-2-amine (722 mg, 4.17 mmol) was dissolved in 8 mL of anhydrous DMF and cooled to 0 °C. Nail (60% in mineral oil, 195 mg, 4.87 mmol) was added. After 10 min the solution was warmed to ambient temperature and stirred for 45 min until bubbling ceased. The solution was cooled to 0 °C again and (6,6-dimethyl1,4-dioxan-2yl)methyl methanesulfonate (520 mg, 2.32 mmol) in 2 mL of DMF was added. After the addition was completed the solution was wanned to ambient temperature and stirred overnight. It was diluted with EtOAc and washed four times with water. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on prep HPLC and the collected fractions were combined, concentrated, basified with Na2CO3 and extracted with EtOAc three times. The organic layers were combined, dried over Na2SO4 and concentrated to give the product as a light yellow oil (270 mg, 39%). LC-MS (m/z): 301.0/303.0 (M+H), retention time = 0.86 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 66 (Compound 307) 5'-chloro-N6-((5,5-dimethyl1,4-dioxan-2-yl)methyl)-N2'-(trans-4- ((R)- 1 -methoxypropan-2-ylamino)cyclohexyl)-2,4'-bipyridine-2',6-diamine H N H Step 1. Preparation of 2-(allyloxy)-2-methylpropan1-ol. 100618] 2,2-Dimethyloxirane (15.0 mL, t69 mmol) was dissolved in allylic alcohol (57.4 mL) and eooted to 0°C. Perchlorie acid (70%, 7.26 mL, 84 mmol) was slowly added. The solution was then warmed to ambient temperature and stirred for 1.5 hr. Saturated NaHCO3 solution was added and extracted three times with ether. The organic layers were combined, dried over Na2 SO4 and concentrated to remove ether. The resulting residue was distilled (allylic alcohol was distilled first then the product was collected at 38 torr, bp 74-76 °C) to give the product as a colorless oil (9.70 g, 44%). LH NMR (400 MHz, CDC13) fi ppm 5.87-5.97 (1H, m), 5.25-5.31 (IH, m), 5.12-5.16 (1H, m), 3.92-3.94 (2H, m), 3.45 (2H, m), t.19 (6H, s). Step 2. Preparation of 2-methyl-2-(oxiran-2-ytmethoxy)propan1-ol. 1006191 2-(allyloxy)-2-methylpropan1-ot (2.37 g, 18.2 mmol) was dissolved in DCM (70 mL) and cooled to 0 °C. mCPBA (77% max, 15.71 g) was added. The suspension was stirred at 0 °C for 6.5 hr before saturated NaHCO3 solution and Na2 S203 solution were added. It was stirred at 0 °C for t 5 min and the two layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc t :0 to 1:2) to give the product as a colorless oil (9t0 mg, 34%). LH NMR (400 MHz, CDCI3) 6 ppm 3.65 (IH, dd, J= 11.2, 2.8 Hz), 3.47 (1H, brs), 3.31-3.41 (3H, m), 3.07-3.09 (1H, m), 2.74 (1H, t, J= 4.8 Hz), 2.63-2.65 (IH, m), 1.12 (6H, s). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 3. Preparation of (5,5-dimethyl1,4-dioxan-2-yl)methanol. [006201 2-Methyl-2-(oxiran-2-ylmethoxy)propan-l-ol (870 mg, 5.95 mmol) and 10-CSA (207 mg, 15%) were dissolved in DCM (70 mL) and stirred at ambient temperature for 24 hr. More 10-CSA (100 mg) was added and the solution was stirred overnight. Saturated NaHCO3 solution was added. The two layers were separated and the aqueous layer was extracted twice with DCM. The organic layers were combined, dried over Na2SO4 and concentrated to give the product as a colorless oil (750 mg, 86%). 1H NMR (400 MHz, CDCI3) 8 ppm 3.69-3.74 (1H, m), 3.52-3.64 (5H, m), 3.43 (IH, dd, J=- 11.6, 0.8 Hz), 2.57 (1H, br s), 1.32 (3H, s), 1.13 (3H, s). Step 4. Preparation of (5,5-dimethyl-l,4-dioxan-2-yl)methyl methanesulfonate. (5,5-Dimethyl-l,4-dioxan-2-yl)methanol (740 mg, 5.06 retool) and TEA (0.988 mL, 7.09 mmol) were dissolved in DCM (20 mL). At 0 °C MsCI (0.473 mL, 6.07 retool) was added dropwise. After the addition the solution was warmed to ambient temperature and stirred for 1 hr. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 4:1 to 1:1) to give the product as a colorless oil (805 mg, 71%). 1H NMR (400 MHz, CDCI3) 8 ppm 4.18-4.19 (2H, m), 3.71-3.76 (1H, m), 3.66 (1H, t, J= 10.8 Hz), 3.52-3.57 (2H, m), 3.37 (IH, d, J= 11.6 Hz), 3.03 (3H, s), 1.28 (3H, s), 1.09 (3H, s). Step 5. Preparation of 6-bromo-N-((5,5-dimethyl1,4-dioxan-2-yl)methyl)pyri din-2-amine. 6-Bromopyridin-2-amine (771 mg, 4.46 mmol) was dissolved in 10 mL of anhydrous DMF and cooled to 0 °C. Nail (60% in mineral oil, 214 mg, 5.35 retool) was added. After l 0 min the solution was warmed to ambient temperature and stirred for 15 rein until bubbling ceased, to give a dark green solution. (5,5-Dimethyl-1,4-dioxan-2-yl)methyl methanesulfonate (500 mg, 2.23 mmol) in 2 mL of DMF was added. After the addition was completed the solution was stirred at ambient temperature for 20 nain, then heated at 60 °C for 1.5 hr. It was diluted with EtOAc and washed four times with water. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 (heptane:EtOAc 1:0 to 1-1) to give the product contaminated with the starting aminopyridine. Another purification on silica gel column (DCM:ether 20: l) gave the pure product (306 mg, 46%). LC-MS (m/z): 301.0/303.0 (M+H), retention time = 0.89 min. Example 67 (Compound 291) Synthesis of 5'-chloro-N2'-(trans-4-((R)-I -methoxypropan-2-yl-amino)cyclohexyl)-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine CI- ÇH3 ',,N ,,'O--cH 3 H H 100623] Step 1. To sodium hydride (0.488 g, 12.21 mmol) in 5 mL of THF was added via synringe(S)-(+)-3-methoxy-2-propanol (1.000 ml, 11.10 mmol) in 25 mL of THF at ambient temperature. The mixture was stirred for 20 min. and followed by addtion ofp-toluenesulfonyl chloñde (2.327 g, 12.21 mmol). The white cloudy solution was stirred at ambient temperature for 18 hrs. The reaction mixture was diluted with saturated aq. NaHCO3 and extracted with EtOAc. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo to give 2 g of colorless liquid. The crude mixture was purified by Analogix system (silica gel column 40 g, gradient: 100%n-heptane to 30% EtOAc in Heptane; min.). The pure fractions were concentrated in vacuo to give 1.22 g of colorless oil. LC-MS (m/z): 245 (M+H), retention time = 0.83 min. Step 2. To the tosylate obtained from step 1 (0.6 g, 2.45 mmol) in DMSO (6 ml) at ambient temperature was added trans-cyclohexane-l,4-diamine (0.84 g, 7.37 mmol). The light brown mixture was heated to 99 °C in a capped glass vial for 1 hr. LC/MS showed nearly complete consumption of the starting material. The mixture was diluted with water and extracted with DCM. The organic extracts were combined, washed with brine, dried with sodium sulfate WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 and concentrated in vacuo to give 0.39 g of light brown liquid. This was used in the next step without further purification. LC-MS (m/z): 187 (M+H), Retention time = 0.14 min. [006251 Step 3. A mixture of Intermediate G (60 mg, 0.168 mmol), the above cyclohexadiamine (100 mg, 0.537 retool) and 2,6-LUTIDINE (0.039 ml, 0.0.337 mmol) in DMSO (1 ml) was heated in a capped vial on a heating block for 18 hrs. LC/MS showed containing about 50% product. The reaction mixture was purified by HPLC (ACN in water with gradient t0% - 50% in 16 minutes) and lyophilized to give 25 mg of light yellow powder. LCMS (m/z): 522/524 (M+H), retention time = 0.62 min. 1H NMR (400 MHz, CDCI3) ì ppm 1.24 - 1.47 (m, 5 H) 1.50 - 1.79 (m, 2 H) t.79 - 2.01 (m, 4 H) 2.11 - 2.31 (m, 4 H) 3.t6 - 3.26 (m, 2H) 3.28 - 3.45 (m, 5 H) 3.45 - 3.66 (m, 4 H) 6.82 (d, J=9.39 Hz, 1 H) 7.05 Çor. s., l H) 7.59 (s, 1 H) 7.78 (d, ,/=9.39 Hz, t H) 7.95 (s, 1 H) 8.76 (br. s., 1 H) Example 68 (Compound 197) -ch r -N6-( 3u r benzy )-N2'-( trans-4-((methy amin )methy )cyc hexyl)-2 4 '-bipyridine2',6-diamine H N ì -,,NH2 Step 1. Preparation of 2'-chloro-5'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6amine: To a solution of 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (636 mg, 2.262 mmol) and 2-chloro-5-fluoropyridin-4-yl-boronic acid (555 mg, 3.17 mmol) in DME (4 ml) and 2M Na2 CO3 aq (2 ml) was added PdCl2 (dppf). CH2 C12 adduct (92 mg, 0.113 mmol). This was then heated at °C for 16 hours. The reaction mixture was allowed to cool and then the DME was evaporated under reduced pressure. The resulting residue was partitioned between EtOAc and water. The organics were combined, then washed with H2 0 (x3), saturated aq. brine (x3), then WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 dried (Na2 SO4 ), filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; 20% EtOAc/hexane) to give 2'-chloro-5'- fluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6-amine (84mg). [006271 Step 2. Preparation of 5'-chloro-N6-(3-fluorobenzyl)-N2'-(trans-4- ((methylamino)methyl)cyclohexyl)-2,4'-bipyridine-2',6-diamine: To a scintillation vial were added 2'-chloro-5'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyfidin-6-amine (34 mg, 0.102 mmol), trans-eyelohexane-1,4-diamine (52.7 mg, 0.461 mmol), 1,3-bis(2,6-di-isopropylphenyl)imidazol2-ylidene(1,4-naphthoquinone)palladium(0) (13.39 mg, 10.25 Iamol), KOH (51.8 mg, 0.922 mmol) and Dioxane (0.6 mL). The resulting mixture was stirred with heating at 70 °C for 16h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc and washed with H20 (x2) followed by saturated brine (x2), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC and then lyophallized to yield 5'-ehloro-N6-(3-fluorobenzyl)-N2'-(trans-4- ((methylamino)methyl)cyclohexyl)-2,4'-bipyñdine-2',6-diamine (7.9mg), LCMS (m/z): 410.3 (MH+), retention time = 0.60 min as a TFA salt. IH-NMR (400 MHz, METHANOL-d4, 25 °C) 1.40 - 1.70 (m, 4 H) 2.05 - 2.25 (m, 4 H) 3.10-3.25 (m, l H) 3.55 - 3.64 (m, l H) 4.57 (s, 2 H) 6.76 (d, J=8.4 Hz, I H) 6.93 -7.00 (m, l H) 7.Il (d, J=10.4 Hz, 1 H) 7.20 (m, 2 H) 7.28-7.36 (m, l H) 7.52 (d, J=6.4 Hz, l H) 7.61 (t, J=8.0 Hz, l H) 7.96 (d, J=4.8 Hz, l H). Example 69 (Compound 180) N2 -(trans-4-amin cy hexy )-N6-(3u r benzy )-5'-meth xy-2 4'-bipyridine-2' 6-diamine Step 1. Preparation of 2'-chloro-N-(3-fluorobenzyl)-5'-methoxy-2,4'-bipyridin-6amine: To a solution of 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (555 mg, 1.974 mmol) and 2-chloro-5-methoxypyridin-4-ylboronic acid (518 mg, 2.76 mmol) in DME (4 ml) and 2M Na2CO3 aq (2 ml) was added PdClffdppf).CH2 Cl2 adduet (81 mg, 0.099 mmol). This was then heated at 110 °C for 5h. The reaction mixture was allowed to cool and then the DME was evaporated under reduced pressure. The resulting residue was partitioned between EtOAe and water. The organics were combined, then washed with H2 0 (x3), saturated aq. brine (x3), then dried (NazSO4 ), filtered and evaporated under reduced pressure. The resulting residue was WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 purified by flash column chromatography (silica gel; 15% to 25% EtOAc/hexane) to give 2'- chloro-N-(3-fluorobenzyl)-5'-methoxy-2,4'-bipyridin-6-amine (53mg). [006291 Step 2. Preparation of N2'-(trans-4-aminocyclohexyl)-N6-(3-fluorobenzyl)-5'- methoxy-2,4'-bipyridine-2',6-diamine: To a scintillation vial was added 2'-chloro-N-(3fluorobenzyl)-5'-methoxy-2,4'-bipyridin-6-amine (30 mg, 0.087 mmol), trans-cyclohexane-1,4diamine (45 mg, 0.394 mmol), 1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidene(l,4naphthoquinone)palladium(0) (11.4 mg, 8.73 lxmol), KOH (45 mg, 0.802 mmol) and Dioxane (0.3 mL). The resulting mixture was stirred at 100 °C for 18h. The mixture was concentrated in vacuo and then diluted with water. The resultant solid was filtered and washed with water (x3). The solid was then purified by reverse phase preparative HPLC and then lyophallized to yield N2'-(trans-4-amin yc hexy )-N6-(3u r benzy )-5'-meth xy-2 4'-bipyridine-2' 6-diamine (6.5 mg), LCMS (m/z): 422.3 (MH÷), retention time = 0.54 min as a TFA sait. tH-NMR (400 MHz, METHANOL-d4, 25 °C) 1.40 - 1.66 (m, 4 H) 2.05 - 2.25 (m, 4 H) 3.10 - 3.25 (m, 1 H) 3.55 - 3.64 (m, 1 H) 3.86 (s, 3 H) 4.57 (s, 2 H) 6.69 (d, J=8.4 Hz, 1 H) 6.92 -7.00 (m, 1 H) 7.10 (d, J=10.0 Hz, 1 H) 7.17 (d, J=7.6 Hz, 1 H) 7.28-7.33 (m, 2 H) 7.48 - 7.52 (m, 2 H) 7.53 - 7.58 (m, 1 H). Example 70 (Compound 211) N2'-(trans-4-aminocyclohexyl)-N6-(3fluorobenzyl)-5'-methyl-2,4'-bipyridine-2',6-diamine H Step 1. Preparation of 2'-fluoro-N-(3-fluorobenzyl)-5'-methyl-2,4'-bipyridin-6amine: To a solution of 6-bromo-N-(3-fluorobenzyl)pyddin-2-amine (85 mg, 0.302 mmol) and 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyridine (102 mg, 0.430 mmol) in DME (2 mL) and 2M Na2 CO3 aq (1 mL) was added PdCl2 (dppf).CH2 C12 adduct (21 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 mg, 0.026 mmol). This was then heated at 110 °C for 16h. The reaction mixture was allowed to cool and then the DME was evaporated under reduced pressure. The resulting residue was partitioned between EtOAc and water. The organics were combined, then washed with H2 0 (x3), saturated aq. brine (x3), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; 15% to 25% EtOAc/hexane) to give 2'-fluoro-N-(3-fluorobenzyl)-5'-methyl-2,4'-bipyridin-6-amine (43 mg). 1006311 Step 2. Preparation of N2'-(trans-4-aminocyclohexyl)-N6-(3-fluorobenzyl)-5'- methyl-2,4'-bipyridine-2',6-diamine: To a solution of 2'-fluoro-N-(3-fluorobenzyl)-5'-methyl2,4'-bipyñdin-6-amine (18 mg, 0.058 mmol) and trans-cyclohexane-1,4-diamine (39.6 mg, 0.347 mmol), in NMP (0.3mL) was added DIPEA (20 tL, 0.115 mmol). The mixture was heated at 130 °C for 48h. The mixture was allowed to cool then diluted with water and then extracted with EtOAc (x3). The combined organics were washed with saturated brine (x2), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC and then lyophallized to yield N2'-(trans-4-aminocyclohexyl)-N6-(3fluorobenzyl)-5'-methyl-2,4'-bipyridine-2',6-diamine (4.2 mg), LCMS (m/z): 406.3 (MH+), retention time = 0.53 min as a TFA sait. Example 71 (Compound 280) Racemie 3 5'-dich r -N6-((tetrahydr -2H-pyran-4-y )methy )-N2'-(trans-4-(tetrahydr furan-3yl-amino)cyelohexyl)-2,4'-bipyridine-2',6-diamine H Step 1. Preparation of racemic benzyl trans-4-(tetrahydrofuran-3-ylamino)cyclohexylcarbamate: [006321 To a stirred solution ofbenzyl trans-4-aminocyclohexylcarbamate (396 mg, 1.595 mmol) in CH2 C12 (9 ml) was added dihydrofuran-3(2H)-one (151 mg, 1.754 mmol) followed by WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 acetic acid (150 p.L, 2.62 retool) and sodium triacetoxyborohyddde (439 mg, 2.073 retool) under Argon. Stirred at 25 °C for 16h, then concentrated in vacuo. The resulting residue was partitioned between EtOAc and 1M NaOH. The organics were combined, then washed with 1M NaOH (x2), water (x2), saturated brine (x2), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure to give racemic benzyl trans-4-(tetrahydrofuran-3-ylamino)cyclohexylcarbamate (495 mg). The resulting residue was used in next step without further purification. Step 2. Preparation of racemic tert-butyl trans-4-aminocyclohexyl(tetrahydrofuran-3yl)carbamate: To a stirred solution ofracemic benzyl trans-4-(tetrahydrofuran-3-ylamino)cyclohexylcarbamate (495 mg, 1.555 mmol) in CH2 C12 (5 ml) was added BOC-Anhydride (0.397 ml, 1.710 mmol)and the resulting mixture was stirred at 25°C under Argon for 21 hours. The mixture was evaporated under reduced pressure and purified by flash column chromatography (silica gel; 15% to 25% EtOAc/hexane). A solution of the resultant Boc protected intermediate (135 mg, 0.323 mmol) in MeOH (5 mL) was hydrogenated under an atmosphere of hydrogen in the presence of 10% Pd/C (24 mg, 0.226 mmol) for 18h. The mixture was then filtered through Celite and the filtrate evaporated under reduced pressure to give racemic tert-butyl trans-4-aminocyclohexyl(tetrahydrofuran-3-yl)carbamate (100mg). The resulting residue was used in next step without further purification Step 3. Preparation of racemic 3,5'-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans4-(tetrahydrofuran-3-yl-amino)cyclohexyl)-2,4'-bipyridine-2',6-diamine: 100634] To a scintillation vial was added 3,5'-dichloro-2'-fluoro-N-((tetrahydro-2H-pyran4-yl)methyl)-2,4'-bipyridin-6-amine (25 mg, 0.070 mmol), racemic tea-butyl trans-4aminocyclohexyl(tetrahydrofuran-3-yl)carbamate (21.95 mg, 0.077 mmol), DIPEA (24.51 ld, 0.140 mmol) and NMP (0.2 ml). This was heated at 110 °C for 48h. The mixture was diluted with EtOAc and washed with water (x2), saturated brine (x2), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure. The resulting residue was dissolved in CH2 C12 (0.4 mL) and treated with TFA (100 lxl, 1.298 mmol). After 30 minutes, the mixture was concentrated in vacuo and the resulting residue was purified by reverse phase preparative HPLC and then lyophallized WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 to yield racemic 3,5'-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4- (tetrahydrofuran-3-yl-amino)cyclohexyl)-2,4'-bipyñdine-2',6-diamine ( 10.8 mg), LC MS (m/z): 520.1/522.0 (bis-chtoro isotopic signature for MH÷), retention time = 0.59 rein as a TFA sait. Example 72 (Compound 320) 3,5'-dichloro-N2'-(trans-4-(((R)-2,2-dimethyl-1,3-dioxolan-4yl)methyl)amin cycl hexyl)-N6-((tetrahydr -2H-pyran-4-yl)methyl)-2 4'-bipyridine-2' 6diamine H H To a stirred solution of N2'-(trans-4-aminocyclohexyl)-3,5'-dichloro-N6- ((tetrahydro-2H-pyran-4-yt)methyl)-2,4'-bipyridine-2',6-diamine (68 mg, 0.151 mmol) in DMF (0.2 ml) was added DIPEA (80 tL, 0.458 mmol) followed by (S)-(2,2-dimethyl-l,3-dioxotan-4yl)methyl 4-methylbenzenesulfonate (42 mg, 0.147 mmol). The mixture was heated at 75 °C for 19 hours. The mixture was allowd to cool, then diluted with water and then extracted with EtOAc (x3). The organics were combined then washed with water (x2), saturated brine (x2), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC and lyaphltized to yield 3,5'-dichloro-N2'-(trans-4-(((R)- 2,2-dimethyl1,3-dioxotan-4-yt)methyt)aminocyclohexyl)-N6-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine (4.4 mg), LCMS (m/z): 564.4/566.3 (bis-chloro isotopic signature for MH+) retention time -- 0.65 min as a TFA sait. Example 73 (Compounds 323 and 327) 1006371 3,5'-dichloro-N2'-(trans-4-((R)- 1 -methoxypropan-2-yl-amino)cyclohexyl)-N6- (((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,4'-bipyridine-2',6-diamine and 3,5'-dichloro-N2'- WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 (trans-4-((R)- 1 -methoxypropan-2-yl-amino)cyclohexyl)-N6-(((R)-tetrahydro-2H-pyran-3yl)methyl)-2,4'-bipyridine-2',6-diamine H H [006381 Step 1. Preparation of racemic (tetrahydro-2H-pyran-3-yl)methyl 4methylbenzenesulfonate: To a stirred solution of (tetrahydro-2H-pyran-3-yl)methanol (I.0 g, 8.61 mmol) and DMAP (0.053 g, 0.430 mmol) in CH2 CI: (5.0 mL) and pyridine (6.96 mL, 86 mmol) was added Tosyl-Cl (1.805 g, 9.47 mmol). (I l:23am). After 16h the mixture was evaporated under reduced pressure and the resulting residue partitioned between EtOAc and water. The organics were separated, then washed with 0.1M HCI (x3), H2 0 (xl), saturated aq. NaHCO3 (x2), H2 0 (xl), saturated brine (xl), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure to give racemic (tetrahydro-2H-pyran-3-yl)methyl 4-methylbenzenesulfonate (2.034g). The resulting residue was used in next step without further purification. Step 2. Preparation ofracemic tert-butyl 6-bromo-5-chloropyridin-2yl((tetrahydro-2H-pyran-3-yl)methyl)carbamate: To a cooled (0 °C), stirred solution oftert-butyl 6-bromo-5-chloropyridin-2-ylcarbamate (1.00 g, 3.25 mmol) in DMF (13.0 mL) was added 60% dispersion Nail (0.156 g, 3.90 mmol) under Argon. Stirred at 0 °C for 30 mins then added racemic (tetrahydro-2H-pyran-3-yl)methyl 4-methylbenzenesulfonate (1.143 g, 4.23 mmol). The mixture was then allowed to warm to 25 °C and stirring continued for 19h. The reaction mixture then was diluted with saturated NH4 C1 and then extracted with EtOAc (x3). Organics washed with water (x2), saturated brine (x2), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; 5% to 15% EtOAc/heptanes) to give racemic ten-butyl 6-bromo-5-chloropyridin-2-yl((tetrahydro-2Hpyran-3-yl)methyl)carbamate (938 mg). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 3. Preparation oftert-butyl 3,5'-dichloro-2'-fluoro-2,4'-bipyridin-6yl((tetrahydro-2H-pyran-3-yl)methyl)carbamate: To a scintillation vial was added racemic tertbutyl 6-bromo-5-ehloropyridin-2-yl((tetrahydro-2H-pyran-3-yl)methyl)carbamate (832 mg, 2.051 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (719 mg, 4.10 mmol) and PdCl2(dppf).CH2Cl2 adduct (167 mg, 0.205 mmol) followed by DME (3 mL) and 2M Na2 CO3 aq (2 mL). The mixture was heated at 90 °C for 20h, then allowed to cool and added water and then extracted with EtOAc (x3). The organics were washed with water (x2), saturated brine (x2), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; 5% to 15% EtOAc/heptanes) to give racemic tert-butyl 3,5'-dichloro-2'-fluoro-2,4'-bipyridin-6-yl((tetrahydro-2H-pyran-3yl)methyl)carbamate (374 mg) [006411 Step 4. Preparation of 3,5'-dichloro-N2'-(trans-4-((R)- l-methoxypropan-2-ylamino)cyclohexyl)-N6- (((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,4'-bipyridine-2',6-diamine and 3,5'-dichloro-N2'-(trans-4-((R)- 1 -methoxypropan-2-yl-amino)cyclohexyl)-N6-(((R)-tetrahydro2H-pyran-3-yl)methyl)-2,4'-bipyridine-2',6-diamine: To a scintillation vial was added racemic tert-butyl 3,5'-dichloro-2'-fluoro-2,4'- bipyridin-6-yl((tetrahydro-2H-pyran-3-yl)methyl)carbamate (114 mg, 0.250 mmol), trans-N1- ((R)-l-methoxypropan-2-yl)cyclohexane-1,4-diamine (70 mg, 0.376 mmol) and DIPEA (0.088 ml, 0.501 mmol) followed by NMP (0.1 ml). The mixture was heated at 110 °C for 60 hr then concentrated in vacuo. The resulting residue was purified by reverse phase prep HPLC and lyapholized. The resulting white solid was flee based by dissolving in EtOAc and then washing with IM NaOH (x3), water (x2), saturated brine (x2), then dried (Na2 SO4 ), filtered and evaporated under reduced pressure. The resulting residue was then purified by chiral separation chromatography to yield 3,5'-dichloro-N2'-(trans-4-((R)- 1 -methoxypropan-2-ylamin ) yc hexy )-N6-(((S)-tetrahydr -2H-pyran-3-y )methy )-2 4'-bipyridine-2' 6-diamine (mg), LCMS (m/z): 522.1/523.9 (MH+), tR = 0.675 min. and 3,5'-dichloro-N2'-(trans-4-((R)-lmethoxyprop an-2 -yl-amino)c yclohexyl)-N 6-(((R) -tetrahydro-2H -pyran3 -yl)methyl )-2,4'- bipyridine-2',6-diamine (mg) LCMS 522.1/523.9 (m/z): (MH÷), retention time = 0.675 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 74 (Compounds 321 and 325) 3,5'-dichlom-N2'-(trans-4-((R)- 1 -methoxypropan-2-yl-amino)cyclohexyl)-N6- (((S)-tetrahydm-2H-pyran-2-yl)methyl)-2,4'-bipyridine-2',6-diamine and 3,5'-dichloro-N2'- (trans-4-((R)- 1 -methoxypropan-2-yl-amino)cyclohexyl)-N6-(((R)-tetrahydro-2H-pyran-2yl)methyl)-2,4'-bipyridine-2',6-diamine H H N/ /O-.. H The compounds were prepared according to Example 73, except using tetrahydro-2H-pyran-2-yl)methanol to give 3,5'-dichloro-N2'-(trans-4-((R)-l-methoxypropan-2y -amin )cyc hexyl)-N6-(((S)-tetrahydr -2H-pyran-2-y )methy )-2 4'-bipyridine-2' 6-diamine LCMS (m/z): 522.1/524.1 (Mit+), retention time = 0308 rein and 3,5'-dichloro-N2'-(trans-4- ((R)- 1 -metho xypropan-2-yl-amino)cyclohexyl )-N6-(((R)-tetrahydro-2H-pyran-2-y l)methyl) -2,4'- bipyridine-2',6-diamine LCMS (m!z): 522. t/524.1 (MH+), retention time = 0.708 rein. Example 75 (Compound 208) trans-4-(5-ch r -4 (6 ((tetrahydr -2H-pyran-4-y )methy )amin pyrazin-2-y )pyridin-2-y - amino)cyclo hexanol H [ N N /'-- H OEO Step 1" Preparation of 6-chloro-N-((tetrahydm-2H-pymn-4-yl)methyl)pyrazin-2-amine: WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 A mixture of 2,6-dichloropyrazine (950 mg, 6.38 mmol), DMSO (14 ml), TEA (t.067 ml, 7.65 mmol) and (tetrahydro-2H-pyran-4-yl)methanarnine (771 mg, 6.70 retool) was stirred at 75 °C for 6 hours, and the reaction progress was followed by LCMS. The crude reaction mixture was cooled to ambient temperature, diluted with 300 ml of ethyl acetate, washed with IMNaOH soln.(tx), water (Ix), saturated sait soin. (Ix), dried with sodium sulfate, filtered, and concentrated to constant mass, giving 1 t 85 mg of titled compound as free base, used without further purification. LCMS (m/z): 228.0 (MH+), retention time = 0.73 min. Step 2. Preparation of 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine: 1006461 A mixture of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (t390 mg, 6.10 mmol), 5-ehloro-2-fluoropyñdin-4-ylboronie acid (2141 mg, 12.21 mmol), PdCl2(dppf).CH2Cl2 adduet (399 mg, 0.488 mmol), DME (24 ml) and 2M sodium carbonate (9.16 ml, 18.31 retool) was stirred at110-115 °C for 90 min and the reaction progress was followed by LCMS. The reaction mixture was cooled, 30 ml ofethyt acetate and 20 ml of methanol were added, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using 80g column eluting with 20-75% ethyl acetate in heptane. The desired fractions were concentrated to constant mass, giving 980 mg of titled compound as free base. LCMS (m/z): 323.0 (Mit+), retention time = 0.81 min. Step 3. Preparation of trans-4-(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin2-yl)pyñdin-2-yl-amino)eyelohexanol: [006471 A mixture of 6-(5-ehloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine (375 mg, 1.162 mmol), DMSO (3.5 ml) and trans-4aminocyclohexanol (1204 mg, t0.46 mmol) was stirred at 100 °C for t8 hours and the progress was followed by LCMS. The reaction mixture was let cool, added 300 ml of ethyl acetate, washed with saturated sodium bicarbonate solution (3x), water (2x), saturated sait solution (1 x), dried with sodium sulfate, filtered and concentrated to crude solid. The crude material was purified by silica gel chromatography using 40g column, eluting slowly from (80% ethyl acetate 20% heptane with 2% MeOH) to 100% ethyl acetate with 2% MeOH. The desired fractions are concentrated to a constant mass, lyapholized from 1:1 ACN/water (does not fully dissolve), reWO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 lyophilized from 80 ml of(60/40) ACN/water solution with sonicating to dissolve solid, giving 270 mg of title compound as free base. LCMS (m/z): 418.3 (MH+), retention time = 0.52 min.; 1H NMR (300 MHz, METHANOL-d4, 25°C) 6 ppm 1.19 - 1.55 (m, 6 H) 1.71 (d, J=- 12.89 Hz, 2 H) 1.85 - 2.15 (m, 5 H) 3.28 - 3.32 (dMeOH, 2H App.) 3.40 (td, J--11.72, 1.76 Hz, 2 H) 3.50 - 3.73 (m, 2 H) 3.94 (dd, J=l 1.28, 3.08 Hz, 2 H) 6.66 (s, 1 H) 7.86 (s, 2 H) 7.99 (s, 1 H) Example 76 (Compound 215 and 216) 1-((R)-3-((2'-(trans-4-aminocyctohexylamino)-5'-chloro-2,4'-bipyridin-6-ylamino)methyl)piperidin-l-yl)ethanone and 1-((R)-3-((2'-(trans-4-aminocyclohexytamino)-2,4'- bipyridin-6-yl-amino)methyl)piperidin-l-yl)ethanone H 21S Step 1. Preparation of(R)-tert-butyl 3-((2'-(trans-4-aminocyctohexylamino)-5'-chloro-2,4'- bipyridin-6yl-amino)methyl)piped dine1 -carboxylate: A mixture oftrans-Nl-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yt)cyclohexane-l,4diamine (Example la, step 2) (50 mg, 0.156 mmol), DMSO (0.75 ml), (R)-tert-butyl 3- (aminomethyl)piperidine-t-carboxylate (167 mg, 0.779 mmol) and TEA (0.033 ml, 0.234 mmol) was stirred at 100-105 °C for 40 hours and the reaction progress was followed by LCMS. The reaction mixture was let cool, added 0.75 ml ofDMSO, filtered and purified by prep LC, and lyapholized to yield 36 mg of titled compound as a TFA sait. LCMS (m/z): 515.4 (MH+), retention time = 0.64 min.; Step 2. Preparation of benzyl trans-4-(5'-chloro-6-((S)-piperidin-3-yl-methylamino)-2,4'- bipyridin-2'-yl-amino)cyclohexylcarbamate: WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 A mixture of (R)-tert-butyl 3-((2'-(trans-4-aminocyclohexylamino)-5'-chloro-2,4'- bipyridin-6-yl-amino)methyl)piperidine-l-carboxylate (36 mg, 0.070 mmol), DCM (1.2 ml), TEA (0.019 ml, 0.140 mmol) and benzyl 2,5-dioxopyrrolidinl-yl carbonate (26.1 mg, 0.105 mmol) was stirred at ambient temperature for 2 hours and the reaction progress was followed by LCMS. To this crude reaction mixture was added 25 ml of ethyl acetate, washed with 2M sodium carbonate, water (2x) and saturated sait solution (Ix), dried with sodium sulfate, filtered, concentrated to crude intermediate. To the crude intermediate was added 4M HCI in Dioxane (2 ml, 8.00 mmol) and stirred at ambient temperature for 1 hour. The crude reaction mixture was concentrated to constant mass, dissolved in lml of DMSO and purified by prep LC. After lypohilization, 15 mg of the title compound, was obtained as a TFA sait. LCMS (m/z): 549.4 (MH+), retention time = 0.67 min. Step 3. Preparation of l-((R)-3-((2'-(trans-4-aminocyclohexylamino)-5'-chloro-2,4'-bipyridin-6yl-amino)methyl)piperidin-l-yl)ethanone and 1-((R)-3-((2'-(trans-4-aminocyclohexylamino)- 2,4'-bipyridin-6-yl-amino)methyl)piperidin-l-yl)ethanone: 1006501 A mixture ofbenzyl trans-4-(5'-chloro-6-((S)-pipeñdin-3-yl-methylamino)-2,4'- bipyridin-2'-yl-amino)cyclohexylcarbamate (15 mg, 0.027 mmol), DCM (2 mL), TEA (0.01 l mL, 0.082 mmol) and acetic anhydride (3.09 I.tL, 0.033 mmol) was stirred at ambient temperature for 2 hours and the reaction progress was followed by LCMS. The solvent was concentrated off. The reaction mixture flask was flushed with argon, 10% palladium on activated carbon (5 mg, 4.70 tmol) was added and followed by careful additon of MeOH (0.8 mL). The resulting mixture was stirred undr hydrogen for 45 minutes at ambient temperature and monitored by LCMS. To the crude reaction mixture was added 2 ml of DCM, filtered and the solvent was concentrated off. The resulting residue was dissolved in 1.0 ml of DMSO, filtered and purified by prep HPLC to give two fractions corresponding to the two title compounds repectively. After lypohilization, 4.0 mg of l-((R)-3-((2'-(trans-4-aminocyclohexylamino)-5'- chloro-2,4'-bipyridin-6-yl-amino)methyl)piperidin-1-yl)ethanone, was obtained as a TFA sait. LCMS (m/z): 457.2 (MH+), retention time = 0.46 min. in addition, 1.0 mg of 1-((R)-3-((2'- (trans-4-aminocyclohexylamino)-2,4'-bipyridin-6-yl-amino)methyl)pipeñdin1-yl)ethanone, as TFA salt was also obtained. LCMS (m/z): 423.2(MH+), retention time ---0.45 rein. This reaction yielded two products which are separated and purified by HPLC. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 77 (Compound 249) 6-(2-(trans-4 (amin methy )cyc hexy amin )-5-ch r pyridin 4-y )-N-methyl-N-((tetrahydr - 2H-pyran-4-yl)methyl)pyrazin-2-ami ne H N NCI "'/N H2 <../o Step 1. Preparation of 6-chloro-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2amine: A mixture of 2,6-dichtoropyrazine (298 mg, 2.000 mmol), DMSO (6 ml), TEA (0.418 ml, 3.00 mmol) and N-methyl1 -(tetrahydro-2H-pyran-4-yl)methanamine (264 mg, 2.040 mmol) was stirred at 70 °C for t6 hours, and the reaction progress was followed by LCMS. The crude reaction mixture was let cool to room temperature, diluted with 150 ml of ethyl acetate, washed with tM NaOH soln.(lx), water (2x), saturated sait soin. (Ix), dried with sodium sulfate, filtered, and concentrated to constant mass, giving 475 mg of the title compound as free base, which was used without further purification. LCMS (m/z): 242.0 (MH+), retention time = 0.85 min. Step 2. Preparation of 6-(5-chloro-2-fluoropyridin-4-yl)-N-methyl-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine: [006521 To 6-chloro-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (450 mg, 1.862 mmol) was added 5-chloro-2-fluoropyridin-4-ylboronic acid (588 mg, 3.35 mmol), PdCl2(dppf).CH2C12 adduct (t82 mg, 0.223 mmot), DME (8 ml) and 2M sodium carbonate (2.79 ml, 5.59 mmol). The resulting reaction mixture was stirred at 110-115°C for minutes, and the reaction progress was followed by LCMS. The reaction mixture was cooled, ml of ethyl acetate and 10 ml of methanol were added, filtered and concentrated to crude WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 product. The crude was purified by silica gel chromatography using 24g column eluting with 20-75% ethyl acetate in heptane. The desired fractions were concentrated to constant mass, giving 499 mg of titled compound as free base. LCMS (m/z): 337.1 (MH+), retention time = 0.90 min. Step 3. Preparation of 6-(2-(trans-4-(aminomethyl)cyclohexylamino)-5-chloropyridin-4-yl)-Nmethyl-N- ((tetrahydro-2H-pyran-4-yl)methyl)p yrazin-2-amine: 100653] A mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-N-methyl-N-((tetrahydro-2Hpyran-4-yl)methyl)pyrazin-2-amine (15 mg, 0.045 mmol), DMSO (0.4 ml), and tea-butyl (trans-4-aminocyclohexyl)methylcarbamate (92 mg, 0.401 mmol) was stirred at t00-105 °C for 18 hours, and the reaction progress was followed by LCMS. To the crude intermediate was added 6 M aq.HC1 (120 lai, 0.720 mmol) and heated at 80°C for 40 minutes, and the reaction progress was followed by LCMS. The reaction mixture was let cool, added 0.5 ml of DMSO, filtered and purified by prep LC. After lypohilization, 15.6 mg of the title compound, as a TFA sait was obtained. LCMS (m/z): 445.2 (MH+), retention time = 0.59 min.; tri NMR (300 MHz, METHANOL-d4, 25°C) ì5 ppm 1.12 - 1.47 (m, 6 H) 1.59 (d, ,/=12.60 Hz, 2 H) 1.67 (ddd, J=7.18, 3.81, 3.66 Hz, 1 H) 1.92 (d, J=12.31 Hz, 2 H)2.01 -2.11 (m, 1 H)2.16 (d, J=l t.43 Hz, 2 H) 2.83 (d, J=7.03 Hz, 2 H) 3.17 (s, 3 H) 3.33 - 3.45 (m, 2 H) 3.56 (d, J=7.33 Hz, 2 H) 3.60 - 3.72 (m, 1 H) 3.93 (dd, J= 11.14, 2.93 Hz, 2 H) 6.92 (s, 1 H) 8.02 (d, J=2.64 Hz, 2 H) 8.11 (s, 1 H). Example 78 (Compound 244) N-(trans-4-(5-ch r -4-(6-((tetrahydr -2H-pyran-4-y )methy )amin pyrazin-2-y )pyridin-2-y - amino)cyclohexyl)acetamide WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H H Step 1: Preparation of N-(trans-4-(5-chloro-4-(6-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazin-2-yl)pyñdin-2-yl-amino)cyclohexyl)acetamide : 1006541 A mixture oftrans-Nl-(5-chloro-4-(6-((tetrahydro-2H-pyran-4yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-l,4-diamine (example 85) (14 mg, 0.034 mmol), DCM (0.5 ml), THF (0.500 ml), TEA (0.014 ml, 0.101 mmol) and acetic anhydride (3.48 lai, 0.037 mmol) was stirred at ambient temperature for 1 hour, and the reaction progress was followed by LCMS. The solvent was concentrated off, added 1.0 ml of DMSO, filtered and purified by prep LC. After lypohilization 6.3 mg of title compound was obtained as a TFA sait. LCMS (m/z): 445.2 (MH+), retention time = 0.59 min.; 1H NMR (300 MHz, METHANOL-d4, 25°C) 6 ppm 1.21 - 1.55 (m, 6 H) 1.70 (d, J=12.89 Hz, 2 H) 1.92 (s, 3 H) 1.93 - 2.06 (m, 3 H) 2.10 (br. s., 2 H) 3.28 - 3.32 (dMeOH, 2H App.) 3.34 - 3.47 (m, 2 H) 3.55 - 3.73 (m, 2 H) 3.94 (dd, J=l 1.28, 3.08 Hz, 2 H) 7.00 (s, 1 H) 7.94 (s, 2 H) 8.01 (s, 1 H). Example 79 (Compound 254) 3,5'-dichloro-N2'- (trans-4 -(2-(methylsulfonyl)ethylamino)c yclohexyl)-N6-((tetrahydro -2H - pyran-4-yl)methyl) -2,4'-bi pyridine-2',6 -diamine H H O WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 1. Preparation of 3,5'-dichloro-N2'-(trans-4-(2-(methylsulfonyl)ethylamino)cyclohexyl)- N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine: 1006551 A mixture of N2'-(trans-4-aminocyclohexyl)-3,5'-dichloro-N6-((tetrahydro-2Hpyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine (Example 87) (40 mg, 0.089 mmol), potassium carbonate (30.7 mg, 0.222 mmol), DMSO (0.4 ml) and 2-(methylsulfonyl)ethyl methanesulfonate (Example 20, stepl) (26.9 mg, 0.133 mmol) was stirred at 100 °C and the reaction progress was followed by LCMS. After 4 hours, to the crude reaction mixture was added 2-(methylsulfonyl)ethyl methanesulfonate (26.9 mg, 0.133 mmol) and stirred at 100 °C for an additional 4 hours. The reaction mixture was cooled to room temperature, 0.5 mL of DMSO added, filtered and purified by prep. LC. After lypohilization to TFA sait, 16.9 mg of title compound was obtained. LCMS (m/z): 556.2 (MH+), retention time - 0.61 min.; 1H NMR (300 MHz, METHANOL-d4, 25°C) 6 ppm 1.18 - 1.53 (m, 4 H) 1.53 - 1.72 (m, 4 H) 1.86 (dddd, ,/=14.83, 7.58, 3.96, 3.81 Hz, 1 H) 2.24 (d, J=10.55 Hz, 4 H) 3.11 (s, 3 H) 3.19 (d, J=6.74 Hz, 2 H) 3.25 (br. s., 1 H) 3.38 (td, J=l 1.72, 1.76 Hz, 2 H) 3.56 (s, 4 H) 3.72 (t, J=l 1.28 Hz, 1 H) 3.92 (dd, J=-I 1.28, 2.78 Hz, 2 H) 6.61 (d, ./--9.08 Hz, 1 H) 6.67 - 6.77 (m, 1 H) 7.50 (d, J=9.08 Hz, 1 H) 8.05 (s, 1 H). Example 80 (Compound 258) 3 5'-dich r -N2'-(tmns-4-(2-meth xyethy amin )cyc hexy )-N6-((tetrahydr -2H-pyran-4yl)methyl)-2,4'-bipyddine-2',6-diamine H Step 1 : Preparation of 3,5'-dichloro-N2'-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine: WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 A mixture of N2'-(trans-4-aminocyclohexyl)-3,5'-dichloro-N6-((tetrahydro-2Hpyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine (example 87)(40 mg, 0.089 mmol), potassium carbonate (30.7 mg, 0.222 mmol), DMSO (0.4 ml) and 1-bromo-2-methoxyethane (18.52 mg, 0.133 mmol) was stirred at 80 °C for 2 hours and the reaction progress was followed by LCMS. To the crude reaction mixture was added BOC-Anhydríde (0.041 mL, 0.178 mmol)and stirred at ambient temperature for 2 hr. The BOC intermediate was purified by prep. LC and lyophilized to TFA sait, which was then mixed with 4M HCL (1 mL, 4.00 mmol) and stirred at ambient temperature for 1 hour. The solvent was concentrated off, the resulting residue dissolved in 1 ml DMSO, filtered and purified by prep. LC. After lypohilization to TFA sait, 5.3 mg of the title compound was obtained. LCMS (m/z): 508.2 (MH+), retention time = 0.63 min, Example 81 (Compound 259) 2-(trans 4-(3,5 -dich r -6-((tetrahydr -2H-pyran-4-y )methy )amin -2 4'-bipyridin-2'-y - amino)cyclohexylamino)ethanol H H Step 1. Preparation of 2-(trans-4-(3,5'-dichloro-6-((tetrahydro-2H-pyran-4-yl)methyl)amino2,4'-bipyridin-2'-yl-amino)cyclohexylamino)ethanoh 1006571 A mixture of N2'-(trans-4-aminocyclohexyl)-3,5'-dichloro-N6-((tetrahydro-2Hpyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine (example 87)(40 mg, 0.089 mmol), potassium carbonate (30.7 mg, 0.222 mmol), DMSO (0.4 ml) and 2-bromoethanol (16.65 mg, 0.133 mmol) was stirred at 80 °C for 2 hours and the reaction progress was followed by LCMSTo this crude reaction mixture was added BOC-Anhydride (0.041 mL, 0.178 mmol) and stirred at ambient temperature for 2 hr. The BOC intermediate was purified by prep LC, and lyophilized to a TFA sait. Then was added 4M HCI in Dioxane (1 mL, 4.00 mmol) and stirred at ambient temperature WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 for 1 hour. The solvent was concentrated off, the resulting residue dissolved in DMSO, purified by prep. LC. After lypohilization to TFA salt, 6.1 mg of the title compound was obtained. LCMS (m/z): 494.2 (MH+), retention time = 0.60 min.; 1H NMR (300 MHz, METHANOL-d4, 25°C) 6 ppm 1.18 - 1.51 (m, 4 H) 1.50 - 1.73 (m, 4 H) 1.78 - 1.95 (m, J=14.80, 7.62, 7.47, 3.66, 3.66 Hz, 1 H) 2.23 (d, J---11.43 Hz, 4 H) 3.09 - 3.24 (m, 5 H) 3.38 (td, J=l 1.79, 1.61 Hz, 2 H) 3.64 - 3.77 (m, 1 H) 3.77 - 3.84 (m, 2 H) 3.92 (dd, J=l 1.28, 3.08 Hz, 2 H) 6.59 (d, J=9.08 Hz, 1 H) 6.66 (s, 1 H) 7.49 (d, ./--8.79 Hz, 1 H) 8.03 (s, 1 H) Example 82 (Compound 265) N2 -(trans-4-amin cyc hexy )-3-ch r -N6-((tetrahydr -2H-pyran-4-y )methy )-2 4'-bipyridine2',6-diamine Step 1. Preparation of 3-chloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyddin6-amine 1006581 A mixture of 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2amine (intermediate E) (630 mg, 2.062 mmol), 2-fluoropyridin-4-ylboronic acid (639 mg, 4.54 mmol), PdC12 (dppf).CH2Cl2 adduct (168 mg, 0.206 mmol), DME (9 ml) and 2M sodium carbonate (3.09 ml, 6.18 mmol) was stirred at 105 °C for 2 hours, and the reaction progress was followed by LCMS. The reaction mixture was let cool to room temperature, diluted with 30ml of ethyl acetate, 10 ml of methanol, filtered and concentrated. The crude material was purified by silica gel chromatography using 40g column and eluting with 5-45% ethyl acetate in heptane. The desired fractions were concentrated to constant mass giving, 516 mg of the title compound as free base. LCMS (m/z): 332.0 (MH+), retention time = 0.88 min WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1006591 Step 2. Preparation of N2'-(trans-4-aminocyclohexyl)-3-chloro-N6-((tetrahydro2H-pyran-4-yl)methyl)-2,4'-bipy6dine-2',6-diamine: A mixture of 3-ehloro-2'-fluoro-N- ((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridin-6-amine (250 mg, 0.777 mmol), DMSO (2 ml), and trans-cyelohexane-l,4-diamine (798 mg, 6.99 mmol) was stirred at 105 °C for 20 hours and the reaction progress was followed by LCMS. The crude reaction mixture was cooled to room temperature, diluted with 250 ml of ethyl acetate, washed with saturated sodium bicarbonate (Ix), water (2x), filtered and the solvent was concentrated off. The crude was dissolved in 5 ml DMSO, filtered and purified by prep. LC. After lyapholization to TFA sait, 180 mg of the title compound was obtained. LCMS (m/z): 416.2 (MH+), retention time = 0.52 min.; 1H NMR (300 MHz, METHANOL-d4, 25°C) 6 ppm 1.20 - 1.41 (m, 2 H) 1.46 - 1.74 (m, 6 H) 1.85 (ddd, J=10.99, 7.33, 4.25 Hz, 1 H) 2.06 - 2.30 (m, 4 H) 3.19 (br. s., 1 H) 3.26 (d, J=-7.03 Hz, 2 H) 3.33 - 3.46 (m, 2 H) 3.59 - 3.76 (m, 1 H) 3.93 (dd, J=l 1.14, 3.22 Hz, 2 H) 6.60 (d, ,/=8.79 Hz, 1 H) 7.23 (d, J=6.74 Hz, 1 H) 7.39 (s, 1 H) 7.49 (d, ,/=8.79 Hz, 1 H) 7.88 (d, J=-6.74 Hz, 1 H) Example 83 (Compound 268) 3,5'-diehloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4- (((R)-tetrahydrofuran-2yl)methyl)aminocyclohexyl)-2,4'-bipyridine-2',6-diamine Step 1. Preparation of (R)-(tetrahydrofuran-2-yl)methyl methanesulfonate: 1006601 A mixture of (R)-(tetrahydrofuran-2-yl)methanol (600 mg, 5.87 mmol), DCM (35 ml), TEA (0.983 ml, 7.05 mmol) was diluted with methanesulfonyl chloride (0.467 ml, 5.99 mmol), via a dropwise addition. The reaction mixture was stirred at ambient temperature for WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 hours and the reaction progress was followed by LCMS. The crude reaction mixture was washed with saturated sodium bicarbonate (lx), water (2x), filtered and concentrated to a constant mass, giving 980 mg of the title compound, which was used without further purification. LCMS (m/z): 181.0 (MH+), retention time = 0.40 min Step 2. Preparation of 3,5'-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2'-(trans-4-(((R)- tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4'-bipyridine-2',6-diamine: 100661] To N2'-(trans-4-aminocyclohexyl)-3,5'-dichloro-N6-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine (example 87) (40 mg, 0.089 mmol) was added potassium carbonate (30.7 mg, 0.222 mmol), DMSO (0.4 ml) and (R)-(tetrahydrofuran-2yl)methyl methanesulfonate (24.01 mg, 0.133 mmol), and the resulting reaction mixture was stirred at 100 °C for 4 hours and the reaction progress was followed by LCMS. After about 4 hours (R)-(tetrahydrofuran-2-yl)methyl methanesulfonate (24.01 mg, 0.133 mmol) was added and the resulting mixture was stirred at 100 °C for 4 hours more. The reaction mixture was cooled to room temperature, 0.5 mL of DMSO added, filtered and purified by prep. LC. After lyapholization to a TFA salt, 9.1 mg of the title compound was obtained. LCMS (m/z): 534.3 (MH+), retention time = 0.62 rein. Example 84 (Compound 272) 3 5 -dich r N2 (trans 4 ((2 meth xyethy )(methy )amin )cyc hexy )-N6-((tetrahydr -2Hpyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine: Step 1. Preparation of (1 s,4s)-4-(3,5'-dichloro-6-((tetrahydro-2H-pyran-4-yl)methyl)amino-2,4'- bipyridin-2'-yl-amino)cyclohexanol: WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 To 3,5'-dichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridin-6amine (intermediate G) (712 mg, 1.999 mmol) was added DMSO (4.5 ml), TEA (1.114 ml, 8.00 mmol) and (l s,4s)-4-aminocyclohexanol (607 mg, 4 mmol), and the reaction mixture was stirred at 95-100 °C for 96 hours and the reaction progress was followed by LCMS. The reaction mixture was cooled, 250 ml of ethyl acetate was added, washed with saturated sodium bicarbonate (lx)water (2x) and concentrated to constant mass. The crude was purified by silica gel chromatography using 40g column eluting with 25-95 % ethyl acetate in heptane. The desired fractions were concentrated to constant mass, giving 380 mg of title compound as free base. LCMS (m/z): 451.1 (MH+), retention time = 0.65 min Step 2. Preparation of (1 s,4s)-4-(3,5'-dichloro-6-((te rahydro-2H-pyran-4-yl)moEhyl)amino-2,4'- bipyñdin-2'-yl-amino)cyclohexyl methanesulfonate: 1006631 To (1 s,4s)-4-(3,5'-dichloro-6-((tetrahydro-2H-pyran-4-yl)methyl)amino-2,4'- bipyridin-2'-yl-amino)cyclohexanol (375 mg, 0.831 mmol) was added DCM (8 ml), and TEA (0.174 ml, 1.246 mmol) and the resulting mixture was cooled in an ice bath to 0 °C. Then with stirring was added methanesulfonyl chloride (0.071 ml, 0.914 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours, and the reaction progress was followed by LCMS. To the crude reaction mixture was added 250 ml of ethyl acetate, washed with saturated sodium bicarbonate (l x) water (2x) and concentrated to constant mass giving, 441mg of title compound as free base, used without further purification. LCMS (m/z): 529.3 (MH+), retention time = 0.75 min. Step 3. Preparation of 3,5'-dichloro-N2'-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)- N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine: 1006641 To (1 s,4s)-4-(3,5'-dichloro-6-((tetrahydro-2H-pyran-4-yl)methyl)amino-2,4'- bipyridin-2'-yl-amino)cyclohexyl methanesulfonate (48 mg, 0.091 mmol) was added t-Butanol (0.22 ml) and 2-methoxy-N-methylethanamine (202 mg, 2.266 mmol). The reaction mixture was stirred at 95100 °C for 5 hours and the reaction progress was followed by LCMS. The reaction mixture was cooled to room temperature, 12 ml of ethyl acetate was added then washed with saturated sodium bicarbonate (1 x) water (2x) and the solvent concentrated off. The resulting residue was dissolved in 1 ml of DMSO, filtered and purified by prep LC. After WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 lyapholization to TFA salt, 8.61 mg of the title compound was obtained. LCMS (m/z): 522.2 (MH+), retention time = 0.63 min.; IH NMR (300 MHz, METHANOL-d4, 25°C) 8 ppm 1.18 - 1.56 (m, 4 H) 1.59 - 1.79 (m, 4 H) 1.79 - 1.95 (m, 1 H) 2.02 - 2.35 (m, 4 H) 2.87 (s, 3 H) 3.19 (d, ,/=6.74 Hz, 2 H) 3.24 (d, ,/--3.52 Hz, 1 H) 3.32 - 3.41 (m, 3 H) 3.42 (s, 3 H) 3.46 - 3.58 (m, 1 H) 3.63 - 3.78 (m, 3 H) 3.92 (dd, J=l 1.t4, 2.93 Hz, 2 H) 6.60 (d, J=9.08 Hz, 1 H) 6.70 (s, 1 H) 7.49 (d, ,/--9.08 Hz, 1 H) 8.04 (s, 1 H) Example 85 (Compound 203) trans-N -(5-ch r -4-(6-((tetrahydr -2H-pyran-4-y )methy )amin pyrazin-2-y )pyridin-2yl)cyclohexane1,4-diamine Step 1. Preparation oftrans-N l-(5-chloro-4-(6-((tetrahydro-2H-pyran-4yl)methyl)amino pyrazin-2-yl)pyridin-2-yl)cyclohexane1,4-diamine [006651 To 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4yl)methyl)pyrazin-2-amine (example 75 step 2) (20 mg, 0.062 mmol) was added DMSO (0.6 ml) and trans-cyclohexane-1,4-diamine (63.7 mg, 0.558 mmol). The reaction mixture then was stirred at 100-105 °C for 18 hours and the reaction progress was followed by LCMS. The reaction mixture was let cool, diluted with 0.5 ml of DMSO, filtered and purified by prep LC. After lyapholization to TFA salt, 13.7 mg of the title compound was obtained. LCMS (m/z): 417.3 (MH+), retention time = 0.46 min.; 1H NMR (300 MHz, METHANOL-d4, 25°C) 8 ppm 1.22 - 1.78 (m, 8 H) 1.81 - 2.01 (m, 1 H) 2.03 - 2.28 (m, 4 H) 3.05 - 3.21 (m, 1 H) 3.28 - 3.32 (dMeOH, 2H App.) 3.39 (td, J=l 1.72, 1.76 Hz, 2 H) 3.62 - 3.79 (m, 1 H) 3.94 (dd, J=l 1.14, 3.22 Hz, 2 H) 6.95 (s, 1 H) 7.92 (d, J=2.93 Hz, 2 H) 8.05 (s, 1 H). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 86 (Compound 243) trans-Nl (5 chl r -4-(6 ((tetrahydr -2H-pyran-4-yl)methyl)amin pyrazin 2-y )pyridin-2-y )- N4- (2-methoxyethyl)cyclo hexane1,4-diamine H H Step 1. Preparation of trans-N 1 - (5-chloro-4-(6- ((tetrahydro-2H-pyran-4yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)-N4-(2-methoxyethyl)cyclohexane1,4-diamine To trans-N 1 -(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2yl)cyclohexane-l,4-diamine (Example 85) (16 mg, 0.038 mmol)was added DMSO (0.4 ml), potassium carbonate (15.91 mg, 0.115 mmol) and 1-bromo-2-methoxyethane (7.47 mg, 0.054 mmol). The reaction mixture then was stirred at 70 °C for 6 hours and the reaction progress was followed by LCMS. The reaction mixture was cooled to room temperature, 0.5 ml of DMSO was added, filtered and purified by prep LC. After lyapholization to TFA salt, 2.7 mg of the title compound was obtained. LCMS (m/z): 475.2 (MH+), retention time = 0.51 min. Example 87 (Compound 253) N2 (trans-4-amin cyc h xy )-3 5'-dichl r -N6-((tetrahydro-2H-pyran-4-yl)methy1)-2 4'- bipyridine-2',6-diamine WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step I. Preparation of N2'-(trans-4-aminocyclohexyl)-3,5'-dichloro-N6-((tetrahydro-2H-pyran4-yl)methyl)-2,4'-bipyridine-2',6-diamine: To 3,5'-dichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyñdin-6amine (Intermediate G)(250 mg, 0.702 mmol) was added DMSO (3 ml) and trans-cyclohexane1,4-diamine (952 mg, 6.32 mmol). The reaction mixture was stirred at 100 °C for 20 hours and the reaction progress was followed by LCMS. The reaction mixture was cooled, diluted with 250 ml ethyl acetate, washed with saturated sodium bicarbonate (lx), water (3x) and concentrated to constant mass, giving 320 mg of product as a free base, which was used without further purification. A portion of the title compound, 25 mg was purified by prep LC and lyapholized to give 17.6 mg of the title compound as a TFA salt. LCMS (m/z): 450.2 (MH+), retention time = 0.58 min.; 1H NMR (300 MHz, METHANOL-d4, 25°C) õ ppm 1.16 - 1.76 (m, 8 H) 1.76 - 1.98 (m, l H) 2.04 - 2.27 (m, 4 H) 3.06 - 3.16 (m, l H) 3.19 (d, ,/=6.74 Hz, 2 H) 3.37 (t, J=l 1.87 Hz, 2 H) 3.62 - 3.77 (m, I H) 3.92 (dd, J=-l 1.28, 3.08 Hz, 2 H) 6.61 (d, ,/--8.79 Hz, l H) 6.73 (s, 1 H) 7.50 (d, ,/=9.08 Hz, l H) 8.04 (s, l H). Example 88 (Compound 178) ! ç ! ç -chloro-N6-(3-fluorobenzyl)-N2 -methyl-2,4 -bipyddine-2,6-diamine CI H Step 1. Preparation of 5'-chloro-N6-(3-fluorobenzyl)-N2'-methyl-2,4'-bipyridine-2',6-diamine: 1006671 A mixture of 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6-amine (Intermediate B ) (15 mg, 0.045 mmol) was added DMSO (0.4 ml) and methyl amine 40% in WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 water (200 1, 2.293 mmol) in a microwave tube was microwaved at 145 °C for 900 seconds and the reaction progress was followed by LCMS. Most of the amine was removed under vaccum, 0.5 ml of DMSO was added, filtered and purified by prep LC. After lyapholization 13.9 mg of the title compound was obtained as a TFA sait. LCMS (m/z): 343.0 (MH+), retention time = 0.67 min.; tri NMR (300 MHz, METHANOL-d4, 25°C) 6 ppm 2.97 (s, 3 H) 4.62 (s, 2 H) 6.81 (d, J=8.50 Hz, 1 H) 6.9t - 7.02 (m, 3 H) 7.09 (d, J=9.96 Hz, 1 H) 7.17 (d, J=-7.62 Hz, t H) 7.27 - 7.39 (m, 1 H) 7.69 (dd, J=8.50, 7.33 Hz, 1 H) 8.03 (s, 1 H). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Example 89 (Compound 332) -ch r -5u r -N6-((4-methy tetrahydr -2H-pyran-4-y )methy )-N2 -(trans 4-(( , 1-dioxohexahydro-l-thiopyran-4-yl)-3-ylamino)cyclohexyl)-2,4'-bipyridine-2',6-diamine H H To a solution of N2'-(trans-4-aminocyclohexyt)-5'-chloro-5-fluoro-N6-((4methyltetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyddine-2',6-diamine (40 mg, 0.089 mmol) in DMF (0.5 ml) was added potassium carbonate (49.4 mg, 0.357 mmol), 3-chloro-l, 1-dioxotetrahydro-l-thiophene (83 mg, 0.536 mmol) and sodium iodide (40.2 mg, 0.268 mmol). The reaction mixture was stirred at 100 °C for 42 hours. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and bñne, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC and lyophilized to give 3.8 mg off-white powder of the title compound as its TFA salt. LCMS (m/z): 566.2 (MH+), rentention time = 0.64 min. Example 90 (Compound 333) 5'-chloro-5-fluoro-N2'-(trans-4-((2-methyl-1,3-dioxolan-2yl)methyl)amin y l hexyl)-N6-((tetrahydr -2H-pyran-4-y )methyl)-2 4'-bipyridine-2' 6diamine H o.<° WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 To a solution of N2'-(trans-4-aminocyclohexyl)-5'-chloro-5-fluoro-N6-((4methyltetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridine-2',6-diamine (21 mg, 0.048 mmot) in DCM (1.0 ml) was added 2-methyl-1,3-dioxolane-2-carbaldehyde (synthesized following the procedure reported in Org. Left., 2009, 11, 3542-3545), sodium triacetoxyborohydride (20.51 mg, 0.097 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC and lyophilized to give t2 mg off-white powder of the title compound as its TFA sait. LCMS (m/z): 534.1 (MH+), retention time = 0.62 min. Example 91 (Compound 349) (4-((5'-ch r -2'-(trans-4-((R)- -meth xypr pan-2-y amin )cyc hexy amin )-2 4'-bipyridin-6ylamino)methyl)tetrahydro-2H-pyran-4-yl)methanol H . N< N « A LA,N O. H <...6 Step 1. Synthesis of methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate 1006711 To l-bromo-2-(2-bromoethoxy)ethane (2.57 g, 11.10 mmol) in DMSO (6 mL, by mistake, should use DMF) at room temperature was added methylcyanoacetate (1 g, 10.09 retool) and DBU (3.35 ml, 22.20 mmol) sequentially. The brown mixture was heated to 85 °C in a capped glass vial for 3 hours. The resulting solution was dark brown. The reaction mixture was poured into water and extracted with EtOAe. The organic extracts were combined, washed with water, brine, dried with sodium sulfate and concentrated in vacuo to give 0.944 g of brown oil. This crude material was used in the next step without further purification. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 2. Synthesis of (4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol To the crude product from step 1 (0.944 g, 5.58 mmol) in THF (5 ml) (a dark brown solution) at 0 °C was added LAH (5.58 ml, 5.58 mmol) dropwíse via a syringe. The brown mixture was warmed to room temperature and stirred for 18 hours. The resulting mixture was yellow cloudy. LC/MS showed containing desired product. To the reaction was added sodium sulfate decahydrate solid at 0 °C. The mixture was stirred at room temperature for min., then filtered and washed with DCM. The yellow filtrate was concentrated in vacuo to give 0.74 g of orange oil. This crude mateñal was used in the next step without further purification. Step 3. Synthesis of (4-((6-bromopyridin-2-ylamino)me hyl)tetrahydro-2H-pyran-4-yl)methanol 100674] To 2-bromo-6-fluoropyridine (0.448 g, 2.55 mmol) in NMP (4 ml) at room temperature was added TRIETHYLAMINE (0.852 ml, 6.12 mmol) and the crude product obtained in step 2 (370 mg, 2.55 mmol) sequentially. The yellow mixture was heated to 75 °C in a capped glass vial for 3 hours. LC/MS showed about 20% conversion to the product. Continued heating at I l 0 °C for 16 hrs. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic extracts were combined, washed with water, brine, dried with sodium sulfate and concentrated in vacuo to give 0.5 g of brown oil. The crude mixture was purified by Analogix system (silica gel column 24 g, gradient: 0 min, 100%nhexane; 2-127 min, 10% EtOAc in Hex; 7-13 min. 20% EtOAc in Hex; 13-16 min. 30% EtOAc in Hex; 16-30 min. 50% EtOAc in Hex; 30-35 min. 100% EtOAc). The pure fractions were combined and concentrated in vacuo to give 0.13 g of desired product as a white crystal. LCMS (m/z): 301/303 (MH+), retention time = 0.67 min. Step 4. Synthesis of (4-((5'-chloro-2'-fluoro-2,4'-bipyridin-6-ylamino)methyl)tetrahydro-2Hpyran-4-yl)methanol [006751 Following the same procedure as in Example lb using (4-((6-bromopyridin-2ylamino)methyl)tetrahydro-2H-pyran-4-yl)methanol (from step 3) and 5-chloro-2-fluoropyridin4-ylboronic acid, the desired product was obtained. LCMS (m/z): 352 (MH+), retention time = 0.54 min. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Step 5. Synthesis of (4-((5'-chloro-2'-(trans-4-((R)- l-methoxypropan-2y amin ) y hexy amin )-2 4'-bipyridin-6-y amin )methy )tetrahydr -2H-pyran-4-y )methan [006761 Following the same procedure as in Example lb using (4-((5'-chloro-2'-fluoro2,4'-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-yl)methanol (from step 4) and trans-N I- ((R)- l-methoxypropan-2-yl)cyclohexane1,4-diamine, the desired product was obtained. LCMS (m/z): 518.2 (MH+), retention time = 0.47 min. Example 92 (Compound 348) 3,5'-dichloro-N6-((tetrahydro-2 H-pyran-4-yl)methyl)-N2'-(trans-4-(l, 1 -dio xo-tetmhydro-2Hthiopyran-4-ylamino)cyclohexyl)-2,4'-bipyñdine-2',6-diamine 1006771 Compound N2'-(4-aminocyclohexyl)-3,5'-dichloro-N6-((tetrahydro-2H-pyran-4yl)methyl)-2,4'-bipyridine-2',6-diamine (0.100 g, 0.222 mmol) (synthesized in the same manner as in Example lb), 2,3,5,6-tetrahydro-4H-thiopyran-4-one 1,1-dioxide (0.036 g, 0.244 mmol), and triethylamine (0.251 ml, 0.182 g, 1.798 mmol) were dissolved in anhydrous CH2 C12 (1.0 ml) and placed under argon. This solution was then treated with sodium triacetoxyborohydride (0.094 g, 0.444 mmol). The reaction was then stirred at room tempereature for 18 hours. At this time a LC-MS was run. The reaction was about 25% complete. Additional 2,3,5,6-tetrahydro4H-thiopyran-4-one 1,1-dioxide (- 4 equivalents) and sodium triacetoxy borohydride (-8 equivalents) were added and the reaction continued for additional 27 hours. The reaction was about 60% complete as indicated by LC/MS. The reaction was quenched with sat NaHCO3 (15 ml). This was extracted with EtOAc (3 x 15 ml). The combined extracts were washed with brine (1 x 15 ml), dried (Na2 SO4 ), filtered and the solvent removed in vacuo. The material was WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 purified using the HPLC and lyophilized to give 19.7 mg off-white powder of the title compound as its TFA sait. LCMS (m/z): 582/584 (MH+), retention time = 0.58 min. Example 93 (Compound 310) 4-((5'-chloro-2'-(trans-4-((R)- 1-methoxypropan-2-yl-amino)cyclohexylamino)-2,4'-bipyridin-6yl ami no)methyl)tetrahydro-2H-pyran-4-carbonitrile H N H "',N O-., H CN This compound was synthesized following the procedure of Example lb using Intermediates AB (40 mg, 0.115mmol) and N 1 -((R)- 1-methoxypropan-2-yl)cyclohexane-trans1,4-diamine (synthesized in step 2 of Example 67, 107mg, 0.577mmol). The product was obtained as an offwhite powder (30.2 mg, 35.5% yield). LCMS (m/z): 513.2 [M+H]+; retention time = 0.531 min. IH NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.04 (d, J=6.26 Hz, 2 H) 1.12 - 1.37 (m, 3 H) 1.84 - 2.06 (m,3 H) 2.10 - 2.25 (m, 2 H) 2.44 - 2.69 (m, 1 H) 2.91 - 3.11 (m, 1 H) 3.20 - 3.39 (m, 3 H) 3.43 - 3.60 (m, 1 H) 3.61 - 3.83 (m, 3 H) 3.90 - 4.08 (m, 2 H) 4.41 (d, J=8.22 Hz, 1 H) 4.67-4.93 (m, l H) 6.37 -6.62 (m, 2 H) 6.97 (d, J=7.43 Hz, 1 H) 7.26 (s, 1 H) 7.39 - 7.58 (m, I H). Example 94 (Synthesis of Compound 340) Synthesis of 4-((5'-chloro-5-fluoro-2'-(trans-4-((R)- 1-methoxypropan-2-ylamin ) y hexy amin )-2 4'-bipyridin-6-y amin )methy )tetrahydr -2H-pyran-4arb nit e WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 F H CN A N H ',,N J'x./O-.. H This compound was synthesized following the procedure of Example lb using intermediates AA( 50 mg, 0.137mmol) and NI-((R)-l-methoxypropan-2-yl)cyclohexane4rans1,4-diamine (synthesized in step 2 of Example 67, 128mg, 0.685mmol). The product was obtained as an off white powder 35mg (33.6% yield). LCMS (m/z): 531.2 [M+H]+; retention time = 0.595 min. Examples in Table 1 were prepared using methods analgous to those described above. The method column in Table 1 indicstes the synthetic procedure, from a specific example, used to synthesize a given compound. Thus for example, Compound 7 is synthesized by the procedure outlined in Example 7, while compound 25 is synthesized by the procedure outlined in Example la, and the like. [006811 Table 1 Compound Structure II A o,.çJ I0...,=, M+H (m/z) retention time (min.) method 426.2 0.7 Example la WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H I N-A N «NH2 H " "71"1 • cI'í N " /"'*N H2 H H I N.A c,-çìJ Ll N MA OcH3 H fF 380.3 415.3 440.2 412.2 504.2 0.61 0.67 0.62 0.6 0.77 Example 2 Example 3 Example 4 Example Example 6 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 N r" *',/' O CHi c.- L'- ".Æt c H i. N..A, c " "oH N NH H H H l N NL ? "N' H F F F 511.3 402.3 441.3 483.2 460.3 0.62 0.41 0.76 0.65 0.72 Example 7 Example 8 Example 9 Example Example 11 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chiral IN NA • C1an "NH2 'L ç.ï. H Chiral IN N- -.-- C1N v "NH2 [ N W- - Chiral C1an " "N H2 C1an "NH2 H I N NA C1N " "NH2 444.2 451.2 469.1 451.2 469.2 0.7 0.67 0.56 0.7 0.56 Example 12 Exa mple 13 Example 14 Example Example 16 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H IJ N« A N HO I N F H H I I N A c,J[ ì" "3" I o,,.o H 470.2 454.2 470.3 532.2 440.3 0.61 0.61 0.58 0.62 0.61 Example 17 Example 18 Example 19 Example Example 21 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H IÇ N,.. A c,.-çY -Lk., "N HN'cH3 F H IN.A, I 1 I A c.íL; -0.,,=., H I1 N« A =JLç ,=., 454.2 498.3 414.3 408.2 409.2 0.64 0.65 0.72 0.61 0.41 Example 22 Example 23 Example la Example la Example la WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 I N« - A "0....2 C1oE 'N H2 H I N-A CIOE v "NH2 F N v INH2 H I N N- , N 'NH2 444.2 444.2 444.3 393.2 374.3 0.63 0.63 0.64 0.54 0.56 Example la Example la Example la Example Example 2 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 N v "NH2 H ì N " "NH2 C1.,' ;.."N ",N H2 H N N,. _---,. ç 71 ClaN V"NH= H I N N A , C1an ,NH2 1N 0 F 392.3 375.3 427.3 410.3 474.2 0.59 0.36 0.61 0.41 0.66 Example 2 Example 2 Example 3 Example 3 Example la WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H IN NA o,í Y Lk.. H i N CI' "NH2 F H I 1 N« A CIOE " "NH2 442.2 427.2 444.2 416.3 426.3 0.66 0.49 0.64 0,46 0.61 Example la Example la Example la Example la Example la WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H I N< NA • C1oE cI'NHz H CIRON "'J'"N H2 H l N N- ..-'-- , Ct N ,,NH2 H I N-A C1oE " "NH2 I ,I ,. c, 'Z.J 442,2 422.3 438.3 492.2 487.1/4 89.2 0.65 0.63 0.59 0.72 0.53 Example la Example la Example la Example la Example la WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 SO H I J N= A "N F _ H [ N NA C1an " "N H2 IN- ' C[OE 'NH:, H ":" "CHz 476.3 486.2/4 88.2 424.2 426.2 422.2 0.69 0.67 0.5 0.6 0.63 Example la Example la Example la Example la Example la WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H N N« F C1an " "N Hz C1an v " "N Hz CIoE "/NH2 H C1aN N ,,/NH2 476.3 474.2 492.2 442.2 428.3 0.7 0.64 0.73 0.66 0.66 Example la Example la Example la Example la Example 4 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H ..IJ H H C1aN N ì],,,,.,... N H2 H CI '"/NH2 L jL, H C1aN N ìl"',-'NH F 422.3 423.3 441,3 423.3 458.3 0.6 0.41 0.5 0.41 0.65 Example 4 Example 4 Example 4 Example 4 Exa tapie 4 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H ...N A C1oE " "" N Hz C1oE """ N H2 H c, "'Çìlv,,,2 F r...N - .., C1oE "- """ N H z 456.3 458.:3 488.3 458.3 440.3 0.67 0.65 0.67 0.66 0.62 Example 4 Example 4 Example 4 Example 4 Example 4 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Ci I N' N yo.. CHa H H I1 N. A H C1aN N "]N H %A WF F 512.3 400.3 394.3 413.2 430.2 0.91 0.64 0.58 0.47 0.63 Example Example Example Example Example WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 N A H H IJ N. A oílìJ Ç == .NI A C1an "/NH2 H N_I N,= A °'Ç LA,= 395.2 428.2 430.2 428.4 422.3 0.39 0.65 0.62 0.68 0.7 Example Example Example Example la Example la WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H .NI N- --- C1oE ' "NH2 c d. "I'" 0 OHm. c Y ; ò 0Ç' N A Chiral H 440.2 518.3 537.3 531.3 0.73 0.74 0.77 0.63 0.64 Example la Example 6 Example 6 Example 7 Example 7 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 N_ = H3 C.N.CH3 JoV eN A Chiral wN A .IN H 0 CH3 'N 525.3 551.3 545.3 497.3 523.3 0.64 0.65 0.66 0.62 0.63 Example 7 Example 7 Example 7 Example 7 Example 7 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 9O H N O ..NI A CI - v ",N" " CH3 N H H Chiral N<-,i/N J" N H k.) H Chiral I i<.T I =y.,«. N H Chiral 517.3 454.3 400.3 402.2 412.2 0.64 0.62 0.65 0.47 0.61 Example 7 Examples 1, Example Example Example WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 i1í yiL,....., o i,= o,- l',v) F i1í r.íL,.... o ,, q"J<1''õg, ÆN...,.I 1 t NH OEiral Chiml iiíN.ì_y "¢" NH Chiml c j ,.....Ç o 430.2 395.2 430.2 400.3 402.2 0.64 0.41 0.63 0.65 0.47 Example Example Example Example Example WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Chiml H Chiral N -.y.- N '- N H o,Ai. LJ F ff.N .y XNH Chiral ° N LJ o <J H IN NA .r ,ì 412.2 430.2 395.2 430.2 427.2 0.61 0.64 0.41 0.64 0.6 Example Example Example Example Example WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H pN ,'ìr N'y' CH3 c, .JJ H C1an N 'IN.cH I N- /F I 1 Chiral C ì }',IN H2 H C/I N H Chiral I I N. A CI Y "T «N H2 468.3 426.2 402.3 437.3 402.3 0.67 0.61 0.46 0.53 0.46 Examples 5, Examples 5, Example la Example la Example la WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H o,í ìJ NH, N j° H íN N A H I -N A c, '2J ;"N.2 H NI NA C1an "INH2 H I N-A CI N "/N H2 416.3 462.3 418.3 427.3 430.3 0.47 0.78 0.43 0.75 0.54 Example la Example la Example la Example 9 Example la WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H J N NA CI NH2 H LENGTH2 i _N A AN.(ì,H3 o " Uç H < ì 425.3 508.2 523.3 494.2 468,2 0.39 0.68 0.6 0,67 0.67 Example la Example lb, intermediate B Example lb, intermediate B Example lb, intermediate B Example lb, intermediate B WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H IN--N-A' C1oE v "OH H c.J " ,,o H c o.. L N /N H2 H H tl N= A c,£Y ,o. 427.2 494.2 496.2 362.3 376.3 0.66 0.64 0,62 0.38 0.37 Example lb, intermediate B Example lb, intermediate B Example lb, intermediate B Example 8 Example 8 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H I N« NA H I N« N H Chiral I d N.. A H I N-A H Chiral I N« N- /. "<3o. 416.3 410.2 416.3 410.2 416.3 0.39 0.42 0.43 0.42 0.41 Example 8 Example 8 Example 8 Example 8 Example 8 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H IN N- -"- c "r-J,o. o II ---.. Chiral c í Y ,o. H I N-A o Yb,,o. " L,..ó I 1 Chiral c "0,,o. H i N- -- c o. 404.2 403.1 417.1 403.1 417.1 0.39 0.49 0.48 0.49 0.5 Example 8 Example 8 Example 8 Example 8 Example 8 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1.31 H H H i N-A H I N A c,.çìJ H I N. NA F 403.3 403.3 389.2 415.2 445.2 0.47 0.49 0.58 0.7 0.71 Example 8 Example 8 Example 8 Example 8 Example 8 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H 1%N-A "r.3,o. H Ci " OH Æ"N H [ N NA L,,,,,,,. N H2 H Chiral [ N. NA CI N "'N H2 H Chiral 1%N`A CI N v "NH2 1421",1" "0 H .,;._ 427.2 419.3 416.3 451.2 469.1 0.66 0.47 0.45 0.67 0.56 Example 8 Example 8 Example 8 Exa tapie 14 Exa tapie WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H N I NA H »N I NA 426.3 397.3 411.3 413.2 427.2 0.61 0.81 0.86 0.71 0.72 Example lb Example lb Example lb Example lb Example lb WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H C1aNN / íNH2 H C1aNN / v " NH2 H C1aNN'v 'OH Chiml 386.2 400.3 387.2 401.2 413.2 0.57 0.58 0.62 0.71 0.7 Example lb Example lb Example lb Example lb Example lb WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H CI N N' FF --.- F H Chiral H IN N A c " ,©. <ì wF o, fL2 .==. N CHa 447.3 413.2 481.2 404.1 426.1 0.87 0.69 0.63 0.62 0,67 Example lb Example lb Example lb Example 32 Example lb WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H H N -x(. N /" N-í'- N H i NA' 565.2 538.1 484.2 509,2 0.75 0.85 0.82 0.63 0.58 Example lb Example 26 Example 27 Example 19 Example lb WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H NT N i NH2 H H [ N1'ì - N / »'- N - C H 3 C N H, H I"" N H ç.y....AJ ,N.CH3 372.2 373.2 428.3 426.3 440.3 0.7 0.75 0.73 0.73 0.73 Example lb Example lb Example lb Example lb Example 8 Example lb, WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chiral H N ç,r,...© c ) r.yl c""' c,- iv.. 426.3 440.3 426.3 440.3 441.3 0.74 0.77 0.76 0.77 0.72 Example lb, Example 8 Example lb, Example 8 Example lb, Example 8 Example lb, Example 8 Example lb, Example 8 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H fAT''NH H #N ,-ìd-N N." ..,íN v x/'x N,,'-,x c L...ó -N H H 440.3 455.3 442.2 371.2 385.2 0.76 0.71 0.75 0.85 0.91 Example lb, Example 8 Example lb Example lb Example lb Example lb WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H qSL'N ] F H C1aNN vN H C1aNN v- " /N iiíoE'-çl;l'c , 441.3 434.2 427.2 434.2 0.86 0.74 0.85 0.73 0,67 Example lb Example lb Example lb Example lb Example 88 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 C1 I NH2 (jL" H H3C'0N N °'tNH2 H I N-A C' N T OH L JLN H Chiral 422.3 441.2 427.1 413.2 0.65 0.54 0.71 0.69 0.68 Example 88 Example 69 Example lb Example lb Example lb WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H c N "'© o. Chiral H I N NA <3 c ;"IT o c., F 413.2 409.3 401.2 443.2 418.2 0.68 0.83 0.65 0.87 0.61 Example lb Example 21 Example lb Example lb Example lb WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 F r N O'CHz H Chiml c,í 7 "D H Chiral H i N c, l ì ,,í - o. f N CHa F 405.2 455.3 412.1 412.1 502.1 0.68 0.8 0.58 0.58 0.65 Example lb Example lb Example 52 Example 52 Example 19 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H I,I N« A o,í ìJ r.yl...ïo. -q.J-N-- H i NA' F N INH2 H F 441.1 402.1 387.1 410.3 472.3 0.75 0.55 0.64 0.6 0.66 Example lb Example lb Examples 1,5 Example 68 Examples 1,10 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 2OO í>7"F o " N CHa H Chiral "--YN"'«'x ,2 c h/' "oH _ 0 Chiral iN.-' c , " " "NH2 N"''T" " L«õ 409.1 484.3 441.1 441.1 417.3 0.64 0.59 0.73 0.73 0.46 Example 21 Example 19 Example 53 Example 53 Example WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 2O4 N H 0 Chiral t N HsC H Chiral %A 'I ìjN. H Chiral o,@ "'O°j.o...0 H t N NA c,J "O,,oH ,lí'ì N N 0 454.2 468.1 549.4 549.4 418.3 0.69 0,72 0.67 0.68 0.52 Example 53 Example 53 Example 76 Exa tapie 76 Example WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 N CHa ç--,. N - N- H °,AÇ "« -M W-1 «o H IN NA H C N "NH2 CI" N " ",NH2 . L.«õ N , .O Chiral 431.3 364.2 406.3 282.9/2 84.9 494.2 0.47 0.47 0.53 0.85 0.85 Example Example Example Example 56 Example 53 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 ... .,..,",. /,o c.i=, 9 L-2"'"1 -c., H Chiral IN N« .--' tA1-', -kc H Chiral N,,e. NA H Chiral iN N« .,',.. N Chiral N 0 454.2 457,2 423.2 457.2 423.3 0.71 0.46 0.45 0.47 0.45 Example 53 Example 76 Example 76 Example 76 Example 76 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chiral IIí'Y" í "', Ci " 0 H Æ"N H Chiral "J-I I A c, Y H jN NC1oE "OH H IJI N A c. Y "L .N.2 CI"'Çí "N N'JL-N H Lvõ 427.1 427.1 451.2 452.1 451.1 0.7 0.7 0.62 0.76 0.63 Example 54 Example 54 Example Example Example 61 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 C1 v °" N H2 H I N NA , H 11I N. A NH2 k.«O H wNI NA • r:. ,L H I1%, N A .,.çY 505.2 432.1 433.1 417.2 0.54 0.64 0.41 0.45 0.51 Example 33 Example 62 Example 63 Example 63 Example 77 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 k«s o O H [ N« NC1 v "'NH2 H ..N I N- ...-- I °'«NH2 ¢ N H N [ NA 418.2 464.1/4 66.1 431.2 417.2 431.2 0.56 0.44 0.49 0.47 0.47 Example 77 Example 57 Example 34 Example 61 Example 64 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H H /CHzChiral N I I -°H °hic' í.» ,©..,,, °" N 426.2 440.2 454.2 426.2 440.2 0.62 0.62 0.64 0.62 0.61 Example 54 Example 54 Example 54 Example 54 Example 54 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 . ì 9" c"i c,- H I N N CI " 'N H2 oH, %..0 H I N= A Lk..o. H N« A CI "HN - O'CHa N/,, -. N .,.",,.,y.,, H Lvó 454.2 457,2 445.2 432.2 475.2 0.62 0.6 0.54 0.56 0.51 Example 54 Example Example 36 Example Example 86 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H _N N,,. A O ° , "-J"N4"C ç --,N H 11íN N A "T q" l 0,, CHa o -"',..-s:o rç"", N /. ..N,...,,,r.. " Lvó CI "/N H2 H 14. N,,. A H c,í ; ...fo ("," c., N N.---.ri-.h " L,..ó H ll N= A CH /0 459.2 495.2 431.2 473.2 431.2 0.54 0.57 0.51 0.57 0.58 Example 78 Examples 6, Examples 77, Example 78 Example 77 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H I N.A c,í ì/L ..2 CH3 k,,./O H CI [ N NA if"," CHa k.«O H I 1 N. A o,..çy -r .,.o. H CI " / «O'cHa CH3 ',...1 0 H I1 N. A o í y "L N.. Q" "N 445.2 432.2 446.2 489.3 450.2 0.59 0.64 0.66 0.57 0.58 Example 77 Example 77 Example 77 Example 77, 86 Example 87 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 o,, CI N H u H 1%N-A « í --,N N HN I° H Chiral I N'A C1aN " "N H2 LCH. " L ò N Chiral CI "NHz i CH L N .,-, -- c -13 " L õ H N N556.2 485.3 444.2 444.2 508.2 0.61 0.63 o si(c18 column), 10.35 (chiralcolumn) 0.51 (C18 column), 17.44 chiral column) 0.63 Example 79 Example 37 Example 24 Example 24 Example WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H H i NA' Fq " 'NH2 H Chiml I N« ». H Chiral i N= ..--._ o,.ç; Lk... H I,I N. A 73..0 . Ç'N N I.e ,,GO 494.2 434.2 417.2 417.2 0.6 0.55 0.49 0.49 Example 81 Example 38 Example 77 Example 77 Chiral 418.2 0.54 Example 77 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chiral 1,1« .Ne /.. c.í ; H I N« NCI'@N H I _N« A • c.í Y cl., '-N ci %.,.o H l N« NC1 " -v OH CI'@N H Ct /N ì]" '., HN ,,'",, Ot" N Chiral 418.2 416.2 451.1 534.3 0.54 0.52 0.7 0.65 0.62 Example 77 Example 82 Example 28 Example 84 Example 83 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H INc NA C1oE 'NH2 H 0: 'O,,% Chiral H o çT o> CI ,"' N O %/o H -N N« /-.- ¢-N--W.1 H c, y v" / "r5 Chi ml 434.1 534.3 550.3 522.2 500.3 0.57 0.64 0.62 0.63 0.58 Example Example 84 Example 84 Example 84 Example 82, 83 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H .N= .Ne A o "[v1.....vo.o H H I1 N= A c, i7 H H Chiral H Chiral 474.3 417.2 474.3 500.3 500.1 0.56 0.5 0.48 0.5 0.49 Example 80, 82 Example 84, Intermediate D Example 80, Intermediate D Example 83, Intermediate D Example 84, Intermediate D WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H H Cl 1 .. N H I N - A Chiral CI " "NH2 F N H Chiral N N" v°'c% vo 488.1 52o.1/5 492.2 0.48 0.59 0.54 0.57 Example 84, Intermediate D Example 71 Example 71 Example 39 Example WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 iií -ç - . o,-- ff I - N ,," 3 /" C H3 " õ CH3 L.3 N,-..T. c,3 o CHa H Chiral IJ N« A B r,,,,T N %/o H Chiml • N r," N ÇHs ç, oE t" " "°'c H Chiml líí ,ì F -F 444.2/4 46.2 502.2/5 04.2 494.2/4 96.1 528.3 0.54 0.56 0.61 0.51 0.53 Example Example Example 41 Example 67, Intermediate D Example 42 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chiral _N N« A " N F F N F " Lvõ H Chiral H Chiral c,..-" " '- O-CH' H Chiral H Chiral ç'*'Y $", Ci/ 1 ' k,v ', N i'.v. OC H' Fy L.N H " t õ 528,3 562.3 554.1 0.53 0.7 0,62 0.61 0.6 Example 42 Example 43 Example 67 Example 44 Example 39 and Example 67 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chiral c -. ÆO.c% H Chiral H Chiral I N NCI' "OH CI'-.T -N N Chiral CI ìl"OH CI' N H Chiral 5o6/5o8 576.2 451.2 479.3 590.5 0.62 0.78 0.65 0.72 0.71 Example 67, Intermediate I Example Example 46 Example 46 Example 47 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chiral N N= " t,«6 Chiral N A Chiral H ç iml r%N CI. H FF HN chiral 590.5 528.4 562.4 0.71 0.47 0.53 0.67 0.48 Example 47 Example lb, Intermediate D Example 48 Example 49 Example lb, Intermediate D WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chirp ,í y.. .... H Chiral N CHa H Chiml ¢'Y""Ol "o c "N v'° cH, " -N HaC.A H Cy c., CF N /'«ì_1 " "J O" C Hs L N O O -CH H Chiral CI "N"k'v'O" CH o CFa jt 518.4 516.5 518.4 0.48 0.511 0.653 0.547 0.73 Example lb, Intermediate D Example 2 Example 2 Example 66 Example 2 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chii-al '- ,,N 1Mo H Chiral ",,,., ', N @ O - C H 3 H «o CI . ì.ì.ì NH2 o 1%H-A C1an INH2 " Lvõ H IN NA 556.4 513.2 430.3 448.2 434.2 0.675 0.563 0.48 0.62 0.5 Example 2 Example 93 Example 29 Example Example 31 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H c "O ..o 0.3 Y, o N Chiral " ÇH3 N Chiral ci " i" " O'CH ,LoYC Y'O,,,«0 "N D /.L ° ,%0 H I1 N,, c.í.Y L ., F-.T,,í "-N Chiml 492.3 534.1 502.3/5 04.3 0.6 0.64 0.86 0.49 0.59 Example lb, Intermeidate I Example lb, Intermeidate W Example Example 58 Example lb WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chinsl _N N= A I CI I - "N Ox CH3 c,y.L. " Lokoum H Chiral çoEY",/" c% o, ZI L..L A.:.o.° Clan L .,.@ " H o H Lv.ò H Chiral ç" N" "1 CI "" k'V2 NJ O" C Ha CI11 H 554.1 564.4/5 66.3 522.1/5 24.0 552.o/5 54.1 522.2/5 24.1 0.59 0.65 0.708 0.589 0.672 Example lb, intermediate I Example 72 Example 74 Example lb, Intermediate t Example 73 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chiral N Chiral '", ÇH3 Ci N- ".,,,,I OCH 3 CI J N H H N% N A H Chiral . N y N, CH3 o L -L3o.o.. H Chiral o L N-'L«°-o. " L..õ 504.1/5 06.1 522.1/5 24.1 540.2/5 42.2 522.1/5 23.9 516.5 0,624 0.724 0.605 0,675 o.55 (ClS column), 9.743(chiral column) Example lb, Intermediate I Example 74 Example lb, Intermediate I Example 73 Example 67, Intermediate J WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 o.-ffæ %.-.'.,r Æo.cH, H H Chital ,........,.. r cH, . t.«ó rí»T 1 °» c t' ..- L.N " =o o c T o H <5, o 516.5 516.5 580.1 566.2 534.1 0.55 0.55 0.59 0.64 0.62 Example XL-1, Intermediate J Example XL-1, Intermediate J Example lb, Intermediate I Example 89 Example WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 t N CH3 çA -.?oE T M Ç o N o " 2 N CH =l'A 548.2 541.3 560.1 571.2 517.2 0.65 0.59 0.55 0.73 0.65 0.576 Example Example Example Example 48 Example 48, 94 Example 94 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H Chital ,...ì N c . N i ,ì ql H Chiml w N " H 531.2 459.2 501.2 543.3 499.1 0.595 0.547 0.627 0.692 0.531 Example 94 Example 94 Example 94 Example lB 441.1 0.502 Example lB Example lB WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H ,0 I I N,, -0 F k o H Il N O í Y q3 oo H I N H N .,o° H CH chr CI " 0" C H = O. -ìA 580.3 512.2 0.64 0.63 0.58 0.47 0.45 0.6 Example 30, 92 Example Example 92 Example 91 Example 91 Example lb, 7 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H H o.i <J...Ao.. H o,-ç7 "G L.o,, <OEM' F <.«O 520.1 483.2 0.72 0.56 0.69 0.78 Example lb, 7 Example lb, 7 Example lb, 7 Example lb, 7 The following compounds were made using pmceduoes outlined above: Compound/EL 357:4-((5'-chloro-5-fluoro-2'-((1 r,4r)-4-hydroxycyclohexylamino)-2,4'- bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 H H F M+I (LC/MS): 460.1; Retention Time (min. LC/MS): 0.62. 1HNMR (400 MHz, METHANOL-d4)6 ppm 1.291.42 (m, 3 H) 1.591.71 (m, 2 H) 1.751.80 (m, 1 H) 1.801.83 (m, 1 H) 1.881.96 (m, 2 H) 1.962.02 (m, 2 IT)2.022.13 (m, 1 H) 3.46 - 3.60 (m, 4 H) 3.72 (s, 2 H) 3.86 (m, J=12.13, 2.35 Hz, 2 H) 6.95 (dd, ./=8.02, 2.93 Hz, 1 IT) 7.10 (s, I H) 7.32 (dd, J= 10.96, 8.22 Hz, 1 H) 7.92 (s, 1 H). Compound/Ex. 358:4-((5'-chloro-2'-((1R,4r)-4-((R)- 1 -methoxypropan-2y amin ) y hexy amin )-2 4'-bipyridin-6-y amin )methy )tetrahydr -2H-pyran-4arb nitri e x KNOWN ÇH3 c,I v'íHN'<vO'cH Compound/Ex. 359:4-((5'-chloro-2'-((1 r,4r)-4-hydroxycyclohexylamino)-2,4'-bipyridin-6ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile H OH °%0 M+I (LC/MS): 442.1; Retention Time (min. LC/MS): 0.55. WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1H NMR (400 MHz, METHANOL-d4) 6 ppm 1.29 - 1.42 (m, 4 H) 1.58 - 1.70 (m, 2 H) 1.75 - 1.84 (m, 2 H) 1.87 - 2.04 (m, 4 H) 3.45 - 3.60 (m, 4 H) 3.66 (s, 2 H) 3.86 (m, J=12.13, 2.74 Hz, 2 H) 6.66 (d, J=8.22 Hz, 1 H) 6.88 (d, J=7.43 Hz, 1 H) 7.07 (s, 1 H) 7.46 - 7.53 (m, 1 H) 7.92 (s, 1 H). Compound/Ex. 360: 4-((5'-ehloro-2'-((l r,4r)-4-(ethylamino)cyclohexylamino)-2,4'-bipyridin-6ylamino)methyl)tetrahydro-2H-pyran-4-carbonitñle H M+I (LC/MS): 469.2; Retention Time (min. LC/MS): 0.55. H NMR (400 MHz, METHANOL-d4) 6 ppm 1.32 (t, J=7.24 Hz, 3 H) 1.49 (br. s., 4 H) 1.66 - 1.82 (m, 2 H) 1.84 - 1.99 (m, 2 H) 2.22 (d, J=12.52 Hz, 4 H) 3.11 (t, J=7.24 Hz, 3 H) 3.56 - 3.72 (m, 3 H) 3.76 (s, 2 H) 3.87 -4.06 (m, 2 H) 6.81 (d, J=8.61 Hz, 1 H) 6.96 (d, J=6.65 Hz, 1 H) 7.06 (s, 1 H) 7.54 - 7.69 (m, 1 H) 8.06 (s, 1 H). Compound/Ex. 361: 4-((5'-chloro-2'-((l r,4r)-4-(dimethylamino)cyclohexylamino)-2,4'- bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile M+I (LC/MS): 469.2; Retention Time (min. LC/MS): 0.52 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.39 - 1.58 (m, 2 H) 1.64 - 1.83 (m, 4 H) 1.90 (dd, J=13.50,1.76 Hz, 2 H) 2.10 - 2.35 (m, 4 H) 2.87 (s, 6 H) 3.57 - 3.72 (m, 3 H) 3.76 (s, 2 H) 3.96 (ddd,J=9.98, 2.35, 2.15 Hz, 2 H) 6.82 (d, J=-7.83 Hz, 1 H) 6.97 (d, J=6.65 Hz, 1 H) 7.06 (s, 1 H) 7.55 - 7.77 (m, 1H) 8.07 (s, 1 H). Compound/Ex. 362: 4-((5'-chloro-2'-((l r,4r)-4-(2- (tri u r meth xy)ethy amin ) y hexy amin )-2 4'-bipyridin-6-y amin )methy )tetrahydr - 2H-pyran-4-carbonitñle M+I (LC/MS): 553.3; Retention Time (min. LC/MS): 0.58. Compound/Ex. 363:4-((5'-chloro-2'-((1 r,40-4-(tetrahydro-2H-pyran-4y amin ) yc hexy amin )-2 4'-bipyridin-6-y amin )methy )tetrahydr -2H-pyran-4-carb nitri e H H M+I (LC/MS): 525.1 ; Retention Time (min. LC/MS): 0.54. IH NMR (400 MHz, METHANOL-d4) ppm 1.38 - 1.82 (m, 8 H) 1.85 - 1.95 (m, 2 H) 1.96 - 2.06 (m, 2 H)2.15 - 2.26 (m, 4 H) 3.40 - 3.56 (m, 3 H) 3.58 - 3.73 (m, 3 H) 3.75 (s, 2 H) 3.90 - 4.10 (m, 4 H) 6.71 - 6.80 (m,l H) 6.94 (s, 2 H) 7.54 - 7.65 (m, 1 H) 8.04 (s, 1 H). WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Compound/Ex. 364: 5'-chloro-N6-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-N2'-((lr,4r)-4- (2-methoxyethylamino)cyclohexyl)-2,4'-bipyridine-2',6-diamine H M+I (LC/MS): 492.2; Retention Time (min. LC/MS): 0.34. 1HNMR (400 MHz, METHANOL-d4) fi ppm 1.32 - 1.48 (m, 2 H) 1.49 - 1.65 (m, 2 H) 1.72 - 1.88 (m, 4 H) 2.16 - 2.26 (m, 4 H) 3.20 - 3.27 (m, 2 H) 3.42 (s, 2 H) 3.60 - 3.76 (m, 6 H) 3.77 - 3.86 (m, 2 H) 6.78 (s, 1 H) 6.91 (d, J=7.04 Hz, 1 H) 6.96 (d, J=8.61 Hz, 1 H) 7.76 (t, J=-8.02 Hz, 1 H)8.06 (s, 1 H). Compound/Ex. 365: H .Ç.H3 'N'f O'cH3 H « o CompoundÆx. 366: 4-((5'-chloro-2'-((lr,4r)-4-(diethylamino)cyclohexylamino)-2,4'-bipyridin6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 M+I (LC/MS): 497.2; Retention Time (min. LC/MS): 0.58. Compound/Ex. 367:2-((5'-chloro-5-fluoro-2'-((1R,4r)-4-((R)-l-methoxypropan-2ylamino)cyclohexylamino)-2,4'-bipyridin-6-ylamino)methyl)propane1,3-diol H F H M+I (LCiMS): 496.2; Retention Time (min. LC/MS): 0.49. Biological Methods Cdk9/cyclinT 1 IMAP Protocol The biological activity of the compounds of the invention can be determined using the assay described below. I00683] Cdk9/cyclinTl is purchased from Millipore, cat #14-685. The final total protein concentration in the assay 4nM. The 5TAMRA-cdk7tide peptide substrate, 5TAMRAWO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 YSPTSPSYSPTSPSYSTPSPS-COOH, is purchased from Molecular Devices, car#R7352. The final concentration of peptide substrate is 100nM. The ATP substrate (Adenosine-5'- triphosphate) is purchased from Roche Diagnostics, cat#1140965. The final concentration of ATP substrate is 6uM. IMAP (Immobilized Metal Assay for Phosphochemicals) Progressive Binding reagent is purchased from Molecular Devices, cat#R8139. Fluorescence polarization (FP) is used for detection. The 5TAMRA-cdk7tide peptide is phosphorylated by Cdk9/cyclinTl kinase using the ATP substrate. The Phospho-5TAMRA-cdk7tide peptide substrate is bound to the IMAP Progressive Binding Reagent. The binding of the IMAP Progressive Binding Reagent changes the fluorescence polarization of the 5TAMRA-cdk7tide peptide which is measured at an excitation of 53 lnm and FP emission of 595nm. Assays are carded out in 100mM Tñs, pli=7.2, 10mM MgCI2, 0.05% NAN3, 0.01% Tween-20, I mM dithíothreitol and 2.5% dimethyl sulfoxide. IMAP Progressive Binding Reagent is diluted 1:800 in 100% IX Solution A from Molecular Devices, cat#R7285. 1006841 General protocol is as follows: To 10ul of cdk9/cyclinT 1, 0.5ul of test compound in dimethyl sulfoxide is added. 5TAMRA-cdk7tide and ATP are mixed. 10ul of the 5TAMRA-cdk7tide/ATP mix is added to start the reaction. The reaction is allowed to proceed for 4.5hrs. 60uL of IMAP Progressive Binding Reagent is added. After > lhr of incubation, plates are read on the Envision 2101 from Perkin-Elmer. The assay is run in a 384-well format using black Coming plates, cat#3573. Cdk9/c¥clinT 1 Alpha Screen Protocol 100685] Full length wild type Cdk9/cyclin T I is purchased from Invitogen, cat#PV4131. The final total protein concentration in the assay lnM. The cdk7tide peptide substrate, biotin-GGGGYSPTSPSYSPTSPSYSPTSPS-OH, is a custom synthesis purchased from the Tufts University Core Facility. The final concentration ofcdk7tide peptide substrate is 200nM. The ATP substrate (Adenosine-5'-triphosphate) is purchased from Roche Diagnostics. The final concentration of ATP substrate is 6uM. Phospho-Rpbl CTD (ser2/5) substrate antibody is purchased from Cell Signaling Technology. The final concentration of antibody is 0.67ug/ml. The Alpha Screen Protein A detection kit containing donor and acceptor beads is purchased from PerkinElmer Life Sciences. The final concentration of both donor and acceptor beads is 15ug/ml. Alpha Screen is used for detection. The biotinylated-cdk7tide peptide is WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 phosphorylated by cdk9/cyclinT1 using the ATP substrate. The biotinylated-cdk7tide peptide substrate is bound to the streptavidin coated donor bead. The antibody is bound to the protein A coated acceptor bead. The antibody will bind to the phosphorylated form of the biotinylatedcdk7tide peptide substrate, bringing the donor and acceptor beads into close proximity. Laser irradiation of the donor bead at 680nm generates a flow of short-lived singlet oxygen molecules. When the donor and acceptor beads are in close proximity, the reactive oxygen generated by the irradiation of the donor beads initiates a luminescence/fluorescence cascade in the acceptor beads. This process leads to a highly amplified signal with output in the 530-620nm range. Assays are carded out in 50mM Hepes, pli=7.5, 10mM MgCl2, 0.1% Bovine Serum Albumin, 0.01% Tween-20, l mM Dithiolthreitol, 2.5% Dimethyl Sulfoxide. Stop and detection steps are combined using 50mM Hepes, pli=7.5, 18mM EDTA, 0.1% Bovine Serum Albumin, 0.01% Tween-20. General protocol is as follows: To 5ul of cdk9/cyclinTl, 0.25ul of test compound in dimethyl sulfoxide is added. CdkTtide peptide and ATP aoe mixed. 5ul of the cdk7tide peptide/ATP mix is added to start the reaction. The reaction is allowed to proceed for 5hrs. 10uL of Ab/Alpha Screen beads/Stop-detection buffer is added. Care is taken to keep Alpha Scoeen beads in the dark at all times. Plates are incubated at room temperature overnight, in the dark, to allow for detection development before being read. The assay is run is a 384-well format using white polypropylene Greiner plates. The data shown in Table 2 below were generated using one of the assays described above. [006881 Table 2 Compound CDK9 # in the CYCLINT1 write-up (IC50) 1 0.007945 2 0.025572 3 0.237603 4 0.009055 0.039655 6 0.136417 7 0.024792 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Compound CDK9 # in the CYCLINT1 write-up (IC50) 8 0.084843 9 0.007945 0.018574 11 0.132509 12 0.007945 13 0.007945 14 0.522 0.007945 16 0.023617 17 0.02323424 18 0.007945 19 0.007945 0.007945 21 0.007945 22 0.007945 23 Ö.OÖ7945 24 0.012416 0.008079 26 0.016256 27 0.007945 27 0.007945 29 0.007945 0.007945 31 0.044838 32 0.015002 33 0.026973 34 0.048274 0.055761 36 0.008906 37 0.007945 38 0.007945 39 0.008896 0.007945 41 0.01288 42 0.048069 43 0.007945 44 0.011238 46 0.007945 47 0.007945 I' 48 0.00794 49 0.01443Ö 0.007945 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Compound # in the write-up CDK9 CYCLINT1 0c5o) 0.017367 0.019224 ö.011128 0.023156 0.007945 0.039262 0.032590 0.031203 0.009128 0.007945 0.018100 0.007945 0.007945 0.054559 0.007945 0.017131 2.550202 0.274123 0.154400 0.173426 0.027388 0.114363 0.035218 0.041585 0.013530 0.011082 0.007945 0.024249 0.007945 0.031705 0.054218 0.009047 0.011615 0.014118 0.068526 0.081460 0.068978 0.011003 2.582156 2.960356 0.335581 0.295616 0.928257 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Compound # in the write-up lO4 COK9 CYCLINT1 0c5o) 0.50746 1.951420 1.276694065 0.339265455 0.415725004 0.679432727 0.308717658 0.007945668 O.12O571151 0.133698728 0.140890633 0.0180851 0.059240258 0.015318231 0.084308021 0.072890252 0.007945668 0.007945668 0.015815541 0.025176571 0.030797253 0.027282158 0.050224047 0.007945668 0.007945668 0.007945668 0.123719173 0.138887135 0.154521231 0.045604039 10.49437327 0.007945668 0.042845475 0.116276412 0.278772642 0.033296354 0.139053728 0.033364795 0.390099615 0.16902747 0.46977199 0.014431175 0.007945668 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Compound CDK9 # in the CYCLINT1 write-up (IC50) 134 0.01051692 135 0.142053718 136 0.204223958 137 0.007945668 138 0.521640084 139 0.030140062 140 0.012553271 141 0.204786235 142 0.025611049 143 0.022738812 144 0.015810302 145 0.007945668 146 0.007945668 147 0.019350577 148 15.62589296 149 0.516196192 150 6.512117546 151 0.007945668 152 0.027 153 1.546 154 0.382 155 0.023 156 0.045 157 0.0079 158 0.011 159 1.383 160 0.019 161 0.026 162 0.014 163 0.013 164 0.039 165 0.0079 166 0.027 167 0.018 168 0.037 169 0.009 170 0.044 171 0.218 172 0.015 173 0.062 174 0.029 175 0.024 176 0.021 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Compound CDK9 # in the CYCUNT1 write-up (IC50) 177 0.013 178 0.103 179 0.544 180 0.01213 181 0.00794 182 0.02111 183 0,00794 184 0.00911 185 0.11048 186 0.00794 187 2.73860 188 0.00794 189 0.00794 190 0.1 191 0.00794 192 0.00794 193 0.00794 194 0.04813 195 0.03556 196 0.81167 197 0.00794 198 0.00794 199 0.00794 200 0.00794 201 0.63424 202 0.01884 203 0.00794 204 0.00794 205 0.01747 206 0.13378 207 0,114147 208 0.00794 209 0.18300 210 0.085970 211 0.02101 212 0.05460 213 0.0142 214 0.04169 215 0.06545 216 0,13825 217 0.03728 218 0.12766 219 0.007945 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Compound CDK9 # in the CYCLINT1 write-up (IC50) 220 0.007945 221 0.007945 222 0.007945 223 0.007945 224 0.091885 225 0.007945 226 0.007945 227 0.025907 228 0.007945 229 0.007945 230 0,007945 231 0.014853 232 0.007945 233 0.007945 234 0.007945 235 0.007945 236 0.007945 237 0.007945 238 0.013635 239 0.018420 24O 0.020961 241 0.06179 242 0.015408 243 0.007945 244 0.078984 245 0.05337 246 0.01154 247 0.02018 248 0.01058 249 0.0318 250 0.02839 251 0.04320 252 0.00794 253 0,00794 254 0.00833 255 0.04232 256 0.00794 257 0.00794 258 0.00794 259 0.00794 260 0.00794 261 0.00794 262 0.00794 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Compound CDK9 # in the CYCLINT1 write-up (IC50) 263 0.00794 264 0.00794 265 0.03258 266 0.00794 267 0.27007 268 0,008143 269 0.007945 270 0.00794 271 0.00794 272 0.00794 273 0.02293 274 0.03777 275 0.14630 276 0.00893 277 0.00794 278 0.00794 279 0.01310 280 0.0161 281 0.06124 282 0.00794 283 0.001 284 0.001 285 0.002 286 0.001 287 0.003 288 0.003 289 0.004 290 0.002 291 0.001 292 0.002 293 0.001 294 0.001 296 0.277 297 0.001 298 0.001 299 0.001 300 0.219 301 0.003 302 0.001 303 1.296 304 6.188 305 0.001 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Compound CDK9 # in the CYCLINT1 write-up (IC50) 306 0.009 307 0.008 308 0.001 309 0.035 310 0.0003 311 0.001 312 O.0003 313 0,001 314 0.001 315 0.018 316 0.009 317 0.099 318 0.00026 319 0.004 320 0.001 321 0.011 322 0.003 323 0.001 324 0.002 325 0.O1 326 0,00049 327 0.001 328 0.001 329 0.001 330 0.002 331 0.001 332 0.001 333 0.004 334 0.001 335 0.00027 339 0.00017 340 0.00023 341 0.00015 342 0.00017 343 0.OOO31 346 0,001 347 0,001 348 0.002 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984 Compound CDK9 # in the CYCLINTI write-up (IC50) 349 O.001 350 0.001 357 0.00016 358 0.00017 359 0.00024 360 0.00028 361 0.00030 362 0.00036 363 O.OOO43 364 0.00063 365 0.00070 366 0.0010 367 0.0031 WO 2011/012661 CA 02767066 2011-12-30 PCT/EP2010/060984