OA17463A

OA17463A - Inhibitors of histone demethylases.

Info

Publication number: OA17463A
Application number: OA1201500336
Authority: OA
Inventors: Marc Labelle; Thomas Boesen; Qasim Khan; Ramkrishna Reddy Vakiti; Utpal Sharma; Ying Yang; Mukund Mehrotra; Neerja Saraswat; Farman Ullah
Original assignee: Epitherapeutics Aps
Priority date: 2013-02-27
Filing date: 2014-02-26
Publication date: 2016-12-30

Abstract

Compounds of the form (formula I) In which Q is selected from -CH=NR12, -W, -CH2NHR13, CH=0 and -CH(OR17)2 capable of modulating the activity of histone demethylases (HDMEs), which are useful for prevention and/or treatment of diseases in which genomic dysregulation is involved in the pathogenesis, such as e.g. cancer and formulations and methods of use of such compounds.

Description

INHIBITORS OF HISTONE DEMETHYLASES

FIELD OF THE INVENTION

The présent invention relates to compounds capable of modulating the activity of histone demethylases (HDMEs), which compounds are useful for the prévention and/or the treatment of diseases in which genomic dysrégulation is involved in the pathogenesis, such as e.g. cancer.

BACKGROUND OF THE INVENTION

The DNA of eukaryotic cells is packaged into chromatin by winding of the DNA around histone proteins to form nucléosomes, the basic unit of chromatin. One ofthe important functions of chromatin is to détermine régions of active and silenced transcription by changing the ordered chromatin structure. Such changes hâve profound effects on cellular fonction since they affect fondamental processes as différentiation, prolifération and apoptosis, and are often referred collectively to as epigenetic since they can lead to heritable changes that do not involve changes in gene sequences (Quina, A.S. et al. (2006), Biochem. Pharmacol. 72; 1563-1569)

These highly controlled chromatin changes are mediated by alterations histone proteins associated with DNA in the nucléosome. Most notably, the N-terminal histone tail of Histone H3 and histone H4 are subject to such covalent changes, which include changes in méthylation, acétylation, phosphorylation and ubiquitination. The addition or removal of these groups on histones is mediated by spécifie enzymes, e.g. histone methyl transferases and histone demethylases for methyl groups, histone acetyltransferases and histone deacetylases for acetyl groups, etc. In the event that the activity or expression of these epigenetic enzymes is not correctly controlled and regulated it may lead to disease. Cancer, in particular, is an area of high importance in relation to dysregulated epigenetic enzyme activity due to the rôle of epigenetics in cell différentiation, prolifération and apoptosis, but epigenetics may also play a rôle in other diseases like metabolic, inflammatory, neurodegenerative and cardiovascular diseases. Therefore the sélective modulation of aberrant action of epigenetic enzymes may hold great promise for the treatment of human disease (Kelly, T.K. et al. (2010), Nat. Biotechnol. 28; 1069-1078, and Cloos, P.a.C. et al. (2008), Genes. Dev. 22; 115-1140).

Méthylation and déméthylation of lysine residues on the histone H3 tail constitute important epigenetic marks delineating transcriptionally active and inactive chromatin. For example, méthylation of lysine 9 on histone H3 (H3K9) is usually associated with epigenetically silenced chromatin (Fischle, W., et. al. (2003), Curr. Opinion Cell Biol. 15, 172-83; Margueron, R., et al. (2005), Curr. Opinion Genet. Dev. 15, 163-76) while méthylation of lysine 4 on histone 3 is associated with transcriptionally active chromatin. Similarly, the lysine 27 histone H3 (H3K27) mark is répressive in its di- and tri-methylated states whereas the lysine 36 histone H3 mark is found in association with gene activation (Barski, A. et al. (2007), Cell, 129, 823-37; Vakoc, C. et al. (2006) Mol. Cell. Biol. 26, 9185-95; Wagner, EJ. & Carpenter, P.B. (2012) Nature Mol. Cell Biol 13, 115

26). There are, however, many exemptions from these general rules of association between méthylation states of epigenetic marks and the effect they hâve on transcription.

As documented by studies of the SUV39H1 knockout mouse, loss of the tri-methyl variant of the H3K9 mark results in chromosomal aberrations and prédisposés to cancer (Peters, A.H. et al., Cell 107, 323-37, 2001). The JMJD2C protein (KDM4C, GASC1) has been identified as an eraser of the H3K9 mark (a histone demethylase) and may therefore promote cancer if its expression and activity is not tightly controlled (Cloos, P. et al. (2006), Nature 442, 307-11; Klose, R.J. et al. (2006), Nature 442, 312-16; Liu, G. et al. (2009), Oncogene 28, 4491-500). For example, JMJD2C has been shown to induce transformed phenotypes like growth factor independent growth, anchorage independent growth and mammosphere formation, if it is overexpressed in cells (Liu, G. et al. (2009), Oncogene 28, 4491-500). These findings are supported by the overexpression of JMJD2C in a range of human tumours like squamous cell carcinoma, metastatic lung carcinoma, prostate cancer, breast cancer and several others (Yang, Z.Q. et al. (2000) Cancer Res. 60, 4735-39; Yang, Z.Q. et al. (2001) Jpn. J. Cancer Res. 92, 423-28; Hu, N. et al. (2005) Cancer Res. 65, 2542-46; Liu, G. et al. (2009) Oncogene 28, 4491-500; Wissmann, M. et al. (2007) Nat. Cell Biol. 9, 347-53), indicating the potential importance of JMJD2C as an oncogene.

The JMJD2A protein (KDM4A, JHDM3A) shows similar properties to JMJD2C. JMJD2A shows high sequence identity to JMJD2C in its JmjC catalytic domain, is an eraser of the H3K9 mark and has also been shown to be overexpressed in prostate cancer (Cloos, P. Et al., Nature 442, 307-11, 2006). JMJD2A has been shown to interact with the estrogen receptor alpha (ER-alpha) and overexpression ofJMJD2A enhances estrogen-dependent transcription and the down-regulation of JMJD2A reduced transcription of a séminal ER-alpha target gene, cyclin DI (Kawazu et al., (2011) PLoS One 6; Berry et al., (2012) Int J Oncol 41). Additionally, it has been shown that catalytically inactive JMJD2A is compromised in its ability to stimulate ER-alpha mediated transcription, suggesting that inhibitors of JMJD2A may be bénéficiai for the treatment of ER-alpha positive breast tumours (Berry et al., (2012) Int J Oncol 41).

Likewise, an eraser of the tri-methyl variant of the H3K4 mark, JARID1B (KDM5B, PLU1) has also been identified as potential oncogene. In cancer JARID1B most likely acts as a repressor of tumour repressor genes via removal of the H3K4 tri-methylation leading to decreased transcriptional activation in the affected chromatin régions. The oncogenic potential of JARID1B is demonstrated by its stimulation of prolifération in cell lines and further validated by shRNA knockdown studies of JARID1B expression showing inhibition of prolifération in MCF7 human breast cancer cells, in SW780 and RT4 bladder cancer cells, in A549 and LC319 lung cancer cells and in 4T1 mouse tumour cells in vitro and/or in mouse xenograft experiments (Yamane K. et al. (2007), Mol. Cell 25, 801-12; Hayami S. et al. (2010) Mol. Cancer 9, 59; Catchpole S et al. (2011), Int. J. Oncol. 38, 1267-77). Finally, JARID1B is overexpressed in prostate cancer and is associated with malignancy and poor prognosis (Xiang Y. et al. (2007) PNAS 104).

JARID1A (KDM5A, RBP2) is also an eraser ofthe tri- and di-methyl variant ofthe H3K4 mark.

JARID1A is overexpressed in gastric cancer (Zeng et al., (2010) Gastroenterology 138) and its gene is amplified in cervix carcinoma (Hidalgo et al, (2005) BMC Cancer 5). It has been suggested that JARID1A is fine-tuning progestérone receptor expression control by estrogens (Stratmann and Haendler (2011) FEBS J 278). Together with JARID1B, JARID1A has been implicated in the maintenance of a slow-growing population of cancer cells that are required for continuous tumor growth and that are résistant to cytotoxîc and targeted therapy (Roesch, et al, (2010) Cell 141; Sharma, et al., (2010) Cell 141). JARID1A is required for the tumor initiation and progression in Rb+/- and Menl-defective mice (Lin, et al., (2011) PNAS 108). Data from Pasini show that JARID1A binds to Polycomb group protein target genes which are involved in regulating important cellular processes such as embryogenesis, cell prolifération, and stem cell self-renewal through the transcriptional repression of genes determining cell fate decisions (Pasini et al., (2008) Genes & Dev 22). Additionally, JARID1A were also shown to binds the PRC2 complex and being regulator of PRC2 target genes (Pasini et al., (2008) Genes & Dev 22).

Another potential oncogene, an eraser ofthe di-methyl variant ofthe H3K36 mark, JHDM1B (KDM2B, FBXL10) has been shown to be highly expressed in human cancers (Tzatsos A et al. (2009), PNAS 106 (8), 2641-6; He, J. et al. (2011), Blood 117 (14), 3869-80). Knock-down of FBXL10 causes senescence in mouse embryonic fibroblasts (MEFs), which can be rescued by expression of catalytic active (but not catalytic inactive) JHDM1B (Pfau R et al. (2008), PNAS 105(6), 1907-12; He J et al. (2008), Nat Struct Mol Biol 15, 1169-75). JHDM1B demethylates H3K36me2 on the tumor-suppressor gene Ink4b (pl5^Ink4b), and thereby silences the expression of this senescence-mediating gene in MEFs and in leukemic cells (He, J. et al. (2008), Nat Struct Mol Biol 15, 1169-75; He, J. et al. (2011), Blood 117 (14), 3869-80). The catalytic dependency of JHDM1B is further shown by He et al. as catalytic activity is required for development of leukemia in a mouse AML model.

Inhibitors of the histone demethylase class of epigenetic enzymes, and in particuiar the potential oncogenes JARID1B, JARID1A, JMJD2C, JMJD2A, and JHDM1B, would présent a novel approach for intervention in cancers and other proliférative diseases. Being one ofthe most devastating diseases, affecting millions of people worldwide, there remains a high need for efficacious and spécifie compounds against cancer.

PCT/EP2013/070457 discloses histone demethylase (HDME) inhibitors or activity modulators.

Embodiments of the invention provide novel sériés of compounds capable of modulating the activity of histone demethylases, at least some of which compounds are useful for the prévention and/or the treatment of diseases in which genomic disregulation is involved in the pathogenesis, such as

e.g. cancer. By way of the invention

The inventors hâve surprisingly found that novel compounds of Formula (I) as defined herein can be used in the treatment of HDME dépendent diseases by inhibiting HDMEs. Inhibiting HDMEs would provide a novel approach to the prévention and treatment of cancer and other proliférative diseases. Accordingly, it is an object of the présent invention to provide compounds that when administered alone or optionally in combination with anti-neoplastic compounds, increases the efficacy of the treatment of HDME dépendent diseases.

Accordingly, a first aspect of the présent invention relates to a compound of the Formula (I)

wherein

Q is selected from -CH=NR¹², -W, -CH2NHR¹³, -CH=O and -CH(OR¹⁷)₂;

A is selected from -CHR²C(O)-, Ci-β alkylene, C₂.₈ alkenylene, C₂.₈ alkynylene, C₃-iocycloalkylene, heterocyclylene, heteroarylene and arylene, which alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene may optionally be substituted with one or more R³; with the proviso that when Q is -CH=O, A is not alkynylene;

Y is selected from -H, -NR⁶R⁷, -OR⁷, Ci-₈ alkyl, C₂.₈alkenyl, C₂.₈alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³ and may form a cyclic structure with R²; with the proviso that when Q is -CH=O, Y is not alkynyl;

R¹ is selected from -H, Ci-₈ alkyl, C₂-₈ alkenyl, C₂-₈ alkynyl, C3-10cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, Ci-₆alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl; or more preferably is selected from -H and CA alkyl; or with -A-Y forms a nitrogen containing optionally substituted heterocyclic group where the optional substitution may be CA alkyl, C₂.₈ alkenyl, C₂-₈ alkynyl, or C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, CA alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl;

R² is selected from -H, Ci.₈ alkyl, C₂-₈alkenyl, C₂-ealkynyl, andC₃-io cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, Ci-₆ alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-5 cycloalkyl, and may form a cyclic structure with Y;

each R³ is independently selected from Ci-6 alkyl, Ci-4fluoroalkyl, C1.4 hydroxyalkyl, C2.6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO2NR⁶R⁷ and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

Z is selected from a single bond, C1-4 alkylene, heterocyclylene and C3-6 cycloalkylene;

each R⁴ is independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-10 cycloalkyl, -N(R^X)2, carbamoyl, and -OH;

each R^s Is Independently selected from Ci-₆ alkyl, C1.4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C₃.₆cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and -OH;

each of R⁶ and R⁷ is independently selected from C_x-₈ alkyl, C_M fluoroalkyl, C1-4 perfluoroalkyl, Ci-₄hydroxyalkyl, C₂.₈ alkenyl, C₂-₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl and -Z-aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸; or, alternatively, R⁶ and R⁷ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R⁸;

each R⁸ is independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2.6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)-NR¹⁰R^u, Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C3-6 cycloalkyl, -Z-heterocyclyl, -Zheteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)-NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴as defîned above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defîned above, and each R⁹ is independently selected from -H, Ci-₈ alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C₂-₈ alkenyl, C₂-₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defîned above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defîned above;

each of R¹⁰ and R¹¹ is independently selected from -H, Ci-₆alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C₂-₈ alkenyl, C₂-₈ alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above, or, altematively, R¹⁰ and R¹¹ may together with the N-atom to which they are attached form an optionally 5 to 7 membered, Nheterocyclic ring optionally substituted with one or more R⁴ as defined above;

with the proviso that Y is not H when A is -CH₂-;

when Q is -CH=NR¹², R¹² is selected from Ci-ioalkyl, C2-io alkenyl, C2-io alkynyl, C3-10 cycloalkyl, -Zheterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷ and -Z-COOR⁷, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

when Q is -CH₂NHR¹³, R¹³ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, -C(O)C(O)OR⁷, Ci-8 alkyl, Ci_4fluoroalkyl, Ci-4 perfluoroalkyl, Ci-4 hydroxyalkyl, C2.8 alkenyl, C2.8 alkynyl, C3-10cycloalkyl, -Z-heterocyclyl, and -Z-monocyclic-heteroaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and moncyclic-heteroaryl may optionally be substituted with one or more independently selected R⁸, or is -CR¹⁴R¹⁵-NR⁶R⁷, -CR¹⁴R¹⁵CN, or -CR¹⁴R¹⁵OR⁷, wherein each of R¹⁴and R¹⁵ is independently selected from -H, Ci-8 alkyl, C₂-₈alkenyl, C₂.₈alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, and wherein R¹⁴ and R¹⁵ together with the intervening carbon atom may designate a C3-10 cycloalkyl or C₅-io-cycloalkenyl ring, which alkyl, alkenyl, alkynyl, cycloalkyl (ring), cycloalkenyl ring, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

when Q is W, W is selected from an l,3-diaza-C₅-7~cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups; a l,3-thiaza-C5-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³ and optionally containing one or two oxo groups; an 1,3-oxaza-Cs₇-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups, wherein in ail three instances two R³'s on the same carbon atom may together form a spiro group;

R¹⁶ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷ and - C(O)C(O)OR⁷;

when Q is -CH(OR¹⁷)₂, each R¹⁷ independently is R³, or wherein two R¹⁷ substituents together with the intervening -O-CH(-)-O- may form a heterocyclyl optionally substituted with one or more R³and containing up to two oxo groups;

or an isomer or a mixture of isomers thereof, or a pharmaceutically acceptable sait, or solvaté or prodrug thereof.

It is considered to be probable that each of the groups Q is converted in vivo to produce the corresponding acid (Q = -C(O)OH) by processes which possibly include or consist of enzymatic processing. Accordingly, many or ail of the compounds of this invention may act in vivo at least principally in the form of corresponding acid dérivatives described in PCT/EP2013/070457. It is thought likely that the enzymatic processing takes place partly or entirely within cells into which the respective compound ofthe invention has penetrated. In view of this, it is probable that différences in activity in vitro seen in compounds ofthe invention that hâve the same -A-Y substituent but differ in the group Q are due to the influence of the different groups Q on cell pénétration and/or the effîciency of conversion to the acid form within the cell. This tentative conclusion is based on détection of the corresponding acid within cells following administration of certain compounds according to the invention and molecular modelling ofthe interaction ofthe acids with relevant enzymes.

Accordingly, in an alternative aspect, the invention provides a compound ofthe general Formula wherein R¹, A, and Y are as defined above or below herein and Q is a group that is converted to COOH or COO' upon administration of said compound to a human, provided that Q is not an amide or an ester of such a -COOH group.

According to a first set of embodiments, the invention provides a compound ofthe Formula (I)

Q wherein

Q is selected from -CH=NR¹² and -W;

A is selected from -CHR²C(O)-, C_x-8 alkylene, C₂-e alkenylene, C₂-₈ alkynylene, C3-10 cycloalkylene, heterocyclylene, heteroarylene and arylene, which alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene may optionally be substituted with one or more R³;

Y is selected from -H, -NR⁶R⁷, -OR⁷, Ci-₈ alkyl, C₂-₈ alkenyl, C₂.₈ alkynyl, C3.10 cycloalkyl, heterocyclyl, heteroaryl and aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

R¹ is selected from -H and Ci-4 alkyl;

R² is selected from -H, Ci-₈ alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl;

each R³ is independently selected from Ci-6 alkyl, Ci-4fluoroalkyl, Cw hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO₂NR⁶R⁷ and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

each R⁴ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-10 cycloalkyl, -N(R¹)₂, carbamoyl, and -OH;

each R⁵ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, Ci^ hydroxyalkyl, C1-4alkoxy, C3-6 cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and -OH;

each of R⁶ and R⁷ is independently selected from -H, Ci-₈ alkyl, C1-4 fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C₂-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl and -Zaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸; or, altematively, R⁶ and R⁷ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R⁸;

each R⁸ is independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR^1OR^U, -Z-C(=O)-NR¹⁰Rⁿ, Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from C1-4 alkyl, Ci_₄ fluoroalkyl, Ci-₄ hydroxyalkyl, C3-6cycloalkyl, -Z-heterocyclyl, -Zheteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)-NR¹⁰R^xl, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴as defined above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defined above, and each R⁹ is independently selected from -H, Ci-₈alkyl, C_wfluoroalkyl, C1.4 hydroxyalkyl, C₂.₈alkenyl, C₂-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above;

each of R¹⁰ and R¹¹ is independently selected from -H, Ci-β alkyl, C^fluoroalkyl, C1-4 hydroxyalkyl, C₂-8 alkenyl, C₂-8alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above, or, altematively, R¹⁰ and R¹¹ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more R⁴as defined above;

R¹² is selected from C1-10 alkyl, C₂-io alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷ and -Z-COOR⁷, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

W Is selected from an l,3-dlaza-Cs-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and an l,3-oxaza-C₅-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, wherein in both instances two R³'s on the same carbon atom may together form a spiro group;

R¹⁶ is selected from hydrogen, -C(O)R⁷, and -C(O)C(O)R⁷;

with the proviso that Y is not H when A is -CH2-;

or an isomer or a mixture of isomers thereof, or a pharmaceutically acceptable sait, solvaté or prodrug thereof,

According to a second set of embodiments, the invention provides a compound ofthe Formula (I)

R¹

wherein

Q is -CH2NHR¹³;

A is selected from -CHR²C(O)-, Ci-₈ alkylene, C₂-e alkenylene, C₂-e alkynylene, C3-10 cycloalkylene, heterocyclylene, heteroarylene and arylene, which alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene may optionally be substituted with one or more R³;

Y is selected from -H, -NR^SR⁷, -OR⁷, Ci-₈ alkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

R¹ is selected from -H and Ci-₄ alkyl;

R² is selected from -H, Ci-₈ alkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C3-10cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, Ci-₆alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C₃-e cycloalkyl;

each R³ is independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, Ci^ hydroxyalkyl, C2.6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO₂NR⁶R⁷ and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

Z Is selected from a single bond, Ciy alkylene, heterocyclylene and C3-6 cycloalkylene;

each R⁴ is independently selected from Ci-₆ alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, Ci^ alkoxy, C3-10 cycloalkyl, -NfR¹)^ carbamoyl, and -OH;

each R⁵ is independently selected from Ci-₆ alkyl, Ciy fluoroalkyl, C1-4 hydroxyalkyl, C1-4alkoxy, C3-6 cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and -OH;

each of R⁶ and R⁷ is independently selected from -H, Ci-₈ alkyl, Ciy fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C₂.₈alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl and -Zaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸; or, altematively, R⁶ and R⁷ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R⁸;

each R⁸ is independently selected from Ci-6 alkyl, Ci^ fluoroalkyl, Ciγ hydroxyalkyl, C2-6 alkenyl, C2.6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)-NR¹⁰R^u, Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from Ci^ alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C3-6 cycloalkyl, -Z-heterocyclyl, -Zheteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)-NR¹⁰R^u, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴as defined above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defined above, and each R⁹ is independently selected from -H, Ci-₈ alkyl, C1-4 fluoroalkyl, Ci^ hydroxyalkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above;

each of R¹⁰ and R¹¹ is independently selected from -H, Ci-6 alkyl, Cwfluoroalkyl, Ci-₄ hydroxyalkyl, C₂-e aikenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above, or, altematively, R¹⁰ and R¹¹ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more R⁴ as defined above;

R¹³ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, -R⁷, -CR¹⁴R¹⁵-NR⁶R⁷, -CR¹⁴R¹⁵CN, -CR¹⁴R¹⁵OR⁷, wherein each of R¹⁴ and R¹⁵ is independently selected from -H, Ci-8 alkyl, C2-8 aikenyl, C2-e alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, and wherein R¹⁴ and R¹⁵ together with the intervening carbon atom may designate a C3-10 cycloalkyl or C5-io-cycloalkenyl ring, which alkyl, aikenyl, alkynyl, cycloalkyl (ring), cydoalkenyi ring, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

with the proviso that Y is not H when A is -CH2-;

or an isomer or a mixture of isomers thereof, or a pharmaceutically acceptable sait, solvaté or prodrug thereof.

Optionally, Q is required to be different from -A-Y. Optionally, at least one of Q and -A-Y is not of the form -alkylene-NH-alkylene-aryl, or more specifically is not of the form -alkylene-NH-alkylenephenyl. For example, one or both of Q and -A-Y may be not of the form -CH2-NH-(CH₂)x-phenyl, where x is 1-6 and may in particular be 4.

Optionally, Q does not comprise a polycyclic heteroaryl group, and in particular, Q may not comprise alkyl and optionally may not be

where 'alkyl' may be methyl.

According to a third set of embodiments, the invention provides a compound ofthe Formula (I)

wherein

Q is selected from -CH=O and -CH(OR¹⁷)₂;

A is selected from -CHR²C(O)-, Ci-₈ alkylene, C₂.₈ alkenylene, C₂.₈ alkynylene, C3-10 cycloalkylene, heterocyclylene, heteroarylene and arylene, which alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene may optionally be substituted with one or more R³;

Y is selected from -H, -NR⁶R⁷, -OR⁷, Ci-₈ alkyl, C₂-8alkenyl, C₂.₈alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

R¹ is selected from -H and C1-4 alkyl;

R² is selected from -H, Ci-₈ alkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C3-10cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl;

each R³ is independently selected from Ci-6 alkyl, Ci^ fluoroalkyl, Cx-4 hydroxyalkyl, C2.s alkenyl, C2.6 alkynyl, C3-10cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO₂NR⁶R⁷ and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

Z is selected from a single bond, C_w alkylene, heterocyclylene and C₃._e cycloalkylene, each R⁴ is independently selected from Ci-₆ alkyl, C·^ fluoroalkyl, O hydroxyalkyl, Ci_₄ alkoxy, C3-10 cycloalkyl, -NCR¹)^ carbamoyl, and -OH;

each R⁵ is independently selected from C1-6 alkyl, O fluoroalkyl, C_w hydroxyalkyl, C1-4 alkoxy, C3-6 cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and -OH;

each of R⁶ and R⁷ is independently selected from -H, Ci-β alkyl, C1-4 fluoroalkyl, Ci^ perfluoroalkyl, C1-4 hydroxyalkyl, C₂.₈ alkenyl, C₂.ealkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl and -Zaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸; or, altematively, R⁶ and R⁷ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R⁸;

each R⁸ is independently selected from C1-6 alkyl, Ci^ fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR^1OR^U, -Z-C(=O)-NR¹⁰Rⁿ, Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from Ci^ alkyl, Ci-₄ fluoroalkyl, C_w hydroxyalkyl, C3-6cycloalkyl, -Z-heterocyclyl, -Zheteroaryl, -Z-aryl, -Z-NR^1OR^U, -Z-C(=O)-NR¹⁰Rⁿ, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴as defîned above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defîned above, and each R⁹ is independently selected from -H, Ci-s alkyl, Ci-4fluoroalkyl, Ci-₄ hydroxyalkyl, C₂.₈alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defîned above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defîned above;

each of R¹⁰ and R¹¹ is independently selected from -H, Ci-₆ alkyl, C1-4 fluoroalkyl, Ci-4 hydroxyalkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defîned above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defîned above, or, altematively, R¹⁰ and R¹¹ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more R⁴ as defîned above;

each R¹⁷ independently is R³, or wherein two R¹⁷ substituents together with the intervening -OCH(-)-O- may form a heterocyclyl optionally substituted with one or more R³ and containing up to two oxo groups;

with the proviso that Y is not H when A is -CH₂-;

In this set of embodiments of the invention, optionally -A-Y does not include an alkynylene moiety.

Optionally, -A-Y does not comprise a moiety of the formula

H___H _____ ^c----^c ------ or more particularly a moiety of the formula

H H _____

---C=C--==---(CH₃)₃

A in any of the compounds defined by general formula herein may be selected from -CHR²C(O)-, or

Ci-s alkylene, or heterocyclylene.

Y In any of the compounds defined by general formula herein may be -NR⁶R⁷.

A in any of the compounds defined by general formula herein may be -CHR²C(O)-.

A in any of the compounds defined by general formula herein may be -CH₂-C(O)-.

Y in any of the compounds defined by general formula herein may be

R¹⁰

wherein n is from 1 to 3 and each of R¹⁰ and R¹¹ independently is as defined in claim 1.

Y in any of the compounds defined by general formula herein may be

R¹⁰

ch₂ch₃for instance

CH₂)_m--CH₃

wherein n is from 1 to 3 and each m independently is from 0 to 2.

Y in any ofthe compounds defined by general formula herein may be selected from heterocyclyl, heteroaryl and aryl, which may be optionally substituted with one or more R³.

R¹³ may be H in any ofthe compounds defined by general formula herein.

Q may be ofthe formula:

R¹⁹

O wherein R18 and R19 are hydrogen, or together form a l,3-diaza-C₅-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups; a l,3-thiaza-Cs-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³ and optionally containing one or two oxo groups; an l,3-oxaza-C5-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups, wherein in ail three instances two R³'s on the same carbon atom may together form a spiro group.

In some preferred instances, the compound may be one wherein the moiety -A-Y includes 1-3 cyclic moieties selected from monocylic cycloalkyl, monocyclic heterocyclyl, monocylic heteroaryl, dicyclic heteroaryl and monocyclic aryl.

In preferred aspects of the invention, the compound may be as shown in Table 1 in the Examples section below.

A compound according to the invention may hâve a molecular weight of 130-1,000 g/mol, such as 180-800 g/mol, e.g. 225-600 g/mol or 250-500 g/mol.

The invention includes a pharmaceutical composition comprising at least one compound of Formula (I) as defined in any paragraph herein containing such a définition and optionally one or more pharmaceutically acceptable excipients, diluents or carriers.

The invention includes such a pharmaceutical composition, which comprises one or more further active substances.

The invention includes a compound for use as a médicament which is a compound of the Formula (I)

wherein

Q is selected from -CH=NR¹², -W, -CH2NHR¹³, -CH=O and -CH(OR¹⁷)2;

A is selected from -CHR²C(O)-, Ci-₈ alkylene, C₂-s alkenylene, C₂.₈ alkynylene, C3-10 cycloalkylene, heterocyclylene, heteroarylene and arylene, which alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene may optionally be substituted with one or more R³; with the proviso that when Q is -CH=O, A is not alkynylene;

Y is selected from -H, -l\IR⁵R⁷, -OR⁷, Ci_₈ alkyl, C₂-₈alkenyl, C₂-₈alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³ and may form a cyclic structure with R²; with the proviso that when Q is -CH=O, Y is not alkynyl;

R¹ is selected from -H, Ci-₈ alkyl, C₂-₈ alkenyl, C₂-₈ alkynyl, C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl; or more preferably is selected from -H and C1-4 alkyl; or with -A-Y forms a nitrogen containing optionally substituted heterocyclic group where the optional substitution may be Ci-₈ alkyl, C₂-₈ alkenyl, C₂-s alkynyl, or C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, Ci_₆alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C₃-₆cycloalkyl;

R² is selected from -H, Ci-₈ alkyl, C₂.₈ alkenyl, C₂.₈alkynyl, andC₃-io cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C₃.₆ cycloalkyl, and may form a cyclic structure with Y;

each R³ is independently selected from Ci-₆ alkyl, fluoroalkyl, Ci_₄ hydroxyalkyl, C₂.₆ alkenyl, C₂.₆ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO2NR⁶R⁷ and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

Z is selected from a single bond, Ci_₄ alkylene, heterocyclylene and C3-6 cycloalkylene;

each R⁴ is independently selected from Ci-6 alkyl, CY fluoroalkyl, Ci-4 hydroxyalkyl, Ci-4alkoxy, C3-10 cycloalkyl, -N(R¹)2, carbamoyl, and -OH;

each R⁵ is independently selected from Ci-β alkyl, C_w fluoroalkyl, Ci^ hydroxyalkyl, Ci-₄ alkoxy, C3-6 cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and -OH;

each of R⁶ and R⁷ is independently selected from -H, Ci-₈alkyl, C1-4 fluoroalkyl, perfluoroalkyl, Ci^ hydroxyalkyl, C₂.₈alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl and -Zaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸; or, alternatively, R⁶ and R⁷ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R⁸;

each R⁸ is independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, C1.4 hydroxyalkyl, C2.6 alkenyl, C2.6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR^R¹¹, -Z-C(=O)-NR¹⁰R^u, Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from Y alkyl, Cw fluoroalkyl, Ci-4 hydroxyalkyl, C3.6 cycloalkyl, -Z-heterocyclyl, -Zheteroaryl, -Z-aryl, -Z-NR^1OR^U, -Z-C(=O)-NR¹⁰R^u, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴as defined above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defined above, and each R⁹ is independently selected from -H, Ci-₈ alkyl, Ci-4 fluoroalkyl, C1-4 hydroxyalkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above;

each of R¹⁰ and R¹¹ is independently selected from -H, Ci-₆ alkyl, Ci-₄ fluoroalkyl, Ci-4 hydroxyalkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above, or, alternatively, R¹⁰ and R¹¹ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more R⁴ as defined above;

with the proviso that Y is not H when A is -CH₂-;

when Q is -CH=NR¹², R¹² is selected from Ci-io alkyl, C2-i0 alkenyl, C2-io alkynyl, C3-10 cycloalkyl, -Zheterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷ and -Z-COOR⁷, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

when Q is -CH₂NHR¹³, R¹³ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, -C(O)C(O)OR⁷, Ci-8 alkyl, Ci^fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2.8 alkenyl, C2.8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, and -Z-monocyclic-heteroaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and monocyclic- heteroaryl may optionally be substituted with one or more independently selected R⁸, or is -CR¹⁴R¹⁵-NR⁶R⁷, -CR¹⁴R¹⁵CN, or -CR¹⁴R¹⁵OR⁷, wherein each of R¹⁴and R¹⁵ is independently selected from -H, Ci-8 alkyl, C₂.₈alkenyl, C₂.₈alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, and wherein R¹⁴ and R¹⁵ together with the intervening carbon atom may designate a C3-10 cycloalkyl or C₅-io-cycloalkenyl ring, which alkyl, alkenyl, alkynyl, cycloalkyl (ring), cycloalkenyl ring, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

when Q is W, W is selected from an l,3-diaza-C5-7’Cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups; a l,3-thiaza-C5-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³ and optionally containing one or two oxo groups; an l,3-oxaza-C57-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups, wherein in ail three instances two R³'s on the same carbon atom may together form a spiro group;

R¹⁶ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, -C(O)C(O)R⁷;

The invention includes a compound for use in the treatment of a HDME dépendent disease which is of the Formula (I)

wherein

Q is selected from -CH=NR¹², -W, -CH2NHR¹³, -CH=O and -CH(OR¹⁷)₂;

A is selected from -CHR²C(O)-, Ci-s alkylene, C2-8 alkenylene, C₂-e alkynylene, C3-10 cycloalkylene, heterocyclylene, heteroarylene and arylene, which alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene may optionally be substituted with one or more R³;

Y is selected from -H, -NR⁶R⁷, -OR⁷, Ci-₈ alkyl, C₂-₈ alkenyl, C₂-₈ alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³ and may form a cyclic structure with R²;

R¹ is selected from -H, Ci-₈ alkyl, C₂-₈ alkenyl, C₂-₈alkynyl, C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl; or more preferably is selected from -H and Ci-4 alkyl; or with -A-Y forms a nitrogen containing optionally substituted heterocyclic group where the optional substitution may be Ci-₈ alkyl, C₂-₈ alkenyl, C₂-b alkynyl, or C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, Ci-₆alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6cycloalkyl;

R² is selected from -H, Ci-₈ alkyl, C2-8 alkenyl, C2-8 alkynyl, andC₃-io cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, Ci-₆alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl, and may form a cyclic structure with Y;

each R³ is independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-b alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO2NR⁶R⁷ and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

Z is selected from a single bond, Ci_₄ alkylene, heterocyclylene and C₃.₆ cycloalkylene;

each R⁴ is independently selected from Ci-6 alkyl, Ci^ fluoroalkyl, Ci-4 hydroxyalkyl, Ci^ alkoxy, C3-10 cycloalkyl, -N(R¹)2, carbamoyl, and -OH;

each R⁵ is independently selected from Ci-β alkyl, Ci_₄ fluoroalkyl, Ciy hydroxyalkyl, C₁.₄alkoxy, C₃.₆ cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and -OH;

each of R⁶ and R⁷ is independently selected from -H, Ci-₈ alkyl, Ci-4fluoroalkyl, Ci-₄ perfluoroalkyl, Ci-4 hydroxyalkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl and -Zaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸; or, altematively, R⁶ and R⁷ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R⁸;

each R⁸ is independently selected from Ci-β alkyl, Ci_4 fluoroalkyl, Ci-4 hydroxyalkyl, C2-6 alkenyl, C2.6 alkynyl, C3.10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)-NR¹⁰Rⁿ, Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from Ciy alkyl, Ciy fluoroalkyl, Ciy hydroxyalkyl, C3-8 cycloalkyl, -Z-heterocyclyl, -Zheteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)-NR¹⁰Rⁿ, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴as defined above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defined above, and each R⁹ is independently selected from -H, Ci-₈ alkyl, Ci-₄ fluoroalkyl, C1-4 hydroxyalkyl, C₂.₈ alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above;

each of R¹⁰ and R¹¹ is independently selected from -H, Ci-₆ alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C₃-io cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above, or, altematively, R¹⁰ and R¹¹ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more R⁴ as defined above;

with the proviso that Y is not H when A is -CH₂-;

when Q is -CH=NR¹², R¹² is selected from C1-10 alkyl, C2-io alkenyl, C2-i0 alkynyl, C3-i0 cycloalkyl, -Zheterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁵-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷ and -Z-COOR⁷, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

when Q is -CH2NHR¹³, R¹³ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, -C(O)C(O)OR⁷, Ci-₈ alkyl, C1-4 fluoroalkyl, C1-4 perfluoroalkyl, C_M hydroxyalkyl, C₂-₈ alkenyl, C₂-₈ alkynyl, C3-10cycloalkyl,

-Z-heterocyclyl, -Z- heteroaryl and -Z-aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸, or is

-CR¹⁴R¹⁵-NR⁶R⁷, -CR¹⁴R¹⁵CN, or -CR¹⁴R¹⁵OR⁷, wherein each of R¹⁴ and R¹⁵ is independently selected from -H, Ci-s alkyl, C₂.₈ alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, and wherein R¹⁴ and R¹⁵ together with the intervening carbon atom may designate a C3-10 cycloalkyl or

Cs-io-cycloalkenyl ring, which alkyl, alkenyl, alkynyl, cycloalkyl (ring), cycloalkenyl ring, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

when Q is W, W is selected from an l,3-diaza-Cs-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups; a l,3-thiaza-C5-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³ and optionally containing one or two oxo groups; an 1,3-oxaza-Cs7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups, wherein in ail three instances two R³'s on the same carbon atom may together form a spiro group;

R¹⁶ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, -C(O)C(O)OR⁷;

when Q is -CH(OR¹⁷)2, each R¹⁷ independently is R³, or wherein two R¹⁷ substituents together with the intervening -O-CH(-)-O- may form a heterocyclyl optionally substituted with one or more R³and containing up to two oxo groups;

The invention includes the use of a compound for the préparation of a pharmaceutical composition for the treatment of a HDME dépendent disease, which compound is of the Formula (I)

Q wherein

Q is selected from -CH=NR¹², -W, -CH2NHR¹³, -CH=O and -CH(OR¹⁷)₂;

A is selected from -CHR²C(O)-, Ci-₈ alkylene, C₂-8alkenylene, C₂.₈ alkynylene, C₃-iocycloalkylene, heterocyclylene, heteroarylene and arylene, which alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene may optionally be substituted with one or more R³;

Y is selected from -H, -NR⁶R⁷, -OR⁷, Ci-₈ alkyl, C₂-₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³ and may form a cyclic structure with R²;

R¹ is selected from -H, CA alkyl, C₂.₈ alkenyl, CA alkynyl, CAo cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, CA alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and CA cycloalkyl; or more preferably is selected from -H and CA alkyl; or with -A-Y forms a nitrogen containing optionally substituted heterocyclic group where the optional substitution may be CA alkyl, CA alkenyl, CA alkynyl, or C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, CA alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and CA cycloalkyl;

R² is selected from -H, CA alkyl, CA alkenyl, CA alkynyl, andCAo cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, CA alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and CA cycloalkyl, and may form a cyclic structure with Y;

each R³ is independently selected from CA alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, CA alkenyl, CA alkynyl, C3-10cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO₂NR⁶R⁷ and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

Z is selected from a single bond, CA alkylene, heterocyclylene and CA cycloalkylene;

each R⁴ is independently selected from CA alkyl, CA fluoroalkyl, CA hydroxyalkyl, CA alkoxy, CAo cycloalkyl, -NCR¹)^ carbamoyl, and -OH;

each R^s is independently selected from CA alkyl, Ci_₄ fluoroalkyl, CA hydroxyalkyl, CA alkoxy, CA cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and -OH;

each of R⁶ and R⁷ is independently selected from -H, Ci-₈ alkyl, C1-4 fluoroalkyl, Ci_4 perfluoroalkyl, Ci-4 hydroxyalkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl and -Zaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸; or, alternatively, R⁵ and R⁷ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R⁸;

each R⁸ is independently selected from Ci-6 alkyl, Ci-4 fluoroalkyl, Ci_4 hydroxyalkyl, C2.6 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)-NR¹⁰R^u, Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from CM alkyl, C_w fluoroalkyl, Ci_4 hydroxyalkyl, C₃-e cycloalkyl, -Z-heterocyclyl, -Zheteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)-NR¹⁰R^u, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴as defined above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defined above, and each R⁹ is independently selected from -H, Ci-₈ alkyl, CVfluoroalkyl, Ci^ hydroxyalkyl, C₂-e aikenyl,

C₂-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above;

each of R¹⁰ and R¹¹ is independently selected from -H, Ci-ealkyl, Ci^fluoroalkyl, Ci^hydroxyalkyl, C₂-8 aikenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above, or, altematively, R¹⁰ and R¹¹ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more R⁴ as defined above;

with the proviso that Y is not H when A is -CH2-;

when Q is -CH=NR¹², R¹² is selected from Ci-io alkyl, C2-10 aikenyl, C2-10 alkynyl, C3-10 cycloalkyl, -Zheterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁵-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷ and -Z-COOR⁷, which alkyl, aikenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

When Q is -CH2NHR¹³, R¹³ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, Ci-8 alkyl, C1-4 fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2-8 aikenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Zheterocyclyl, -Z-heteroaryl and -Z-aryl, which alkyl, aikenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸, or is -CR¹⁴R¹⁵-NR⁶R⁷, -CR¹⁴R¹⁵CN, or -CR¹⁴R¹⁵OR⁷, wherein each of R¹⁴ and R¹⁵ is independently selected from -H, Ci-s alkyl, C2.₈ aikenyl, C₂-₈ alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, and wherein R¹⁴ and R¹⁵ together with the intervening carbon atom may designate a C3-10 cycloalkyl or C₅-io-cycloalkenyl ring, which alkyl, aikenyl, alkynyl, cycloalkyl (ring), cydoalkenyi ring, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

when Q is W, W is selected from an l,3-diaza-C₅-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups; a l,3-thiaza-C₅-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³ and optionally containing one or two oxo groups; an 1,3-oxaza-Cs7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups, wherein in ail three instances two R³'s on the same carbon atom may together form a spiro group;

R¹⁶ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, -C(O)C(O)OR⁷;

The invention includes a method of treating a HDME dépendent disease in a subject, said method comprises administering to said subject a therapeutically effective amount of at least one compound of Formula (I) as defined in any one of the above paragraphs.

Conditions treatable using compounds or formulations or compositions according to the invention include cancer in the broadest sense, including solid and non-solid tumours. Further details of treatable conditions appear below.

DETAILED DISCLOSURE OF THE INVENTION

The above définitions of the compounds of Formula (I) are referred to herein by the expressions compounds of Formula (1) as defined herein, compound of Formula (I) as defined herein, or simply compounds of Formula (I), etc. It should be understood, that such references are intended to encompass not only the above general formula in its stated aspects, but also each and every ofthe embodiments, etc. discussed above or in the following. It should also be understood, that unless stated to the opposite, such references also encompass isomers, mixtures of isomers, isotopic variants, pharmaceutically acceptable salts, solvatés and prodrugs of the compounds of Formula (I).

Without being bound by any particuiar theory, the current results give reasons to believe that each of the values of Q plays an important rôle when designing compounds capable of modulating the in vivo activity of histone demethylases (HDMEs), whilst in each case the group Q is transformed in vivo to -COOH. Additionally, it is believed that the substituent combination -A-Y plays a rôle in establishing affinity for said histone demethylases. Furthermore, it is believed that the pyridine nitrogen and the nitrogen atom of Formula (I) also play a rôle in the binding of a particuiar cavity of the histone demethylases where the iron atom lies. It is also believed that the A-Y chain itself, and through its substituents, interacts with the area ofthe demethylase known to accommodate the lysine chain of the substrate.

A is typically selected from -CHR²C(O)-, Ci-₈ alkylene, C₂.₈alkenylene, C₂.₈ alkynylene, C3-10 cycloalkylene, heterocyclylene, heteroarylene and arylene.

The alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene as A may optionally be substituted with one or more R³ (see further below).

A may be selected from -CHR²C(O)-, Ci-8 alkylene, C310 cycloalkylene, heterocyclylene, heteroarylene and arylene, in particuiar from -CHR²C(O)-, Ci-8 alkylene and heterocyclylene, such as -CHR²C(O)-, or Ci_₈ alkylene, or heterocyclylene.

Y is typically selected from -H, -NR⁶R⁷, -OR⁷, Ci-₈ alkyl, C₂-₈alkenyl, C₂-₈alkynyl, C₃ 10 cycloalkyl, heterocyclyl, heteroaryl and aryl. R⁶ and R⁷ are exemplified further below.

The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl as Y may optionally be substituted with one or more R³ (see further below);

In some embodiments, Y is -NR⁶R⁷. In one variant type, A is -CHR²C(O)- and Y is -NR⁶R⁷. In another variant type, A is Ci-8 alkyl and Y is -NR⁶R⁷. In one scénario within these embodiments and these variants, -NR⁶R⁷ represents an N-heterocyclic ring optionally substituted with one or more independently selected R⁸, preferably substituted with one to two independently selected R⁸. In another scénario within these embodiments and these variants wherein Y is -NR⁶R⁷, one of R⁶ and R⁷ represents -H or Ci-β alkyl. In still another scénario within these embodiment types and these variants wherein Y is -NR⁶R⁷, R⁶ and R⁷ are independently selected from Ci-8 alkyl, Ci-4fluoroalkyl, Ci-4 hydroxyalkyl, C2-₈ alkenyl, and C₂-₈ alkynyl, e.g. such that R⁶ and R⁷ are the same. In still another scénario within these embodiment types and these variants wherein Y is -NR⁶R⁷, one of R⁶and R⁷ is selected from heterocyclyl, heteroaryl and aryl.

Y may be -H. In such compounds and in others , A may be selected from Ci-₈ alkylene, C₂.₈alkenylene, C₂.₈alkynylene, and C₃-iocycloalkylene. In such compounds and in others, A may also be selected from heterocyclyl.

Y may be selected from heterocyclyl, heteroaryl and aryl. In such compounds and others, A may be selected from Ci-₈ alkylene, C₂.₈ alkenylene, C₂.₈ alkynylene, in particular from Ci-₈ alkylene, such as from Ci-6 alkylene, in particular from C1-4 alkylene.

R¹ is typically selected from -H and C1-4 alkyl (such as methyl, ethyl, propyl and butyl), in particular from -H and methyl.

R² is typically selected from -H, Ci-₈ alkyl, C₂-₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, Ci-₆ alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C₃-e cycloalkyl. In some embodiments, R²is selected from -H, C1-4 alkyl (such as methyl, ethyl, propyl and butyl) and Ci-4 hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl), in particular from -H, methyl and hydroxymethyl.

The R³ (possible substituents to some of the meanings of A and Y) is typically independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2.8 alkynyl, C3-i0 cycloalkyl, Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO₂NR⁶R⁷and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵.

Z Is typically selected from a single bond, C1.4 alkylene, heterocyclylene and C₃.₆ cycloalkylene. In one embodiment, Z is selected from C1-4 alkylene. In another embodiment, Z is selected from a single bond. It should be understood that the group Z may appear several times in Formula (I) and that such Z's are independently selected.

Each R⁴ (possible substituents of heterocyclyl) may be independently selected from Ci_₆ alkyl, fluoroalkyl, C1-4 hydroxyalkyl, Ci^alkoxy, C3-10cycloalkyl, -N<R¹)2, carbamoyl, and -OH,

Each R⁵ (possible substituents of heteroaryl and aryl) may be independently selected from Ci-β alkyl, C_M fluoroalkyl, C1-4 hydroxyalkyl, Ci^alkoxy, C₃-e cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and -OH.

Each of R⁶ and R⁷ (e.g. of the moiety -NR⁶R⁷) may be independently selected from -H (in certain aspects), Ci-₈ alkyl, C1-4 fluoroalkyl, Ci^ perfluoroalkyl, C1-4 hydroxyalkyl, C₂-₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl and -Z-aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸; or, altematively, R⁶ and R⁷ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R⁸.

Each R⁸ may be independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)NR¹⁰Rⁿ, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from Ci-4alkyl, C1-4fluoroalkyl, Ci^hydroxyalkyl, C₃.₆cycloalkyl, -Z-heterocyclyl, -Zheteroaryl, -Z-aryl, -Z-NR¹⁰Rⁿ, -Z-C(=O)-NR¹⁰R^u, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴as defined above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defined above.

Each R⁹ may be independently selected from -H, Ci_₈ alkyl, Ci^fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C₂-s alkynyl, C₃-i₀ cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above.

Each of R¹⁰ and R¹¹ (ofthe moiety -NR¹⁰R¹¹) may be independently selected from -H, Ci-₆ alkyl, C_wfluoroalkyl, C1.4 hydroxyalkyl, C₂.₈ alkenyl, C₂.₈ alkynyl, C₃-i₀ cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above, or, altematively, R¹⁰ and R¹¹ may together with the N-atom to which they are attached form an Nheterocyclic ring optionally substituted with one or more R⁴ as defined above.

In some embodiments, Q is -CH=N-R¹². If so, R¹² may be selected from C1-10 alkyl, C2-10 alkenyl, C2. 10 alkynyl, C3-i0 cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -ZNR⁶-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷ and -Z-COOR⁷, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³. In some embodiments hereof, R¹² is Ci-₈ alkyl, C1-4 fluoroalkyl, C_Mperfluoroalkyl, C₂.₈ alkenyl, C₂-₈ alkynyl, C₃-₈cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z

NR⁶R⁷, and -Z-OR⁷, wherein -Z- is a single bond or alkylene, which alkyi, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³.

In other embodiments, Q is -W, wherein -W may be an l,3-azo-Cs-7-cycloalk-2-yl group which is Nsubstituted with R¹⁶ and optionally further substituted with one or more R³. W may be 1,3diazacyclopent-2-yl (imidazolidin-2-yl), l,3-diazacyclohex-2-yl (hexahydropyrimidin-2-yl), or 1,3diazacydohept-2-yl, for example. The N-substituent may be selected among those defîned for R¹⁶(see above). W may be further substituted with one or more R³, wherein two R³'s on the same carbon atom may together form a spiro group.

In yet other embodiments, Q is -W, wherein -W may be an l,3-oxaza-C₅-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³. W may be l,3-oxazacyclopent-2-yl, l,3-oxazacyclohex-2-yl, l,3-oxazacyclohept-2-yl, or 7-oxa-9azaspiro[4,5]decan-8-yl, for example. The N-substituent may be selected among those defîned for R¹⁶ (see above). W may be further substituted with one or more R³, wherein two R³'s on the same carbon atom may together form a spiro group.

In some embodiments of the above, W may be further substituted with one or more R³, but is typically not further substituted.

R¹⁶ may be selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷ , and -C(O)C(O)OR⁷, in particular from hydrogen and -C(O)R⁷.

In some embodiments Q is -CH₂NHR¹³, and R¹³ may be selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, -R⁷ (in some aspects), -CR¹⁴R¹⁵-NR⁶R⁷, -CR¹⁴R¹⁵CN, -CR¹⁴R¹⁵OR⁷, wherein each of R¹⁴and R¹⁵ is independently selected from -H, Ci-8 alkyi, C2.8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, and wherein R¹⁴ and R¹⁵ together with the intervening carbon atom may designate a C3-10 cycloalkyl or Cs-io-cycloalkenyl ring, which alkyi, alkenyl, alkynyl, cycloalkyl (ring), cycloalkenyl ring, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³. In some aspects, rather than -R⁷, R¹³ may be Ci-₈ alkyi, Ci^fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C₂-₈ alkenyl, C₂.₈ alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, and -Zmonocyclic-heteroaryl, which alkyi, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl may optionally be substituted with one or more independently selected R⁸.

In some embodiments Q is -CH(OR¹⁷)₂ and each R¹⁷ independently may be R³, or the two R¹⁷substituents together with the intervening -O-CH(-)-O- may form a heterocyclyl optionally substituted with one or more R³.

It is to be understood that in the Formula (I), Y is not H when A is -CH₂-. Generally speaking, it is believed to be advantageous if the moiety -A-Y has a certain size with respect to the number of atom (disregarding hydrogen atoms) and/or the molecular weight. Also a limited flexibility of the moiety -A-Y appears to play a certain rôle.

Hence, it is believed that the moiety -A-Y should preferably consist of at the most 40 heavy atoms, such as at the most 30 heavy atoms, or at the most 25 heavy atoms, or at the most 20 heavy atoms. Preferably, the moiety -A-Y will consist of at least 3, or at least 4, or at least 8 or at least 10 heavy atoms. In some embodiments, the moiety -A-Y preferably consiste of 3-40 heavy atoms, such as 4-30 heavy atoms, or 4-25 heavy atoms, or 4-20, or 8-30, or 8-20, or 8-15 heavy atoms. By the term heavy atom is meant ail atoms in the moiety except the hydrogen atom(s).

Moreover, it is believed that the compounds of Formula (I) should preferably hâve a molecular weight of at least 130, or at least 150, or at least 180, or at least 250, but not more than 1000, or not more than 800, or not more than 500, or not more than 400 and may be within any range constructable from these preferred upper and lower limits, such as 130-1,000 g/mol, or 150-1,000 g/mol, such as 180-800 g/mol, e.g. 225-600 g/mol or 250-500 g/mol, or 250 to 400.

In some embodiments, and in order to introduce a limited flexibility ofthe moiety -A-Y, the moiety includes 1-4 rings, i.e. rings derived from cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl and/or aryl. In some variant, the moiety -A-Y includes 1-3 cyclic moieties selected from monocylic cycloalkyl, monocyclic heterocyclyl, monocylic heteroaryl, dicyclic heteroaryl and monocyclic aryl. Small substituents such as alkyls groups or hydroxyl on alkyl chains also reduce flexibility and favor certain conformations.

It may be préférable that if -A-Y does not include a ring, it includes at least one, for instance from 1 to 3, branches, each of which independently may be of from one heavy atom to six heavy atoms, for instance from one to three heavy atoms, or from one to two heavy atoms. It is preferred that A-Y should contain at least one hetero-atom, preferably at least one nitrogen atom or at least one oxygen.

Définitions

The term alkyl as used herein refers to a saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to 8 carbon atoms (Ci-₈-alkyl), more preferred from one to six carbon atoms (Ci-₆-alkyl), in particular from one to four carbon atoms (Ci-₄-alkyl), including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl, isohexyl, heptyl and octyl. In a preferred embodiment alkyl represents a Cw-alkyl group, which may in particular include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl. Correspondingly, the term alkylene means the corresponding biradical (-alkyl-).

The term cycloalkyl as used herein refers to a cyclic alkyl group, preferably containing from three to ten carbon atoms (C₃-i₀-cycloalkyl), such as from three to eight carbon atoms (C₃-₈-cycloalkyl), preferably from three to six carbon atoms (C₃-6-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Furthermore, the term cycloalkyl as used herein may also include polycyclic groups such as for example bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptanyl, decalinyl and adamantyl. Correspondingly, the term cycloalkylene means the corresponding biradical (-cycloalkyl-).

The term alkenyl as used herein refers to a straight or branched hydrocarbon chain or cyclic hydrocarbons containing one or more double bonds, including di-enes, tri-enes and poly-enes. Typically, the alkenyl group comprises from two to eight carbon atoms (C2-8-alkenyl), such as from two to six carbon atoms (C₂.₆-alkenyl), in particular from two to four carbon atoms (C₂-4-alkenyl), including at least one double bond. Examples of alkenyl groups include ethenyl; 1- or 2-propenyl;

1- , 2- or 3-butenyl, or 1,3-but-dienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or 1,3-hex-dienyl, or 1,3,5-hextrienyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-octenyl, or 1,3-octadienyl, or 1,3,5-octatrienyl, or 1,3,5,7octatetraenyl, or cyclohexenyl. Correspondingly, the term alkenylene means the corresponding biradical (-alkenyl-).

The term alkynyl as used herein refers to a straight or branched hydrocarbon chain containing one or more triple bonds, including di-ynes, tri-ynes and poly-ynes. Typically, the alkynyl group comprises of from two to eight carbon atoms (C₂-8-alkynyl), such as from two to six carbon atoms (C₂-6-alkynyl), in particular from two to four carbon atoms (C2^-alkynyl), including at least one triple bond. Examples of preferred alkynyl groups include ethynyl; 1- or 2-propynyl; 1-, 2- or 3butynyl, or 1,3-but-diynyl; 1-, 2-, 3-, 4- or 5-hexynyl, or 1,3-hex-diynyl, or 1,3,5-hex-triynyl; 1-,

2- , 3-, 4-, 5-, 6-, or 7-octynyl, or 1,3-oct-diynyl, or 1,3,5-oct-triynyl, or 1,3,5,7-oct-tetraynyl. Correspondingly, the term alkynylene means the corresponding biradical (-alkynyl-).

The terrns halo and halogen as used herein refer to fluoro, chloro, bromo or iodo. Thus a trihalomethyl group represents e.g. a trifluoromethyl group, or a trichloromethyl group. Preferably, the terrns halo and halogen designate fluoro or chloro.

The term fluoroalkyl as used herein refers to an alkyl group as defined herein which is substituted one or more times with one or more fluorohalo, preferably perfluorated. The term perfluoroalkyl as used herein refers to an alkyl group as defined herein wherein ail hydrogen atoms are replaced by fluoro atoms. Preferred fluoroalkyl groups include trifluoromethyl, pentafluoroethyl, etc.

The term alkoxy as used herein refers to an alkyl-O- group, wherein alkyl is as defined above.

The term hydroxyalkyl as used herein refers to an alkyl group (as defined hereinabove), which alkyl group is substituted one or more times with hydroxy. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2- and CH₃-CH(OH)-.

The term oxy as used herein refers to an -O- group.

The term oxo as used herein refers to an =O group.

The term amine as used herein refers to primary (R-NH₂, R * H), secondary (R₂-NH, R₂ * H) and tertiary (R₃-N, R * H) amines. A substituted amine is intended to mean an amine where at least one of the hydrogen atoms has been repiaced by the substituent.

The term carbamoyl as used herein refers to a H₂N(C=O)- group.

The term aryl, as used herein, unless otherwise indicated, includes carbocyclic aromatic ring Systems derived from an aromatic hydrocarbon by removal of a hydrogen atom. Aryl furthermore includes bi-, tri- and polycyclic ring Systems. Examples of preferred aryl moieties include phenyl, naphthyl, indenyl, indanyl, fluorenyl, biphenyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, pentalenyl, azulenyl, and biphenylenyl. Preferred aryl is phenyl, naphthyl or indanyl, in particular phenyl, unless otherwise stated. Any aryl used may be optionally substituted. Correspondingly, the term arylene means the corresponding biradical (-aryl-).

The term heteroaryl, as used herein, refers to aromatic groups containing one or more heteroatoms selected from O, S, and N, preferably from one to four heteroatoms, and more preferably from one to three heteroatoms. Heteroaryl furthermore includes bi-, tri- and polycyclic groups, wherein at least one ring of the group is aromatic, and at least one of the rings contains a heteroatom selected from O, S, and N. Heteroaryl also include ring Systems substituted with one or more oxo moieties. Examples of preferred heteroaryl moieties include N-hydroxytetrazolyl, Nhydroxytriazolyl, N-hydroxyimidazolyl, furanyl, triazolyl, pyranyl, thiadiazinyl, benzothiophenyl, dihydro-benzo[b]thiophenyl, xanthenyl, isoindanyl, acridinyl, benzisoxazolyl, quinolinyl, isoquinolinyl, phteridinyl, azepinyl, diazepinyl, imidazolyl, thiazolyl, carbazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, azaindolyl, pyrazolinyl, and pyrazolidinyl. Non-limiting examples of partially hydrogenated dérivatives are 1,2,3,4-tetrahydronaphthyl, 1,4dihydronaphthyl, and 1-octalin. Correspondingly, the term heteroarylene means the corresponding biradical (-heteroaryl-).

The term heterocyclyl as used herein, refers to cyclic non-aromatic groups containing one or more heteroatoms selected from O, S, and N, preferably from one to four heteroatoms, and more preferably from one to three heteroatoms. Heterocyclyl furthermore includes bi-, tri- and polycyclic non-aromatic groups, and at least one ofthe rings contains a heteroatom selected from O, S, and N. Heterocyclyl also include ring Systems substituted with one or more oxo moieties. Examples of heterocyclic groups are oxetane, pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,3oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2,5-oxadiazolyl, piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl,

4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1,2-diazinanyl, pyrimidinyl, 1,3-diazinanyt, pyrazinyl, piperazinyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-diazinanyl, 1,4-oxazinyl, morpholinyl, thiomorpholinyl, 1,4-oxathianyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, chromayl, isochromanyl, 4H-chromenyl, lH-isochromenyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, purinyl, naphthyridinyl, pteridinyl, indolizinyl, 1Hpyrrolizinyl, 4H-quinolizinyl and aza-8-bicyclo[3.2.1]octane. Correspond!ngly, the term heterocyclylene means the corresponding biradical (-heterocyclyl-).

The term N-heterocyclic ring as used herein, refers to a heterocyclyl or a heteroaryl as defined hereinabove having at least one nitrogen atom, and being bound via a nitrogen atom. Examples of such N-heterocyclic rings are pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, piperidinyl, pyridinyl, pyridazinyl, pyrazinyl, piperazinyl, morpholinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, etc.

Isomers

The compounds of Formula (I) may exist as géométrie isomers (i.e. cis-trans isomers), optical isomers or stereoisomers, such as diastereomers, as well as tautomers. Accordingly, it should be understood that the définition of compounds of Formula (I) includes each and every individual isomers corresponding to the structural formula: Formula (I), încluding cis-trans isomers, stereoisomers and tautomers, as well as racemic mixtures of these and pharmaceutically acceptable salts thereof. Hence, the définition of compounds of Formula (I) is also intended to encompass ail R- and S-isomers of a chemical structure in any ratio, e.g. with enrichment (i.e. enantiomeric excess or diastereomeric excess) of one ofthe possible isomers and corresponding smaller ratios of other isomers.

Diastereoisomers, i.e. non-superimposable stereochemical isomers, can be separated by conventional means such as chromatography, distillation, crystallization or sublimation. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids include, without limitation, tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. The mixture of diastereomers can be separated by crystallization followed by libération of the optically active bases from these salts. An alternative process for séparation of optical isomers includes the use of a chiral chromatography column optimally chosen to maximize the séparation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molécules by reacting compounds of Formula (I) with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain the enantiomerically pure compound. The optically active compounds of Formula (I) can likewise be obtained by utilizing optically active starting materials and/or by utilizing a chiral catalyst. These isomers may be in the form of a free acid, a free base, an ester or a sait. Examples of chiral séparation techniques are given in Chiral Séparation Techniques, A Practical Approach, 2^nd ed. by G. Subramanian, Wiley-VCH,

2001.

Pharmaceutically acceptable salts

The compound of Formula (I) may be provided in any form suitable for the întended administration, in particular including pharmaceutically acceptable salts, solvatés and prodrugs ofthe compound of Formula (I).

Pharmaceutically acceptable salts refer to salts ofthe compounds of Formula (I), which are considered to be acceptable for clinîcal and/or veterinary use. Typical pharmaceutically acceptable salts include those salts prepared by reaction ofthe compounds of Formula (I) a minerai or organic acid or an organic or inorganic base. Such salts are known as acid addition salts and base addition salts, respectively. It will be recognized that the particular counter-ion or multiple counter-ions forming a part of any sait is not of a critical nature, so long as the sait as a whole is pharmaceutically acceptable and as long as the counter-ion does not contribute undesired qualities to the sait as a whole. These salts may be prepared by methods known to the skilled person. Pharmaceutically acceptable salts are, e.g., those described and discussed in Remington's Pharmaceutical Sciences, 17. Ed. Alfonso R. Gennaro (Ed.), Mack Publishing Company, Easton, PA, U.S.A., 1985 and more recent éditions and in Encyclopédie of Pharmaceutical Technology.

Examples of pharmaceutically acceptable addition salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric, or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinilic, alginic and galacturonic acid; and arylsulfonic, for example benzenesulfonic, p-toluenesulfonic, oxalic, methanesulfonic or naphthalenesulfonic acid; and base addition salts formed with alkali metals and alkaline earth metals and organic bases such as Ν,Ν-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and internally formed salts.

Solvatés

The compound of Formula (I) may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvent such as water, éthanol, and the like. Dissoluble forms may also include hydrated forms such as the mono-hydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like.

Isotopic variations

Elemental symbols and element names are used herein to include isotopes ofthe named éléments.

In particuiar one, some, or ail hydrogens may be deuterium. Radioactive isotopes may be used, for instance to facilitate tracing the fate of the compounds or their metabolic products after administration.

Prodruqs

The compound of Formula (I) may be provided as a prodrug. The term prodrug used herein is intended to mean a compound which - upon exposure to certain physiological conditions - will liberate the compound of Formula (I) which then will be able to exhibit the desired biological action. A typical example is a labile carbamate of an amine and a further example would be a trialkylsilyl ether of an alcohol or a trialkylsilyl ester of an acid, each optionally being trimethylsilyl.

Inhibitory effect

The inventors hâve surprisingly found that compounds of Formula (I) as defined herein hâve an inhibitory effect on the activity of one or more HDMEs. In this respect said one or more HDMEs may be any HDME, however preferably the one or more HDMEs are selected from the JmjC (Jumonji) family, more preferably said one or more HDME(s) are HDME ofthe human JmjC family and even more preferably are HDME belonging to the KDM6, KDM5, KDM4 or KDM2 families. The présent invention also relates to a compound of Formula (I) as defined herein in a method for inhibiting HDMEs. The method includes contacting a cell with a compound of Formula (I). In a related embodiment, the method further provides that the compound is présent in an amount effective to produce a concentration sufficient to inhibit the déméthylation of a histone in the cell.

Thus, preferably in an assay for déméthylation of a histone substrate by said HDME, then preferred compounds of Formula (I) are compounds capable of reducing or preferably inhibiting said déméthylation by said HDME. Said histone substrate may be any histone, but preferably is histone H3 or a fragment thereof, even more preferred: a fragment comprising K4, K9, K27, or K36 of H3. Preferably, said inhibition is determined as the ICso of said compound of Formula (I) in respect of the said déméthylation assay.

Preferred compounds of Formula (I) which hâve an IC₅o at or below 1 μΜ, more preferably less than 300 nM, for example less than 100 nM, such as less than 50 nM in respect of déméthylation of any of said histone substrates by any of said HDME. Thus very preferred compounds of Formula (I) which hâve an ICso at or below 1 μΜ, more preferably less than 500 nM, for example less than 100 nM, such as less than 50 nM in respect of déméthylation of histone H3 methylated at least on one lysine.

In a preferred embodiment ICso is determined as described in Example 2 herein below. Thus, particularly preferred are compounds of Formula (I) which hâve an IC₅o at or below 1 μΜ, more preferably less than 500 nM, for example less than 100 nM, such as less than 50 nM when said ICso is determined as described in and one ofthe Examples herein below.

Particularly preferred compounds of Formula (I) are compounds that lead to a decreased tumour size and/or decreased number of métastasés when tested in a xenograft model (Morton and

Houghton, Nature Protocols, 2 (2) 247-250, 2007).

Pharmaceutical compositions

In one aspect of this invention, there is provided a pharmaceutical composition comprising at, as an active ingrédient, at least one compound of Formula (I) as defined herein and optionally one or more pharmaceutically acceptable excipients, diluents and/or carriers. The compounds of Formula (I) may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. Suitable pharmaceutically acceptable carriers, diluents and excipients include inert solid diluents or fillers, stérile aqueous solutions and various organic solvents.

The pharmaceutical compositions may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 21st Edition, 2000, Lippincott Williams & Wilkins.

The pharmaceutical compositions formed by combining a compound of Formula (I) as defined herein with pharmaceutically acceptable carriers, diluents or excipients can be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, suppositories, injectable solutions and the like. In powders, the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The pharmaceutical compositions may be specifically prepared for administration by any suitable route such as the oral and parentéral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route. It will be appreciated that the preferred route will dépend on the general condition and âge of the subject to be treated, the nature of the condition to be treated and the active ingrédient chosen.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be prepared so as to provide controlled release of the active ingrédient such as sustained or prolonged release according to methods well known in the art.

For oral administration in the form of a tablet or capsule, a compound of Formula (I) as defined herein may suitably be combined with an oral, non-toxic, pharmaceutically acceptable carrier such as éthanol, glycerol, water or the like. Furthermore, suitable binders, lubricants, disintegrating agents, flavouring agents and colourants may be added to the mixture, as appropriate. Suitable binders include, e.g., lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes or the like. Lubricants include, e.g., sodium oleate, sodium stéarate, magnésium stéarate, sodium benzoate, sodium acetate, sodium chloride or the like. Disintegrating agents include, e.g., starch, methyl cellulose, agar, bentonite, xanthan gum, sodium starch glycolate, crospovidone, croscarmellose sodium or the like. Additional excipients for capsules include macrogols or lipids.

For the préparation of solid compositions such as tablets, the active compound of Formula (I) is mixed with one or more excipients, such as the ones described above, and other pharmaceutical diluents such as water to make a solid pre-formulation composition containing a homogenous mixture of a compound of Formula (I). The term homogenous is understood to mean that the compound of Formula (I) is dispersed evenly throughout the composition so that the composition may readily be subdivided into equally effective unit dosage forms such as tablets or capsules.

Liquid compositions for either oral or parentéral administration of the compound of Formula (I) include, e.g., aqueous solutions, syrups, élixirs, aqueous or oil suspensions and émulsion with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinylpyrolidone.

Pharmaceutical compositions for parentéral administration include stérile aqueous and non-aqueous injectable solutions, dispersions, suspensions or émulsions as well as stérile powders to be reconstituted in stérile injectable solutions or dispersions prior to use. For parentéral administration, solutions containing a compound of Formula (I) in sesame or peanut oil, aqueous propylene glycol, or in stérile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonie with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subeutaneous and intraperitoneal administration. The oily solutions are suitable for intra-articular, intra-muscular and subeutaneous injection purposes.

The préparation of ail these solutions under stérile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

Depot injectable compositions are also contemplated as being within the scope of the présent invention.

In addition to the aforementioned ingrédients, the compositions of a compound of Formula (I) may include one or more additional ingrédients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, preservatives, e.g. methyl hydroxybenzoate (including antioxidants), emulsifying agents and the like.

A suitable dosage of the compound of Formula (I) will dépend on the âge and condition of the patient, the severity ofthe disease to be treated and other factors well known to the practicing physician. The compound may be administered for example either orally, parenterally or topically according to different dosing schedules, e.g. daily or with intervals, such as weekly intervals. In general a single dose will be in the range from 0.01 to 100 mg/kg body weight, preferably from about 0.05 to 75 mg/kg body weight, more preferably between 0.1 to 50 mg/kg body weight, and most preferably between 0.1 to 25 mg/kg body weight. The compound may be administered as a bolus (i.e. the entire daily dose is administered at once) or in divided doses two or more times a day. Variations based on the aforementioned dosage ranges may be made by a physician of ordinary skill taking into account known considérations such as weight, âge, and condition ofthe person being treated, the severity of the affliction, and the particular route of administration.

The compounds of Formula (I) may also be prepared in a pharmaceutical composition comprising one or more further active substances alone, or in combination with pharmaceutically acceptable carriers, diluents, or excipients in either single or multiple doses. The suitable pharmaceutically acceptable carriers, diluents and excipients are as described herein above, and the one or more further active substances may be any active substances, or preferably an active substance as described in the section combination treatment herein below.

Clinical conditions and other uses of compounds

The compounds according to Formula (I) as defined herein are useful for treatment of a HDME dépendent disease, disorder or condition. The treatment may include administering to a mammal, preferably a human, more preferably a human suffering from a HDME dépendent disease, a therapeutically effective amount of a compound according to Formula (I) as defined herein.

Said HDME may be any HDME, however preferably the HDME ofthe présent method is selected from the JmjC (Jumonji) family, as described in Cloos et. al., Genes & Development 22, 1115-1140, 2008, which is incorporated herein by reference in its entirety. More preferably said HDME is a HDME of the human JmjC family.

The présent invention also relates to a compound of Formula (I) as defined herein for use in the treatment of a HDME dépendent disease, such as for the treatment of cancer.

By the term HDME dépendent disease is meant any disease characterized by elevated HDME expression and/or activity in at least in some instances ofthe disease, or a disease which is ameliorated by lowering the activity of HDMEs. Thus, the disease to be treated with the inhibitors of HDME, i.e. compounds of Formula (I), may be a proliférative or hyperproliferative disease, which includes benign or malignant tumors, for example a proliférative or hyperproliferative disease selected from the group consisting of a carcinoma ofthe brain, kidney, liver, adrenal gland, bladder, breast, stomach (for example gastric tumors), ovaries, esophagus, colon, rectum, prostate, pancréas, lung, vagina, thyroid, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, for example, colon carcinoma or colorectal adenoma, or a tumor of the neck and head, an epidermal hyperproliferation, for example, psoriasis, prostate hyperplasia, a neoplasia, including a neoplasia of épithélial character, including mammary carcinoma, and a leukemia.

In one embodiment, compounds of Formula (I) as defîned herein are useful in the treatment of one or more cancers. The term cancer refers to any cancer caused by the prolifération of neoplastic cells, such as solid tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. In particular, cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma, (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancréas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm’s tumor, nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcfnoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: ostéogénie sarcoma (osteosarcoma), fibrosarcoma, malignant fïbrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (réticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), méningés (meningioma, meningiosarcorna, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congénital tumors), spinal cord (neurofibroma, meningioma, glioma, sarcoma); Gynecological: utérus (endométrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadénocarcinome, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithélial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hématologie: blood (acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

In one embodiment, the compounds of Formula (I) as defîned herein are useful in the treatment of one or more cancers selected from the group consisting of: Ieukemias including acute leukemias and chronic leukemias such as acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and Hairy Cell Leukemia; lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T- cell lymphotrophic virus (HTLV) such as adult Tcell leukemia/Iymphoma (ATLL), Hodgkin's disease and non-Hodgkin's lymphomas, large-cell lymphomas, diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mesothelioma, primary central nervous system (CNS) lymphoma; multiple myeloma; childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilm's tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genito urinary cancers (e.g., prostate, bladder, rénal, uterine, ovarian, testicular, rectal and colon), lung cancer, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, liver cancer and thyroid cancer.

In another very preferred embodiment, the compound of Formula (I) as defîned herein are useful for the treatment of squamous cell carcinomas. Preferably said squamous cell carclnomas are cancers ofthe carcinoma type of squamous epithelium that may occur in many different organs, including the skin, lips, mouth, esophagus, urinary bladder, prostate, lungs, vagina, and cervix; brain cancer, that is neuroblastoma, glioblastoma and other malignant and benign brain tumors; breast cancer, pancreatic cancer, and multiple myeloma.

In yet another embodiment, the compounds of Formula (I) as defîned herein are useful for treatment of brain cancer, tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genito urinary cancers (e.g., prostate, bladder, rénal, uterine, ovarian, testicular, rectal and colon), and breast cancer.

Other cancer forms for which the compounds of Formula (I) are useful as treatment can be found in Stedman's Medical Dictionary (Lippincott Williams & Wilkins, 28^th Ed., 2005), which is incorporated herein by reference in its entirety.

In still another related embodiment, the disease to be treated by compounds of Formula (I) as defîned herein is selected from persistent proliférative or hyperproliferative conditions such as angiogenesis, such as psoriasis; Kaposi's sarcoma; restenosis, e.g., stent-induced restenosis; endometriosis; Hodgkin's disease; leukemia; hemangioma; angiofibroma; eye diseases, such as neovascular glaucoma; rénal diseases, such as glomerulonephritis; malignant nephrosclerosis; thrombotic microangiopathic syndromes; transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis ofthe liver; mesangial cell-proliferative diseases; injuries ofthe nerve tissue; and inhibiting the re-occlusion of vessels after balloon cathéter treatment, for use in vascular prosthetics or after inserting mechanical devices for holding vessels open, such as, e.g., stents, as immune-suppressants, as an aid in scar-free wound healing, and treating âge spots and contact dermatitis.

The compounds of Formula (I) are suitable as active agents in pharmaceutical compositions that are efficacious particularly for treating cellular proliférative or hyperproliferative ailments and/or ailments associated with dysregulated gene expression. Such pharmaceutical compositions hâve a therapeutically effective amount ofthe compound of Formula (I) along with other pharmaceutically acceptable excipients, carriers, and diluents and. The phrase, therapeutically effective amount as used herein indicates an amount necessary to administer to a host, or to a cell, tissue, or organ of a host, to achieve a therapeutic effect, such as an ameliorating or altematively a curative effect, for example an anti-tumor effect, e.g. réduction of or preferably inhibition of prolifération of malignant cancer cells, benign tumor cells or other proliférative cells, or of any other HDME dépendent disease.

Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I) as defined herein, or a pharmaceutically acceptable sait, solvaté or prodrug thereof, in combination with at least one further anti-neoplastic compound, and a pharmaceutically acceptable excipient, carrier or diluent.

Method of treatment

In a further aspect the présent invention relates to a method of treating a diseases in a subject, said method comprises administering to said subject a therapeutically effective amount of at least one compound of Formula (I) as defined herein. The disease may be any disease or disorder as mentioned herein, such as for example mentioned in the section HDME dépendent diseases, and the compound may be administered alone or in a pharmaceutical composition, such as for example mentioned in the section Pharmaceutical compositions.

Hence, the invention also relates to a compound of Formula (I) as defined herein for use as a médicament.

The term treating and treatment, as used herein, unless otherwise indicated, refers to reversing, alleviating, inhibiting the process of, or preventing the disease, disorder or condition to which such term applies, or one or more symptoms of such disease, disorder or condition and includes the administration of a compound of Formula (I) to prevent the onset of the symptoms or the complications, or alleviating the symptoms or the complications, or eliminating the disease, condition, or disorder. Preferably treatment is curative or ameliorating.

In a preferred embodiment of this aspect of the invention the method is a method of treating a HDME dépendent disease in a subject, said method comprises administering to said subject a therapeutically effective amount of a compound of Formula (I) as defined herein to a subject in need of such treatment. The HDME dépendent disease may be any HDME dépendent disease as described herein above. Preferably the HDME dépendent disease is squamous cell carcinomas or any other of the cancer conditions mentioned above.

Hence, the invention also relates to a compound of Formula (I) as defined herein for use in the treatment of a HDME dépendent disease, such as for the treatment of cancer.

Further, the invention relates to the use of a compound of Formula (I) as defined herein for the préparation of a pharmaceutical composition for the treatment of a HDME dépendent disease.

In one embodiment of the method of treatment of a HDME dépendent disease, the compound of Formula (I) as defined herein is administered in combination with one or more further active substances. The active substances may be any active substances, and preferably an active substance as described herein above in the section combination treatment. More preferably the one or more additional active substances are selected from the group consisting of anti-proliferative or anti-neoplastic agents.

Combination treatment

A compound of Formula (I) may also be used to advantage in combination with one or more other anti-proliferative or anti-neoplastic agents. Such anti-proliferative agents include, but are not limited to other HDME inhibitors, protéasome inhibitors, including bortezomib (Valcade) and Carfilzomib, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone deacetylase inhibitors; compounds which induce cell différentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein tyrosine or serine or threonine kinase activity; compounds targeting/decreasing a lipid kinase activity; compounds targeting/decreasing a carbohydrate kinase activity and further antiangiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; angiostatic steroids; méthionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliférative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; protéasome inhibitors; agents used in the treatment of hématologie malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors; temozolomide (TEMOD AL(R)); leucovorin; immune stimulating agents, such as BCG, IL-2 or IFN-α, antibodies such as anti-CTLA-4 monoclonal antibody ipilimumab (Yervoy), rituximab or herceptin and cancer vaccines; inhibitors/modulators of mitochondrial activity such as metformin.

A compound of Formula (I) as defined herein may also be used to advantage in combination with known therapeutic processes, e.g., the administration of hormones or tumor cell damaging approaches, especially ionizing radiation.

A compound of Formula (I) as defined herein may also be used as a radiosensitizer, including, for example, the treatment of tumors which exhibit poor sensitivity to radiotherapy.

By the term combination, is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of Formula (I) and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect, or any combination thereof.

The phrase, aromatase inhibitor as used herein relates to a compound which inhibits the estrogen production, i.e., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutéthimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark AROMASIN. Formestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark LENTARON. Fadrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark AFEMA. Anastrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark ARIMIDEX. Letrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark FEMARA or FEMAR. Aminoglutéthimide can be administered, e.g., in the form as it is marketed, e.g., under the trademark ORIMETEN. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.

The term antiestrogen as used herein relates to a compound that antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOLVADEX. Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g., under the trademark EVISTA. Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g., under the trademark FASLODEX. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g., breast tumors.

The term anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgénie hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g., as dîsclosed in US 4,636,505.

The phrase, gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin is dîsclosed in US 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZOLADEX. Abarelix can be formulated, e.g., as dîsclosed in US 5,843,901.

The phrase, topoisomerase I inhibitor as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecan and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound Al in WO99/ 17804). Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR. Topotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark HYCAMTIN.

The phrase, topoisomerase II inhibitor as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, e.g., CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark ETOPOPHOS. Teniposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark VM 26-BRISTOL. Doxorubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMORUBICIN. Idarubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZAVEDOS. Mitoxantrone can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOVANTRON.

The phrase, microtubule active agent relates to microtubule stabilizing, microtubule destabilizing agents and microtublin polymerization inhibitors including, but not limited to taxanes, e.g., paclitaxel and docetaxel, vinca alkaloids, e.g., Vinblastine, including Vinblastine sulfate, vincristine including vincristine sulfate, and vinorelbine, discodermolides, cochicine and epothilones and dérivatives thereof, e.g., epothilone B or D or dérivatives thereof. Paclitaxel may be administered e.g., in the fo[pi]n as it is marketed, e.g., TAXOL. Docetaxel can be administered, e.g., in the form as it is marketed, e.g., under the trademark TAXOTERE. Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark VINBLASTIN R.P. Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMISTIN. Discodermolide can be obtained, e.g., as dîsclosed in US 5,010,099. Also included are Epothilone dérivatives which are dîsclosed in WO 98/10121, US 6,194,181, WO 98/25929, WO 98/08849, WO

99/43653, WO 98/22461 and WO 00/31247. Included are Epothilone A and/or B.

The phrase, alkylating agent as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark CYCLOSTIN. Ifosfamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark HOLOXAN.

The phrase, histone deacetylase inhibitors or HDAC inhibitors relates to compounds which inhibit at least one example of the class of enzymes known as a histone deacetylase, and which compounds generally possess antiproliférative activity. Previously disclosed HDAC inhibitors include compounds disclosed in, e.g., WO 02/22577, including N-hydroxy-3-[4-{[(2-hydroxyethyl)[2-(IHindol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, N-hydroxy-3-[4-[[[2-(2-methyl-IHindol-3-yl)-ethylJ-amino]methyl]phenyl]-2E-2- propenamide and pharmaceutically acceptable salts thereof. It further includes Suberoylanilide hydroxamic acid (SAHA). Other publicly disclosed HDAC inhibitors include butyric acid and its dérivatives, including sodium phenylbutyrate, thalidomide, trichostatin A and trapoxin.

The term antineoplastic antimetabolite includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating agents, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folie acid antagonists such as pemetrexed. Capecitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark XELODA. Gemcitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark GEMZAR. Also included is the monoclonal antibody trastuzumab which can be administered, e.g., in the form as it is marketed, e.g., under the trademark HERCEPTIN.

The phrase, platin compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ELOXATIN.

The phrase, compounds targeting/decreasing a protein tyrosine or serine or threonine kinase activity as used herein includes, but is not limited to, gefinitib, erlotinib, lapatinib, foretinib, cabozantinib, vemurafenib or selumetinib (AZD6244). Gefinitib can be administered, e.g., in the form as it is marketed, e.g., under the trademark IRESSA. Erlotinib can be administered, e.g., in the form as it is marketed, e.g., under the trademark TARCEVA. Lapatinib can be administered, e.g., in the form as it is marketed, e.g., under the trademarks TYKERB and TYVERB. Cabozantinib can be administered, e.g., in the form as it is marketed, e.g., under the trademark COMETRIQ. Vemurafenib can be administered, e.g., in the form as it is marketed, e.g., under the trademark CELBORAF. Foretinib can be formulated, e.g., as disclosed in US 20,120,282,179. Selumetinib (AZD6244) can be formulated, e.g., as disclosed in US 20,080,177,082 and US 20,090,246,274. Other suitable protein kinase inhibitors include without limitation Afatanib (Gilotrif, Boeringer Ingelheim), Axitinib (Inlyta, Pfizer), Bosutinib (Bosulif, Wyeth), Crizotinib (Xalkori, Pfizer), Dabrafenib (Tafinlar, GSK), Dasatinib (Sprycel, Bristol-Myers Squib), Elotinib (Tarceva, OSI), Everolimus (Afinitor, Novartis), Gefitinib (Iressa, Astrazeneca), Ibrutinib (Imbruvica, Pharmacyclics and J&J), Imatanib (Gleevec, Novartis), Nilotinib (Tasigna, Novartis), Pazopanib (Votrient, GlaxoSmithKline), Ponatinib (Iclusig, Ariad), Regorafenib (Stivarga, Bayer), Ruxolitinib (Jakafi, Incyte), Sirolimus (Rapamune, Wyeth), Sorafenib (Nexavar, Bayer), Sunitinib (Sutent, Pfizer), Tofacitinib (Xeljanz, Pfizer), Temsirolimus (Torisel, Wyeth), Trametinib (Mekinist, GSK), Vandetanib (Caprelsa, IPR Pharms) as well as other proposed protein kinase inhibitors that can be found in the literature.

Tumor cell damaging approaches refer to approaches such as ionizing radiation. The phrase, ionizing radiation referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See, e.g., Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).

The phrase, angiostatic steroids as used herein refers to agents which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, ll-[alpha]-epihydrocotisol, cortexolone, 17[alpha]-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

Other chemotherapeutic agents include, but are not limited to, plant alkaloids, hormonal agents and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide dérivatives; or miscellaneous agents or agents with other or unknown mechanism of action.

The structure of the active agents identified by code numbers, generic or trade names may be taken from the actual édition of the standard compendium 'The Merck Index or from databases, e.g., Patents International (e.g., IMS World Publications).

The above-mentioned compounds, which can be used in combination with a compound of Formula (I), can be prepared and administered as described in the art such as in the documents cited above. Furthermore, the compounds of the invention may be used in a method of profiling the functional and structural similarity of histone demethylases comprising taking a panel of at least two histone demethylases and a panel of at least two compounds of formula 1 and determining the extent to which each said compound of formula 1 inhibits the activity of each of said histone demethylases, and generating a similarity index reflecting the degree of similarity between the histone demethylases in respect of their inhibition by said compounds.

Préparation of Compounds of Formula (D: Q is CH?N H R¹³

Scheme 1

Method A - Reductive amination

Compounds of Formula (I) may be prepared from 4-formyl pyridines according to Scheme 1, where R' is a suitable protecting group or R¹, in one-pot or by a stepwise procedure by mixing with an amine, optionally containing orthogonal protected reactive sites, and a reducing agent such as NaBH₄, NaBH(OAc)3, NaCNBhh, or Et₃SiH, either at room température or by heating for up to several hours by use of a solvent such as an alcohol, DCE, DCM, water, or toluene, optionally adding a catalyst such as an acid or a Lewis acid. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Scheme 2 - Réduction of hydroxylamine to primary amine

Q

Compounds of Formula (I) may be prepared from hydroxyl amines, optionally containing orthogonally protected reactive sites, according to Scheme 2, where R' is a suitable protecting group or R¹, by use of reducing agents, such as a hydrogen atmosphère over a suitable catalyst, such as palladium on charcoal, in a suitable solvent, such as an alcohol. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Scheme 3 - Reductive amination

Q

Compounds of Formula (I) may be prepared from 2-formyl pyridines according to Scheme 3 analogously to Method A.

Scheme 4

Method D - Buchwald coupling to aryls

Compounds of Formula (I) may be prepared according to Scheme 4 using a suitable solvent such as toluene or tetrahydrofuran, a base such as césium carbonate or potassium t-butoxide, a suitable catalyst such as Pd₂(dba)₃, optionally a suitable sait such as lithium chloride and the desired electrophile such as arylbromide or heteroarylbromide. The compounds of Formula I are generated at room température or by heating for several hours, such as for 2 to 5 hours. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Method E - Reductive amination

Compounds of Formula (I) may be prepared from amines according to Scheme 4 according to method A.

Method F - Alkylation/Acylation

The compounds of Formula (I) may be prepared according to scheme 4 by use of a solvent such as DMF or THF, a base such as sodium hydride or césium carbonate and a suitable electrophilic species such as an epoxide, a heteroaromatic chloride, an aliphatic, allylic or benzylic bromide, chloride or sulfonate, or a carbonyl chloride. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Scheme 5 - Réduction of amide

R13

Q

Method G

Compounds of Formula (I) may be prepared from amides, optionally containing orthogonal protected reactive sites, according to Scheme 5, where R' is a suitable protecting group or Ri, by use of reducing agents, such as lithium aluminium hydride or borane-complexes, in a suitable solvent, such as an ether or tetrahydrofuran. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Préparation of Compounds of Formula fl): Q is CH=NR¹²

Scheme 6

Q

Compounds of Formula (I) may be prepared from 4-formyI pyridines according to Scheme 6, where R' is a suitable protecting group or RI, by mixing with an amine, optionally containing orthogonally protected reactive sites, either at room température or by heating for up to several hours by use of a solvent such as an alcohol, DCE, DCM, water, or toluene, optionally adding a catalyst such as a Lewis acid. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Préparation of Compounds of Formula fl): Q is CH=O

Scheme 7

Q

Method I

Compounds of General Formula (I) may be prepared according to Scheme 7, where R' is a suitable protecting group or Rl, by a Swern or altematively a Dess-Martin oxidation of alcohol to aldéhyde. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Scheme 8

Q

Compounds of General Formula (I) may be prepared from esters, where R' is a suitable protecting group or Rl, optionally containing orthogonal protected reactive sites, according to Scheme 8, by use of reducing agents, such as DIBAL-H, in a suitable solvent, such as toluene. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Scheme 9 x Q

Method K

Compounds of General Formula (I) may prepared at low température, e.g. at -78 °C, from halides, where R' is a suitable protecting group or Rl, optionally containing orthogonal protected reactive sites according to Scheme 9 (X désignâtes a halogen atom) by halogen métal exchange, e.g. by treatment with an alkyl lithium reagent, followed by addition of DMF in a solvent, such as dichloromethane. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Préparation of Compounds of Formula fl): Q is CHfOR¹⁷)?

Scheme 10

Q

Method L

Compounds of General Formula (I) may prepared from 4-formyl pyridines according to Scheme 10 by stirring in an alcohol in the presence of a Lewis acid or an acid, such as HCL or Pyridinium toluene-4-sulphonate, optionally by reacting with trialkyl orthoformate or in the presence of a drying agent such as an inorganic dry sait, or with azeotropic removal of water, at room température or by heating for several hours depending on the method. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Préparation of Compounds of Formula fl): Q is W and R¹⁶ is H

Method M

Compounds of General Formula (I) may prepared from 4-formyl pyridines according to Scheme 10 by stirring in a diamine, an aminoalcohol or an aminothiol, optionally in the presence of an acid such as HCL or Pyridinium toluene-4-sulphonate, optionally in the presence of a drying agent such as an inorganic dry sait or molecular sieves, or with azeotropic removal of water, at room température or by heating for several hours depending on the method. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Préparation of Compounds of Formula (I): Q is W and R³ is not H

Method N

Compounds of General Formula (I) may prepared from the aforementioned compound where Q is W and R¹⁶ is H, by reacting with a suitably activated acyl group such as an acyl halide or acyl anhydride at room température or by heating for several hours is a solvent such as dichloroethane or THF. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Préparation of Intermediates for Compounds of Formula fl)

Scheme 11

Method AA

Intermediates may be prepared from 2-formyl pyridines according to Scheme 11 analogously to Method A.

Scheme 12

Method AB

Intermediates, where X désignâtes halides or OTf, may be prepared from 2-formyl pyridines according to Scheme 12 analogously to Method A.

Scheme 13

Method AC

Intermediates, where Pg désignâtes a suitable protecting group, such as TBMDS or TIPS, may be prepared from 2-formyl pyridines according to Scheme 13 analogously to Method A.

Scheme 14

Method AD

Intermediates be prepared according to scheme 14, where R' is a suitable protecting group or R_x, by use of a solvent such as DMF or THF, a base such as a hindered tertiary amine, a dehydrating agent such as EDCI or DCC and an amine, and by mixing at or above room température for a period up to several hours. Optionally, the said protecting group may be removed, and a purification method such as silica gel chromatography is employed if needed.

Scheme 15

Method AE

Intermediates may be prepared according to Scheme 15 analogously to Method AD.

Scheme 16

N

OH

N

Method AF

Intermediates may be prepared according to Scheme 16 analogously to Method AD.

Scheme 17

Method AG

Intermediates may be prepared according to scheme 17 from, where R' is a suitable protecting group or R¹ and R is an orthogonal protecting group, which may be selectively removed, such as removal of R: ‘Bu in presence of R': CF₃CO by treating with trifluoroacetic acid in a solvent such as dichloromethane at room température for several hours. A purification method such as silica gel chromatography is employed if needed.

Scheme 18

Method AH

Intermediates may be prepared according to Scheme 18 analogously to Method AG.

Scheme 19

Method AI

Intermediates may be prepared according to Scheme 19 analogously to Method AG.

Scheme 20

Method AJ

Intermediates may be prepared from aldéhydes and intermediates, where L désignâtes a bond or an aliphatic linker, which may comprise an amide bond, attached to an aliphatic heterocycle, according to Scheme 20 analogously to Method A Method AK

Intermediates may be prepared according to Scheme 20 analogously to Method F.

Scheme 21

Method AL

Intermediates may be prepared according to Scheme 21 analogously to Method AJ.

Method AM

Intermediates may be prepared according to Scheme 21 analogously to Method F.

Scheme 22

>►

Method AN

Intermediates may be prepared according to Scheme 22 analogously to Method AJ.

Method AO

Intermediates may be prepared according to Scheme 22 analogously to Method F.

Scheme 23

Alkyl

I

N '''Re

Method AP

Intermediates, where L désignâtes an aliphatic linker, which may comprise an amide bond, may be prepared from aldéhydes according to Scheme 23 analogously to Method E.

Method AQ

Intermediates may be prepared according to Scheme 23 analogously to Method F.

Method AR

Intermediates, where L désignâtes an aliphatic linker, which may comprise an amide bond, may be prepared from aldéhydes according to Scheme 24 analogously to Method E.

Method AS

Intermediates may be prepared according to Scheme 24 analogously to Method F.

Scheme 25

Pg ,ο >►

Alkyl

Method AT

Intermediates, where L désignâtes an aliphatic linker, which may comprise an amide bond, may be prepared from aldéhydes according to Scheme 25 analogously to Method E.

Method AU

Intermediates may be prepared according to Scheme 25 analogously to Method F.

Scheme 26 ,0 ,NH ’N

Method AV

Intermediates may be prepared according to Scheme 26 analogously to Method A.

Scheme 27 ,NH

Method AW

Intermediates may be prepared according to Scheme 27 analogously to Method A.

Scheme 28

Method ΑΧ

Intermediates may be prepared according to Scheme 28 analogously to Method A.

Scheme 29

Alkyl

Method AZ

Intermediates may be prepared from esters, optionally containing orthogonal protected reactive sites, according to Scheme 29, by use of reducing agents, such as DIBAL-H, in a suitable solvent, such as toluene. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Scheme 30

Alkyl

Method BA

Intermediates may be prepared from esters, optionally containing orthogonal protected reactive sites, according to Scheme 30, by use of reducing agents, such as lithium aluminiumhydride or borane-complexes, in a suitable solvent, such as an ether or tetrahydrofuran. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Scheme 31

Method BB

Intermediates may be prepared according to Scheme 31 using method K

Method BC

Intermediates may be prepared according to scheme 31 either at room température or by heating for several hours by use of a solvent such as toluene or tetrahydrofuran, a base such as césium carbonate or potassium t-butoxide, a catalyst such as Pd₂(dba)₃, optionally a sait such as lithium chloride and the desired nucleophile such as carbon monoxide. A purification method such as silica gel chromatography is employed if needed.

Scheme 32

Method BD

Intermediates may be prepared according to scheme 32 analogously to Method AD.

Scheme 33

Alkyl

Method BE

Intermediates may be prepared according to Scheme 33 by use of a solvent such as DMF or THF, a base such as césium carbonate and an electrophile such as an alkyl halide, heteroaromatic halide, alkenyl halide, etc., and by mixing at or above room température for several hours. A purification method such as silica gel chromatography or trituration is employed if needed.

Method BF

Intermediates may be prepared according to Scheme 33 by use of acetic catalysis in an alcohol at room température or at reflux. A purification method such as silica gel chromatography or trituration is employed if needed.

Scheme 34

Method BG

Intermediates may be prepared according to scheme 34 from 4-formyl pyridines by reaction with hydroxylamine in a solvent such as an alcohol or water.

Scheme 35

Method BH

Intermediates may be prepared according to scheme 35 from 4-formyl pyridines by with reaction an amine, optionally containing orthogonally protected reactive sites, either at room température or by heating for up to several hours by use of a solvent such as an alcohol, DCE, DCM, THF water, or toluene, optionally adding a catalyst such as a Lewis acid. Subsequently reacting with TMSCN in a solvent such as acetonitrile. Optionally, protecting groups may be removed and a purification method such as silica gel chromatography is employed if needed.

Scheme 36

Method BI

Intermediates may be prepared according to Scheme 36 either at room température or by heating for several hours by use of a solvent such as wet toluene or tetrahydrofuran, a base such as césium carbonate or potassium t-butoxide, a catalyst such as Pd₂(dba)₃, optionally a sait such as lithium chloride and the desired nucleophile such as carbon monoxide. A purification method such as silica gel chromatography is employed if needed.

Scheme 37

>►

Method BJ

Intermediates may be prepared according to Scheme 37 from pyridine 2-carboxylates analogously to Method J.

Scheme 38

Method BK

Intermediates may be prepared according to Scheme 38 from pyridine 2-halides analogously to Method K.

EXAMPLES

Example 1 - Préparation of compounds ofthe invention

General Methods and Materials

Ail chemicals were purchased from Sigma-Aldrich, Alfa Aesar, Matrix, Combiblock, Oakwood, and Chembridge. Anhydrous solvents were Aldrich Sure/Seal™ brand. Ail réactions were carried out under a dry nitrogen atmosphère using dry solvents. Reactions were monitored by thin-layer chromatography carried out on Sigma-Aldrich 0.25 mm silica gel plates (60 Â, fluorescent indicator). Spots were visualized under UV light (254 nm). Flash column chromatography was performed on Biotage SNAP Flash System, or silica gel 60 (particle size 0.032-0.063 mm) obtained from Silicycle, Inc. Low-resolution ES (electrospray) mass spectra were obtained using a Micromass Quattro Ultima mass spectrometer in the electrospray positive (ES+) or négative (ES-) ion mode. 1H-NMR spectra were recorded on a Bruker AM-300 spectrometer and were calibrated using residual nondeuterated solvent as internai reference. Spectra were processed using Spinworks version 2.5 (developed by Dr. Kirk Marat, Department of Chemistry, University of Manitoba). Préparative HPLC was performed on Waters 2996 with Photodiode Array Detector, Waters 600

Controller, Waters 100 pump, and Waters 717 auto sampler, with UV détection at 254 and 280 nm. Flow rate: 15 mL/minute, run time 30 minutes. Solvents: 0-100% (HiO-MeOH), with and without added TFA (0.1%). Column used was Supelco C18, 25 cm x 21.2 mm, particle size 10 micrometer.

Ethyl 2-formylpyridine-4-carboxylate was prepared analogously to Queguiner, G. and Pastour, P. (Comptes Rendus des Séances de l'Académie des Sciences, Série C: Sciences Chimiques (1969), 268(2), 182-5).

Examples of Compounds of Formula (I)

TABLE 1

\ z- (	/ - z	Y
t b	h	w	Structure
	V /
Z T ΙΌ	( z T ΓΌ	“Π
ω	ro	h-··	*
[2-«[3- (dimethylamino)propyl]a mino}methyl)pyridin-4yljmethanamine	[2-«[4- (dimethylamino)butyl]am ino}methyl)pyridin-4yl]methanamine	N-{[2-«[4(diethylamino)butyl]amin o}methyl)pyridin-4yl]methyl}-2,2,2trifluoroacetamide	Name
CD	CD	>	May be prepared analogously to Synthetic Route
C? NJ oo 3 3 oc ' i· h! g: z t nj^t· ω 3 <” “ω <-> T α n ££ -N oo 3» N nj— g Μ-^ω CH	Y-NMR (300MHz, MeOD), δ ppm: 8.80 (d, 1H), 4.60 (s, 2H), 2.95 (s, 6H), 1.95 (m, 4H).	QN?Ç03£ en- m S²— ûj 3 - CL O 73 lO' O ^A vC - -r a. ω o o. 2 3 ’cn-o - ω-ο.^Νi-*— g en	z 3 jO

OJ

CD

Cb ω


	ω π; Η =C
z	Cb + Ο 2
s
73	^ÙT *
	Η·· UD ⁰¹7Τ
ω ο ο	“Π Îj,^w Έ> ο
2	Y? b-> - 2
X Ν	LY9°S
	3^ Y
	' ιθ^
	lD Q-

en A □3

NJ ι r-*-.

&

< O ro OSH rt3 3 SSüTM ^3.ά 3 □ r—i

QJ Ό o Ul q ·< ‘

=. □ T3 D Q. 5 -ô S

AO ¹ eu

CD tu k) Ul a> 3

i

I

σ» ui

/ - ζ	\ ζ-
?	°ί	ΞΕ	ζ /
ΖΙ	/	'ΤΑ ,^ζ~
<
		< ΖΙ
/ ²	Q	<>ο
	$	- ζ \
S=o
- ζ	)
\	( “Π
I-¹	h-*·	Μ*
U1	A	W
	ζ±
·< _. ο.	>< C	*< r—1
9: g* ο 3 3 ro'S’S- _Κ1	Q.X θ =· 3 ο 3 φ π> ,	ο-Έ' D 3«S“
<-»· 3 ξγ	(T) rtt.., rr NJ	(t> CX ΣΤ 2
rr =Γ α> < '	4 =Γ -X =Γ .’	rt *< Ο
=Γ ~< S7A	3·~< S < ώ 0, Qj — ÇU -U	3<ç; 3 ’y ω ω 5 r> 3 “< £ 5· &S t SJ ο □ a>
\|\|Oé Ε ο -· π> 7J	ο 3 ^— —4 · α> =· ζ> 2. hs ? ο Ο Ν)
	3 Ύ ¹ g D*	3^’3 2. ι μ 3 Q. Z ' 5‘ n>^ i J—i
α. ζ 3 <. '-? to'yrf \| fi)
¹ 3		' 3
Ο	ο	m
' JL· (Τ)	?° ² £	0? ^?°²£ ~ A. n>
Ê 5 ζ	en - σ	NJ 5 ζ
ΣΕ ro <—> Q)	□ζ OJ/'-x fi) 2	ΣΕ -p..-'· Q» S
'—· · Q- D το	Q. 3 X	— · CL = 73
• 10' Ο	• <0' ο	^l-1' o S
θ' I-¹ i UJ		⁰⁰ -Τω
Ο Ύ Û-n	ζ·—*. Ί ό- ο	-σ· =r p- o
	,^ω ο	y ï-'ôo
0Ί W Φ 3	Ù? ο·, 3	n -t> 05 2
3’ο-σ S - Ο “Ο	Ch-D ' σι-q U	3ω_Ό J ' N-O.^N
³	!^³	3 • (Λ Γ.
Ν)	θ'	ο-
U1	σ>	ο

σ> σ>

σι XJ

σ> οο

O H¹ CO ά>3

ΖΕ

Ν

		~z. \
		Z /	\
		/
ζ	T	IZ
	/=\ Y		\
			)
Λ )—λ			/
Υ7 _ζ_	(		// 4
/ τ	\ ZI		<^z )
ΖΙ	<		^z \
	(		IZ
\ ζ-	Y		)
/	d		$ - Z \
NJ	NJ		NJ
-U	U)		NJ
	*< Q r—n		S 3 &
3 3. S	O ¹—’ O* ΖΓ CT fl)
2. ³ 3	3 C 3		3 = 3
?	fl) & N CT *< Kl		ro o (t>
Y			=Γ3Υ
3 Y* Μ π> ³ V-< 3χ	c: - 3 -< <-> 0) Q. 3 (-> HS = 3 3 3 °		2 SH rt Q) r^
ο rocs 3 ίο	» 2. . Ο το Λ		2- 3 A
13- o)propyl] pyridin-4 )acetonitr	D A 3		fD 3 Ό O Hs
{4- apyl)ami -nethyljp ojaceton		O ”>< '*~^X «““H <>-i ό eu o s 3 O 3 O 13 . O) -P» C3
=: · w	Fr < ³		3 ¹ Or
	7\	X—1
οω oo 2 Z 3 3 co £ κΔ ω 5 2	qsih n.i L33 ο T o- - O 2		ΣΣ NJ 00 V _r ' 3^ iY UJ - ^1-1 3 5
NJ-ο δ> 3	<O f—* OJ “ 2
Q. 3 T LD- o ω 0.5 σι QQ 3 3^υ S	R (300MHz, i, δ ppm: 8.4 .20-7.00 (m .40 (m, 12H m, 4H), pprr		o^ - CL 3 XJ ID- O η- Ο I cl n W o^ § 2 os 2 3 L-σ X ω? n
' -
NJ/—s 3 - ω ri	• en		ω ri
hj-			en
en	Q.		A

σ> ιο

	\	Tl _	/
	>		- Z
		/ Tl'X _	)
	\	-Z >o	<
		? A	°Ζ^Λ
		,^zvv	) 1Z
		o=< /—f y	>
	<	V_{z z=}/	//^ZA
	>=ζ Ζ λ		Q.
	V	Z-n	V. _Z -Π
		ΤΊ
	ΣΕ /	7 1
ο 'X	_ζ_/ /		O ~n
Z ο	Ο
ΣΕ
	NJ	N)	NJ
	V1	en	en
	*<? — Q.	FJ — F CL	A Jû-
	ο ά	F°xiA 3^’	s *< — c =>’ - 3
	mT ?	N) Y O P Λ Z	- · — ο P. m
	({[2-«[4iylamino)butyl Tiethyl)pyridin îthyljcarbamo mic acid	l “T ü) rt \|	•h 1—t LU ₇
	[(2-{[N-«[2 hylamino)eth rbamoyljmet 2,2,2oacetamido]r din-4-yl)metl trifluoroaceta	l-[(2-{[«[2hylamino)eth rbamoyljmet methyl Jpyrid methyl]-2,2/ uoroacetamii
	S ω¹	3-^g ^3'	UL ix* —· -r*<
	8* ' 1.	φ Vg T'Îd
	“* 3		^w r-r
ζ	n	r~
	^XH NMR Méthane 8.40 (d, 2H), 2.7 8H), 1.0	h» c? σ> xi o· o _r M³3M³ A jl - ι-^ n z — ¥ zr^ ² 3 3-^33' Τ’	PQ FJ S Z £ nj' T en' £. 4L μ. ω_Η5^ζ T χ Q) Z rr F · (Λ---ΞΞ5 73 NJ' 'O
	Ç l lû-o 3 o Ch L 41 3° a? n 3^3' ω ··	(300MHz, δ ppm 8.50 7.88 (m, 1H) , 2H), 4.53 (m 3 (m 4H), 2.4 2.23 (m, 6H) , 3H).	ω NJ ^ω FJ NI V3Ê?S* cbF σι , . 9° n T _w x CB 00' '
		' JL - '	NJ

VJ ο

	o
Z
ο >=/	\
ο	/
>ο	\
ΞΕΖ	ZEE
	/
	\= Z y_?
□ΕΖ
ο=?	ΖΣΕ
Ζ^.	°K
< ^χ	>= o
>	o
— ζ	\
\
NJ	NJ
Ο	CO
5 ZJ 3 2. ° S η> ς? Γ+ 1—1 QJ ί-ρ ΣΤ q -τ ΞΓ ^——-”·< -3 CT ·< NJ £ ω ι S siΙ\|2 Ο Ο ‘ν' — 2 NJ 0) 01 Ό S-» ο \|	tert-butyl «[: (diethylamino)b o}methyl)pyr yljmethyljcarb; mate
® 3 Y 3¥ £ ° Ξ£35 .—; 5’ 3< ί-4 ι < Ο NJ	2-«[4utyljar ïdin-4amoyl)
> ω <ξ	3* 5. ' “t □
I^-	Z
Ι-F -pÀ (~) ·-*	t-* '-‘C? o -£
-Û τ Σ I ω- i? 2 ι CO Μ' _hQZ ΣΕ A Ο Z	nj en 3^ ο σι O 2 i Z
Ο cn<5' 73	3 1-..0- X>
ω m°' οιο ΣΕ (JlÇ xj_	' · ' Oi^ SA2g
- rt hjX3 O	<ji 5 o ’ 3 ° Ξ 3
Z
“· ’ ’ Œ	- „ i
en 3 co rt	h3 ?°.^N
ΣΕ -	ω* en
C3 k en ” - o A	ZnO rt σε
o

\	\ Z-	P $
$	^rv
<	'Ζ.'Σ.	ZI
Λ¹	\=Z
V Z	y //
ΞΕ / ΊΊ -Z-J I /		ZI
/ 1	“ΠL⁷¹	O=A -r,
^Z -π O	-Λ,-η	X
	Λ
(jü NJ	UJ H¹	U> o
N-[(2-{[«[2(dimethylarnino)ethyl](et hyl)carbamoyl}methyl)a mino]methyl}pyridin-4yl)methyl]-2,2difluorobutanamide	N-[(2-{[«[2(dimethylamino)ethylj(et hyl)carbamoyl}methyl)a mino]methyl}pyridin-4yl)methyl]-2,2,3,3,4,4,4heptafluorobutanamide	N-[(2-{[«[2-(azetidin-lyl)ethyl](ethyl)carbamoyl }methyl)amino]methyl}p yridin-4-yl)methyl]2,2,2-trifluoroacetamide
1“	1“	>
^XH NMR (300 MHz, Methanol-d₄), δ 8.60 (d, IH), 7.39 (s, IH), 7.36 (d, IH), 4.48 (m, 4H), 4.24 (S, 2H), 3.82 (t, 2H), 3.38 (m, 4H), 2.98 (s, 6H), 2.32 (m, 2H), 1.24 (t, 3H), 1.02 (t, 3H).	^XH NMR (300 MHz, Methanol-d₄), δ ppm: 8.70, (d, IH), 4.51 (s, 2H), 2.98 (s, 6H), 1.22 (m, 3H),	O T Û 3 · ω s / / NJ ' O O NJ V frGY ÎS-oi CO — bJ . . bJ en Qx xo * en o	H* ΞΕ Z 3 73 G) O O 3 X N

XJ NJ

	b	°Y IZ 0	A Q<î
	ZI	//	$=o
	/	Z	- Z
	\	\	\
	>0	/
- Z \	ΛΛ
CO	CO	CO
en	-&	CO
<_ ³ 5* (D 3 * 5 ol	3 z » z JT 1 < CL n =>'	·< Ό 2* 2 —3 CD X~ =5 3 £.-<.? 5~< -O CL	·< X A § 3 g = CD «t l—1 H NJ
Ml z _ Q) <_ O ZT g- q TJ TJ nj~< <0 =. < 2 > T => 2. O NJ ⁰ °--< A ûJ* Ξ3 Ο r? 0 ' r> m M ni -p.	3 Q. S χ <-r n» 2. cl ωΞ 3 = 3 . θ ¹ —· NJ jÿ 10 = 1 S ¹ ° r? 2. Σ3 <-*->	-[«4-[(Njpylcarboximi pyridin-2hyl)amino]-N thylacetamid
r-r ·	“1 «	CD ·* CL
QJ	zr zz	θ' Φ T	Z O
3	o z X ’	i. 5	« ·<,
0	Z	Z
''Z' h¹	Π X	c? >-. n 4:	c? t-¹ 0
P-1	σΐ	3 2Z C	3 ΞΓ cA
ch^ Q ²X. 03^, 3	' n z	' ir n z £«,^3
*>	NJ T	N-' en'
0 0 “A		Ch ⁰¹ 7? nj — ω • TJ Q <D ω TJ § σ> '3 °	(300 1 δ pprr 2 (s, , 2.96
	rt S	t± rt 3	^. ^ 3
3 5	CO =3= . N	°-5 co l	A 00 1 ” iA - N
	en' X]	X > NJ	Ch , , <JJ~ x H en
	NJ/-S
’ en	Q.	’ en cl	NJ CL

CO

	\ z-	\ Z—
	$	°Y
	<	/ IZ
	ZI	z7
	Y Z	// Ά
		//
~z.~ /		Z
/		Y
UJ		W
		en
3 ”S S		0 75
_ o □ g sa® ®		9V ô 3 m 5 m kj S 3* «>< ·—· ^-7 ·< So φ γή
1 ϊηΊ rr «* Qj ÜJ
^^3 A 3 O·—‘ 3 i—i 3	üJ	Q) QJ 5 8 3 â^.A
oj t? ο ω o 3 ¹ -5” = &o 3 ^φ D Ί3 Ό s		’ a f 3
		Φ
Z	0
^ΧΗ NMR (300 M CDCh), δ ppm: 1H), 8.24 (s, 1 (s, 6H), 2.19 (i		³Η NMR (300 M CDCI3), δ ppm: 1H), 8.26 (s, Il (d, 6H), 1.78-0 13H).
' -ô 00 J «i		oo3 00 X CO S— 4* _K, en M
• k)/->		3
0 Q.		' en Q.
Cl		*
'

		/	\ Z-
	L	\ ω s		ZI
	EZ	) IZ		\=Z
Z	A	zV		4 à
//	V»	// A		Y //
		v=/		z=/
	X Z V	X _z L		s Z
				\
		eu		eu
	o	o		00
	N-{[2-({[2-( methylpyrrolidi yl)ethyl]amino}mi yridin-4yl]methylidene}cy	< <--
οι D ω 3 d CD	N-{[2-«[2ethylsulfanyl)ethi o}methyl)pyridi l]methylidene}cy anamine	mine	a ₃ 9: 3 o 3 0) _ 2. η··< □ 3 s-3 Z3 £.·< 3 l ³·< ^Ό nÎ ° O < Sm g wôifi- ’
	n (D Z5 l-fc O =r M *	ⁿ 3 — o Xo/		o 55 “O « <
	U ·< 1	TD T =s ³ i ό		«< Ml—·
	8 -		ω ’ 3
	D
	WHO-	ω m- q X		<-> l-k ΓΊ ·* ” x8=c
	X X Ο X	X X d’T
		^Qz		σ>^ Q z
	h*· <x>ib 3	t-¹ 00 ü, 3		x oo is 3
	O A '	o L '
	Olz-> z-> z—s , . 3 ? *□ Q i—L Q o oo x	□ yi ό “ 4r ό g -L TZZ oo n:		M 00 ” X · · i cb oo x
	en- 00	un-		Ο
	Q-	Q-		• GJz-s
		t-T **		O Q.

Z=\ p ZI - Z \		ZI 1 b
W	NJ	f—*
N-{[2-«[(2E)-4(dimethylamino)but-2en-1yl]amino}methyl)pyridin- 4yl]methylidene}cycloprop anamine	N-{[2-({[3-(pyrrolidin-lyl)propyl]amino}methyl) pyridin-4yl]methylidene}cycloprop anamine	N-«2-[({3- [benzyl(methyl)amino]pr opyl}amino)methyl]pyrid in-4yi}methylidene)cycloprop anamine
	σ	<0
^XH NMR (300 MHz, CDCb), δ ppm: 8.59 (d, 1H), 8.41 (s, 1H), 2.23 (s, 6H), 0.94 (m, 4H).	^XH-NMR (300 MHz, Methanol-d4), δ ppm: 8.58 (m, 1H), 8.40 (s, 1H), 2.78-2.60 (m, 6H), 1.90-1.75 (m, 6H).	^XH NMR (300 MHz, CDCB), □ ppm: 8.55 (d, 1H), 8.50 (s, 1H), 7.287.22 (m, 5H), 1.04-0.97 (m, 4H).

XJ en

\ Y	/ - z	C
V
z						Cz
zy		/				/ \
c 1		v	z			S /
					/
	<1	<\	/)		V
- z		v	JJ			z
	\ /
		_H=/		<		f
4^
σ»		Ul				A
*< n «—»		S _.Œ 3 g 3			·<
Ÿ n2 3 ‘z? F? 5				U—J 3	S^zσ-Λ
£ ΣΤ 5a j Sz		Π) Hr» Π) rt· Σ rf 3 5 3*			Φ ΓΨ 3-	C 1—1 ·< y
= 3 3 ¹³ => 3 <^S	ω - £-T. ⁰¹ (D < 3 M		Q) D ω	< s (D	< o> <-> Ξ3Τ
	□ ³ T		3	2	□ 3 A
5· to ~< g. S-?		— φ “d 2 o			Φ	i O 0)
	□ ςρ O		2	S-»	4* Sr¹ N
^ro -5 Sz^-S't: r> 2 o 3 i o g g.	ro n ζ.σ^ o^S. ¹O ³ <		(D	n *< n o	’ 3 S £· 9: ΞΤ 3
η 35 O 3 *<		Ό O '			TD n	*< 1
σ o >—		O 3			TD	TD ¹
z	-1	ω
?l8£			n .p X ίπ-?- O ï
o^y n z	o h» Q z			Q	\|_x O z
Z OOÎL		Z u> 3				Z 3
Y^' *					B	Y' XJ
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2-[{[2-({[4(diethylamino)butyljamin o}methyl)pyridin-4yl]methylidene}amino]et han-l-ol	[4- (diethylamino)butyl]({4- [[(2methoxyethyl)imino]met hyl]pyridin-2yl}methyl)amine	methyl 2-[({4-[Ncyclopropylcarboximidoyl ]pyridin-2yl}methyl)amino]acetate
	x	Q
¹H-NMR(300 MHz, CDCh), δ ppm: 8.6 (d, 1H), 8.3 (s, 1H), 1.5 (m, 4H), 1.0 (t, 6H)	^XH NMR (300 MHz, CDCh), δ ppm: 8.61 (d, 1H), 8.29 (s, 1H), 2.51 (q, 4H), 1.01 (t, 6H).	^XH-NMR (300 MHz, CDCh), δ ppm: 8.6 (d, 1H), 8.3 (s, 1H), 3.7 (s, 3H), 3.1 (m, 1H)

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2-[{[2-«[4 diethylamino)but o}methyl)pyrid yl]methylidene}a 2-phenylethan	l-[{[2-« diethylamino)b o}methyl)pyr ’ljmethylidene] opan-2-		i__i 3: 3 O 0> 3 rt- φ 2 zr ο·?β\|α 3 £0 o 2 NJ i D -D O i		[4diethylamino)but {7-oxa-9azaspiro[4.5]dec yl}pyridin-2 yl)methyl]ami
2-^ Œ& A
Λ 3 3'3 ¹	1. â-S ¹		i.· -t i 1—»		3’0) < Φ =5 C3
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o' O	h- (U^ NJ °	z	nj o q	Z	nj - ω q	z
3 m? θ' É	Œ A-~- ° r-r-^ . q. -n ' ' uu., O	3 TJ	<—» GJ O r+O · Q. 73» * o* 2	3 70	T?3 F cl §> ' ' θ' °	3 T>
(300 MF rm-d): δ 1H), 8.3 17 (m, 6F , 2.51 (q 6H).	rm-d): δ 1H), 8.3 1 (m, 1H 2.52 (q, 6H).	*UJ o o 3 T	P A \|_l n ** s—* NJ 00 ” ^3 ώ o	ω o o 3 ΞΕ	m-d): δ 1H), 7.4- 8 (s, 1H) 1.57 (m, 6H).	w o o s X
\ OO N	A^ 0-0	N	_W' NJ Ό	N	- 4^TJ 22 nj^-o
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N-ethyl-2-[«4-[[(2hydroxyethyl)imino]meth yl]pyridin-2yl}methyl)amino]-N-[(lmethylpyrrolidin-2yl)methyl]acetamide	N-[2(dimethylamino)ethyl]-Nethyl-2-[({4-[[(3hydroxypropyl)imino]met hyl]pyridin-2yl}methyl)amino]acetami de	(l-{[<[2-({[4(diethylamino)butyljamin o}methyl)pyridin-4yl]methylidene}amino]m ethyl}cyclopropyl)metha nol	3-[{[2-({[4(diethylamino)butyl]amin o}methyl)pyridin-4yl]methylidene}amino]2,2-dimethylpropan-l-ol
x	x	x	x
1H NMR (300 MHz, CDCI3): δ ppm 8.59 (d, 1H), 8.31 (s, 1H), 3.98 (s, 2H), , 2.44 (m, 1H), 2.37 and 2.28 (two singlets, 3H),, 1.16-1.10 (m, 3H).	1H NMR (300 MHz, chloroform-d): δ: 8.6 (m, 1H), 8.2 (s, 1H), 3.5 (m, 2H), 2.3 (s, 3H), 2.2 (s, 3H), 1.1 (m, 3H).	1H NMR (300 MHz, chloroform-d): δ ppm 8.64 (d, 1H), 8.19 (s, 1H), 3.94 (s, 2H), 2.53 (q, 4H), 1.02 (t, 6H), 0.52 (m, 4H).	chloroform-d): δ ppm 8.54 (d, 1H),7.45 (s, lh), 3.91 (s, 2H), 2.52 (q, 4H), 1.00 (t, 6H), 0.96 (s, 6H).	1H NMR (300 MHz,

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2-[({4-[5-benzyl-3- (trifluoroacetyl)-l,3oxazinan-2-yl]pyridin-2yl}methyl)amino]-N-[2(dimethylamino)ethyl]-Nethylacetamide	2-[«4-[[(2-benzyl-3hydroxypropyl)imino]met hyl]pyridin-2yl}methyl)amino]-N-[2(dimethylamino)ethyl]-Nethylacetamide
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1H-NMR (300 MHz, CD₃0D), δ 8.70 (d, 1H ), 7.40 (m, 2H), 7.25 (m, 5H), 4.50 (s, 1H), 4.20 (m, 4H), 3.80 (m, 3H), 3.05 (s, 6H), 2.60 (m, 4H), 1.20 (t, 3H).	1H-NMR (300 MHz, CD3OD), δ 8.75 (d, 1H ), 7.70 (s, 1H), 7.60 (d, 1H), 7.30 (m, 5H), 5.70 (s, 1H), 4.50 (s, 2H), 4.25 (m, 2H), 3.80 (m, 3H), 3.00 (s, 6H), 2.60 (m, 4H), 1.20 (t, 3H)

T ο
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2-[({2-[«2-[2- (benzyloxy)phenyljethyl} amino)methyl]pyridin-4yl}methylidene)amino]et han-l-ol	N-[(2fluorophenyl)methyl]-2[«4-[[(2hy d roxyethy 1 ) i m i no] meth yl]pyridin-2yl}methyl)amino]-Nmethylacetamide	N-[2(dimethylamino)ethyl]-Nethyl-2-[«4-[7(trifluoroacetyl)-5-oxa-7azaspiro[2.5]octan-6yl]pyridin-2yl}methyl)amino]acetami de
	O	-<
NMR (300 MHz, chloroform-d): δ ppm 8.60 (m, 1H), 8.20 (s, 1H), 6.90 (m, 3H), 5.10 (s, 2H), 2.96 (m, 4H).	1H-NMR (300 MHz, CD₃OD), δ 8.55 (d, 1H ), 7.55 (s, 1H), 7.50 (s, 1H 7.30 (m, 3H), 7.10 (m, 3H), 5.50 (s, 1H), 4.70 (s, 2H), 4.50 (s, 2H), 3.30 (s, 2H), 3.00 (m, 6H), 2.60 (m, 4H).	1H-NMR (300 MHz, CD3OD), δ ppm: 8.8 (d, 1H), 7.5 (m, 2H), 6.7 (m, 1H), 4.5 (s, 2H), 4.2 (S, 2H), 3.7 (t, 2H), 3.4 (m, 6H), 3.0 (m, 8H), 1.2 (m, 3H), 0.6 (m, 2H), 0.4 (m, 2H).

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---NI - O	:/ -TO' 73		' UJ' 73
σ> ·_ι —	0 Ol^-s		t-L a 01^
ί ο. W	UJ		in τ> ^w
DO MHz, 4), δ ppm: 1), 5.76 (s, m, 4H), 3.	00MHz, >pm: 8.90 s, IH), 7.5 90 (m, 4H		00MHz, pm: 8.85 1 s, IH), 2.9 10 (m, 4H)
05			⁰ Q.

<x> 00

\ Z-	/=\ o 4 \__/J	O IV	O \\
<	/ ^Z
/	-Z.7L	ZI	^z \
	$=o IZ H	Y IZ )	>
\= Z O	b		r^zx
(\		\	L)
o			A/
w* A	l-k l-k ω	M· NJ	H-*· 1-»· M·
2-«[5- (dimethylamino)pentyl]a mino}methyl)pyridine-4carbaldehyde	N-(l-benzylpyrrolidin-3- , yl)-2-{[(4-formylpyridin- 2- yl)methyl]amino}acetami de	N-[4- (diethylamino)butyl]-2{[(4-formylpyridin-2yl)methyl]amino}acetami de	2-«[3-(pyrrolidin-lyl)propyl]amino}methyl) pyridine-4-carbaldehyde
N	> CD	> CD	N
1H-NMR (300MHz, MeOD), δ ppm: 8.80 (d, 1H), 8.20 (s, 1H), 2.90 (s, 6H), 1.80 (m, 4H)	1H-NMR (300MHz, MeOD), δ ppm: 8.90 (m, 2H), 8.30 (m, 1H), 7.40 (m, 5H), 2.00 (m, 2H)	1H NMR (300 MHz, Methanol-d4), δ ppm: 8.84 (d, 0.5H), 5.71 (s, 1H), 1.61 (m, 2H), 1.35 (m, 6H).	1H-NMR (300MHz, Methanol-d4), δ ppm: 8.80 (s, 1H), 5.70 (s, 1H), 4.10-3.40 (m, 6H), 2.98-2.40 (m, 2H).

kD kD

100

101

102

Ν-{Τ2-(·{Τ4-(0ί6107ΐ3ΐηίηο)0υί7ΐΊ3ΐτιΐηο>Γη61Ιΐ7ΐ)Ρ7η0ΐη-4-7ΐ1ΠΊ6107ΐ)—2,2,2-trifluoroacetamide (#1)

Synthetic Route A

General Procedure K

Starting

General Procedure J

Material (i) >

(H)

General Procedure L

(iü)

General Procedure N

General Procedure M

General Procedure A

--------->

(iv)

General Procedure C

(v) (vi)

Title Compound

General Procedure A (Reductive Amination)

A solution of aldéhyde (2,2,2-trifluoro-N-[(2-formylpyridin-4-yl)methyl]acetamide) and amine ((4aminobutyl)diethylamine) (1.3 equiv.) in 1,2-dichloroethane was stirred for 2h at room température, before NaBH(AcO)3 (2 eq) was added. The mixture was stirred overnight at room température. The solvents were removed in vacuo and the residue was purified by préparative TLC (40% MeOH in DCM). The title product was isolated as colorless oil as the acetate sait. ^XH NMR (300 MHz, CD₃OD) δ ppm: 8.57 (d, 1H), 7.38 (s, 1H), 7.29 (d, 1H), 4.53 (s, 2H), 4.13 (s, 2H), 3.13 (q, 4H), 3.04 (t, 2H), 2.91 (t, 2H), 1.94 (s, 6H), 1.77 (m, 4H), 1.25 (t, 6H). ES-MS: 361 [M+H].

103

Synthetic Route B

General Procedure A

Starting

Material

General Procedure Q

--------->

General Procedure B

--------->

General Procedure O

--------->

(vii) (viii)

General Procedure L (x) ^> (xi)

Title Compound

General Procedure P

--------->

(ix)

General Procedure M (xü)

General Procedure B (Amines from tert-butyl carbamates)

Concentrated hydrochloric acid was added dropwise to the tert-butyl carbamate (tert-butyl N-{[4(aminomethyl)pyridin-2-yl]methyl}-N-[4-(diethylamino)butyl]carbamate (I)) at 0 °C. The resulting solution was reduced to dryness in vacuo to yield the title product as colorless solid as the hydrochloric acid sait. ^-NMR (300MHz, MeOD): δ 8.82 (d, IH), 8.05 (s, IH), 7.80 (d, IH), 4.65 (s, 2H), 4.05 (s, 2H), 3.20 (m, 9H), 1.85 (m, 4H), 1.30 (t, 6H) ppm. ES-MS: 265 [M+H⁺],

N-r4-(diethylamino)butvl1-2.2.2-trifluoro-N-(-f4-r(trifluoroacetamido)methyllpyridin-2viymethyllacetamide (#6)

Synthetic Route C

Synthetic Route B

General Procedure C

Starting

Material #5 or analogue

Title Compound

104

General Procedure C (Formation of trifluoroacetamide or trifluoroacetate)

Trifluoroacetic anhydride (2.2 equiv.) was added dropwise to a solution ofthe amine ([2-({[4(diethylamino)butyI]amino}methyl)pyridin-4-yl]methanamine) (1 equiv.) and DIPEA (2.5 equiv.) in anhydrous DCM at 0°C. The mixture was allowed to warm to room température and stirred for 12 hours. Quenched with sat. NaHCO₃ (aq.). Aqueous work up gave the title compound. ’H-NMR. (300MHz, CDCI3): δ 11.60, 11.45 (d, IH), 9.10, 8.70 (d, IH), 8.45, 8.40 (s, IH), 7.20, 7.10 (d, IH), 4.70 (d, 2H), 4.50 (t, 2H), 3.10 (m, 4H), 1.50 (t, 6H) ppm. ES-MS: 457 [M+1].

r2-(H4-(azetidin-l-vl)butyl~|amino~Î-methvl)pvridin-4-vllmethanamine (#7)

Synthetic Route D

Starting

General Procedure A

Material

General Procedure T

--------->

General Procedure L

--------->

General Procedure R

General Procedure S

--------->

(xiii)

General Procedure U (xix) (xvi) ⁷

General Procedure M

--------->

(xiv) (xvii) (xix)

General Procedure V

General Procedure B

(xv) (xviii)

Title Compound

General Procedure B from tert-butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N-[4-(azetidin-lyl)butyl]carbamate yielded the hydrochloric acid sait ofthe title product as colorless solid. ’H-NMR (300MHz, CDCI₃): δ 8.70 (d, IH), 7.60 (s, IH), 7.40 (d, IH), 4.40 (s, 2H), 4.20 (s, 2H), 3.20 (s, 4H), 2.20 (m, 2H), 1.80 (m, 4H), 1.20 (m 4H) ppm. ES-MS: 249 [M+1],

105

N-<r2-(-Cr4-(dimethylamino)butvnamino)-roethvl)pyridio-4-vllmethyl)-cyclopropaoamioe (#10)

Synthetic Route E

	Synthetic Route A		General Procedure A	General Procedure N

Starting Material	P	(ii)	P	s (xxi)

(xxîi)

General Procedure A

Title Compound

By General Procedure A from (4-[(cyclopropylamino)methyl]pyridine-2-carbaldehyde and (4aminobutyl)dimethylamine) (1.0 equiv.). Purification by column chromatography (CH2CI2/MeOH/NH4OH, 90:10:1) yielded the title compound as a colorless glue. ’Ή NMR (300 MHz, CDCI3): δ 8.42 (d, IH), 7.22 (S, IH), 6.95 (m, IH), 3.70 (s, 2H), 3.65 (s, 2H), 2.65 (m, 2H), 2.25 (m, 2H), 2.20 (s, 6H), 2.15 (m, IH), 2.10 - 2.00 (m, 4H), 1.62 - 1.52 (m, 2H), 0.5 - 0.38 (m, 4H).

2-(174-( r(CY80Or0ethyl)8Oli0Olr0etliyl)-pyridiO-2-yl)methvn3mi00)--N,N-dir0ethyl8Cet3mide (#13)

Syothetic Route F

General Procedure A

106

General Procedure R

Starting

Material (xxiii)

General Procedure U

(xxiv) (xxv)

General Procedure Q

(xxvi)

General Procedure L

(xxvii)

General Procedure M

(xxviii)

General Procedure T

General Procedure D

Title Compound

General Procedure D (Acids from tert-butyl esters or amines from tert-butyl carbamates)

Tri fl u oro acetic acid (100 equiv.) was added to a solution of the tert-butyl carbamate (or tert-butyl ester) (tert-butyl N-[(4-{[(cyanomethyl)amino]methyl} pyridin-2-yl)methyl]-N[(dimethylcarbamoyl)methyljcarbamate) (1 equiv.) in DCM at 0 °C. The mixture was stirred at room température for 3 h. Evaporated to dryness to give the title product as trifluoroacetic acid sait. NMR (300 MHz, methanol-d₄): δ ppm 8.72 (d, 1H), 7.57 (s, 1H), 7.53 (d, 1H), 4.37 (s, 2H), 4.36 (s, 2H), 4.29 (s, 2H), 4.18 (s, 2H), 3.00 (s, 6H). ES-MS: 262 [M+l].

2-(Π4-(< Γ2-(άΐπΐ6ίΐΊνΐ3Γηίηο)6θΊνΙ18ΓηΐηοΤπηβίΐΊνΙ)ρνπάίη-2-νΙ1Γη6ΐηνΙ>3Γηΐηο)-Ν,Ν-8ΐΓη6ίΐΊνΐ3ε618ΐτΗ06 (#15)

Synthetic Route G

General Procedure A

General Procedure C

General Procedure P

Starting

Material (xxx) (xxxi) (xxxii)

General Procedure Q

(xxxiii)

General Procedure A

(xxxiv)

General Procedure E

107

Title Compound

General Procedure E (Hvdrolvsis of trifluoroacetamide)

KOH (1.0 M in H₂O, 2.0 equiv.) was added to a solution of the trifluoroacetamide (N-{[4-({[2(Dimethylamino)ethyl]amino}methyl)pyridin-2-yl]methyl}-N-[(dimethylcarbamoyl)methyl]-2,2,2trifluoroacetamide) MeOH/H₂O (1:1 vol). Stirred at 60 °C for about 1.0 h. Evaporated to dryness. Aqueous work up gave the title product as oil. ¹H NMR (300 MHz, methanol-dzi): δ ppm 8.44 (d, IH), 7.47 (s, IH), 7.32 (d, IH), 3.90 (s, 2H), 3.83 (s, 2H), 3.50 (s, 2H), 2.96 (d, 6H), 2.71 (t, 2H), 2.49 (t, 2H), 2.25 (s, 6H). ES-MS: 294 [M+l].

Benzvl(methvl)-f3-Γ(^f4-Γ(methγlamino)methγl1pyridin-2-γll·methγl)amino^propyll·amine (#17)

Synthetic Route H

General Procedure A

Starting	------>	(xxxv)
Material

General Procedure C

(xxxvi)

General Procedure X

(xxxvii)

General Procedure A

General Procedure U

General Procedure Q

General Procedure R (xxxviii) (xxxix) (xl) (xli)

General Procedure Q

(xlü)

General Procedure A

(xliil)

General Procedure B

--------->

Title Compound

108

General Procedure B from tert-butyl N-{3-[benzyl(methyl)amino]propyl}-N-({4[(methylamino)methyl]pyridin-2-yl}methyl)carbamate gave the hydrochloric acid sait of title compound. ^XH NMR (300 MHz, CDCI₃), δ ppm: 8.8(d, IH), 8.0 - 7.4 (m, 7H), 4.6 - 4.2 (m, 6H), 3.9 (s,

2H), 3.5 - 3.2 (m, 4H), 3.0 - 2.7 (m, 4H), 2.4 - 2.2 (m, 2H), 1.2 - 0.9 (m, 4H).

2-Γ«4-Γ fcvcloDroDvlamino)methvl1pyridin-2-vll·methvΠamino1-N-f l-r(2-ethoxyphenyl)methylT DiDeridin-4-yiyacetamide (#20)

Synthetic Route I

	General Procedure A V.	General Procedure C V	General Procedure D V
Starting	P
		(xliv)	(xlv)
Material

General Procedure D (xlvi)

General Procedure Y

(xlvii) (xlviii)

General Procedure A

(xlix)

General Procedure U

(0

General Procedure R

(li)

General Procedure Q

(Hi)

General Procedure A

(liii)

General Procedure B

Title Compound

By General procedure B from tert-butyl N-«4-[(cyclopropylamino)methyl]pyridin-2-yl}methyl)-N-[({l[(2-methoxyphenyl)methyl]piperidin-4-yl}carbamoyI)methyl]carbamate to give the title product as colorless sticky gum. ^XH-NMR (300MHz, CD₃OD): δ 8.78 (m, IH), 7.90 (d, IH), 7.80 (m, IH), 7.45 (m, 2H), 7.10 (m, IH), 7.02 (m, IH), 4.58 & 4.50 (2s, 2H, rotamer), 4.40 &4.30 (2S, 2H; rotamer), 4.10 (m, IH), 3.90 (m, 5H), 3.60 - 3.65 (m, 2H), 3.20 (m, 2H), 2.60 (m, IH), 2.18 (m, 2H), 1.82 (m, 2H), 0.9 - 0.8 (m,4H).

109

2-Γ2-(< r3-(dimethvlamino)propvnaminolmethvnpvridin-4-vl1-2-fmethvlamino)acetonitrile (#24)

Synthetic Route J

General Procedure A

General Procedure R

Starting

Material (liv) »

(lv)

General Procedure U

(Ivi)

General Procedure Q

(Ivii)

General Procedure Z

(Iviii)

General Procedure D

Title Compound

By General procedure D from tert-butyl N-({4-[cyano(methylamino)methyl]pyridin-2-yl}methyl)-N-[3(dimethylamino)propyl]carbamate. Evaporation gave the title product as trifluoroacetic acid sait. ^XH NMR (300 MHz, CD₃OD) δ ppm: 8.83 (d, 1H), 7.75 (s, 1H), 7.68 (dd, 1H), 4.54 (s, 3H), 3.27 (m, 4H), 2.93 (s, 6H), 2.83 (s, 3H), 2.25 (m, 2H). ES-MS: 262 [M+1J.

110

2Τ(<2-Γ(·(4-Π36ηζνΙ(ονυορΓθρνΙ)3Γηΐηο'^υίνΙΤ3ΐιηΐηο)πΊ6ΗΊνΠρνπόΐη-4-νΙ>ηη6ΗΊνΙ)3Γηΐηοΐ3θ6ΐοηί1ΓΊΐ6 (#23)

Synthetic Route K

Synthetic Route D

General Procedure Q

General Procedure A

Starting

Material »

(xiv) »

(lix) »

(ix)

General Procedure U

(Ixi)

General Procedure Q

(Ixii)

General Procedure L

(Ixiii)

General Procedure M

(Ixiv)

General Procedure T

(Ixv)

General Procedure D

Title Compound

By General procedure D from tert-butyl N-{4-[benzyl(cyclopropyl)amino]butyl}-N-[(4{[(cyanomethyl)amino]methyl}pyridin-2-yl)methyl]carbamate. Purification by prep TLC (10% MeOH, 1% NH4OH in DCM) gave the title compound as colorless viscous oil. ^XH-NMR (300MHz, CDCI₃): δ 8.45 (d, 1H), 7.20-7.00 (m, 7H), 4.50 (m, 2H), 3.90 (s, 2H), 3.70 (s, 2H), 3.00 (m, 2H), 2.50 (m, 2H), 1.80 (m, 4H), 1.40 (m, 12H) 0.40 (m, 4H), ppm. ES-MS: 378 [M+l].

Ν-Γ(2-Π(Π2-(Ρΐη^ΐΊνΐ3Γηίηο)6ΐΐΊγΠ(61ΐΊγΙ)03Γό3ΓηονΙ1Γη6ίΐΊνΙ)3ΓηΙηο]Γη6ΐΐΊνΙ)·ργΓΐάίη-4-γΙ)Γη6ίΐΊνΙ1-2,2difluorobutanamide (#32)

Synthetic Route L

Synthetic Route B

General Procedure Y

General Procedure D

Starting

Material (Or General

Analogue '

Procedure C) (Ixvi) of (xii)

Title Compound

By General procedure D from tert-butyl N-({4-[(2,2-difluorobutanamido)methyl]pyridin-2-yl}methyl)N-(<[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)carbamate to get the title compound as it's trifluoroacetic acid sait as colorless oil. ¹H NMR (300 MHz, CD3OD) δ 8.60 (d, IH), 7.39 (s, IH), 7.36 (d, IH), 4.48 (m, 4H), 4.24 (s, 2H), 3.82 (t, 2H), 3.38 (m, 4H), 2.98 (s, 6H), 2.32 (m, 2H), 1.24 (t, 3H), 1.02 (t, 3H). ES-MS: 400.61 [M + l] (<Γ2-((Τ4-^ϊ6ΐΙινΐ8ΠΊΐηο'^υίνΠ8ΠΊΐηο>Γη61ίΊνΠρνπόΐη-4-νΠΓη61ΙινΙΗ3ΐΐ>8ΠΊονΙ)(οπΊΊΐο acid (#27)

O^'OH

Synthetic Route M

112

Synthetic Route C

General Procedure AA

General Procedure E

Starting

Material

#6 or analogue »

(Ixvii)

Title Compound

By General Procedure E from tert-butyl «[2-«N-[4-(diethylamino)butyl]-2,2,2trifluoroacetamido}methyi)pyridin-4-yl]methyl}carbamoyl)formate. Concurrent hydrolysis of the tertbutyl ester and the trifluoroacetamide gave the title product as a yellow sticky gum. ^XH NMR (300 MHz, methanol-d): δ ppm 8.40 (d, 1H), 7.38 (s, 1H), 7.20 (d, 1H), 4.45 (s, 2H), 3.80 (s, 2H), 2.70 - 2.40 (m, 8H), 1.60 - 1.42 (m, 4H), 1.00 (m, 6H). ES-MS: 337.58 [M + 1]

2-|7-(4-r(N-CYCIoDropylcarboximidoYllpyridin-2-yl>methyl)amino~|-N,N-dimethylacetamide (#33)

Synthetic Route N

Synthetic Route F

Starting

Material »

(xxvii)

General Procedure F

(Ixviii)

General Procedure D

Title Compound

General Procedure D from tert-butyl-N-({4-[(E)-N-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)-N[(dimethylcarbamoyl)methyl]carbamate) gave the title product as it's trifluoroacetic acid sait as yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.55 (d, 1H), 8.52 (s, 1H), 7.73 (s, 1H), 7.56 (d, 1H), 3.96 (s, 2H), 3.55 (s, 2H), 3.17 (m, 1H), 2.96 (d, 6H), 1.00 (m, 4H). ES-MS: 261 [M+1].

113

Ν,Ν-όίωείήνΙ-Σ-ΓίΜ-ΓΝ-ίΣ-ωβίΑνΙ^άορίΌρνΙ'Ιεάΐ'όοχίΓηίόονΙίρνίΊΰίη^-γΙ'Ι-ΓηβΗ'ΐνΙ'ΙάΓηΐηο'^εβίΒΓηίάΒ (#35)

Synthetic Route Ο

Synthetic Route F

General Procedure C

General Procedure Q

Starting Material	--------->	---------> ---	------>	(ΐχχ)
(xxiv)	(Ixix)
	General Procedure F	General Procedure E

(Ixxi)

Title Compound

General Procedure E from N-[(dimethylcarbamoyl)methyl]-2,2,2-tnfluoro-N-«4-[N-(2methylcyclopropyl)carboximidoyl]pyridio-2-yl}methyl)acetamide gave the title product as yellow oil. ^XH

NMR (300 MHz, chloroform-d): δ ppm 8.57 (d, 1H), 8.36 (s, 1H), 7.64 (s, 1H), 7.42 (d, 1H), 4.99 (s, 2H), 3.46 (s, 2H), 2.96 (d, 6H), 2.77 (m, 1H), 1.29 (m, 2H), 1.15 (d, 3H), 0.81 (m, 1H). ES-MS: 275 [M+l].

Ν~Η2-(·{Τ2-(60ΐ7ΐ5υΙί3Ο7ΐ)60Ί7ΐΐ3ηηίθΟ>Π160ΐ7ΐ)Ρ7θ8ΪΟ-4-7ΐΊπΐ60ΐ7ΐΪ86Ο6~)<70ΐθΡΓΟΡ3Ο3ΓηΐΟ6 (#391

Synthetic Route P

114

General Procedure A General Procedure P General Procedure Q

Starting ⁷ ~ (Ixxii) (Ixxiii) (Ixxiv)

Material

General Procedure F

Title Compound

General Procedure F (Formation of imine)

Amine (cyclopropylamine) (10 equiv.) was added to a solution of aldéhyde (2-«[2(methylsulfanyl)ethyl]amino}methyl)pyridine-4-carbaldehyde) (1 equiv.) in DCE. Stirred at room température overnight. Evaporated to dryness. Purification by préparative TLC (DCM/MeOH/NH₄OH (95/5/1)) gave the title product as pale yellow oil. ¹H-NMR (300MHz, CDCI₃): δ 8.5 (d, 1H), 8.4 (s, 1H), 7.6 (s, 1H), 7.4 (d, 1H), 3.9 (s, 2H), 3.0 (s, 1H), 2.8 (m, 2H),2.7 (m, 2H) 2.5 (m, 2H), 1.2 (t, 3H), 1.0 (m, 4H).

N-(f2T(f3-Γbenzyl(methvl)amino1propyll·amino)mettΊyΠpyridin-4-yll·methvlidene)cyclopropanamine (#41)

Synthetic Route Q

Starting

Material

Synthetic Route H

--------->

General Procedure F

-------->

(xlii) (Ixxv)

General Procedure D

Title Compound

115

General Procedure D from tert-butyl N-{3-[benzyl(methyl)amino]propyl}-N-«4-[(Ncyclopropylcarboximidoyl]pyridin-2-yl}methyl)carbamate. Evaporated to dryness to give the title product as trifluoroacetic acid sait without further purification. ³H NMR (300 MHz, CDCh), δ ppm: 8.55 (d, 1H), 8.50 (s, 1H), 7.69 (s, 1H), 7.56 (dd, 1H), 7.28-7.22 (m, 5H), 3.89 (s, 2H), 3.50 (s, 2H), 3.203.13 (m, 1H), 2.65 (t, 2H), 2.45 (t, 2H), 2.11 (s, 3H), 1.82-1.73 (m, 2H), 1.04-0.97 (m, 4H).

N-(-r2T(<3-rbenzvl(methyl)8minolDropyl43mino')methyllDyridin-4-vl>methvlidene')cyclopropanamine £#43)

Synthetic Route R

General Procedure A

Starting

Material

General Procedure R

General Procedure P

> --	-----> ---	------>
(Ixxvi)	(Ixxvii)		(Ixxviii)

General Procedure Q

(Ixxix)

General Procedure F

(Ixxx)

General Procedure D

Title Compound

By Generel Procedure D from tert-butyl N-({4-[N-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)-N[(2E)-4-(dimethyl8mino)but-2-en-l-yl]C3rb8m8te. Purified by préparative TLC with 1% NH₄OH end 10% MeOH in DCM to give title product es light yellow oil. *H NMR (300 MHz, chlorofbrm-d): δ ppm 8.59 (d, 1H), 8.41 (s, 1H), 7.55 (s, 1H), 7.42 (d, 1H), 5.71 (m, 2H), 3.93 (s, 2H), 3.31 (d, 2H), 3.08 (m, 1H), 2.92 (d, 2H), 2.23 (s, 6H), 0.94 (m, 4H). ES-MS: 273 [M+l].

116

Ν-<Γ2-(ίr4-(azetidin-l-yl')butvl1amino>methyl’)pyridin-4-vl1methvlidene'Î-cycloDropanamine (#44)

Synthetic Route S

Startlng

Material

Synthetic Route D »

(xviii)

General Procedure F

(Ixxxi)

General Procedure D

Title Compound

General Procedure D from tert-butyl N-[4-(azetidin-l-yl)butyl]-N-({4-[Ncyclopropylcarboximidoyl]pyridin-2-yl}methyl)carbamate. Evaporation gave the title product as it tri fl uoro acetic acid sait without further purification. ’H-NMR (300MHz, CDCh): δ 8.50 (d, 1H), 8.40 (s, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 3.90 (s, 2H), 3.00 (m, 1H), 2.70 (m, 2H), 2.50 (m, 4H), 1.80 (m, 2H), 1.50 (m 6H), 1.00 (m, 4H) ppm. ES-MS: 287 [M+l],

N-<Γ2-(<Γ4-(dimethvlamino)butvl1aminol·methvl)pvridin-4-ynmethvlidenel·cvclopropanamine (#45)

Synthetic Route T

Starting

General Procedure A

General Procedure C ( Ixxxi i) >

(Ixxxiii)

General Procedure P

(Ixxxiv)

Material

117
General Procedure V	General Procedure F ......x -------------->	General Procedure E .....n ----------->

(Ixxxv) (Ixxxvi)

Title Compound

By General Procedure E from N-«4-[N-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)-N-[4(dimethylamino)butyl]-2,2,2-trifluoroacetamide. Evaporated to and the residue was neutralized with cyclopropylamine. IM KOH solution was added and work-up gave the title product as colorless viscous oil without further purification. ’H-NMR (300MHz, CDCI3): δ 8.50 (s, IH), 8.30 (s, IH), 7.50 (s, IH), 7.30 (d, IH), 3.90 (s, 2H), 2.70 (m, 2H), 2.25 (m, 2H), 2.20 (s, 6H), 1.50 (m, 4H), 1.00 (m, 4H), ppm.

N-f r2-(<r5-(dimethvlamino)pentvl1aminoTmethvl)pvridin-4-vnmethylideneTcyclopropanamine (#47)

Synthetic Route U

Starting

Material

General Procedure A

(Ixxxvii)

General Procedure R

General Procedure Q

General Procedure A (xc)

General Procedure U

General Procedure F

General Procedure D

(Ixxxviii) (xci)

General Procedure Q

(Ixxxvix) (xcii) (xciii)

Title Compound

By General Procedure D from tert-butyl N-«4-[N-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)-N-[5(dimethylamino)pentyl]carbamate. Evaporated to and the residue was neutralized with cyclopropylamine. IM KOH solution was added and work-up gave the title product as colorless viscous

118 oil without further purification. ^-NMR (300MHz, CDCI3): δ 8.50 (d, 1H), 8.40 (s, 1H), 7.50 (s, 1H),

7.40 (d, 1H), 3.90 (s, 2H), 3.00 (m, 1H), 2.60 (m, 2H), 2.20 (m, 2H), 2.15 (s, 6H), 1.50-1.30 (m, 6H),

0.88 (m, 4H) ppm. ES-MS: 289 [M+1].

2-Γ(·Τ4-ΓΝ-ον€ΐορΓθρνΐ€3Γΐί>οχΐΓηΐάογΙ1ρνΐΊάίη-2-νΙ'}·ηΐ6ίΙινΡ3Γηΐηο'Ι-Ν-Γ4-(όϊ61ΐΊγΐ3ΠΊίηο)ί>υίνΠ3θ6ί3Γηΐά6 (#48)

Synthetic Route V

General Procedure Y

Synthetic Route I

Starting	------>	(xlvi)
Material

General Procedure U

> --	------>
(xciv)

(xcv)

General Procedure R

(xcvi)

General Procedure Q

(xcvii)

General Procedure F

(xcviii)

General Procedure D

Title Compound

By General Procedure D from tert-butyl-N-«4-[(E)-N-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)N-({[4-(diethylamino)butyl]carbamoyl}methyl)carbamate. Purified by préparative TLC (10% MeOH and 1% NH₄OH in DCM) to give title product as yellow oil. ³H NMR (300 MHz, chloroform-d): δ ppm 8.61 (d, 1H), 8.41 (s, 1H), 7.57 (t, 1H), 7.50 (s, 1H), 7.41 (d, 1H), 3.90 (s, 2H), 3.32 (s, 2H), 3.29 (m, 2H), 3.09 (m, 1H), 2.67 (q, 4H), 2.60 (m, 2H), 1.56 (m, 4H), 1.09 (t, 6H), 1.03 (m, 4H). ES-MS: 360 [M + 1],

119

2-Γ(·Γ4-ΓΓ(2-€νάοΗ6χν16ΰΊνΙ)ΐΠΊϊηοΐΓηθίήνΙΐργπ{ϋη-2-νΙ>ΠΊ6ΐηνΙ)3Πΐΐηο1-Ν-Γ2-((1ΐη6ΐΝνΐ3ΠΊΐηο)6^νΠ-Νethylacetamide (#63)

Synthetic Route X

	General Procedure A X	General Procedure U X	General Procedure R .. x
Startlng		P		-
		(xcix)	(C)
Material

General Procedure G (ci)

General Procedure Q

(cii)

General Procedure D

(ciii)

Title Compound

General Procedure G (Formation of imine)

To a stirred solution of aldéhyde (N-[2-(dimethylamino)ethyl]-N-ethyl-2-{[(4-formylpyridin-2yl)methyl]amino}acetamide) (1 equiv.) in 1,2-DCE and H2O were added amine (2cyclohexylethylamine) (1.01 equiv.) and Na₂CC>3 (2 equiv.) at room température and stirred for 3 hours. Evaporated to dryness. Suspended in DCM, fiîtered and evaporated to give the title compound as brown oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.56 (d, 1H), 8.22 (s, 1H), 7.63 (s, 1H), 7.45 (dd, 1H), 3.96 (s, 2H), 3.63 (t, 2H), 3.45 (s, 2H), 3.45-3.34 (m, 2H), 3.27-3.19 (m, 2H), 2.43-2.33 (m, 2H), 2.23 and 2.17 (2 singlets, 6H), 1.76-1.51 (m, 7H), 1.38-1.25 (m, 1H), 1.22-1.07 (m, 6H), 0.98-0.89 (m, 2H). ESI-MS (m/z): 402 [M+IJ.

120

2-Γ(<4-Γ5-ό6ηζνΙ-3-(ίήΑυοΓ0306ΐ:νΠ-1,3-οχ3ζίη3η-2-νΙ1ρνΐΊ(1ίη-2-γΙ>Γη61:1ΊνΠ3Γηίηο1-Ν-Γ2(dimethylamino)ethyll-N-ethvlacetamide (#90)

Synthetic Route Y

Starting

Material

Synthetic Route B

--------->

General Procedure

AB

General Procedure D

Analogue of (x)

--------->

(civ)

Title Compound

By General Procedure D from tert-butyl N-({4-[5-benzyl-3-(trifluoroacetyl)-l,3-oxazinan-2-yl]pyridin2-yl}methyl)-N-({[2-(dimethyIamino)ethyl](ethyl)carbamoyl}methyl)carbamate without any purification gave the trifluoroacetic acid sait of the title product as yellow oil ¹H-NMR (300MHz, CD3OD): δ 8.70 (d, 1H ), 7.40 (m, 2H), 7.25 (m, 5H), 4.50 (s, 1H), 4.20 (m, 4H), 3.80 (m, 3H), 3.05 (s, 6H), 2.60 (m, 4H), 1.20 (t, 3H). ES-MS: 536 [M+l]

2-i'r(<4-r(dimethvlamino)methyl'|cvclohexyl>methyl)aminolmethvl')pyridine-4-carbaldehyde (#97)

NH

121

Synthetic Route Z

General Procedure A

General Procedure R

General Procedure U

Starting

Material (cv) (cvi) (cvii)

General Procedure Q

General Procedure B (cviii)

Title Compound

By General Procedure B from tert-butyl N-({4-[(dimethylamino)methyl]cydohexyl}methyl)-N-[(4formylpyridin-2-yl)methyl]carbamate to yield the title product as colorless solid as the hydrochloric acid sait. NMR (300 MHz, methanol-d₄): δ ppm 8.89 (d, 1H), 8.26 (s, 1H), 8.05 (d, 1H), 5.73 (s, 1H), 4.66 (s, 2H), 3.12 (d, 2H), 3.04 (d, 2H), 2.91 (s, 6H), 1.95 (m, 6H), 1.20 (m, 4H). ES-MS: 290 [M+1], 2^(£]X2Z}24z[dimethyiamino)buti22en£12Ynamino}inethYlJpyridjne342çai^aldehYde_(#99)

Synthetic Route AA

	General Procedure A X.	General Procedure U 'x	General Procedure R _
Starting	-		-
		(cix)		(ex)	(exi)
Material
	General Procedure Q X.		General Procedure H
	-	(cxii)		Title Compound

General Procedure H (Amines from tert butvl carbamates)

HCl in dioxane (4M) was added to a solution of tert butyl carbamate ((Z)-tert-butyl 4(dimethylamino)but-2-enyl((4-fbrmylpyridin-2-yl)methyl)carbamate)) in DCM. The mixture was stirred at room température for 1 hour. Evaporated to give the title compound. 1H NMR (300 MHz, MeOH - d₄: (δ 8.8(d, 1H), 8.0 (s, 1H), 7.7 (d, 1H), 6.2 (m, 2H), 4.5 (m, 2H), 4.1 (m, 2H), 2.9 (s, 6H), 2.2 (s, 6H).

122

2-Γ(Τ 2-Οχο-2Τ(2Κ)-2-(ργΓΓθΙίΡίη-1-νΙπΊ6ίΐΊνΙ)ρνπΌΐΐΡΐη-1-νΙ'|6ύΊνΙΤ3ΐ'ηΐηο)πΊ6ίΐΊνΙ1ρνπάίη6-4carbaldehvde (#102)

Synthetic Route AB

Synthetic Route I	General Procedure Y	General Procedure U
					-
Starting Material	-	(xlvii)	-	(cxiii)		(cxiv)
	General Procedure R		General Procedure V		General Procedure B
			_
	---------z	(cxv)		(cxvi)	s

Title Compound

By General Procedure B from tert-butyl N-[(4-formylpyridin-2-yl)methyl]-N-{2-oxo-2-[(2R)-2(pyrrolidin-l-ylmethyl)pyrrolidin-l-yl]ethyl}carbamate. Evaporation gave the title product as brown solid. ^XH NMR (300 MHz, CD₃OD), δ ppm: 8.91 (m, IH), 8.36 (s, IH), 8.12 (m, IH), 5.77 (s, IH), 4.854.75 (m, 2H), 4.56 (m, IH), 4.38-4.23 (m, 2H), 4.14 (m, IH), 3.84 (m, IH), 3.64-3.44 (m, 3H), 3.303.19 (m, 2H), 3.11 (m, IH), 2.27-2.00 (m, 7H), 1.85 (m, IH).

123

2-r(<4-rBenzyl(cycloDroDvl)amino'lbutvl~Î-amino')methvllpyridine-4-carbaldehyde (#109)

Synthetic Route AC

Synthetic Route D

Starting

Material

General Procedure Q

General Procedure A

	------> ---	------>
(xiv)	(cxvii)

(cxviii)

General Procedure U

(cxix)

General Procedure Q

(cxx)

General Procedure B

Title Compound

By General Procedure B from tert-butyl N-{4-[benzyl(cyclopropyl)amino]butyl}-N-[(4-formylpyridin-2yl)methyl]carbamate. Evaporation gave the title product as yellow oil. ^-NMR (300MHz, MeOD): δ 8.90 (d, IH), 8.40 (s, IH), 8.10 (d, IH), 7.50 (m, 5H), 5.70 (s, 1H),4.7O (m, 2H), 4.50 (m, 2H), 2.80 (m, 2H), 2.00 (m, 5H), 0.90 (m, 4H) ppm.

124

N-r4-(diethvlamino)butyl1-2,2,2-trifluoro-N-r(4-formylpvridin-2-vl)methvl1acetamide (#115)

Synthetic Route AD

Synthethic Route B

Starting

Material (x)

General Procedure I

Title Compound

General Procedure I (Trifluoroacetamides from tert-butyl carbamates)

Concentrated H₂SO₄ (2 drops) was added to the tert butyl carbamate (tert-butyl N-[4(diethylamino)butyl]-N-[(4-formylpyridin-2-yl)methyl]carbamate) (1 equiv.) in trifluoracetic anhydride at 0 °C. The mixture was stirred for 2h at 0 °C. Solid NaHCO₃ was added. Diluted with DCM before evaporating to dryness. Purification by préparative TLC (10% MeOH in DCM) gave the title compound as yellow oil. ^XH NMR (300 MHz, CDCI₃), δ ppm: 10.09 (d, 1H), 8.83 (dd, 1H), 7.68 (m, 2H), 4.85 (d, 2H), 3.53 (m, 2H), 3.10 (m, 6H), 1.76 (m, 4H), 1.33 (m, 6H). ES-MS: 360 [M + 1J.

Intermediates

Ethyl 2-(dimethoxvmethvl)pyridine-4-carboxylate (i) - General Procedure J (Formation of methyl acetal)

Pyridinium toluene-4-sulphonate (0.1 equiv.) was added to a solution of aldéhyde (ethyl 2formylpyridine-4-carboxylate) (1.0 equiv.) and trimethyl orthoformate (6.5 equiv.) in methanol. Heated at 60 °C overnight. Aqueous work up (EtOAc/NaHCO₃) gave the title compound as oil. ^XH NMR (300 MHz, CDCI3), δ ppm: 8.77 (dd, 1H), 8.09 (s, 1H), 7.82 (dd, 1H), 5.44 (s, 1H), 4.41 (q, 2H), 3.42 (s, 6H), 1.41 (t, 3H).

125

2-(Dimethoxymethvl)pyridine-4-carbaldehyde (ii) - General Procedure K (Réduction of ester to aldéhyde)

DIBAL-H (1.5 equiv., 1.0 M in toluene) was added slowly to a solution ofthe ester (Ethyl 2(dimethoxymethyl)pyridine-4-carboxylate) (1.0 equiv.) in toluene at -78 °C. Stirring continued for 1.5 h before the reaction was quenched by dropwise addition of sat. NH₄CI. Allowed to warm to room température. EtOAc and a satd. solution of sodium potassium tartrate (excess) were added and stirring was continued ovemight. Aqueous work up gave the title product, which was used without further purification. ’Ή NMR (300 MHz, CDCh), δ ppm: 10.10 (s, IH), 8.86 (d, IH), 7.97 (s, IH), 7.68 (dd, IH), 5.46 (s, IH), 3.42 (s, 6H).

N-ΓΓ2-(dimethoxvmethvl)pvridin-4-yl1methvlidenel·hydroxvlamine (iii) - General Procedure L (Formation of Hydroxylamine)

Aldéhyde (2-(dimethoxymethyl)pyridine-4-carbaldehyde) (1.0 equiv.) was dissolved in a mixture of éthanol and water (3:1) and hydroxylamine hydrochloride (1.5 equiv.) was added followed by addition of Na₂CO₃ (1.7 equiv.) The suspension was stirred at room température for three hours after that solvent was removed in vacuum. EtOH was added to the residue, filtered and washed with EtOH. The combined filtrâtes were evaporated. Triturated with H₂O and filtered to give the title product as colorless solid, which was used without further purification. ^XH NMR (300 MHz, CDCI₃), δ ppm: 9.95 (s, IH), 8.65 (d, IH), 8.14 (s, IH), 7.74 (s, IH), 7.50 (d, IH), 5.45 (S, IH), 3.43 (s, 6H).

r2-(dimethoxvmethyl)pvridin-4-vllmethanamine (iv) - General Procedure M (Hydrogénation to form amines)

A solution of hydroxyl amine (N-{[2-(dimethoxymethyl)pyridin-4-yl]methylidene}hydroxylamine) (1.0 equiv.) in MeOH over 10 Pd/C (0.2 equiv. w/w) was charged with H₂ (45 psi). The reaction was followed by TLC. Filtered and evaporated to give the title compound. *H NMR (300 MHz, CDCI3), δ ppm: 8.54 (dd, IH), 7.50 (s, IH), 7.22 (dt, IH), 5.35 (s, IH), 3.91 (s, 2H), 3.40 (s, 6H).

N-f r2-(dimethoxvmethvl)pvridin-4-vl1methyl)-2,2,2-trifluoroacetamide (v)

By General Procedure C from 2-(dimethoxymethyl)pyridin-4-yl)methanamine. Evaporated to give the title compound. ¹H-NMR (300MHz, CDCI3): δ 8.6 (d, IH), 7.4 (s, IH), 7.2 (d, IH), 5.4 (s, 2H), 4.6 (d, 2H), 3.4 (s, 6H). ES-MS: 277 [M+1] and 321 [M+23]

2.2.2-trifluoro-N-r(2-formvtovridin-4-vl)methvllacetamide (vi) - General Procedure N (Hvdrolvsis of acetal)

Concentrated hydrochloric acid (3.5 eq) was added to a solution the acetal (N-{[2(dimethoxymethyl)pyridin-4-yl]methyl}-2,2,2-trifluoroacetamide) (1 equiv.) in THF. The mixture was

126 stirred for 2h at 60 °C. Solid NaHCO₃ (5 eq) was added at 0 °C and the suspension was filtered to remove the solids, which were washed with dichloromethane. The combined filtrâtes were evaporated to dryness and the residual was purified by column chromatography (0-20% MeOH/DCM) to yield the title product. ^XH NMR (300 MHz, CDCI₃) δ ppm: 10.05 (s, IH), 8.77 (d, IH), 7.86 (m, IH), 7.47 (dd,

IH), 7.44 (bs, IH), 4.65 (d, 2H). ES-MS: 233 [M+HJ.

Γ(4-ΓΓ(tert-butvldimethvlsilvl)oxvΊmethvll·pyridin-2-vl)methvΠΓ4-(diethvlamino)butvl1amine (vii)

By General Procedure A from 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde and 4(diethylamino)butyljamine. Purification by column chromatography (5% MeOH/DCM) gave the target compound as greenish oil. ¹H-NMR (300MHz, CDCh): δ 8.46 (d, IH), 7.20 (s, 2H), 7.10 (d, IH), 4.70 (s, 2H), 3.90 (s, 2H), 2.50 (m, 8H), 1.50 (m, 4H), 1.00 (t, 6H, 0.9 (s, 9H, 0.05 (s, 6H) ppm. tert-butyl N-Γ(4-<Γ(tert-butyldimethylsilvl)oxv1methvll·pyridin-2-vl)methyl1-N-Γ4(diethvlamino)butyllcarbamate fviii) - General Procedure O (Boc protection)

Di-tert-butyl dicarbonate (1.2 equiv.) was added to a solution of the amine ([(4-{[(tertbutyldimethylsilyl)oxy]methyl}pyridin-2-yl)methyl][4-(diethylamino)butyl]amine) (1.0 equiv.) and triethylamine (1.3 equiv.) in anhydrous DCM at 0 °C. The reaction mixture was stirred at room température for 12 hours. Na₂CO₃ was added and the mixture was stirred for 30 min. Evaporated to dryness and the residual was extracted with DCM. Evaporation of the extract gave the title compound, which was used without any further purification.

Tert-butyl N-r4-fdiethylamino)butyll-N-f r4-(hvdroxymethyl)pvridin-2-vnmethyl)-carbamate (ix) General Procedure P (Removal of Silvl Alcohol Protecting Group)

TBAF (2 equiv.) was added at room température to a solution of the silyl ether (tert-butyl N-[(4{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methyl]-N-[4-(diethylamino)butyl]carbamate) (1 equiv.) in THF and the reaction mixture was stirred ovemight. Sat. NaHCO₃ (aq) was added. Stirred for 30 min, before work-up with DCM. Purification by column chromatography (DCM, MEOH and NH₄ (aq.)) gave the title product as colorless oil. Y-NMR (300MHz, CDCh): δ 8.40 (d, IH), 7.00 (m, 2H), 4.60 (s, 2H), 4.40 (m, 2H), 3.20 (m, 2H), 2.40 (m, 6H), 1.40 (m, 9H), 1.00 (t, 6H) ppm.

Tert-butyl N-r4-(diethylamino)butvn-N-r(4-formvlpvridin-2-vl)methvllcarbamate (x) - General Procedure Q fSwem Oxidation)

DMSO (4 equiv.) in anhydrous DCM was cooled to -78 °C and oxalyl chloride (2 equiv.) was added drop-by-drop and stirred for 30 min at -78 °C. The alcohol (tert-butyl N-[4-(diethylamino)butyl]-N-{[4(hydroxymethyl)pyridin-2-yl]methyl}carbamate) (1.0 equiv.) was dissolved in DCM and added slowly atthe same température and the reaction mixture was stirred for one hour. Triethylamine (5.0 equiv.)

127 was added and reaction mixture was stirred ovemight in the same cooling bath. Quenched with water, and worked up by extraction with DCM. Purification by column chromatography using ethyl acetate/hexane 20-50% yielded the title product. ¹H-NMR (300MHz, CDCI₃): δ 10.05 (s, 1H), 8.80 (d,

1H), 7.50 (m, 2H), 4.50 (d, 2H), 3.30 (d, 2H), 2.50 (m, 6H), 1.4-1.5 (br d, 16H) 1.00 (t, 6H) ppm. ESMS: 364 [M+1].

tert-butyl N-Γ4-(diethvlamino')butvll-N-(Γ4-Γ(hvdroxvimino]methvl1pyridin-2-yll·methyl)carbamate (xi]

By General Procedure L from tert-butyl N-[4-(diethylamino)butyl]-N-[(4-formylpyridin-2yl)methyl]carbamate. Evaporated to dryness. The residue was suspended in dichloromethane, filtered, and the filtrate was evaporated to give the crude title product, which was used without further purification. ^-NMR (300MHz, CDCI₃): δ 8.40 (d, 1H), 8.00 (s, 1H), 7.39 (m, 2H), 4.45 (m, 2H), 3.35 (m, 2H), 2.60 (m, 8H), 1.60-1.20 (m, 18H) ppm.

tert-butyl Ν-ΠΑ-^ΓηίηοπΊΒίΐΊνΙίρνπΡίη^-νΙίΓηΒΗΊνΙΤ-Ν-ΐνΐ-^ίΒΐΐΊνΙάΠΊΐηο^υΐΎΐΙεΒΗίΒπίΒΐΒ (xiil

By General Procedure M from tert-butyl N-[4-(diethylamino)butyl]-N-«4-[(hydroxyimino)methyl]pyridin-2-yl}methyl)carbamate to give the title product which was used without further purification.

Ethyl 2T(4-hydroxvbutyl]carbamoyllpyridine-4-carboxylate (xiii)

By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and 4-aminobutan-l-ol. Purification by column chromatography (5% MeOH/DCM) gave the target compound as greenish oil. ^XH-NMR (300MHz, CDCI₃): δ 8.60 (d, 1H), 7.80 (s, 1H), 7.70 (d, 1H), 4.40 (q, 2H), 4.05 (s, 1H), 3.60 (m, 2H),

2.80 (m, 2H), 1.70 (m, 4H), 1.40 (t, 3H) ppm.

EthyLTsHIitertibutoxyjçaifoonyniâ^iiYdrOJiYbutYDaniinol^artonyQpyndinesA^arfrpiÇYlateTidYl^ General Procedure R (Boc protection of amine)

Aqueous solution NaHCO₃ (5.0 equiv.) was added to a solution of the amine (ethyl 2-[(4hydroxybutyl)carbamoyl]pyridine-4-carboxylate) (1.0 equiv.) in THF. Stirred for 5 min, before a solution of di-tert-butyl dicarbonate (1.2 equiv.) in THF was added. The reaction mixture was stirred over night at room température. Evaporated to dryness and extracted with ethyl acetate to give the title product as a white solid. ¹H-NMR (300MHz, CDCI₃): δ 8.60 (d, 1H), 7.80 (s, 1H), 7.70 (d, 1H), 4.50 (m, 2H), 4.40 (q, 2H), 3.60 (m, 2H), 3.30 (m, 2H), 1.70-1.35 (m, 17H) ppm.

Ethyl 2-fr(4-bromobutyl)r(tert-butoxy)carbonvllaminolcarbonyl>pyridine-4-carboxvlate (xv) - General Procedure S (Alcohol to bromide)

CBr₄ (1.1 equiv.) was added to a cold (0 °C) solution of alcohol (ethyl 2-({[(tert-butoxy)carbonyl](4hydroxybutyl)amino}carbonyl)pyridine-4-carboxylate) (1 equiv.) and PPh₃ ((1.1 équivalent). Stirred for 20 min and then allowed to warm to room température over 3-4 hour. Aqueous work up and

128 purification by column chromatography using (DCM:MeOH (95:5)) gave the title product as white solid.

^XH-NMR (300MHz, CDCI₃): δ 8.50 (d, 1H), 7.80 (s, 1H), 7.60 (d, 1H), 4.50 (m, 2H), 4.40 (q, 2H), 3.60 (m, 2H), 3.30 (m, 2H), 1.80 (m 2H), 1.60 (m, 2H), 130 (m, 12H) ppm. ES-MS: 415 [M+l].

Ethyl 2-(^,<r4-(azetidin-l-yl)butvl~ir(tert-butoxv)carbonynamino>carbonvl)pvridine-4-carboxylate (xvi) General Procedure T (Nucleophilic substitution with amine)

The amine (azetidine hydrochloride) (5.0 equiv.) and subsequently DIPEA (6.0 equiv.) was added to a solution of the bromide (ethyl 2-{[(4-bromobutyl)[(tert-butoxy)carbonyl]amino]carbonyl}pyridine-4carboxylate) (1 equiv.) in acetonitrile. Stirred at 60 °C for 12 hours. Evaporated to dryness and purified by column chromatography (DCM/MeOH (95:5)) to give the title product as colorless oil. ^XH-NMR (300MHz, CDCI₃): δ 8.58 (d, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 4.40 (m, 2H), 4.30 (q, 2H), 3.60 (m, 2H), 3.30 (m, 2H), 3.00 (m, 4H), 1.60 (m 4H), 1.40 (m, 12H) ppm. ES-MS: 392 [M+l],

Tert-butyl N-r4-(azetidin-l-vl)butyll-N-r4-(hvdroxvmethvl)pvridine-2-carbonyl1carbamate (xvii) General Procedure U (Réduction of ester to alcohol)

NaBH₄ (2.0 equiv.) was added at room température to a solution of ester (ethyl 2-({[4-(azetidin-lyl)butyl][(tert-butoxy)carbonyl]amino}carbonyl)pyridine-4-carboxylate) (1.0 equiv.) in EtOH. Stirred at room température for 10 min and then reflux for 3 hours. Cooled to room température and sat. NH₄CI solution was added. Evaporated to dryness and extracted with DCM. Purification by column chromatography (DCM, MeOH and HN₄0H (aq.) (85:10:5) gave the title product as viscous oil. ^XH-NMR (300MHz, CDCI3): δ 8.40 (d, 1H), 7.35 (s, 1H), 7.00 (d, 1H), 4.60 (s, 2H), 4.50 (m, 2H), 3.25 (m, 6H), 3.20 (m, 2H), 2.00 (m, 2H), 1.40 (m 14H) ppm.

Tert-butyl N-r4-(azetidin-l-vl)butyll-N-(4-formylpyridine-2-carbonyl)carbamate (xviii) - General Procedure V (Dess-Martin oxidation) l,l,l-Triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (1.1 equiv.) was added at 0 °C to a solution of alcohol (tert-butyl N-[4-(azetidin-l-yl)butyl]-N-[4-(hydroxymethyl)pyridine-2-carbonyl]carbamate) in anhydrous DCM. Stirred for 10 min. and then allowed to warm to room température and stirred for two to three hours. KOH solution (IM) was added and extraction with DCM gave the title product as light yellow oil. ^XH-NMR (300MHz, CDCI3): δ δ 10.0 (s, 1H), 8.70 (d, 1H), 7.55 (s, 1H), 7.50 (d, 1H), 4.50 (m, 2H), 3.20 (m, 2H), 2.50 (m, 4H), 1.80 (m, 2H), 1.40 (m 15H) ppm.

Tert-butyl ΝΤ4-(3Ζ6ίίάίη-1-νΙ^υίνΙ1-Ν-(4Τ((ΐΊνΰΓθχνίπΊΐηο)ηΊ6ΠΊνΙ1ρνΓΐ4ΐη6-2-^Η3οηνΙ)οΗ33Γη3ί6 (xix)

General Procedure L from tert-butyl N-[4-(azetidin-l-yl)butyl]-N-(4-formylpyridine-2carbonyl)carbamate gave the title product which was used without further purification. ^XH-NMR

129 (300MHz, CDCh): δ 8.40 (d, 1H), 8.00 (s, 1H), 7.30 (s, 1H), 7.25 (d, 1H), 4.40 (m, 2H), 3.20 (m, 4H),

2.00 (m, 2H), 1.60-1.20 (m 20H) ppm.

Tert-butyl N-r4-faminomethyl)pyridine-2-carbonyll-N-r4-(azetidin-l-vl)butvncarbamate (xx)

General Procedure M from tert-butyl N-[4-(azetidin-l-yl)butyl]-N-{4-[((hydroxyimino)methyl]pyridine2-carbonyl}carbamate gave the title product as colorless oil, which was used without further purification.

Ν-(Γ2-(8ίΐ'η6ίΙ~ιοχνΐ'η6ίΙινΗρνη8ίη-4-νΙ1Γη6θινΙΊ<νάορΓθΡ3η3ΠΊίη6 (xxi)

By General Procedure A from 2-(dimethoxymethyl)pyridine-4-carbaldehyde, cyclopropylamine, and acetic acid (1 equiv.). Purification by column chromatography (CHzCIVMeOH, 97:3) gave the title compound as a colorless oil. ^XH NMR (300 MHz, CDCI₃): δ 8.55 (d, 1H), 7.50 (S, 1H), 7.22 (m, 1H), 5.40 (s, 1H), 3.90 (s, 2H), 3.40 (s, 6H), 2.18 (m, 1H), 0.5 (m, 4H).

4-rfcvclopropvlamino)methvllpyridine-2-carbaldehvde (xxii)

By General Procedure N from N-{[2-(dimethoxymethyl)pyridin-4-yl]methyl}cyclopropanamine. Used without further purification. ^XH-NMR (300MHz, CDCI3): δ 10.02 (s, 1H), 8.70 (d, 1H), 7.98 (s, 2H), 7.50 (m, 1H), 3.98 (s, 2H), 2.25 (m, 1H), 0.50 - 0.40 (m, 4H).

EthyLZ^jHdimethylçarbamoYlJmethYlJaminolniettiYDEYiidinezlxçarboxYlateTxxiiü

By General Procedure A from Ethyl 2-formylpyridine-4-carboxylate, N,N-dimethylglycineamide hydrochloride, and triethylamine. Purification by column chromatography with a gradient of 0-10% MeOH in DCM gave the title product as yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.69 (s, 1H), 7.94 (s, 1H), 7.72 (d, 1H), 4.40 (q, 2H), 4.03 (s, 2H), 3.48 (s, 2H), 2.95 (d, 6H), 1.40 (t, 3H).

2-(f r4-(Hvdroxvmethvl)pvridin-2-vllmethvl>amino)-N,N-dimethvlacetamide(xxiv)

By General Procedure U from ethyl 2-({[(dimethylcarbamoyl)methyl]amino}methyl)pyridine-4carboxylate. Purification by column chromatography (10% MeOH and 1% NH₄OH in DCM) gave the title product as light yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.44 (d, 1H), 7.47(s, 1H), 7.30 (d, 1H), 4.67 (s, 2H), 3.93 (s, 2H), 3.53 (s, 2H), 2.96 (d, 6H).

Tert-Butvl Ν-Γ(8ίηΊ6ίΐΊνΙο3ΓΡ3ΓηογΙ)[η6ϋΊνΙ1-Ν-Π4-(ΐΊν8ΓθχνπΊ6ΜΊνΙ)ρνπ8ΐη-2-νΙ1πΐ6ΚΊγΙ'}θΓδ3ΠΊ3ί6 (xxv)

General Procedure R from 2-({[4-(Hydroxymethyl)pyridin-2-yl]methyl}amino)-N,N-dimethylacetamide. Purification by column chromatography (10% MeOH and 1% NH₄0H in DCM) gave the title product as light yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.46 (m, 1H), 7.36 (m, 1H), 7.19 (m, 1H), 4.72 (m, 2H), 4.60 (m, 2H), 4.11 (m, 2H), 2.95 (m, 6H), 1.43 (m, 9H).

130

Tert-Butyl N-r(dimethvlcarbamovDmethvl1-N-r(4-formylDvridin-2-vl)methvl1carbamate (xxvi)

General Procedure Q from tert-butyl N-[(dimethylcarbamoyl)methyl]-N-{[4-(hydroxymethyl)pyridin-2yl]methyl}carbamate. The title product was isolated after extractions as yellow sticky oil and used without further purification. ^XH NMR (300 MHz, chloroform-d): δ ppm 10.09 (m, 1H), 8.79 (m, 1H),

7.80 (m, 1H), 7.60 (m, 1H), 4.72 (m, 2H), 4.18 (m, 2H), 2.97 (m, 6H), 1.43 (m, 9H).

tert-Butyl N-r(dimethvlcarbamoyDmethvlTN-(-f4-r(lE)-(hydroxvimino)methvl1pyridin-2vITmethyDcarbamate (xxvii)

General Procedure L from tert-Butyl N-[(dimethylcarbamoyl)methyl]-N-[(4-formylpyridin-2yl)methyl]carbamate. The title product was isolated after extraction as light yellow oil and used without further purification. ^XH NMR (300 MHz, methanol-d,»): δ ppm 8.47 (m, 1H), 8.10 (d, 1H), 7.61(d, 1H), 7.46 (m, 1H), 4.58 (m, 2H), 4.20 (m, 2H), 2.98 (m, 6H), 1.40 (m, 9H).

Tert-Butyl N-<Γ4-(aminomethvl)pyridin-2-y^1methvll·-N-Γ(dimethvlcarbamovΠmethvl1carbamate (xxviii)

General Procedure M from tert-Butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N[(dimethylcarbamoyl)methyl]carbamate. Purification by column chromatography ( 0-15% MeOH in DCM) gave the product as light yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.38 (m, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 4.55 (m, 2H), 4.05 (m, 2H), 3.84 (m, 2H), 2.89 (m, 6H), 1.36 (m, 9H).

Tert-Butvl N-i(4-f Γ(cvanomethyl)amino^methyll·Pvridin-2-yl)methyl1-Nr(dimethylcarbamoyl)methyl1carbamate (xxix)

General Procedure T from tert-butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N[(dimethylcarbamoyl)methyl]carbamate (1.0 equiv.), DIPEA (2.0 equiv.) and bromoacetonitrile (1.1 equiv.). Purification by préparative TLC (10% MeOH and 1% NH4OH in DCM) gave the title product as light yellow oil. ^XH NMR (300 MHz, methanol-d4): δ ppm 8.42 (d, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 4.58 (m, 2H), 4.19 (m, 2H), 3.93 (s, 2H), 3.65 (s, 2H), 2.98 (m, 6H), 1.42 (m, 9H).

2-(Τί4-(Τ(16Η:-ΒυίνΙάΐΓη6Α~ινΐ5ΐΙν1)οχν1πΊ61Ι·ινΙ>ρνΓΐάΐη-2-νΙ)ΓΠ6ίΐΊνΠ3Γηΐηο>-Ν,Ν^ίιτΐ6ΜΊνΐ306ί3ηΓ^6 (xxx)

By General Procedure A from Ν,Ν-dimethylglydneamide hydrochloride, triethylamine, and 4-<[(tertbutyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde. Purification by column chromatography (010% MeOH in DCM) gave the title product as yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.49 (d, 1H), 7.32 (s, 1H), 7.17 (d, 1H), 4.74 (s, 2H), 3.97 (s, 2H), 3.47 (s, 2H), 2.95 (d, 6H), 0.95 (s, 9H), 0.11 (s, 6H).

131

N-Γί4-Π(tert-ButvldimethvlsilvltoxvΊmethvll·pyridin-2-yl)methvll-N-Γ(dimethvlcarbamovDmethvll2,2,2-trifluoroacetamide (xxxi)

By General Procedure C from 2-{[(4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2yl)methyl]amino}-N,N-dimethylacetamide. Evaporation gave the product as yellow oil, which was used without further purification. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.50 (m, 1H), 7.25 (m, 2H), 4.80 (m, 4H), 4.33 (m, 2H), 2.99 (m, 6H), 0.96 (s, 9H), 0.13 (s, 6H).

N-Γ(Dimethvlcarbamovl)methvΠ-2,2,2-trifluoro-N-ίΓ4-(hvdroxvmethvl)Dvridin-2-vllmethyll·acetamide fxxxii)

By General Procedure P from N-[(4-{[(tert-butyldimethylsilyl)oxy]methyl)-pyridin-2-yl)methyl]-N[(dimethylcarbamoyl)methyl]-2,2,2-trifluoroacetamide. Purification by column chromatography (0-10% MeOH in DCM) gave the title product as yellow oil. ’H NMR (300 MHz, chloroform-d): δ ppm 8.45 (m, 1H), 7.26 (m, 2H), 4.74 (m, 4H), 4.33 (m, 2H), 3.88 (s(br), 1H), 2.92 (m, 6H).

N-r(Dimethvlcarbamoyl)methyll-2,2,2-trifluoro-N-r(4-formvlpyridin-2-vnmethvl'lacetamide (xxxiii)

By General Procedure Q from N-[(dimethylcarbamoyl)methyl]-2,2,2-trifluoro-N-{[4hydroxymethyl)pyridin-2-yl]methyl}acetamide. Purification by column chromatography (30-60% EtOAc in DCM) gave the title product as yellow oil. ’H NMR (300 MHz, chloroform-d): δ ppm 10.01 (d, 1H), 8.74 (m, 1H), 7.63 (m, 2H), 4.82 (m, 2H), 4.29 (m, 2H), 2.90 (m, 6H).

N-rfDimethylcarbamovnmethvl1-2,2,2-trifluoro-N-r(4-formylpvridin-2-vDmethvl1acetamide (xxxiv)

By General Procedure A from N-[(dimethylcarbamoyl)methyl]-2,2,2-trifluoro-N-[(4-formylpyridin-2yl)methyl]acetamide and Ν,Ν-dimethylethylenediamine. Purification by préparative TLC (10% MeOH, 1% NH4OH in DCM) gave the title product as colorless oil. *H NMR (300 MHz, chloroform-d): δ ppm

8.48 (m, 1H), 7.29 (m, 2H), 4.80 (m, 2H), 4.37 (m, 2H), 3.84 (m, 2H), 2.98 (m, 6H), 2.71 (t, 2H),

2.49 (t, 2H), 2.26 (m, 6H). ES-MS: 390 [M+1J.

EthyLZAUâihYdrojürBrOBYlJaminolmettTYllEYridinesl^çarboxYlateJxxxv)

By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and 3-aminopropan-l-ol. Purification by column chromatography (0-5% MeOH in DCM) gave the title compound. ¹H NMR (300 MHz, CDCI3), δ ppm: 8.72 (d, 1H), 7.98 (s, 1H), 7.75 (d, 1H), 4.45(q, 2H), 3.95 (s, 2H), 3.70 (t, 2H),

2.80 (t, 2H), 1.75 (m, 2H), 1.40 (t, 3H).

132

Ethyl 2Τ(2,2,2-ίπί1υθΓθ-Ν-<3-Γ(1ΓΐΑυοΓθ9€βίνΙ)οχν1ΡΓΌΡνΙ>3ε6ί3Γηΐ<1ο)ηΊ6ίΐΊνΠρνπ<1ΐη6-4-€3Γί)θχνΐ3ί6 (xxxvi)

By General Procedure C from ethyl 2-{[(3-hydroxypropyl)amino]methyl}pyridine-4-carboxylate (1 equiv.), DIPEA (7.0 equiv.), and trifluoroacetic anhydride (5.0 equiv.). The title product was isolated after extractions and used without further purification. ¹H-NMR (300MHz, CDCI₃), (rotamers): δ 8.74 (dd, 0.5H), 8.70 (dd, 0.5H), 7.85 (s, 0.5H), 7.83-7.78 (m, 1H), 7.74 (s, 0.5H), 4.81 (s, 1H), 4.77 (s, 1H), 4.47-4.35 (m, 4H), 3.70 (t, 1H), 3.58 (t, 1H), 2.23-2.13 (m, 1H), 2.10-2.01 (m, 1H), 1.42 (td, 3H).

Ethyl 2-<Γ2,2,2-trifluoro-N-f3-hvdroxvpropyl)acetamido1methvll·Pvridine-4-carboxvlate (xxxvii) General Procedure X (ester hvdrolysis)

IM LiOH (aq, 1.0 equiv) was added to a solution of ester (ethyl 2-[(2,2,2-trifluoro-N-{3[(trifluoroacetyl)oxy]propyl}acetamido)methyl]pyridine-4-carboxylate) (1.0 equiv.) in THF-MeOH-H₂O (1:1:1). Stirred at room température, while following the reaction by TLC. Evaporated to dryness and purified by flash chromatography using MeOH:DCM (10:90) to yield the title compound. *H NMR (300 MHz, CDCI₃), (rotamers) δ ppm: 8.74 (two d, 1H), 7.80 (m, 2H), 4.85(s, 2H), 4.45 (m, 2H), 3.65 (m, 4H), 1.90 (m, 2H), 1.45 (m, 3H).

Ethyl 2--{Τ2,2,2-ύΊΑυθΓθ-Ν-(3-οχορΓθρνΙ)3θ6ί3ΐτ^οΐΓη6θΊνΙ>ρνι^ΐη6-4-θ3ΓΡοχνΐ3ί6 (xxxviii)

By General Procedure Q from ethyl 2-{[2,2,2-trifluoro-N-(3-hydroxypropyl)acetamido]methyl}pyridine4-carboxylate to give the title product. Ψ NMR (300 MHz, CDCI₃), (rotamers) δ ppm: 9.80 (two singlets, 1H), 8.70 (two doublets, 1H), 7.80 (m, 2H), 4.90/4.75 (two singlets, 2H), 4.45 (m, 2H), 3.95/3.75 (m, 2H), 2.90 (two t, 2H), 1.45 (m, 3H).

Ethyl 2-Γ(N-f3-Γbenzvl(methvl)aminolpropvll·-2,2,2-trifluoroacetamido)methvl1pvridine-4-carboxvlate (xxxix)

By General Procedure A from ethyl 2-{[2,2,2-trifluoro-N-(3-oxopropyl)acetamido]methyl}pyridine-4carboxylate and benzyl(methyl)amine to give the title product. ³H NMR (300 MHz, CDCI3), (rotamers) δ ppm: 8.7 (dd, 1H), 7.90 - 7.75 (m, 2H), 7.4 - 7.2 (m, 5H), 4.8 (d, 2H), 4.4 (q, 2H), 4.0 (q, 2H), 3.7 3.4 (m, 2H), 2.8 - 2.5 (m, 2H), 2.0 - 1.8 (m, 7H), 1.4 (t, 3H).

f2-Γ(<3-ΓBenzvl(methvl)amino1propvll·amino)methvl1pvridin-4-yll·methanol (xl)

By General Procedure U from ethyl 2-[(N-{3-[benzyl(methyl)amino]propyl}-2,2,2trifluoroacetamido)methyl]pyridine-4-carboxylate using 5.0 equiv. of NaBH₄. Purification by column chromatography gave the title product. ^XH NMR (300 MHz, CDCI3) δ ppm: 8.5 (dd, 1H), 7.80 (s, 1H),

133

7.6 - 7.3 (m, IH), 4.6 (s, 2H), 4.3 (s, 2H), 3.6 - 3.2 (m, 4H), 2.8 (s, 3H), 2.2 - 2.0 (m, 2H), 1.7 - 1.3 (m, 3H).

Tert-butyl N-f 3-rbenzyl(methvl)amino)propvl>-N-Tr4-(hvdroxvmethyl)pyridin-2-yl1methvl~Î-carbamate ixii}

By General Procedure R from, {2-[({3-[benzyl(methyl)amino]propyl}amino)methyl]pyridin-4yljmethanol to give the title product. ^XH NMR (300 MHz, CDCI3), (rotamers) δ ppm: 8.6 (d, IH), 7.4 7.1 (m, 8H), 4.8 (s, 2H), 4.6 - 4.4 (m, 2H), 3.4 - 3.2 (m, 2H), 2.5 - 2.2 (m, 2H), 2.1 (s, 3H), 1.9 -

1.3 (m, 11H).

Tert-butyl N-f'3-rbenzvl(methyl)aminolpropvl')-N-r(4-formvlpvridin-2-yl)methvl1carbamate (xlii)

General Procedure Q from tert-butyl N-{3-[benzyl(methyl)amino]propyl}-N-{[4(hydroxymethyl)pyridin-2-yl]methyl}carbamate. ^XH NMR (300 MHz, CDCI3), (rotamers) δ ppm: 10.0 (s, IH), 8.8 (d, IH), 7.7 - 7.1 (m, 7H), 4.8 - 4.6 (m, 2H), 3.6 - 3.2 (m, 4H), 2.5 - 2.3 (m, 2H), 2.2 (s, 3H), 1.9 - 1.3 (m, 11H).

Tert-butyl N-r3-rbenzvl(methvl)aminolpropyl)--N-(-(4-r(cyclopropvlamino)methyl'|pvndin-2vITmethyDcarbamate (xliii)

By General Procedure A from tert-butyl N-{3-[benzyl(methyl)amino]propyl}-N-[(4-formylpyridin-2yl)methyl]carbamate and cyclopropanamine. Purification by column chromatography using DCM:Me0H:NH₄0H (8:2:1) gave the title compound. ^XH NMR (300 MHz, CDCI3), (rotamers) δ ppm: 8.4 (d, IH), 7.4 - 7.2 (m, 7H), 4.5 (s, 2H), 3.9 (s, 2H), 3.7 - 3.2 (m, 4H), 2.6 - 1.7 (m, 8H), 1.4 (d, 9H), 0.6 - 01.3 (m, 4H).

Ethyl 2-(-ί~Γ2-(ί6Η:-όυίοχν)-2-οχο6ΐ:ΚνΙΊ3ΓηίηοΤΐ'η6ίηνΙ)ρνπόίη6-4-ε3ΓΪ>οχνΐ3ί6 (xliv)

Prepared by General Procedure A from ethyl 2-formylpyridine-4-carboxylate and tert-butyl 2aminoacetate. Title compound isolated as yellow oil by column chromatography (EtOAc/hexanes). ^XHNMR (300MHz, MeOH-d₄): δ 8.7 (d, IH), 7.8 (s, IH), 7.7 (d, IH), 4.4 (s, 2H), 4.3 (q, 2), 3.8 (s, 2H),

3.3 (s, 2H), 1.4 (s, (H), 1.3 (t, 3H). ES-MS: 295 [M + 1].

Ethyl 2-(·(Ν-Γ2-(ί6Γΐ-δυίοχν)-2-οχο61ΐΊνΙ1-2·2.2-1πΒυοΓθ3ε613πιΙόοΤΓη6ύΊνΙ)ρνί^Ιη6-4-€3Η3θχνΐ8ί6 (xlv)

By General Procedure C from ethyl 2-({[2-(tert-butoxy)-2-oxoethyl]amino}methyl)pyridine-4carboxylate in anhydrous DCM. Aqueous work up gave the title compound, which was used without further purification. ^XH-NMR (300MHz, CDQ3), (rotamers): δ 8.7 (dd, IH), 7.8 (ss, IH), 7.7 (dd, IH), 4.8 (SS, 2H), 4.3 (q, 2), 4.2 (ss, 2H), 1.4 (s, 9H), 1.3 (t, 3H).

134

2-CN-f r4-(ethoxvcarbonvl)pvridin-2-vl1methvl)--2.2,2-trifluoroacetamido)acetic acid (xlvi)

By General Procedure D from ethyl 2-«N-[2-(tert-butoxy)-2-oxoethyl]-2,2,2trifluoroacetamido}methyl)pyridine-4-carboxylate. Evaporation gave the title compound, which was used without further purification. ¹H-NMR (300MHz, CD3OD): δ 8.75 (m, 1H), 7.8 8.00 (m, 2H), 5.45, 4.99 (2s, 2H; rotamer), 4.20 - 4.40 (m, 4H), 1.40 (t, 3H).

Ethyl 2-i-f Ν-Γ(·{Ί-ΓΠ:6ΐ1:-όυίοχν)θ3Ηκ)ηνΙ1ρΐρ6πόίη-4-νΙ'}θΓυ3ΓηονΙ)ηΊ6ϋΊνΙ1-2,2,2trifluoroacetamido>methvl)pyridine-4-carboxvlate (xlviB - General Procedure Y (Amide formation^

An amine (tert-butyl 4-aminopiperidine-l-carboxylate) (2 equiv.) was added to a solution of an acid (2(N-{[4-(ethoxycarbonyl)pyridin-2-yl]methyl}-2,2,2-trifluoroacetamido)acetic acid) (1 equiv.) in DMF. Cooled to 0 °C before EDC HCl (1.5 équivalent) and ethyl(hydroxyl iminocyanoaectate (oxyma; 1.5 équivalent) were added. The reaction mixture was allowed to warm slowly to room température and stirred ovemight. Aqueous work up and purification by column chromatography gave the title compound as brown foam. ^-NMR (300MHz, CDCI3): δ 8.70 & 8.60 (2d, 1H; rotamer ), 7.80 (m, 2H), 4.90 & 4.78 (2s, 2H, rotamer), 4.42 (q, 2H), 4.30 & 4.10 (2s, 2H; rotamer), 4.10 (m, 1H), 2.80 (m, 2H) 2.0 (m, 2H), 1.48 (s, 9H), 1.40 (t, 3H).

Ethyl 2-Γ(2,2,2-trifluoro-N-ΓΓ(piperidin-4-vl)carbamovnmethyll·acetamido)methvllpvridine-4carboxvlate (xlviii)

Prepared by General Procedure D from ethyl 2-({N-[({l-[(tert-butoxy)carbonyl]piperidin-4yl}carbamoyl)methyl]-2,2,2-trifluoroacetamido}methyl)pyridine-4-carboxylate. Purification by column chromatography (MeOH/DCM and 1% NH4OH) gave the title compound as a brown foam. ¹H-NMR (300MHz, CD3OD): δ 8.75 (m, 1H ), 7.90 (m, 2H), 5.00 &4.90 (2s, 2H, rotamer), 4.42 (q, 2H), 4.32 & 4.12 (2s, 2H; rotamer), 3.95 (m, 1H), 3.40 (m, 2H) 3.10 (m, 2H), 2.10 (m, 2H), 1.80 (m, 2H), 1.38 (t, 3H).

Ethyl 2-(<2.2,2-trifluoro-N-r(<l-r(2-methoxvphenvDmethvllpiperidin-4νΙ>ο3Γ03ΓηονΙ)πΊ6ίΐΊνΙΐ3ε6ί3πηίάο)·Γη6ΜΊνΙ)ρνηάΐη6-4-θ3Η3θχνΐ316 (xlix)

Prepared by General Procedure A from 2-methoxybenzaldehyde and ethyl 2-[(2,2,2-trifluoro-N{[(piperidin-4-yl)carbamoyl]methyl}acetamido)methyl]pyridine-4-carboxylate. ^XH-NMR (300MHz, CDCI3): δ 8.75 &8.71 (2d, 1H; rotamer ), 7.91 - 7.78 (m, 2H), 7.36 (m, 1H), 7.25 (m, 1H), 7.99 7.86 (m, 2H), 4.95 & 4.72 (2s, 2H, rotamer), 4.45 (q, 2H), 4.30 &4.08 (2s, 2H; rotamer), 3.83 (m, 4H), 3.60 (m, 2H) 2.95 (m, 2H), 2.22 (m, 2H), 1.90 (m, 2H), 1.60 (m, 2H), 1.40 (t, 3H).

135

2-(^,ir4-('hydroxymethyl)pyridin-2-yl']methyiyamino)-N-<l-r(2-methoxyphenvl')methyllpiperidin-4ylïacetamide (I)

By General Procedure U from ethyl 2-({2,2,2-trifluoro-N-[({l-[(2-methoxyphenyl)methyl]piperidin-4yl}carbamoyl)methyl]acetamido}methyl)pyridine-4-carboxylate using 5 equiv. of NaBH₄. Purification by column chromatography using 1% MeOH/DCM to 28% MeOH/DCM/l%NH₄OH as elutentto get the product as an off white solid. ^XH-NMR (300MHz, CDCI₃): δ 8.42 (d, IH), 7.42 (d, IH), 7.35 (d, IH), 7.25 (m, 2H), 7.15 (m, IH), 6.99 - 6.85 (m, 2H), 4.65 (s, 2H), 3.80 (m, 4H), 3.60 (s, 2H), 3.45 (s, 2H), 3.25 (s, 2H), 2.90 (m, 2H), 2.22 (m, 2H), 1.90 (m, 2H), 1.60 (m, 2H).

tert-butyl Ν-<Γ4-(ΐΊνάΓ0χγηπ611ΊνΙ')ρνΓΐάΐη-2-γΙ'|ηη6ΗΊνΙ'}-ΝΤ(·ί'lT(2-methoxvDhenvDmethvHpiperidin-4yl>carbamoyl)methyllcarbamate (li)

By General Procedure R from 2-({[4-(hydroxymethyl)pyridin-2-yl]methyl)amino)-N-{l-[(2methoxyphenyl)methyl]piperidin-4-yl}acetamide to get the title compound as a white foam. ¹H-NMR (300MHz, CDCia): δ 9.80 (d, IH), 8.70 (d, IH), 7.50 - 7.40 (m, 2H), 7.25 (m, 2H), 7.10 - 6.80 (m, 2H), 4.70 (s, 2H), 4.50 (d, 2H), 4.12 (d, 2H), 3.98 (m, 3H), 3.85 (s, 3H), 3.35 (d, 2H), 2.80 - 2.50 (m, 2H), 2.10 - 1.80 (m, 4H), 1.40, 1.20 (ss, 9H).

tert-butyl N-r(4-formylpvridin-2-vnmethvl1-N-rf-fl-r(2-methoxyphenyl)methYllpiperidin-4yll-carbamoyDmethylIcarbamate (lii)

By General Procedure Q from tert-butyl N-{[4-(hydroxymethyl)pyridin-2-yl]methyl}-N-[({l-[(2methoxyphenyl)methyl]piperidin-4-yl)carbamoyl)methyl]carbamate to get the title compound as a light yellow foam. ^XH-NMR (300MHz, CDCI₃): δ 10.00 (s, IH), 9.00 - 8.20 (m, 2H), 7.76 (2d, IH; rotamer ), 7.40 (m, IH), 7.30 (m, IH), 7.00 - 6.80 (m, 2H), 4.52 (m, 2H), 4.42 (q, 2H), 4.20 & 4.00 (2s, 2H; rotamer), 3.90 (m, 4H), 3.55 (s, 2H) 3.00 (m, 2H), 2.22 (m, 2H), 2.00 (m, 2H), 1.80 - 1.50 (m, 4H), 1.40, 1.20 (2s, 9H; rotamer).

tert-butyl Ν-(·Γ4-Γ^νυοΡΓθρνΐ3ΠΊίηο)ηΊ6ίΐΊνΙ1ργπδίη-2-γΙ'}·Γη6ϋΊνΙ)-ΝΤ(·ίΊ-Γ(2methoxyphenyl’)methyllpiperidin-4-yl'Î-carbamoyl)methyllcarbamate (liii)

By General Procedure A from tert-butyl N-[(4-fbrmylpyridin-2-yl)methyl]-N-[({l-[(2methoxyphenyl)methyl]piperidin-4-yl)carbamoyl)methyl]carbamate and cyclopropylamine. Purification by column chromatography (CH2CI2/MeOH/NH₄OH, 90:10:1) gave the title compound as a colorless glue. ^XH NMR (300 MHz, CDCI₃): δ 9.40 (br s, IH), 8.62 (2S, IH; rotamer), 8.40 (s, IH), 7.50 - 7.40 (m, 2H), 7.38 (m, IH), 7.20 (m, IH), 7.00 - 6.80 (m, 2H), 4.58 &4.48 (2S, 2H; rotamer), 4.00 - 3.60 (m, 8H), 3.18 - 2.99 (m, 4H), 2.40 - 2.20 (m, 2H), 1.80 (m, 2H), 1.70 (m, 2H), 1.40 & 1.20 (2S, 9H; rotamer), 1.00 (m, 4H).

136

Ethyl 2-(-!T3-(dimethylamino^,)DroDvl'lamino'j-methvl’)Dvridine-4-carboxylate (liv)

By General Procedure A from Ethyl 2-formylpyridine-4-carboxylate and (3-aminopropyl)dimethylamine to get the title compound as dark-orange oil. ^XH NMR (300 MHz, CDCI₃): δ 8.53 (dd, 1H), 7.70 (s, 1H), 7.56 (dd, 1H), 4.24 (q, 2H), 3.86 (s, 2H), 2.60 (t, 2H), 2.26 (t, 2H), 2.10 (s, 6H), 1.58 (t, 2H), 1.24 (t, 3H). ES-MS: 266 [M + l].

Ethyl 2-(-fr(tert-butoxy)carbonynr3-(dimethvlamino)propynamino>methyl)pyridine-4-carboxylate (lv)

General Procedure R from Ethyl 2-({[3-(dimethylamino)propyl]amino}methyl)pyridine-4-carboxylate. Purification by column chromatography (0-20% MeOH/DCM) gave the title product. ^XH NMR (300 MHz, CDCI₃) δ ppm: 8.68 (dd, 1H), 7.79 (s, 1H), 7.73 (d, 1H), 4.62 (d, 2H), 4.41 (q, 2H), 3.34 (m, 2H), 2.26 (m, 2H), 2.19 (s, 6H), 1.72 (m, 2H), 1.47 (m, 12H). ES-MS: 366 [M+l].

Tert-butyl N-r3-(dimethvlamino)propyll-N-f Γ4-(hydroxymethyl)pvridin-2-yllmethvl'}-carbamate (Ivi)

By General Procedure U from Ethyl 2-({[(tert-butoxy)carbonyl][3-(dimethylamino)propyl]amino}methyl)pyridine-4-carboxylate. Purification by column chromatography (0-30% MeOH/DCM) gave the title product. ^XH NMR (300 MHz, CDCI₃) δ ppm: 8.34 (d, 1H), 7.15 (s, 1H), 7.10 (d, 1H),5.18 (bs, 1H), 4.58 (s, 2H), 4.46 (d, 2H), 3.22 (m, 2H), 2.19 (m, 2H), 2.10 (s, 6H), 1.61 (m, 2H), 1.36 (d, 9H). ES-MS: 324 [M+l]

Tert-butyl N-r3-(dimethylamino)propyl~l-N-r(4-formylDyridin-2-vl)methyl1carbamate (Ivii)

General Procedure Q from tert-butyl N-[3-(dimethylamino)propyl]-N-{[4-(hydroxymethyl)pyridin-2yl]methyl}carbamate. Purification by column chromatography (0-20% MeOH/DCM) gave the title product. ^XH NMR (300 MHz, CDCI3) δ ppm: 10.00 (s, 1H), 8.72 (d, 1H), 7.57 (s, 1H), 7.52 (m, 1H), 4.59 (d, 2H), 3.28 (m, 2H), 2.20 (m, 2H), 2.12 (s, 6H), 1.66 (m, 2H), 1.38 (d, 9H). ES-MS: 322 [M + l].

Tert-butyl N-(f4-Γcvano(methylamino)methyllpyridin-2-yll·methyl)-N-Γ3(dimethylamino)propyllcarbamate (Iviii) - General Procedure Z (Formation of amino alkyl nitriles)

A solution of aldéhyde (tert-butyl N-[3-(dimethylamino)propyl]-N-[(4-formylpyridin-2yl)methyl]carbamate) (1 equiv.) and amine (methylamine) (2 equiv.) in anhydrous THF was stirred overnight at room température. Evaporated to dryness and re-dissolved in anhydrous acetonitrile, before TMSCN (1.1 equiv.) was added. The mixture was stirred overnight at room température. Aqueous work-up and purification by préparative TLC (3% TEA in 20% MeOH/DCM) gave the title product. ^XH NMR (300 MHz, CDCI3) δ ppm: 8.58 (d, 1H), 7.45 (s, 1H), 7.38 (d, 1H), 4.81(s, 1H), 4.58 (m, 2H), 3.35 (m, 4H), 2.57 (s, 3H), 2.30 (m, 4H), 1.78 (m, 2H), 1.46 (d, 9H). ES-MS: 362 [M+l],

137

Ethyl 2-(<Γ^βΓί-όυίοχν)θ9ΓΡοηνΙ1(4-οχοόυίγΙ)3ηΊΐηο>ω6^νΙ)ρνηόίη6-4-ε3Γόοχνΐ316 (lix)

By General Procedure Q from ethyl 2-({[(tert-butoxy)carbonyl](4-hydroxybutyl)amino}methyl)pyridine-4-carboxylate. Purified by column chromatography (ethyl acetate/hexane 20-40%) to give the title product. ²H-NMR (300MHz, CDCI₃): δ 9.70 (s, IH), 8.60 (d, IH), 7.70 (s, IH), 7.60 (d, IH), 4.55 (d, 2H), 4.40 (q, 2H), 3.40 (m, 2H), 2.480 (m, 2H), 1.85 (m, 2H), 1.50-1.20 (m, 12H) ppm.

Ethyl 2-Γ(ί4-Γbenzylίcvclopropvl)amino1butvll·Γ(tert-butoxv)carbonvllamino)methvl1pyridine-4carboxylate (Ix)

By General Procedure A from ethyl 2-({[(tert-butoxy)carbonyl](4-oxobutyl)amino}methyl)pyridine-4carboxylate and N-benzylcyclopropanamine. Purification by column chromatography (5% MeOH/DCM) gave the title compound as colorless oil. ¹H-NMR (300MHz, CDCI₃): δ 8.60 (d, IH), 7.70 (s, IH), 7.60 (d, IH), 7.10 (m, 5H), 4.50 (d, 2H), 4.40 (q, 2H), 3.50 (m, 2H), 3.15 (m, 2H), 2.50 (m, 2H), 1.60 (m, IH), 1.45 (m, 16H), 0.4 (m, 4H) ppm.

Tert-butyl Ν~ί4-Π36ηζνΙ(ονάορΓθρνΙ)3Γηΐηο~^υίνΙ3-Ν-( r4-(hvdroxvmethyl)pyridin-2yllmethylTcarbamate (Ixi)

By General Procedure U from ethyl 2-[«4-[benzyl(cyclopropyl)amino]butyl}[(tertbutoxy)carbony!]amino)methyl]pyridine-4-carboxylate. Purification by column chromatography (DCM, MeOH and HN4OH (85; 10:5)) gave the title product as viscous oil. ^XH-NMR (300MHz, CDCI3): δ 8.45 (d, IH), 7.20 (m, 6H), 7.00 (d, IH), 4.70 (m, 2H), 4.50 (m, 2H), 3.60 (m, 2H), 3.10 (m, 2H), 2.40 (m, 2H), 1.55 (m, 2H), 1.40 (m, 13H) ppm.

Tert-butyl N-f4-Γbenzvl(cyclopropvl)amino1butvll·-N-Γ(4-fbrmvlpvridin-2-yl)methyllcarbamate (Ixii)

By General Procedure Q from tert-butyl N-{4-[benzyl(cyclopropyl)amino]butyl}-N-{[4(hydroxymethyl)pyridin-2-yl]methyl}carbamate. Purification by column chromatography (ethyl acetate/hexane 20-50%) gave the title product. ^XH-NMR (300MHz, CDCI₃): δ 10.0 (s, IH), 8.70 (d, IH), 7.50 (m, 2H), 7.20 (m, 5H), 4.50 (m, 2H), 3.80 (m, 2H), 3.15 (m, 2H), 2.50 (m, 2H), 1.60 (m, 2H), 1.45 (m, 12H), 0.40 (m, 4H) ppm.

Tert-butyl Ν-Τ4-Π36ηζνΙ(ονόορΓορνΙ)3ηιΐηο^,^υίνΙ>-Ν-(·Γ4-Γί1Ε)-(ίινόΓθχνίηιΐηο)Γη6ίΐΊνΙ1ρνΐΊόΐη-2vil·methyl jcarbamate (Ixiii)

By General Procedure L from tert-butyl N-{4-[benzyl(cyclopropyl)amino]butyl}-N-[(4-formylpyridin-2yl)methyl]carbamate. Evaporation gave the title product, which was used without further purification.

^XH-NMR (300MHz, CDCI3): δ 8.45 (d, IH), 8.00 (s, IH), 7.20-7.00 (m, 7H), 4.50 (m, 2H), 3.70 (s, 2H), 3.20 (m, 2H), 2.50 (m, 2H), 1.60-1.20 (m, 14H), 0.40 (m, 4H) ppm.

138

Tert-butyl N-<Γ4-(aminomethvl)pyridin-2-yllmethyll·-N-f4-Γbenzyl(cycloDropyl)aminolbutvl>carbamate (Ixiv)

By General Procedure M from tert-butyl N-{4-[benzyl(cyclopropyl)amino]butyl}-N-({4-[(lE)(hydroxyimino)methyl]pyridin-2-yl}methyl)carbamate. Purification by column chromatography (DCM, MeOH and HN₄0H (85; 10:5)) gave the title product as colorless oil. ¹H-NMR (300MHz, CDCI₃): δ 8.45 (d, 1H), 7.20-7.00 (m, 7H), 4.50 (m, 2H), 3.90 (s, 2H), 3.70 (s, 2H), 3.00 (m, 2H), 2.50 (m, 2H), 1.80 (m, 4H), 1.40 (m, 12H) 0.40 (m, 4H), ppm.

Tert-butyl Ν-Γ4-Π36ηζνΙ(ονόορΓθΡνΙ)3ΐ'ηίηο1ΡυίνΙ>-Ν-Γ(4-(Τ(ον3ηοΐΊΊ6ΐΐΊγΙ)3ΓηΙηο1πΊ6ϋΊγΙ>ργι^ΐη-2yl)methvl1carbamate (Ixv)

By General Procedure T from tert-butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N-{4[benzyl(cyclopropyl)amino]butyl)-carbamate (1 equiv.) and bromoacetonitrile (1.1 equiv.), using 2 equiv. DIPEA. Aqueous work up gave the title product, which was used without further purification.

Tert-butyl N-(^f4-Γ(2,2-difluorobutanamido)methvllρyridin-2-vll·methyl)-N-(ίT2(dimethvlamino)ethyll(ethyl)carbamoviy methvDcarbamate (IXVÎ)

By General Procedure Y from tert-butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N-({[2(dimethylamino)ethyl](ethyl)carbamoyl)-nriethyl)carbamate (prepared by synthetic route B (analogously to intermediate xii)) and 2,2-difluorobutanoic acid to get the title compound as colorless oil. ^XH NMR (300 MHz, CDCI3) δ 8.48 (m, 1H), 7.27 (m, 1H), 7.07 (m, 2H), 4.55 (m, 4H), 4.10 (m, 2H), 3.33 (m, 5H), 2.26 (m, 14H), 1.43 (m, 9H), 1.13 (m, 9H).

Tert-butyl (<Γ2-« N-r4-(diethvlamino)butvl1-2,2.2-trifluoroacetamido>methvl)pyridin-4γΙ1Γη6ίΐΊγΙ>ε3Η33ΓηογΠΐΌπη3ί6 (IxviD - General Procedure AA (Amide from acid chloride)

The acid chloride (tert-Butyl 2-chloro-2-oxoacetate (2 equiv.) was added dropwise to a solution of the amine or trifluoroacetamide (N-[4-(diethylamino)butyl]-2,2,2-trifluoro-N-({4[(trifluoroacetamido)methyl]pyridin-2-yl}methyl)acetamide) and DIPEA in anhydrous DCM at 0 °C. The mixture was allowed to warm to room température and stirred for 12 hours. Quenched with sat. NHaHCO₃ (aq.). Aqueous work up (in case of reaction from acetamide: basic workup (NaOH IN)) product as yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.50 (m, 1H), 7.35 (br s, 1H), 7.10 6.90 (m, 2H), 4.70 (m, 2H), 4.50 (m, 2H), 3.55 - 3.30 (m, 2H), 2.58 - 2.40 (m, 6H), 1.70 - 1.25 (m, 4H), 1.00 (m, 6H). ES-MS: 489.54 [M + 1],

139 tert-Butyl N-('<4-riN-cvclODropylcarboximidoyllpyridin-2-yl'}-methyl)-NΓ(dimethylcarbamoyl)methvllcarbamate (Ixviii)

By General Procedure F from tert-butyl N-[(dimethylcarbamoyl)methyl]-N-[(4-formylpyridin-2yl)methyl]carbamate (1.0 equiv.) and cyclopropylamine (1.2 equiv.). Evaporated to give the title product as yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.55 (d, IH), 8.52 (s, IH), 7.73 (s, IH), 7.56 (d, IH), 3.96 (s, 2H), 3.55 (s, 2H), 3.17 (m, IH), 2.96 (d, 6H), 1.00 (m, 4H). ES-MS: 261 [M+1J.

N-rfDimethYlcarbamovl)methvl1-2,2,2-trifluoro-N-f r4-(hydroxymethvl)pyridin-2-yl1 methyl Vacetamide (lxix)

General Procedure C from 2-({[4-(hydroxymethyl)pyridin-2-yl]methyl}amino)-N,N-dimethylacetamide gave the title product as yellow oil. ^rH NMR (300 MHz, chlorofbrm-d): δ ppm 8.45 (m, IH), 7.26 (m, 2H), 4.74 (m, 4H), 4.33 (m, 2H), 3.88 (s(br), IH), 2.92 (m, 6H).

N-r(DimethylcarbamoyDmethyl'|-2,2,2-trifluoro-N-r(4-formvlpyridin-2-vl)methyHacetamide flxx)

By General Procedure Q from N-[(dimethylcarbamoyl)methyl]-2,2,2-trifluoro-N-{[4(hydroxymethyl)pyridin-2-yl]methyl)-acetamide. Purification by column chromatography (EtOAc 3060% in DCM) gave the title product as yellow sticky oil. ^XH NMR (300 MHz, chiorofbrm-d): δ ppm 10.01 (d, IH), 8.74 (m, IH), 7.63 (m, 2H), 4.82 (m, 2H), 4.29 (m, 2H), 2.90 (m, 6H).

N-rfDimethvlcarbamovl)methyl'l-2,2,2-trifluoro-N-(-f4-r(N-(2-methvlcyclopropvl)carboximidoynpvridin2-yllmethyl)acetamide flxxi)

By General Procedure F from N-[(dimethylcarbamoyl)methyl]-2,2,2-trifluoro-N-[(4-formylpyridin-2yl)methyl]acetamide (1.0 equiv.) and 2-methylcyclopropan-l-amine (1.2 equiv.). Evaporation gave the title product as oil. Used with out further purification. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.56 (m, IH), 8.37 (m, IH), 7.52 (m, 2H), 4.84 (m, 2H), 4.36 (m, 2H), 2.99 (m, 6H), 2.78 (m, IH), 1.43 (m, IH), 1.25 (m, IH), 1.15 (m, 3H), 0.83 (m, IH).

ΙΉ-ΤΓίΙβΓί-ϋυίνΙΡίΓηβΑΊγΐΒίΙνΡοχνΊπΊβύΊνΙΪΡνΓίδΙη-Ζ-νΠπΊβΙΡγΙΙΙ^-ίπΓίβυΊγβυ^ΒηνΠβίΐΊγΠΒΓηΐηβ (Ixxii)

By General Procedure A from 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde and 2(methylsulfanyl)ethan-l-amine. Purification by column chromatography (DCM/Me0H/NH40H (90:10:1)) gave the title compound as yellow oil. ^XH NMR (300 MHz, Methanol-d4): δ 8.4 (d, IH), 7.3 (s, IH), 7.1 (d, IH), 4.7 (s, 2H), 3.9 (s, 2H), 2.7 (t, 2H), 2.6 (t, 2H), 2.58 (q, 2H), 1.2 (t, 3H), 0.9 (s, 9H).

140 r2-(<F2-(methvlsulfanyl')ethvl1amino'!-methvl)pvridin-4-vllmethanol (Ixxiii)

General Procedure P from [(4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methyl][2(methylsulfanyl)ethyl]amine gave the title compound as yellow oil. ^XH NMR (300 MHz, CDCI₃): δ 8.4 (d, 1H), 7.3 (s, 1H), 7.1 (d, 1H), 4.7 (s, 2H), 3.8 (s, 2H), 2.7 (t, 2H), 2.6 (t, 2H), 2.5 (q, 2H), 1.2 (t, 3H).

2-(ίΓ2-(πΊ61ΐΊνΐ5υΙί3ηνΙ)6ίΐΊνΠ3ηηίηο>ΠΊ6ϋΊνΙ)ρνπάΐη6-4-03Γδ3^6ΐ·^6 (Ixxiv)

By General Procedure Q from [2-({[2-(methylsulfanyl)ethyl]amino}methyl)pyridin-4-yl]methanol. The title compound was isolated after évaporation and used without further purification.

ylïmethyltcarbamate (Ixxv)

General Procedure F from tert-butyl N-{3-[benzyl(methyl)amino]propyl}-N-[(4-formylpyridin-2yl)methyl]carbamate (1.0 equiv.) and cyclopropanamine (2 equiv.). Purified by column chromatography (0-5% MeOH in DCM) to give the title compound.

Γ(4-< Γ(tert-Butvldimethvlsilyl)oxy1methvll·pvridin-2-yl)methyllΓf2E)-4-(dimethylamino)but-2-en-lvitamine flxxvi)

By General Procedure A from 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde (1.0 equiv.), [(2E)-4-aminobut-2-en-l-yl]dimethylamine hydrochloride (1.0 equiv.), and triethylamine (1.0 equiv.). Purification by column chromatography (0-10% MeOH in DCM) gave the title product as yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.45 (d, 1H), 7.20 (s, 1H), 7.11 (d, 1H), 5.67 (m, 2H), 4.68 (s, 2H), 3.85 (s, 2H), 2.89 (s, 2H), 2.19 (s, 6H), 0.89 (m, 9H), 0.07 (m, 6H).

tert-Butyl N-f(4-fΓ(tert-butvldίmethylsilvl)oxv1methvll·pvridin-2-vΠmethvlTN-Γ(2E)-4(dimethylaminotbut-2-en-l-vllcarbamate (Ixxvii)

By General Procedure R from [(4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methyl][(2E)-4(dimethylamino)but-2-en-l-yl]amine. Purification by column chromatography (10% MeOH and 1% NH₄OH in DCM) gave the title product as light yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.41 (m, 1H), 7.12 (m, 2H), 5.55 (m, 2H), 4.68 (s, 2H), 4.49 (m, 2H), 3.83 (m, 2H), 2.85 (m, 2H), 2.15 (s, 6H), 1.40 (m, 9H), 0.91 (s, 9H), 0.07 (s, 6H).

tert-Butvl N-r(2E)-4-(dimethvlamino)but-2-en-l-vl1-N-{T4-(hydroxvmethyl)pyridin-2vltmethylIcarbamate (Ixxviii)

By General Procedure P from tert-butyl N-[(4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2yl)methyl]-N-[(2E)-4-(dimethylamino)but-2-en-l-yl]carbamate. Purification by column chromatography (10% MeOH and 1% NH₄0H in DCM) gave the title product as light yellow oil. ^XH NMR

141 (300 MHz, chloroform-d): δ ppm 8.36 (d, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 5.50 (m, 2H), 4.61 (s, 2H),

4.48 (m, 2H), 3.82 (m, 2H), 2.80 (d, 2H), 2.09 (s, 6H), 1.39 (m, 9H).

tert-Butvl NT(2E)-4-(dimethvlamino)but-2-en-l-vl1-N-r(4-formvlpyridin-2-vl)methvllcarbamate (Ixxix)

By General Procedure Q from tert-butyl N-[(2E)-4-(dimethylamino)but-2-en-l-yl]-N-{[4(hydroxymethyl)pyridin-2-yl]methyl}carbamate. Evaporation gave the title product as yellow sticky oil. Used without further purification. ^XH NMR (300 MHz, chloroform-d): δ ppm 10.07 (d, 1H), 8.79 (m, 1H), 7.61 (m, 2H), 5.61 (m, 2H), 4.61 (m, 2H), 3.95 (m, 2H), 2.90 (m, 2H), 2.20 (s, 6H), 1.45 (m, 9H).

tert-Butvl Ν-('·Γ4ΤΝ-ενεΙορΓθρνΐΕ3Η3θχίΓηΐάονΠρνπάίη-2-νΙ'}·Γηβ1ΙινΠ-ΝΤ(2Ε)-4-(άΐΓηβίΙ'ΐνΐ3ηηίηο)δυί-2en-l-vllcarbamate (Ixxx)

By General Procedure F from tert-butyl N-[(2E)-4-(dimethylamino)but-2-en-l-yl]-N-[(4-formylpyridin2-yl)methyl]carbamate (1. Equiv.) and cyclopropanamine(1.2 equiv.). Evaporation gave the title product as oil. Used without further purification. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.53 (d, 1H), 8.38 (s, 1H), 7.43 (m, 2H), 5.61 (m, 2H), 4.51 (m, 2H), 3.89 (m, 2H), 3.06 (m, 1H), 2.94 (m, 2H), 2.24 (s, 6H), 1.44 (m, 9H), 0.99 (m, 4H).

tert-Butvl N-r4-(azetidin-l-yDbutyl'l-N-(-f4T(N-cvdopropYlcarboximidoyllpyridin-2vlïmethyncarbamate (Ixxxi)

General Procedure F from tert-butyl N-[4-(azetidin-l-yl)butyl]-N-(4-formylpyridine-2carbonyl)carbamate (1.0 equiv.) and cyclopropylamine (5 equiv.). Evaporation gave the title product, which was used without without further purification. ^-NMR (300MHz, CDCh): δ 8.50 (d, 1H), 8.35 (s, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 4.50 (m, 2H), 3.20 (m, 2H), 3.00 (m, 2H), 2.90 (m, 2H), 2.10 (m, 2H), 1.70 (m, 2H), 1.45 (m, 15H), 1.00 (m, 4H) ppm.

Γ(4-<Γftert-ButyldimethylsilyΠoxv1methvll·pyridin-2-ynmethγl1Γ4-(dimethylamino)butyllamine (Ixxxii)

By General Procedure A from 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde and (4aminobutyl)dimethylamine. Purification by column chromatography (DCM/MeOH (95:5)) gave the title compound as greenish oil. ¹H-NMR (300MHz, CDCI3): δ 8.48 (d, 1H), 7.25 (s, 2H), 7.10 (d, 1H), 4.70 (s, 2H), 3.90 (s, 2H), 2.60 (m, 2H), 2.30 (m, 2H), 2.20 (s, 6H), 1.50 (m, 4H), 1.00 (s, 9H, 0.9 (s, 9H), 0.1 (s, 6H) ppm.

142

N-r(4-<r(tert-Butvldimethvlsilvlk>xv'|methvl}pyridin-2-vl)rnethvl1-N-r4-(dimethvlamino)butvll-2,2,2trifluoroacetamide (Ixxxiii)

By General Procedure C from [(4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methyl][4(dimethylamino)butyl]amine. Evaporation gave the title compounds, which was used without further purification.

Ν-Γ4-(ΡΐΠΊ6ίΐΊνΐ3πηΐηο)ΡυίνΠ-2.2.2-ίπί1υθΓθ-Ν-(Τ4-(Ι'ηΛ1Γθχνπη6ίΐΊνΠρνπΡΐη-2-νΠπΊ61ΐΊνΙ>3θ6ί3ηΊίά6 (Ixxxiv)

By General Procedure P from N-[(4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methyl]-N-[4(dimethylamino)butyl]-2,2,2-trifluoroacetamide. Purification by column chromatography (DCM/MeOH (90:10)) gave the title compound as greenish oil. ^XH-NMR (300MHz, CDCh): δ 8.40 (m, 1H), 7.30 (m, 1H), 7.20 (m, 1H), 4.70 (m, 4H), 3.45 (m, 2H), 2.20 (m, 6H), 2.00 (s, 2H), 1.50 (m 4H) ppm.

N-r4-(Dimethylamino)butvl1-2,2,2-trifluoro-N-rf4-formylpvridin-2-yl)methvnacetamide (Ixxxv)

By General Procedure V from N-[4-(dimethylamino)butyl]-2,2,2-trifluoro-N-{[4(hydroxymethyl)pyridin-2-yl]methyl}acetamide. Aqueous work up gave the title compound as light yellow oil. ^XH-NMR (300MHz, CDCI3): δ 10.0 (s, 1H), 8.80 (d, 1H), 7.55 (s, 2H), 4.80 (m, 2H), 3.50 (m, 2H), 2.25 (m, 2H), 2.20 (s, 6H), 1.70 (m, 2H), 1.50 (m, 2H) ppm.

Ν-(·(4-Γ(Ν-ΟνοΙορΓθρνΙθ3ήκ>χΐηηίΡονΙ1ρνΓΐΡΐη-2-νΙ>ιτΐ61Ι·ΊνΙ)-Ν-Γ4-(άίηπ6υΊνΐ3ΠΊίηο^υ1νΙ'|-2,2,2trifluoroacetamide (Ixxxvi)

By General Procedure F from N-[4-(dimethylamino)butyl]-2,2,2-trifluoro-N-[(4-formylpyridin-2yl)methyl]acetamide (1.0 equiv.) and cyclopropylamine (5 equiv.). Evaporation gave the title product, which was used without further purification. ^-NMR (300MHz, CDCh): δ 8.65, 8.50 (d, 1H), 8.45, 8.40 (s, 1H), 7.45 (m, 2H), 4.70 (m, 2H), 3.00 (m, 2H), 2.75 (m, 1H), 2.55 (s, 6H), 1.80 (m, 1H), 1.50 (m, 5H), 1.00 (m, 4H) ppm.

EthyLZsiliSshydroxYpentyljaminplmethYllEYndinez^sçarboxYiateJbgomi)

Prepared by General Procedure A from ethyl 2-formylpyridine-4-carboxylate (1.0 equiv.) and 5aminopentan-l-ol (1.2 equiv.). Purification by column chromatography (DCM/MeOH (85:15) gave the title compound as greenish oil. ^XH-NMR (300MHz, CDCI₃): δ 8.60 (d, 1H), 7.80 (s, 1H), 7.00 (d, 1H), 4.30 (q, 2H), 3.90 (s, 2H), 3.50 (t 2H), 3.10 (s, 2H), 2.60 (m, 2H), 1.50 (m, 4H), 1.30 (t, 3H) ppm.

Ethyl 2-(-(r(tert-butoxv)carbonvll(5-hvdroxvpentvl)amino'}-methvl)Dvridine-4-carboxvlate (Ixxxviii)

Prepared by General Procedure R from ethyl 2-{[(5-hydroxypentyl)amino]methyl}pyridine-4carboxylate. Evaporation gave the title product as white solid. Used without further purification. ^XH17463

143

NMR (300MHz, CDCh): δ 8.60 (d, 1H), 7.75 (s, 1H), 7.60 (d, 1H), 4.50 (m, 2H), 4.30 (q, 2H), 3.50 (t

2H), 3.20 (m, 2H), 2.20 (m, 1H), 1.60-1.20 (m, 18H) ppm.

Ethyl 2-(^,<r(tert-butoxv)carbonvll(5-oxopentvl)amino)methvl)pvridine-4-carboxvlate (Ixxxix)

Prepared by General Procedure Q from Ethyl 2-({[(tert-butoxy)carbonyl](5hydroxypentyl)amino}methyl)pyridine-4-carboxylate. Purification by column chromatography (EtOAc/hexane 20-50%) gave the title product. ¹H-NMR (300MHz, CDCI₃): δ 9.70 (s, 1H), 8.60 (d, 1H), 7.75 (s, 1H), 7.60 (d, 1H), 4.50 (m, 2H), 4.40 (q, 2H), 3.20 (m, 2H), 2.45 (m, 2H), 1.70-1.30 (m, 17H)ppm.

Ethyl 2-(·{'Γ(ί6Γΐ-Ρυ1οχγ)ε3Η3οηγΙΊΓ5-^ΐΠΊβ1ΐΊγΐ3ηιΐηο)ρ6ηίνΠ3ΠΊΐηο'ί·Γη6ίΐΊνΡρνΐΊάΐηβ-4-ε3ΓΡοχνΐ3ί6 fxc)

Prepared by General Procedure A from ethyl 2-«[(tert-butoxy)carbonyl](5oxopentyl)amino)methyl)pyridine-4-carboxylate (1.0 equiv.), dimethylamine hydrochloride (1.2 equiv.), and triethylamine (1.3 equiv.). Purification by column chromatography (MeOH/DCM (5:95)) gave the title compound as colorless oil. ¹H-NMR (300MHz, CDCI3): δ 8.50 (d, 1H), 7.60 (s, 1H), 7.50 (d, 1H), 4.50 (d, 2H), 4.20 (q, 2H), 3.05 (m, 2H), 2.01 (s, 6H), 1.50-1.05 (m, 20H) ppm.

tert-Butyl N-Γ5-(dimethvlamino)pentyl'l-N~ί'Γ4-(hvdroxymethvl)pvridin-2-yl1methvll·carbamate fxci)

Prepared by General Procedure U from ethyl 2-({[(tert-butoxy)carbonyl][5(dimethylamino)pentyl]amino)methyl)pyridine-4-carboxylate. Purification by column chromatography (NH₄0H MeOH/DCM (5:10:85)) gave the title compound as colorless viscous oil. ^XH-NMR (300MHz, CDCI3): δ 8.40 (d, 1H), 7.20 (s, 1H), 7.10 (d, 1H), 4.65 (s, 2H), 4.40 (m, 2H), 3.20 (m, 2H), 2.20 (m, 2H), 2.10 (s, 6H), 1.50-1.20 (m, 15H) ppm.

tert-Butvl N-r5-(dimethvlamino)pentyl1-N-[(4-formylpvridin-2-yl)methvl1carbamate (xcii)

Prepared by General Procedure Q tert-butyl N-[5-(dimethylamino)pentyl]-N-{[4(hydroxymethyl)pyridin-2-yl]methyl}carbamate. ^XH-NMR (300MHz, CDCI3): δ 10.05 (s, 1H), 8.70 (d, 1H), 7.50 (m, 2H), 4.50 (m, 2H), 3.20 (m, 2H), 2.40 (s, 6H), 1.60-1.00 (m, 15H) ppm.

tert-Butvl N-(-i'4-FN-cyclopropvlcarboximidoynpyridin-2-vl'Î-methyl')-N-r5(dimethvlamino)pentyl'lcarbamate (xciii)

Prepared by General Procedure F from tert-butyl N-[5-(dimethylamino)pentyl]-N-[(4-fbrmylpyridin-2yl)methyl]carbamate (1 equiv.) and cyclorpropylamine (5 equiv.). Evaporation gave the title product, which was used without further purification. ¹H-NMR (300MHz, CDC1₃): δ δ 8.50 (d, 1H), 8.40 (s, 1H), 7.45 (m, 2H), 4.45 (m, 2H), 3.10 (m, 4H), 2.75 (m, 2H), 2.60 (s, 6H), 1.80 (m, 1H), 1.45 (m, 13H), 0.95 (m, 4H) ppm.

144

Ethyl 2-ίΓΝ-(<r4-(diethvlamino)but?/l1carbamovl)methvl')-2,2,2-trifluoroacetamido1methvl'Î-pyridine-4carboxylate (xciv)

By General procedure Y from (4-aminobutyl)diethylamine and 2-(N-{[4-(ethoxycarbonyl)pyridin-2yl]methyl}-2,2,2-trifluoroacetamido)acetic acid. Purification by column chromatography gave the title compound as oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 9.09 (t, IH), 8.67 (m, IH), 7.83 (m, 2H), 4.85 (m, 2H), 4.42 (q, 2H), 4.17 (m, 2H), 3.26 (m, 2H), 2.46 (m, 6H), 1.52 (m, 4H), 1.40 (t, 3H), 0.97 (m, 6H).

N-r4-(Diethvlamino)butvll-2-(-f r4-(hvdroxvmethvDpvridin-2-yllmethvl)amino)acetamide (xcv)

Prepared by General Procedure U from ethyl 2-{[N-«[4-(diethylamino)butyl]carbamoyl}methyl)-2,2,2trifluoroacetamido]methyl}pyridine-4-carboxylate, using 5 équivalents of NaBH₄. Purification by column chromatography with (10% MeOH and 1% NH₄OH in DCM) gave the title product as light yellow oil. ^XH NMR (300 MHz, methanol-d₄): δ ppm 8.45 (d, IH), 7.47 (s, IH), 7.31 (d, IH), 4.68 (s, 2H), 3.88 (s, 2H), 3.28 (m, 4H), 2.59 (q, 4H), 2.51 (m, 2H), 1.52 (m, 4H), 1.05 (t, 6H).

tert-Butvl N-(/r4-(diethvlamino)butyl~|carbamovl>nnethvl)-N-i r4-(hvdroxymethyl)pyridin-2vllmethyn-carbamate (xcvi)

Prepared by General Procedure R from N-[4-(diethylamino)butyl]-2-«[4-(hydroxymethyl)pyridin-2yl]methyl}amino)acetamide. Purification by column chromatography with (0-20% MeOH in DCM) gave the title product as light yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.55 (s, IH), 8.47 (m, IH), 7.38 (s, IH), 7.33 (m, IH), 4.69 (s, 2H), 4.61 (m, 2H), 3.99 (m, 2H), 3.58 (t, 0.5H), 3.22 (m, IH), 2.97 (m, 5H), 2.25 (t, 0.5 H), 1.82 (m, IH), 1.64 (m, 4H), 1.36 (m, 9H), 1.22 (m, 6H).

tert-Butvl Ν-ί/Μ-ίάίβΟΊνίΒΠΐΐηο^υΙνΙΙεΒΓόβΓηονΗ-αιβϋινΠ-Ν-ΓΜ-ίοπιηγΙρνπάίη-Σ-νΡΓηΒίΙιγΙΙσβΗχιπηΒΐβ (xcvii)

Prepared by General Procedure Q from tert-butyl N-«[4-(diethylamino)butyl]carbamoyl}methyl)-N{[4-(hydroxymethyl)pyridin-2-yl]methyl}carbamate. Evaporated to give the title product as a yellow oil, which was used without further purification. ^XH NMR (300 MHz, chloroform-d): δ ppm 11.8 (m, 0.5H), 10.1 (s, IH), 9.17 (m, 0.5H), 8.80 (m, IH), 7.68 (m, 2H), 4.67 (m, 2H), 4.05 (m, 2H), 3.36 (m, 2H), 3.05 (m, 6H), 1.91 (m, 2H), 1.66 (m, 2H), 1.38 (m, 9H), 1.17 (m, 6H).

tert-Butvl Ν-(/'4-ΓΝ-€νΗορΓθρνΐ€3^οχίΓηι^ονΙ1ρνηάίη-2-νΙ)η6ίΚνΙ)-Ν-«Γ4(diethvlamino'lbutvllcarbamoyl'l-methyl’lcarbamate (xcviii)

Prepared by General Procedure F from tert-butyl N-«[4-(diethylamino)butyl]carbamoyl}methyl)-N-[(4formylpyridin-2-yl)methyl]carbamate and cyclopropyl amine. Evaporated to give the title product as yellow oil, which was used without further purification. ^XH NMR (300 MHz, chloroform-d): δ ppm 9.60

145 (t, 1H), 8.51 (m, 1H), 8.39 (s, 1H), 7.46 (m, 2H), 4.53 (m, 2H), 3.97 (m, 2H), 3.48 (m, 1H), 3.32 (m,

2H), 2.94 (m, 6H), 1.80 (m, 2H), 1.61 (m, 1H), 1.33 (m, 9H), 1.08 (m, 6H).

Ethyl 2-f^-(Ρ^β^νίΒωίηο^β^γΙΙίβίΐΊνΡεΒΓόΒίτιονβπΊΒΟ'ΐνΙ'ΙάΠΊίηοΙπΊβίΐΊνβργπόίηβ-Α-εΒΓίιοχνΙβίε (xcix)

By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and 2-amino-N-[2(dimethylamino)ethyl]-N-ethylacetamide. ^XH NMR (300 MHz, CDCh), δ ppm: 3.47-3.32 (m, 4H), 3.273.20 (m, 2H), 2.44-2.35 (m, 2H), 2.22 (s, 6H), 1.53 (s, 2H), 1.15-1.06 (m, 3H).

N-r2-(dimethylamino)ethvl'l-N-ethvl-2-(<r4-(hvdroxymethvl)Dyridin-2-vl'lmethyl'Î-amino)acetamide (c)

By General Procedure U from ethyl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-carboxylate. ^XH NMR (300 MHz, CDCI₃), δ ppm: 8.45 (d, 1H), 7.39 and 7.36 (2 singlets, 1H), 7.14 (d, 1H), 4.67 (s, 2H), 3.94 (s, 2H), 3.54-3.47 (m, 4H), 3.32-3.24 (m, 2H), 2.602.40 (m, 2H), 2.37 and 2.24 (2 singlets, 6H), 1.18-1.10 (m, 3H).

tert-Butyl N-(fr2-(dimethylamino)ethvll(ethyl)carbamoyl)-methyl)-N-fr4-(hydroxymethyl)Dvridin-2yllmethyllcarbamate (ci)

By General Procedure R from N-[2-(dimethylamino)ethyl]-N-ethyl-2-({[4-(hydroxymethyl)pyridin-2yl]methyl}amino)acetamide. ^XH NMR (300 MHz, CDCI₃), δ ppm: 8.49 (d, 1H), 7.37 and 7.32 (2 singlets, 1H), 7.19 (d, 1H), 4.73 (s, 2H), 4.67 and 4.63 (2 singlets, 2H), 4.20 and 4.07 (2 singlets, 2H), 3.48-3.22 (m, 4H), 2.49-2.39 (m, 2H), 2.27 and 2.23 (2 singlets, 6H), 1.46 and 1.41 (2 singlets, 9H), 1.21-1.09 (m, 3H).

tert-butyl Ν-(·(Γ2-(όΐιτΐ6ίΐΊνΐ3ΐΊΊΐηο)6ίΐΊνΠ(6ΐΐΊγΙ)ο3Γ63ΠΊονΙ>πΊ6ϋΊνΙ)-Ν-Γ(4-(οπ·ηνΙρνπόΐη-2yl)methyl]carbamate (cii)

By General Procedure Q from tert-buty-N-({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)-N-{[4(hydroxymethyl)pyridin-2-yl]methyl}carbamate. ^XH NMR (300 MHz, CDCI₃), δ ppm: 10.07 and 10.06 (2 singlets, 1H), 8.78 and 8.75 (2 doublets, 1H), 7.80 and 7.74 (2 doublets, 1H), 7.58 and 7.57 (2 singlets, 1H), 4.75 and 4.70 (2 singlets, 2H), 4.24 and 4.09 (2 singlets, 2H), 3.54-3.21 (m, 4H), 2.602.39 (m, 2H), 2.37, 2.33 and 2.22 (3 singlets, 6H), 1.44 and 1.36 (2 singlets, 9H), 1.23-1.08 (m, 3H).

N-r2-(dimethvlamino)ethvn-N-ethvl-2-(~ri4-formylpyridin-2-yl)methyl'lamino')-acetamide (ciii)

By General Procedure D from tert-butyl-N-({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)-N-[(4formylpyridin-2-yl)methyl]carbamate. ^XH NMR (300 MHz, CD3OD), δ ppm: 8.94 (d, 1H), 8.42 (s, 1H), 8.17 (dd, 1H), 5.79 (s, 1H), 4.85 (s, 2H), 4.44 (s, 2H), 3.86 (t, 2H), 3.49-3.41 (m, 4H), 2.99 (s, 6H), 1.29 (t, 3H).

146

Tert-butyl N-(i4-r5-benzvl-3-(trifluoroacetvl)-l,3-oxazinan-2-vl]pvridin-2-vl>methvl')-N-(<r2(άίηιβΙΐΊνίΒΓηίηοΙβϋΊνΙΙίθίΐΊνΙΊΕΒΓϋάηίΊονΙΙηΊβΙΚγΙίΕΒΓόάΓηΒίβ (civ) - General Procedure AB (Préparation of N-acyl-l,3-oxazinanes]

Optionally substituted 3-aminopropanol (3-amino-2-phenylpropan-l-ol) (1.1 eq) was added to a stirred solution of aldéhyde (tert-butyl N-«[2 (dimethylamino)ethyl] (ethyl)carbamoyl}methyl)-N-[(4formylpyridin-2-yl)methyl]carbamate) (1.0 eq) in toluene. Stirred at room température for 2 h.

Anhydride (trifluoroacetic anhydride) (1.5 equiv.) was added dropwise to the solution followed by 5 équivalent of DIPEA. The mixture was heated at 80°C for two hours. Aqueous work up and purification by HPLC (0.1% TFA solution/MeOH) gave the title product. ^XH-NMR (300MHz, CD₃OD): δ 8.50 (d, 1H ), 7.45 (m, 1H), 7.25 (m, 6H), 4.60 (s, 2H), 4.30 (m, 2H), 3.70 (m, 3H), 2.90 (s, 6H), 1.50 (s, 9H), 1.30 (t, 3H) ppm. ES-MS: 636 [M+1]

Ethyl 2-(Γ(<4-['^ΐΓη61ΐΊγΐ3Γηΐηο)Γη61ΐΊνΙ1ενάοΐΊ6χνΙ>ηη61ΐΊνΙ]3ηΓΐΐηο'|ιιη61ΐΊνΙ>ργ»^ίη6-4-ε3ΐΐ>οχγΐ3ΐ6 (cv~)

By General Procedure A from ethyl 2-formylpyridine-4-carboxylateand {4[(dimethylamino)methyl]cyclohexyl}methanamine. Aqueous work up gave the title compound as a yellow oil. Used without further purification. ¹H NMR (300 MHz, chloroform-d): δ ppm 8.41 (d, 1H), 8.04 (s, 1H), 7.49 (d, 1H), 4.04 (q, 2H), 3.39 (s, 2H), 2.46 (m, 4H), 2.38 (d, 6H), 1.60 (m, 4H), 1.34 (t, 3H), 1.03 (m, 2H), 0.68 (m, 4H).

Ethyl 2-(·(Γ(ΐ6ΐΐ^υΐοχνΧ:3Ηχ>ηγΙ1(·ί4-Γ^ίΓη6ΐ1Ίνΐ3ΠΊίηο)ΐ'η6ΐΐΊγΙ1ονυοΐΊ6χνΙ>ΠΊ6ίΐΊγΙ)3ΠΊίηο>methvl)pyridine-4-carboxylate (cvi)

By General Procedure R from ethyl 2-{[({4[(dimethylamino)methyl]cyclohexyl}methyl)amino]methyl}pyridine-4-carboxylate. Purification by column chromatography (0-10% MeOH in DCM) gave the title product as light yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.62 (m, 1H), 7.71 (m, 2H), 4.56 (m, 2H), 4.36 (m, 2H), 3.11 (m, 2H), 2.17 (s, 6H), 2.05 (m, 2H), 1.74 (m, 4H), 1.40 (m, 14 H), 0.85 (m, 4H).

tert-Butvl Ν-(<4-Γ^ΐΠΊβθΊνΐ3ΠΊΐηο)Γη6ίΐΊγΙ'ΐ€γυοΐΊ6χγΙ>Γη6ίΐΊνΙ)-Ν-(Γ4-(>ΊνδΓθχνΓη6ΐΐΊνΙ)ρνπδΐη-2vllmethyiycarbamate (cvii)

By General Procedure U from ethyl 2-«[(tert-butoxy)carbonyl]({4[(dimethylamino)methyl]cyclohexyl}methyl)amino}methyl)pyridine-4-carboxylate) (1.0 equiv.) in EtOH. Stirred at reflux for 2 hours. Cooled to room température and sat. NH₄Ci solution was added. Evaporated to dryness. Purification by column chromatography (DCM, MeOH (10%) and HN₄OH (1 %)) gave the title product as light yellow oil. ^XH NMR (300 MHz, chloroform-d): δ ppm 8.41 (d, 1H), 7.17 (m, 2H), 4.65 (s, 2H), 4.50 (d, 2H), 3.10 (m, 2H), 2.17 (s, 6H), 2.07 (d, 2H), 1.74 (m, 4H), 1.41 (m, 11H), 0.87 (m, 4H).

147 tert-Butvl N-ÎM-ridimethylamino^ethvllcvclohexyiymethvD-N-r^-formylpvridin^vDmethyllcarbamate (cviii)

General Procedure Q from tert-butyl N-«4-[(dimethylamino)methyl]-cyclohexyl}methyl)-N-{[4(hydroxymethyl)pyridin-2-yl]methyl}carbamate gave the title product as yellow sticky oil without further purification. ^XH NMR (300 MHz, chloroform-d): δ ppm 10.07 (s, IH), 8.79 (m, IH), 7.61 (m, 2H), 4.63 (d, 2H), 3.18 (m, 2H), 2.22 (s, 6H), 2.10 (d, 2H), 1.79 (m, 4H), 1.45 (m, 11H), 0.91 (m, 4H).

Ethyl 2-(-fΓ(2Z)-4-fdimethvlamino)but-2-en-l-vl1aminol·methvl)pvridine-4-carboxvlate fcix)

By General Procedure A from ethyl 2-formylpyridine-4-carboxylate, (Z)-Nl,Nl-dimethylbut-2-ene-l,4diamine. Purification by column chromatography (DCM/MeOH/NH₄OH, 90:10:1) gave the title compound as yellow viscous oil. ^XH NMR (300 MHz, CDCI₃): δ 8.8 (d, IH), 7.8 (s, IH), 7.7 (d, IH), 5.7 (m, 2H), 4.34 (q, 2H), 4.0 (s, 2H), 3.4 (d, 2H), 2.9 (d, 2H), 2.2 (s, 6H), 1.32 (t, 3H).

Γ2-(<Γ(2Z)-4-(Dimethvlamiπo)but-2-en-l-vllaminol·methyl)pvridin-4-vl1methanol (ex)

By General Procedure U from ethyl 2-({[(2Z)-4-(dimethylamino)but-2-en-l-yl]amino}methyl)pyridine4-carboxylate. Purification by column chromatography (DCM/MeOH/NH₄OH, 85:15:1 gave the title compound as yellow viscous oil. ¹H NMR (300 MHz, CDCI₃): δ 8.5 (d, IH), 7.2 (s, IH), 7.1 (d, IH), 5.8 (m, 2H), 5.4 (s, 2H), 3.9 (s, 2H), 3.4 (d, 2H), 2.9 (d, 2H), 2.2 (s, 6H).

tert-Butvl N-rf2Z)-4-fdimethvlamino)but-2-en-l-vl1-N-fr4-(hvdroxvmethvl)pyridin-2yllmethylIcarbamate (exi)

By General Procedure R from [2-({[(2Z)-4-(dimethylamino)but-2-en-l-yl]amino}methyl)pyridin-4yl]methanol. Evaporation gave the title compound as a colorless glue, which was used without further purification. ^XH NMR (300 MHz, CDCh): δ 8.5 (d, IH), 7.2 (s, IH), 7.1 (d, IH), 5.8 (m, 2H), 4.6 (s, 2H), 4.4 (s, 2H), 3.9 (s, 2H), 2.9 (d, 2H), 2.2 (s, 6H), 1.3 (s, 9H).

tert-Butvl N-r(2Z)-4-(dimethylamino)but-2-en-l-vll-N-r(4-formylpyridin-2-vDmethyllcarbamate (exii)

By General Procedure Q from tert-butyl-N-[(2Z)-4-(dimethylamino)but-2-en-l-yl]-N-{[4(hydroxymethyl)pyridin-2-yl]methyl}carbamate. ^XH NMR (300 MHz, CDCh), (rotamers): δ 10.1 (s, IH), 8.8 (d, IH), 7.5 (m, 2H), 5.8 (m, 2H), 4.6 (s, 2H), 3.9 (s, 2H), 2.9 (d, 2H), 2.2 (s, 6H), 1.3 (s, 9H).

148

Ethyl 2-r(2,2,2-trifiuoro-N-f2-oxo-2-r(2R)-2-(pvrrolidin-l-vlmethvl)pvrrolidin-l-yl1ethvl')acetamido)methvllpyridine-4-carboxvlate (cxiii)

General Procedure Y from (2R)-2-(pyrrolidin-l-ylmethyl)pyrrolidine and 2-(N-{[4(ethoxycarbonyl)pyridin-2-yl]methyl}-2,2,2-trifluoroacetamido)acetic acid gave the title product as yellow oil, which was used without further purification.

2-(<Γ4-(Hvdroxvmethvl)pvridin-2-vl1methvll·amino)-l-Γί2R)-2-(pvrrolidin-l-vlmethvl)Pvrrolidin-lyllethan-l-one (cxiv)

Prepared by General Procedure U from ethyl 2-[(2,2,2-trifluoro-N-{2-oxo-2-[(2R)-2-(pyrrolidin-lylmethyl)pyrrolidin-l-yl]ethyl}acetamido)methyl]pyridine-4-carboxylate, using 5 equiv. of NaBH₄. The residue was purified by column chromatography on silica gel using NH₄OH(2%) + MeOH (20%) in CH2CI2 to give the title as yellow oil. ^XH NMR (300 MHz, CD3OD), δ ppm: 8.44 (d, 1H), 7.49 (s, 1H), 7.31 (d, 1H), 4.90 (s, 2H), 4.69 (s, 2H), 4.24 (m, 1H), 3.93 (s, 2H), 3.50-3.36 (m, 3H), 2.67-2.42 (m, 6H), 2.06-1.89 (m, 4H), 1.84-1.72 (s, 4H). ESI-MS (m/z): 333 [M+1J.

tert-Butyl Ν--Γr4-(^,hydroxvmethyl)pyridin-2-vllmethvl'Î--N-r2-oxo-2-rf2R)-2-ÎPvrrolidin-lYlmethyDpyrrolidin-l-ynethylIcarbamate fcxv)

Prepared by General Procedure R from 2-({[4-(hydroxymethyl)pyridin-2-yl]methyl}amino)-l-[(2R)-2(pyrrolidin-l-ylmethyl)pyrrolidin-l-yl]ethan-l-one. Purified by column chromatography on silica gel using NH₄0H (1.5%) + MeOH (15%) in CHzChto give the title compound as brown oil. ^XH NMR (300 MHz, CDCh), δ ppm: 8.44 (d, 1H), 7.35 and 7.31 (2 singlets, 1H), 7.18 (d, 1H), 4.71 and 4.68 (2 singlets, 2H), 4.61 (s, 2H), 4.29 (m, 1H), 4.08 and 4.07 (2 singlets, 2H), 3.95 (m, 1H), 3.48-3.01(m, 7H), 2.87 (m, 1H), 2.35 (m, 1H), 2.07-1.93(m, 7H), 1.43 and 1.41 (2 singlets, 9H). ESI-MS: 433 [M + l].

tert-Butyl N-r(4-formvlpvridin-2-vl)methvl1-N-f2-oxo-2-r(2R)-2-(pvrrolidin-l-vlmethvl)pyrrolidin-lyllethvlj-carbamate (cxvi)

General Procedure V from 2-«[4-(hydroxymethyl)pyridin-2-yl]methyl}amino)-l-[(2R)-2-(pyrrolidin-lylmethyl)pyrrolidin-l-yl]ethan-l-one gave the title compound as yellow oil. ^XH NMR (300 MHz, CDCh), δ ppm: 10.09 (s, 1H), 8.78 (m, 1H), 7.81 (m, 1H), 7.60 (m, 1H), 4.87-4.51 (m, 2H), 4.42- 3.87 (m, 2H), 3.66-3.17 (m, 3H), 2.80-2.38 (m, 6H), 2.17-1.74 (m, 8H), 1.46 and 1.39 (2 singlets, 9H).

Ethyl 2-(·ίΤ(16ΐ1:^υίοχν)θ3Η3οηνΙ1ί4-οχοδυΙγΙ)3ΠΊΐηο>ιτΐ6ίΐΊνΙ)ρνι^ΐη6-4-€3Η3θχνΐ3ί6 (cxvii)

By General Procedure Q from ethyl 2-({[(tert-butoxy)carbonyl](4-hydroxybutyl)amino}methyl)pyridine-4-carboxylate. Purified by column chromatography (ethyl acetate/hexane 20-40%) to give the

149 title product. ¹H-NMR (300MHz, CDCI₃): δ 9.70 (s, 1H), 8.60 (d, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 4.55 (d, 2H), 4.40 (q, 2H), 3.40 (m, 2H), 2.480 (m, 2H), 1.85 (m, 2H), 1.50-1.20 (m, 12H) ppm.

Ethyl 2-r(<4-rbenzvl(cvclopropvl)amino1butvlir(tert-butoxv)carbonvnamino)methvllpyridine-4carboxylate fcxviii)

By General Procedure A from ethyl 2-({[(tert-butoxy)carbonyl](4-oxobutyl)amino}methyl)pyridine-4carboxylate and N-benzylcyclopropanamine. Purification by column chromatography (5% MeOH/DCM) gave the title compound as colorless oil. ¹H-NMR (300MHz, CDC1₃): δ 8.60 (d, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 7.10 (m, 5H), 4.50 (d, 2H), 4.40 (q, 2H), 3.50 (m, 2H), 3.15 (m, 2H), 2.50 (m, 2H), 1.60 (m, 1H), 1.45 (m, 16H), 0.4 (m, 4H) ppm.

tert-Butyl N-f4-rbenzvl(cycloproDvl)aminolbutvl>-N-f r4-(hvdroxvmethvl)pvridin-2yl~)methyl~i-carbamate (cxix)

By General Procedure U from ethyl 2-[({4-[benzyl(cyclopropyl)amino]butyl}[(tertbutoxy)carbonyl]amino)methyl]pyridine-4-carboxylate. Purification by column chromatography (DCM, MeOH and HN₄OH (85; 10:5)) gave the title product as viscous oil. ^-NMR (300MHz, CDCI₃): δ 8.45 (d, 1H), 7.20 (m, 6H), 7.00 (d, 1H), 4.70 (m, 2H), 4.50 (m, 2H), 3.60 (m, 2H), 3.10 (m, 2H), 2.40 (m, 2H), 1.55 (m, 2H), 1.40 (m, 13H) ppm.

tert-Butvl N-f4-Γbenzyl(cvclopropyl)aminolbutyll·-N-Γ(4-formylpvridin-2-yl)methylΊcarbamate (cxx)

By General Procedure Q from tert-butyl N-{4-[benzyl(cyclopropyl)amino]butyi}-N-{[4(hydroxymethyl)pyridin-2-yl]methyl}carbamate. Purification by column chromatography (ethyl acetate/hexane 20-50%) gave the title product. ^XH-NMR (300MHz, CDCI₃): δ 10.0 (s, 1H), 8.70 (d, 1H), 7.50 (m, 2H), 7.20 (m, 5H), 4.50 (m, 2H), 3.80 (m, 2H), 3.15 (m, 2H), 2.50 (m, 2H), 1.60 (m, 2H), 1.45 (m, 12H), 0.40 (m, 4H) ppm.

Reaqents

Methyl 4-<Γ(ί6ΐ·ί^υίνΜΐΓη6ΑΊνΐ5ΐΙγΙ)οχν1ιη6ίΚγΙ>ρνΐΊάίη6-2-αή3θχγΐ3ί6 - General Procedure AC (Formation of Silvl Ether)

Tert-butyldimethylsilyl chloride (1.2 equiv) was added to a solution of alcohol (4(hydroxymethyl)pyridine-2-carboxylate) (l.equiv.), triethylamine (2.30 equiv.) and 4dimethylaminopyridine (0.10 equiv.) in dichloromethane at 0 °C., Stirred at room température ovemight. Aqueous work up and purification by flash chromatography (Hexane-EtOAc, 5-25 %) gave the title compound as colorless oil. ¹H-NMR (300MHz, CD₃OD): δ 8.60 (d, 1H), 8.15 (s, 1H), 7.60 (d, 1H), 4.88 (s, 2H), 3.97 (s, 3H), 0.98 (s, 9H), 0.15 (s, 6H).

150

4-<Γ(16ΐΐ-ϋυΐνΙ<1ίω61ήνΐ5ΐΙνΠοχν1ω6ίήνΙ>ρνπ<1ΐη6-2-ε9Γΰ3ΐό6Μνά6

By General Procedure K from methyl 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carboxylate (1 equiv.). Aqueous work up gave the title compound, which was used without further purification. ^XHNMR (300MHz, CDCI₃): δ 10.11 (s, 1H), 8.75 (d, 1H), 7.92 (s, 1H), 7.54 (d, 1H), 7.27 (s, 1H), 4.83 (s, 2H), 0.98 (s, 9H), 0.15 (s, 6H).

Ethyl 2-rfchlorocarbonvl)oxylbenzoate - General Procedure AD (acid chloride from carboxylic acid)

The carboxylic acid (Ethyl 2-hydroxybenzoate) (1 eq) in toluene was cooled to 0 °C, N, N-dimethyl amine (leq) was added, phosgene (1 eq) was added dropwise and stirred at same température for 2 h. The solid was filtered off and the filtrate was concentrated and used as reagent without further purification.

2-amino-(N-r2-(dimethvlamino)ethyll-N-ethvl)acetamide

By General Procedure Y from 2-{[(tert-butoxy)carbonyl]amino}acetic acid and [2(dimethylamino)ethyl](ethyl)amine. The product was treated with concentrated hydrochloric acid to get the title compound as hydrochloric acid sait. ^XH NMR (300 MHz, CDCh), δ ppm: 3.47-3.32 (m, 4H), 3.27-3.20 (m, 2H), 2.44-2.35 (m, 2H), 2.22 (s, 6H), 1.53 (s, 2H), 1.15-1.06 (m, 3H).

Tert-butyl 2-r(lEH)-(ethvlimino)methvllpyrrolidine-l-carboxvlate

By General Procedure G from tert-Butyl 2-fbrmylpyrrolidine-l-carboxylate and ethylamine. Used without further purification

Ethvir(l-methylpvrrolidin-2-yl)methvl1amine - General Procedure AE (Amines from amides)

LAH was added to a solution of tert-butyl 2-[(lE)-(ethylimino)methyl]pyrrolidine-l-carboxylate in THF and refluxed for 6 hr. Aqueous work up. NaBH₄ and AcOH were added to a methanolic solution of the resulting intermediate. Aqueous work up gave the title compound as yellow oil. ^XH NMR (300 MHz, CDCI3): δ ppm 3.05 (m, 1H), 2.77 (dd, 1H), 2.68 (q, 2H), 2.55(m, 1H), 2.35 (s, 3H), 2.26-2.15 (m, 2H), 1.94 (m, 1H), 1.81-1.57 (m, 5H), 1.12 (t, 3H).

syn-2-(dimethylamino)-N-ethylcyclopentane-l-carboxamide

General Procedure Y from Ethyl[(l-methylpyrrolidin-2-yl)methyl]amine and ethylamine gave the product as yellow oil. ^XH NMR (300 MHz, CDCI3): δ ppm 3.10 (q, 2H), 3.07 - 2.98 (m, 2H), 2.75 (s, 6H), 2.10 - 1.81 (m, 6H), 1.10 (t, 3H). ESI-MS (m/z): 185 [M+l].

syn-2-r(ethylamino)methvl1-N,N-dimethvlcvclopentan-l-amine

General Procedure AE from syn-2-(dimethylamino)-N-ethylcyclopentane-l-carboxamide gave the title compound as yellow oil ^XH NMR (300 MHz, CDCI3): δ ppm 2.76 (dd, 1H), 2.71-2.57 (m, 2H), 2.34 (m,

151

IH), 2.23 (m, IH), 2.22 (s, 6H), 2.16 (m, IH), 1.84-1.69 (m, 2H), 1.68-1.56 (m, 3H), 1.51-1.42 (m,

IH), 1.11 (t, 3H).

r2-(Dimethylamino)-2-methylpropvn(ethvl)amine

Prepared by General Procedure A from 2-(dimethylamino)-2-methylpropanal and ethylamine to get the title compound as colorless oil/H NMR (300 MHz, CDCI3) δ 2.63 (q, 2H), 2.50 (s, 2H), 2.19 (s, 6H), 1.11 (t, 3H), 1.01 (s, 6H).

3-(aminomethvD-N,N-dimethvlcyclopentan-l-amine

General procedure M from 3-(dimethylamino)cyclopentane-l-carbonitrile to get the title product. ’ΉNMR (300MHz, CDCI3), δ ppm: 2.8 (m, 2H), 2.5 (m, IH), 2.6 (m, IH), 2.2 (s, 3H), 2.1 (s, 3H).

Example 2: Histone lysine demethvlase AlphaLISA assays for IC50 value détermination.

This example demonstrates the ability of compounds of the invention to inhibit the activity in vitro of tested enzymes.

Assays are performed analogously to the protocol described by PerkinElmer (Roy et al. PerkinElmer Technical Note: AlphaLISA #12, Apr. 2011)

General method

Enzymes are dissolved in enzyme buffer and incubated for 10 min before being added to 3% DMSO solutions of compounds in enzyme buffer. Incubated for another 10 minutes, before substrate solution is added and the reaction mixture is incubated at room température. 10 pL acceptor beads, suspended in Epigenetic Buffer (Perkin Elmer AL008) from stock, are added and the suspension is incubated in the dark at room température, before a suspension of streptavidin donor beads (Perkin Elmer 6760002) in Epigenetic Buffer is added. After incubation at room température in the dark the plates are read.

Enzymes:

Protein name	Vendor/source	Sequence	Expression organism
KDM2B (FBXL10)	BPS, Bioscience, US	1-650	Bac
KDM3B (JMJD1B)	BRIC	842-1761	Bac

152

KDM4A (JMJD2A)	BPS, Bioscience, US	1-350	E.coli
KDM4B (JMJD2B)	BPS	2-500	Bac
KDM4C (JMJD2C)	BRIC, Denmark	1-349	E.coli
KDM5C (JARID1C)	BPS	2-1560	Bac
KDM5B(PLU-1)	BRIC	1-809	E.coli
KDM6A (UTX)	BRIC	919-1401	E.coli
KDM6B(JMJD3)	BPS	1043-end	Bac
KDM7 (PHF8)	BRIC	1-1322	Bac
KDM3A (JMJD1A)	BPS, Bioscience, US	2-end	Bac

Substrates:

BK9M3: Biotin-ARTKQTAR(KMe₃)STGGKAPRKQ-NH₂ (Caslo, Denmark) SEQ ID NO.:1

BK9M2: Biotin-ARTKQTAR(KMe₂)STGGKAPRKQ-NH₂ (AnaSpec 64359) SEQ ID NO.:2

BK9M1: Biotin-ARTKQTAR(KMei)STGGKAPRKQ-NH₂ (AnaSpec 64358) SEQ ID NO.:3

H3K4M3B: H-ART(Kme3)QTARKSTGGKAPRKQLA-NH-Biotin (Caslo, Denmark) SEQ ID NO.: 4

BK27M3: Biotin-ATKAAR(Kme3)SAPATGGVKKPHRY-NH2 (Caslo, Denmark) SEQ ID NO.: 5

BH3K36M2: RKAAPATGGVK(Me2)KPHRYRPGTVK-(BIOTIN) (Anaspec) SEQ ID NO.: 6

Enzyme Buffer: 50 mM Hepes (pH 7.4 or 8.0), 0.003% Tween-20, 0.1% BSA; 5 μΜ (NH^FetSOY

Buffer A: 50 mM Hepes (pH 7.4 or 8.0), 0.003% Tween-20, 0.1% BSA

Substrate Solution: Substrate, 25 pM L-Asc, and 10 pM α-KG in Buffer A.

[2-({[3- (dimethylamino)propyl]a mlno}methyl)pyridin-4yljmethanamine	[2-({[4- (dimethylamino)butyl]ami no}methyl)pyridin-4yljmethanamine	N-{[2-«[4(diethylamino)butyljamin o}methyl)pyridin-4yl]methyl}-2,2,2trifluoroacetamide	Compound Name
	M	I—⁴	Compound #
+	+	+	KDM4C
+	+	+	KDM2B
+ + +		+ +	KDM5C
	+	+	KDM3 A
+	+	+	KDM3B
+ + +	+	+ +	KDM4A
+++	+	+ + +	KDM4B
+	+	+	KDM6B
+ +	+	+ +	PHF8 I i_______________________________________________________________________________________________________________________________________________________
	+	+	KDM6A
+ +	+	+ +	KDM5B

HDME INHIBITION

[2-({[4-(azetidin-lyl)butyl]amino}methyl)py ridin-4-yl]methanamine	N-[4(diethylamlno)butyl]2,2,2-trifluoro-N-({4[(trifluoroacetamido)meth yl]pyridln-2yl}methyl)acetamide	[2-({[4- (diethylamino)butyl]amin o}methyl)pyridin-4yljmethanamlne	2-«[4- (aminomethyl)pyridin-2- yl]methyl}amino)-N-[2(dimethylamino)ethyl]-Nethylacetamide
Xj	en	Ul	-N
+	+	+	+ +
+	+	+	+
	+		+++
+	+	+	+
+	+	+	+
+	+ +	+	+ +
+ + +	+ + +	+	+++
+	+	+	+
+	+ +	+	+ +
+		+	+
++	+	+	+ + +

154

N-<[2-({[3-(2methylpiperidln-1yl)propyl]amlno}methyl)p y ridin-4yl]methyl}cyclopropanam ine	N-{[2-({[4(dimethylamino)butyl]ami no}methyl)pyridin-4yl]methyl}cyclopropanam ine	2-«[4- (aminomethyl)pyrldin-2- yl]methyl}amino)-N-(l- [(2- methoxyphenyl)methyl]pi peridin-4-yl}acetamide	[2-({[5- (dimethylamino)pentyl]a mlno}methyl)pyridin-4yljmethanamine
H* H*	H¹O		00
+	+	+	+
+	+	+	4-
		+ + +	+++
+	+	+	+
+	+	+	+
+	+	+	+
+	+	+	+
+	+	+	+
+	+	+	+
+	+	+	+
+ +		+ +	+ + +

155

2-({[4-({[2(dlmethylamino)ethyl]ami no}methyl)pyridin-2yl]methyl}amino)-N,Ndimethylacetamide	2-{[(4-{[(2fluoroethyl)amino]methyl }pyridin-2- yl)methyl]amlno}-N,Ndimethylacetamide	2-{[(4{[(cyanomethyl)aminojm ethyl}pyrldin-2yl)methyl]amlno}-N,Ndimethylacetamide	N-«2- [(propylamino)methyl]pyr idin-4- yl}methyl)cyclopropanam ine
15	H* A	I—¹ U)	Î-* NJ
+ +	+ +	+	+
+		+	+
+ +	+ +	+	+
+	+		+
+	+	+	+
+	+	+	+
+ +	+ +	+	+ + +
+	+	+	+
+	+	+	+
+	+	+	+
+ + +	+ +	+ +	+ +

156

benzyl(3-{[(4-{[(2methoxyethyl)amino]met hyl}pyridin-2yl)methyl]amino}propyl) methylamine	benzyl[3-({[4-({[2(dimethylamino)ethyl]ami no}methyl)pyridin-2yl]methyl}amino)propyl] methylamine	benzyl(methy!){3-[({4[(methylamino)methyljpy ridin-2yl}methyl)amino]propyl} amine	<[(2S)-1benzylpyrrolidin-2yl]methyl}[(4{[(cyclopropylmethyl)ami no]methyljpyridin-2yl)methyl]amine
19	I-» 03	I-* Xj	16
+	+	+ +	+
+	+	+	+
+		+ + +	+ +
+	+	+	+
+	+	+	+
+	+	+	4-
+		+ +	+
+	+	+	+
+	+	+	+ +
+	+	+	+
+ +	++	+++	+ +

157

2-[({2-[«4- [benzyl(cyclopropyl)amin o]butyl}amino)methyl]py ridin-4- yl}methyl)amino]acetonit rile	2-«[2-({[3(dimethylamino)propyl]a mlno}methyl)pyridin-4yl]methyl}amino)propane nitrile	2-cyclopropyl-2-({[2- «[2(dimethylamlno)ethyl]ami no}methyl)pyridin-4yl]methyl}amino)acetonit rile	2-[({4[(cyclopropylamino)meth y l]py ridin-2yl}methyl)amino]-N-{l[(2methoxyphenyl)methyl]pi peridin-4-yl}acetamide
M üü	NJ NJ	NJ >-*	N» O
+		+	+ +
+	+	+	+
+++	+ + +	+	+ + +
+	+	+	+
4-	+	+	+
+	+	+	+++
+	+	+	+++
+		+	+
+	+	+	+ + +
+	+	+
+ +	+ +	+	+ + +

158

(<[2-«[4- (diethylamino)butyljamin o}methyl)pyridin-4yl]methyl}carbamoyl)for mic acid	N-[(2-{[N-({[2- (dimethylamino)ethyl](et hyl)carbamoyl}methyl)- 2,2,2- trifluoroacetamidojmethyl }pyridln-4-yl)methyl]2,2,2-trifluoroacetamide	N-[(2-{[«[2(dimethylamino)ethyl](et hyl)carbamoyl}methyl)a mino]methyl}pyridin-4yl)methyl]-2,2,2trifluoroacetamide	2-[2-({[3- (dimethylamino)propylja mino}methyl)pyridin-4- yi]-2- (methylamino)acetonitrlle
M Xl	26	N) en	M A
+	+	+	+ +
+		+	+
		+ +	+++
		+	+
		+	+
		+	+ +
		+	+++
		+	+
+		+	+
+	+	+	+
+ + +	+	+ +	+ + +

159

N-[(2-{[({[2(dimethylamino)ethylj(et hyl)carbamoyl}methyl)a mino]methyl}pyridin-4yl)methyl]-2,2,3,3,4,4,4heptafluorobutanamide	N-[(2-{[({[2-(azetidin-lyl)ethyl](ethyl)carbamoyl }methyl)amino]methyl}p yridin-4-yl)methyl]-2,2,2trifluoroacetamide
Lü l·-¹	30
+	+
+	+







+	+
+	+ +

ethyl 2-({[(2-{[({[2(dimethylamino)ethylj(et hyl)carbamoyl}methyl)a mino]methyl}pyridin-4yl)methyl]carbamoyl}oxy jbenzoate	tert-butyl (<[2-({[4(diethylamino)butyl]amin o}methyl)pyridin-4yl]methyl}carbamoyl)for mate
ru kD	NJ 00
+	+








+	+
+ +	+ +

160

N,N-dimethyl-2-[({4-[N- (2methylcyclopropyl)carbox lmidoyl]pyridin-2yl}methyl)amino]acetami de	N,N-dimethyl-2-[({4- [[(3phenylpropyl)imino]meth yl]pyridin-2yl}methyl)amino]acetami de	2-[«4-[(Ncyclopropylcarboximidoyl] pyridin-2yl}methyl)amino]-N,Ndimethylacetamide	N-[(2-{[({[2(dimethylamino)ethylj(et hyl)carbamoyl}methyl)a mino]methyl}pyridin-4yl)methyl]-2,2difluorobutanamide
35	<o •N	co CO	ω M
+ +	+	+ + +	+
+ +	+	ΜΗ-	+
+ + +	+ + +	+ + +
+	+
+	+	+
+ + +	+	+ + +
+ + +	+	+
+	+	+
+ + +	+	+
+	+	+	+
ΜΗ-	+ + +	+ + +	+ + +

161

N-{[2-«[2(ethylsulfanyl)ethyl]amin o}methyl)pyridin-4yl]methylidene}cycloprop anamine	«4-[{[2- (dimethylamino)ethyl]imi no}methyl]pyridin-2yl}methyl)[3(dimethylamino)propylja mine	[3(dimethylamino)propyl]({ 4-[{[3(dimethylamino)propylji mino}methyl]pyridin-2yl}methyl)amine	2-[«4-[[(2cyclohexylethyOiminoJme thyl]pyridin-2yl}methyl)amino]-N,Ndimethylacetamide
39	38	ω •Sj	ω σι
+	+ +	+	+ +
t	+	+	+
+++	+ + +	+++	+ + +
+	+	+	+
+	+	+	+
+ +	+	+	+ +
+ + +	+	+ +	+++
+	+	+	+
+ + +	+	+	+ +
+	+		+
+ +	+ + +	+++	+++

162

N-{[2-«[(2E)-4(dimethylamino)but-2en-1yl]amino}methyl)pyridin4yl]methylidene}cycloprop anamine	N-{[2-({[3-(pyrrolidin-lyl)propyl]amino}methyl)p yridin-4yl]methylidene}cycloprop anamine
-N U)	42
+ + +	+
+	+
+++	+++
+	+
+	+
+ +	+
+ + +	+ +
+	+
+ +	+
+	+
+++	+ + +

N-«2-[«3- [benzyl(methyl)amino]pr opyl}amino)methyl]pyridi n-4yl}methylidene)cycloprop anamine	N-<[2-«[2-(lmethylpyrrolidin-2yl)ethyl]amino}methyl)py ridin-4yl]methylidene}cycloprop anamine
41	40
++	+
+	+
	+++
	+
+	+
+++	+
+++	+ +
+	+
+	+
+	+
+++	+ + +

163

N-{[2-«[5- (dirnethylamino)pentylja mino}methyl)pyridin-4yl]methylidene}cycloprop anamine	N-[(2-{[«4[(dimethylamino)methyl] cyclohexyl}methyl)amino ]methyl}pyridin-4yl)methylidene]cycloprop anamine	N-{[2-({[4(dimethylamino)butyl]ami no}methyl)pyridin-4yljmethylidenejcycloprop anamine	N-{[2-«[4-(azetidin-lyl)butyl]amino}methyl)py ridin-4- yl]methylidene}cycloprop anamine
47	46	45	44
+	+	+	+ + +
+	+	+	+
+ + +	+ + +	+ + +	+ + +
+	4-	+	+
+	+	+	+
+	+ +	+	+
+ +	+ +	+ +	+
+	+	+	+ +
+	+	+	+
+	+	+	+
+++	+ +	ΜΗ-	+++

164

2-[({4-[N- cyclopropylcarboximidoyl] pyridin-2- yl}methyl)amino]-N-[(lethylpyrrolidin-2yl)methyl]acetamide	N -(2-cyanoethy l)-2-[({4[Ncyclopropylcarboximidoyl] pyridin-2yl}methyl)amino]-Nethylacetamide	2-[({4-[Ncyclopropylcarboximidoyl] pyridin-2yl}methyl)amino]-l[(2R)-2-(pyrrolidin-l ylmethyl)pyrrc>lidin-lyl]ethan-l-one	2-[({4-[N- cyclopropylcarboximidoyl] pyridin-2- yl}methyl)amino]-N-[4(diethylamino)butyl]aceta mide
U1 f—¹	U1 o	A tO	A 00
+	+ +	+ +	+ +
+	+ +	+	+
+ + +	+ + +	+ + +	+ + +
+	+	+	+
+	+	+	+
+ +	+ + +	+ + +	+++
+ + +	+ + +	+ + +	+++
+		+	+
++	+ + +	+ +	+ + +
+	+	+	+
+++	+ + +	+ + +	+ + +

165

1 -(4-benzylpiperldin-l yl)-2-[({4-[Ncyclopropylcarboximidoyl] pyridin-2yl}methyl)amino]ethan1-one	2-[({4-[N- cyclopropylcarboximidoyl] pyridln-2- yl}methyl)amino]-l-(4methylpiperazin-1yl)ethan-l-one	N-(l-benzylpyrrolidin-3yl)-2-[«4-[Ncyclopropylcarboximidoyl] pyridin-2yl}methyl)amino]acetami de	2-[({4-[N- cyclopropylcarboximidoyl] pyridin-2yl}methyl)amino]-Nmethyl-N-[3-(lH-pyrazoll-yl)propyl]acetamide
σι σι	<J1 -N	σι ω	σι M
+ +	+ +	+ +	+ +
+	+	+ +	+ +
+ +	+ + +	+ + +	+ + +
+	+	+ +	+
+	+ +	+	+
+ +	+ +	+ + +	+ +
+++	+ +	+ + +	+++
+	+	+ +	+
+ +	+	+ + +
+	+	+	+
+ + +	+ + +	1 +++	+ + +

166

methyl 2-[({4-[Ncyclopropylcarboximidoyl] pyridin-2yl}methyl)amino]acetate	N,N-diethyl-2-[({4[(octylimino)methyl]pyrid in-2yl}methyl)amino]acetami de	2-[({4-[[(2cyclohexylethyl)imlno]me thyi]pyridin-2yl}methyl)amlno]-N,Ndiethylacetamide	2-[«4-[N- cyclopropylcarboximidoyl] pyridin-2yl}methyl)amino]-Nmethyl-N-(prop-2-yn-lyl)acetamide
U1	U1 00	U1 M	m en
+	+ +	+ +	+
	+ +	+ +
+ + +	+ + +	+ + +	+ +
+	+		+
+	+	+	+
+ +	+	+ +	+ +
+++	+	+ + +	+ +
+	+	+	+
+ +	+	+	+ +
+	+	+	+
+++	+ + +	+ + +	+ +

167

2-[«4-[[(2cyclohexylethyl)imino]me thyl]pyridin-2yl}methyl)amino]-N-[2(dimethylamlno)ethylJ-Nethylacetamide	<[2-({[4- (diethylamino)butyl]amin o}methyl)pyridin-4yl]methylidene}(2,2,3,3, 3- pentafluoropropyl)amine	2-[{[2-«[4(diethylamino)butyljamin o}methyl)pyridin-4yl]methylidene}amino]et han-l-ol	[4- (diethylamino)butyl]({4- [[(2methoxyethyl)imino]meth yl]pyridin-2yl}methyl)amine
63	NJ	σ» H¹	σ» o
+ + +	+	+ +	+
+ +	+	+	+
1 1 +++	+ + +	+ + +	+ + +
	+	+	+
+	+	+	+
+	+	+	+ + +
+ +	+ +	+ + +	+ + +
+	+	+	+
+	+	+	+ +
+	+	+	+
+ + +	+ + +	+ + +	+ + +

168

(2-cyclohexylethyl)({[2- ({[4- (diethylamino)butyl]amin o}methyl)pyridin-4yl]methylidene})amine	N-[2(dimethylamino)ethyl]-Nethyl-2-[«4-[([(2hydroxyethyl)lmino]meth yl]pyridin-2yl}methyl)amino]acetami de	[4- (diethylamino)butyl]({[4(l-methylimidazolidin-2yl)pyridin-2yl]methyl})amine	[3- (dimethylamino)propyl]« 4- [(methoxyimino)methyl]p yridin-2-yl}methyl)amine
67	en	en en	en A
+ +	+ + +	+ +	+
	+	+	+
+ + +	+ + +	+ + +	+
+	+	+	+
+	+	+	+
+	+ + +	+	+ +
+	+++	+	+ + +
	+	+	+
+	+ +	+	+
+	+	+	+
+++	+++	+ + +	+ + +

169

3-[{[2-({[4(diethylamino)butyl]amin o}methyl)pyridin-4yl]methylidene}amino]pr opan-l-ol	4-[2-{[2-({[4(diethylamino)butyljamin o}methyl)pyridin-4yl]methylidene}hydrazinl-yl]benzonitrile	N,N-dlethyl-2-[({4-[{[2- (4- methylphenyl)ethyl]imino }methyl]pyridin-2yl}methyl)amlno]acetami de	[4- (diethylamino)butyl]({[4(l-methyl-l,3-diazinan2-yl)pyridin-2yl]methyl})amine
71	70	69	68
	+	++	+ +








+	+	+	+
+ + +	+ +	+ +	+ + +

170

2-[{[2-({[4(diethylamino)butyl]amin o}methyl)pyridin-4yl]methylidene}amino]2-phenylethan-l-ol	l-[{[2-({[4(diethylamino)butyljamin o}methyl)pyridin-4yl]methylidene}amino]pr opan-2-ol	2-[{[2-({[4(diethylamino)butyljamin o}methyl)pyridin-4yl]methylidene}amino]pr opan-l-ol	[4- (diethylamino)butyl][(4{7-oxa-9azaspiro[4.5]decan-8yl}pyridin-2yl)methyl]amine
U1	M A	73	XJ NJ
+	+	+	+
			+







			+
+++	+ + +	+ + +	+ +

171

N-ethyl-2-[«4-[[(2hydroxyethyl)imino]meth y l]pyridin-2yl}methyl)amlno]-N-[(lmethylpyrrolidin-2yl)methyl]acetamide	N-[2(dimethylamino)ethyl]-Nethyl-2-[«4-[[(3hydroxypropyl)lmino]met hyl]pyridin-2yl}methyl)amino]acetami de	(l-{[{[2-({[4(diethylamino)butyljamin o}methyl)pyridin-4yl]rriethylidene}amino]m ethyl}cyclopropyl)methan ol	3-[{[2-({[4(diethylamino)butyl]amin o}methyl)pyridin-4yl]methylidene}amino]2,2-dimethylpropan-l-ol
79	78	LL	76
+ +	+ +	4-	4-
+	+	4-	4-








+++	+ + +	+ 4-	4- 4-

172

N-[2(dimethylamino)propyl]N-ethyl-2-[«4-[[(2hydroxyethyl)imino]meth yl]pyridin-2yl}methyl)amino]acetami de	N-[3(dimethylamino)propyl]N-ethyl-2-[({4-[[(2hydroxyethyl)imino]meth yl]pyridin-2yl}methyl)amlno]acetami de	2-[({4-[[(2-cyclohexyl-3hydroxypropyl)imino]met hyl]pyridin-2yl}methyl)amino]-N-[2(dimethylamino)ethyl]-Nethylacetamide	2-{[{[2-({[4(diethylamino)butyl]amin o}methyl)pyridin-4yl]methylidene}amino]m ethyl}-3-phenylpropan-lol
1 1 83	00 NJ	00 H*	80
++	+	+ +	+ + +
+	+	+	+ +







	+	+	+
+ + +	+	+ + +	+++

173

2-({[4-(5,5-dimethyl-l,3oxazinan-2-yl)pyridin-2yl]methyl}amino)-N-[2(dimethylamino)ethyl]-Nethylacetamide	2-[«4-[{[3- (dimethylamlno)-2hydroxypropyl]imino}met hyl]pyridin-2yl}methyl)amino]-N-[2(dimethylamino)ethyl]-Nethylacetamlde
00 VJ	86
+ +
+	+







	+
+++	+ + +

N-{[(lS,2S)-2- (dimethylamino)cyclopent yl]methyl}-N-ethyl-2- [({4-[[(2hydroxyethyl)imino]meth yl]pyridin-2yl}methyl)amino]acetami de	l-[{[2-({[4(diethylamino)butyljamin o}methyl)pyridin-4yljmethylidenejaminoj3-phenylpropan-2-ol
85	00 A
+ + +	+
+	+







+	+
+++	+ +

174

N-[2(dimethylamino)ethylJ-Nethyl-2-[({4-[7(trifluoroacetyl)-5-oxa-7azaspiro[2.5]octan-6y l]py ridin-2yl}methyl)amino]acetami de	2-[({4-[5-benzyl-3- (trifluoroacetyl)-l,3oxazinan-2-yl]pyridin-2yl}methyl)amino]-N-[2(dimethylamino)ethyl]-Nethylacetamide	2-[({4-[[(2-benzyl-3hydroxypropyl)imlno]met hyl]pyridin-2yl}methyl)amino]-N-[2(dimethylamino)ethyl]-Nethylacetamide	N-[2(dimethylamino)ethyl]-Nethyl-2-[«4-[«[l( hy d roxy methy 1) cy clop ro pyl]methyl}imino)methyl] pyridin-2yl}methyl)amino]acetami de
ID w	90	89	CO 00
+ +		+ +	++
+	+	+	+






+	+		+
+	+	+	+
+	+ + +	+ + +	+ + +

175

(2S)-2-[({4-[[(2hydroxyethyl)lmino]meth yl]pyridin-2yl}methyl)amino]-4methyl-l-(piperidin-lyl)pentan-l-one	N-(2-cyanoethyl)-Nethyl-2-[({4-[[(2hydroxyethyl)imino]meth y 1] pyridin-2yl}methyl)amlno]acetami de	2-[({2-[({2-[2- (benzyloxy)phenyl]ethyl} amino)methyl]pyridin-4yl}methylidene)amino]et han-l-ol	N-[(2fluorophenyl)methyl]-2[«4-[[(2hydroxyethyl)imino]meth yl]pyridin-2yl}methyl)amino]-Nmethylacetamide
95	94 1	93	KD NJ
+	+ +	+	+
+	+ +	+	+






	+ +	+	+
+	+	+	+
+	+ +	+	+ +

176

2-(<[(l -methylpiperidin- 4- yl)methyl]amino)-methyl) pyridine-4-carbaldehyde	2-({[(2Z)-4(dimethylamino)but-2en-1yl]amino}methyl)pyridine -4-carbaldehyde	2-({[(2E)-4(dimethylamino)but-2en-1yl]amino}methyl)pyridine -4-carbaldehyde	2-{[«4[(dimethylamino)methyl] cyclohexyl}methyl)amino ]methyl}pyridine-4carbaldehyde
100	66	86	kO Xj
+	+	+ +	+
+	+	+	+
+++	+ + +	+++ 1
+	+	+	+
+	+	+	+
	+	+	+
		+
+	+	+	+
+	+	+	+
+	+	+	+
+ + +	+++	+++	+ +

177

N-[(1 -ethy lpyrrolidin-2yl)methyl]-2-{[(4formylpyrldin-2yl)methyl]amino}acetami de	2-«[2-(4methylplperazin-l-yl)-2oxoethyl]amino}methyl)p yridine-4-carbaldehyde	2-[«2-oxo-2-[(2R)-2(pyrrolidin-1 ylmethyl)pyrrolidin-lyl]ethyl}amino)methyl]py ridine-4-carbaldehyde	N-[2(dimethylamino)ethyl]-Nethyl-2-{[(4formylpyridin-2yl)methyl]amino}acetami de
104	103	102	101
ΜΗ-	+	+++	+++
+	+	+	+
+ + +	+++	+++	+ + +
+	+	+	+
+	+	+	+
	+	+	+ + +
+ +	+	+ +	+++
+	+	+	+
+ +	+	+	+ +
+	+	+	+
+ + +	+ +	! ⁺⁺⁺	+ + +

178

2-({[4- (dimethylamino)butyl]ami no}methyl)pyridine-4carbaldehyde	2-({[4- (diethylamino)butyljamin o}methyl)pyridine-4carbaldehyde	2-({[2-(4benzylplperidin-l-yl)-2oxoethyl]amino}methyl)p yridine-4-carbaldehyde	N,N-diethyl-2-{[(4formylpyridin-2yl)methyl]amino}acetami de
108	107	106	105
+	+	+ +	+
+	+	+	+
+++	+ + +	+
+	+	+	+
+	+	+	+
+	+	+ +	+
	+++	+ + +	+++
+	+	+	+
+	+	+ +
+	+	+	+
+ +	+ + +	+ + +	+ +

179

N-[4- (dlethylamino)butyl]-2{[(4-formylpyridin-2yl)methyl]amino}acetami de	2-({[3-(pyrrolidin-lyl)propyl]amino}methyl)p yridine-4-carbaldehyde	2-({[2- (dimethylamino)ethyl]ami no}methyl)pyridine-4carbaldehyde	2-[( [benzyl(cyclo o]butyl}amin ridine-4-car
propyl)amin o)methyl]py -baldehyde	HS -N 1
112	lll	110	109
+ +	+	4-	+ 4-
+	4-	4-
+++	4- 4- 4-	+ + +
+	+	4-	+
+	+	4-	4-
+++		+ +	4-
	4-4-		4-4-4-
+	4-	4-
+ + +	4-	4*	4-
4-	+	+	+
	+ + +	+ 4-	4-+4-

180

N-[2(diethylamino)ethyl]-Nethyl-2-{[(4formylpyridin-2yl)methyl]amino}acetami de	N-[4- (diethylamino)butyl]2,2,2-trifluoro-N-[(4formylpyridin-2yl)methyl]acetamide	2-({[5- (dimethylamino)pentylja mino}methyl)pyridlne-4carbaldehyde	N-(l-benzylpyrrolidin-3- yl)-2-{[(4-formylpyridin- 2- yl)methyl]amino}acetaml de
116	115	114	113
+++	+	+	+ +
	+	+
	+ + +	+ + +	+ +
	+	+	+
	+	+	+
	+ +	+	+ +
		+ +	+ + +
	+	+	+
	+ +	+	+
+	+		+
+ + +	+	+ + +	+ + +

181

182

2-({methyl[2-oxo-2(piperidin-1 yl)ethyl]amino}methyl)py ridine-4-carbaldehyde	N-ethyl-2-{[(4formylpyridin-2yl)methyl]amino}-N-[(lmethylpyrrolidin-2yl)methyl]acetamlde	N-[2-(dimethylamino)-2methylpropyl]-N-ethyl-2{[(4-formylpyridin-2yl)methyl]amino}acetami de	2-[«[3- (dimethylamino)cyclopent yl]methyl}amino)methyl] pyridine-4-carbaldehyde
120	119	118	117
	+	+ + +	++
4-		+






++ 1		+ +
+		+	+
+	+++	1 +++	+ + +

183

Example 3: Cell Assavs for IC50 value Détermination

Histone Lysine Demethylase Immunofluorescence Assays for IC50 value Détermination, nontransfected cells

This example demonstrates the ability of compounds of the invention to inhibit déméthylation of a spécifie histone lysine mark in a human osteosarcoma cancer cell line.

General method

U2OS cells were harvested and seeded into multi well plates into media contaîning compound. The media used was DMEM contaîning 5 % FBS and pen/strep. 20 hours after incubation of cells with compounds, the cells were washed once in PBS, harvested by fixation with formaldéhyde 4 % aqueous solution, and washed in PBS. Subsequently, the cells were permeabilized in PBS with 0.2 % Triton X100. Blocking was performed in PBS with 0.2 % Triton X-100 and 5 % FBS. The cells were incubated with aH3K4me3 primary antibody (Cell Signaling, #9751S) in blocking solution over night at 4°C. After incubation with primary antibody, the cells were washed with PBS, incubated with secondary antibody (Alexa fluor 594 goat anti rabbit IgG, Invitrogen, A11012) and Hoechst, (Sigma, 33342) in blocking solution, and washed again with PBS. Finally, PBS was added and high throughput imaging and analysis were performed by an IN Cell Analyzer 1000 (GE Healthcare). The IC50 values were based on an average measure ofthe staining ofthe H3K4me3 mark in cells.

184

Compound Name	Compound #	IC50
N-{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin- 4-yl]methyl}-2,2,2-trifluoroacetamide	1	+++
[2-({[3-(dimethylamino)propyl]amino}methyl)pyridin- 4-yl]methanamine	3	+++
2-({[4-(aminomethyl)pyridin-2-yl]methyl}amino)-N-[2(dimethylamino)ethylJ-N-ethylacetamide	4	+++
N-[4-(diethylamino)butyl]-2,2,2-trifluoro-N-({4[(trifluoroacetamido)methyl]pyridin-2yl}methyl)acetamide	6	+++
[2-({[4-(azetidin-l-yl)butyl]amino}methyl)pyridin-4yljmethanamine	7	+++
2-({[4-(aminomethyl)pyridin-2-yl]methyl}amino)-N-{l[(2-methoxyphenyl)methyl]piperidin-4-yl}acetamide	9	++

185

2-{[(4-{[(cyanomethyl)amino]methyl}pyridin-2yl)methyl]amino}-N,N-dimethylacetamide	13	++
2-[({4-[(cyclopropylamino)methyl]pyrïdin-2yl}methyl)amino]-N-{l-[(2methoxyphenyl)methyl]piperidin-4-yl}acetamide	20	++
2-«[2-«[3- (dimethylamino)propyl]amino}methyl)pyridin-4yl]methyl}amino)propanenitrile	22	+++
2-[({2-[({4- [benzyl(cyclopropyl)amino]butyl}amino)methyl]pyridin- 4-yl}methyl)amino]acetonitrile	23	+++
2-[2-«[3- (dimethylamino)propyl]amino}methyl)pyridin-4-yl]-2- (methylamino)acetonitrile	24	+++
N-[(2-{[({[2- (dimethylamino)ethyl](ethyi)carbamoyl}methyl)amino] methyl}pyridin-4-yl)methyl]-2,2,2-trifluoroacetamide	25	+++
({[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methyl}carbamoyl)formic acid	27	+++

186

tert-butyl (<[2-({[4- (diethylamino)butyl]amino}methyl)pyridin-4yl]methyl}carbamoyl)formate	28	++
N-[(2-{[({[2-(azetidin-l- yl)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridin -4-yl)methyl]-2,2,2-trifluoroacetamide	30	+++
N-[(2-{[«[2- (dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino) methyl}pyridin-4-yl)methyl]-2,2-difluorobutanamide	32	+
2-[({4-[(N-cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]-N,N-dimethylacetamide	33	++
2-[({4-[[(2-cyclohexylethyl)imino]methyl]pyridin-2ν^ΓηβίΡνΟθΓηίηοΙ-Ν,Ν-άϊΓηείΙτνίΒσεΙάΓηίΡε	36	+++
({4-[{[2-(dimethylamino)ethyl]imino}methyl]pyridin-2yl}methyl)[3-(dimethylamino)propyl]amine	38	+++
N-{[2-({[2-(l-methylpyrrolidin-2yl)ethyl]amino}methyl)pyridin-4yl]methylidene]-cyclopropanamine	40	+++

187

N-{[2-({[(2E)-4-(dimethylamino)but-2-en-lyl]amino}methyl)pyridin-4yl]methylidene}cyclopropanamine	43	+++
N-{[2-({[4-(azetidin-l-yl)butyl]amino}methyl)pyridin- 4-yl]methylidene}cyclopropanamine	44	+++
N-[(2-{[«4- [(dimethylamino)methyl]cyclohexyl}methyl)amino]meth yl}pyridin-4-yl)methylidene]cyclopropanamine	46	+++
2-[({4-[[(2-cyclohexylethyl)imino]methyl]pyridin-2yl}methyl)amino]-N,N-diethylacetamide	57	++
N,N-diethyl-2-[({4-[(octylimino)methyl]pyridin-2yl}methyl)amino]acetamide	58	+
2-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin- 4-yl]methylidene}amino]ethan-l-ol	61	+++
{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}(2,2,3,3,3-pentafluoropropyl)amine	62	+++

188

[3-(dimethylamino)propyl]({4- [(methoxyimino)methyl]pyridin-2-yl}methyl)amine	64	++
(2-cyclohexylethyl)({[2-({[4- (diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene})amine	67	+++
[4-(diethylamino)butyl]({[4-(l-methyl-l,3-diazinan-2yl)pyridin-2-yl]methyl})amine	68	+++
4-[2-{[2-«[4- (diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}hydrazin-l-yl]benzonitrile	70	++
l-[<[2-({[4-(diethylamino)butyl]amino}methyl)pyridin- 4-yl]methylidene}amino]propan-2-ol	74	+++
(l-<[<[2-«[4- (diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}amino]methyl}cyclopropyl)methanol	77	+++
N-ethyl-2-[({4-[[(2-hydroxyethyl)imino]methyl]pyridin2-yl}methyl)amino]-N-[(l-methylpyrrolidin-2yl)methyl]acetamide	79	+++

189

N-[3-(dimethylamino)propyl]-N-ethyl-2-[({4-[[(2hydroxyethyl)imino]methyl]pyridin-2yl}methyl)amino]acetamide	82	+++
N-[2-(dimethylamino)propyl]-N-ethyl-2-[({4-[[(2hydroxyethyl)imino]methyl]pyridin-2yl}methyl)amino]acetamide	83	+++
N-{[(lS,2S)-2-(dimethylamino)cyclopentyl]methyl}-Nethyl-2-[({4-[[(2-hydroxyethyl)imino]methyl]pyridin-2yl}methyl)amino]acetamide	85	+++
N-[2-(dimethylamino)ethyl]-N-ethyl-2-[({4-[({[l(hydroxymethyl)cyclopropyl]methyl}imino)methyl]pyridi n-2-yl}methyl)amino]acetamide	88	+++
2-[({4-[5-benzyl-3-(trifluoroacetyl)-l,3-oxazinan-2yl]pyridin-2-yl}methyl)amino]-N-[2(dimethylamino)ethylJ-N-ethylacetamide	90	+++
N-[2-(dimethylamino)ethyl]-N-ethyl-2-[({4-[7(trifluoroacetyl)-5-oxa-7-azaspiro[2.5]octan-6yl]pyridin-2-yl}methyl)amino]acetamide	91	+++
2-{[({4- [(dimethylamino)methyl]cyclohexyl}-methyl)amino]meth yl}pyridine-4-carbaldehyde	97	+++

190

2-({[(2Z)-4-(dimethylamino)but-2-en-lyl]amino}methyl)pyridine-4-carbaldehyde	99	++
2-({[(l-methylpiperidin-4- yl)methyl]amino}methyl)pyridine-4-carbaldehyde	100	+++
N-[2-(dimethylamino)ethyl]-N-ethyl-2-{[(4formylpyridin-2-yl)methyl]amino}acetamide	101	+++
2-({[4-(diethylamino)butyl]amino}methyl)pyridine-4carbaldehyde	107	+++
2-({[3-(pyrrolidin-l-yl)propyl]amino}methyl)pyridine-4carbaldehyde	lll	+++
N-[4-(diethylamino)butyl]-2,2,2-trifluoro-N-[(4formylpyridin-2-yl)methyl]acetamide	115	+++
N-[2-(diethylamino)ethyl]-N-ethyl-2-{[(4-formylpyridin- 2-yl)methyl]amino}acetamide	116	+++

191

N-[2-(dimethylamino)-2-methylpropyl]-N-ethyl-2-{[(4formylpyridin-2-yl)methyl]amino}acetamide	118	+++
N-ethyl-2-{[(4-formylpyridin-2-yl)methyl]amino}-N-[(lmethylpyrrolidin-2-yl)methyl]acetamide	119	+++

(a) +++: IC50 <250 nM; ++: 250 nM < ICso < 2500 nM; +: IC50 > 2500 nM

Example 4: Histone Lysine Demethvlase Immunofluorescence Assays for IC50 value Détermination

This example demonstrates the ability of the compounds of the invention to inhibit spécifie histone lysine demethylases expressed in a human osteosarcoma cell line.

General method

U2OS cells were seeded 24 hours before transfection. Transfection was performed with Fugene HD transfection reagent as recommended by the manufacturer. 6 hours after transfection, the cells were harvested and seeded into multi well plates into media containing compound. The media used was DMEM containing 10 % FBS and pen/strep. 20 hours after incubation of cells with compounds, the cells were washed in PBS, harvested by fixation with formaldéhyde 4 % aqueous solution, and washed in PBS. Subsequently, the cells were permeabilized in PBS with 0.2 % Triton X-100 for. Blocking was performed in PBS with 0.2 % Triton X-100 and 5 % FBS. The cells were incubated with primary antibodies in blocking solution over night at 4°C. The primary antibodies used in the assays were HA.11 (Covance, MMS-101P) and the antibody detecting the mark specified in the table below. After incubation with primary antibodies, the cells were washed with PBS, incubated with secondary antibodies (Alexa fluor 594 goat anti rabbit IgG, Invitrogen, A11012; Alexa flour 488 donkey anti mouse IgG, Invitrogen, A21202) and Hoechst, (Sigma, 33342) in blocking solution, and washed again with PBS. Finally, PBS was added and high throughput imaging and analysis were performed by an IN Cell Analyzer 1000 (GE Healthcare). The robot software analyzed individual cells and divided these into

192

HA⁺ (transfected cells) and HA' (non-transfected cells). The IC50 values were based on an average measure ofthe staining ofthe mark specified in the table below in the transfected cells.

Construct name	Vendor / source	Sequence	Mark detected	Primary antibody used for détection of mark	mRNA NCBI ID
pCMVHA KDM2A	Kazusa	Full length	H3K36me2	Milipore 7369-1	NM_012308
pCMVHA KDM4A	BRIC	Full length	H3K9me3	Abcam Ab8898	NM_015061
pCMVHA KDM4C	BRIC	Full length	H3K9me3	Abcam Ab8898	NM_014663
pCMVHA KDM5B	BRIC	Fragment (a.a. 1-752)	H3K4me2	Millipore 07-030	NM_006618
pCMVHA KDM6B	BRIC	Fragment (a.a. 1026- 1682)	H3K27me2	Abcam Ab24684	NM_001080424

HDME INHIBITION

193

194

2-(<[4-(aminomethyl)pyridin-2- yl]methyl}amino)-N-[2(dimethylamino)ethyl]-Nethylacetamide	[2-({[3- (dimethylamino)propyl]amino}meth yl)pyridin-4-yl]methanamine	[2-({[4- (dimethylamino)butyl]amino}methy l)pyridin-4-yl]methanamine	N-{[2-({[4- (diethylamino)butyl]amino}methyl) pyridin-4-yl]methyl}-2,2,2trifluoroacetamide	Compound Name
-N	ω	NJ	h*	Compound #
++	+	+ +	++	KDM4C
				KDM4A
+				KDM6B
+ + +	+++	+++	+++	KDM5B
				KDM2A

195

2-({[4-(aminomethyl)pyridin-2- yl]methyl}amino)-N-{l-[(2- methoxyphenyl)methyl]piperidin-4yl/acetamide	[2-({[5- (dimethylamino)pentyl]amino}meth yl)pyridin-4-yl]methanamine	[2-({[4-(azetidin-l- yl)butyl]amino}methyl)pyridin-4- yl]methanamine	N-[4-(diethylamino)butyl]-2,2,2trifluoro-N-({4[(trifluoroacetamido)methyl]pyridin2-yl}methyl)acetamide	[2-«[4- (diethylamino)butyl]amino}methyl) pyridin-4-yl]methanamine
ID	00	M	σι	en
+	+ +	4-	+	+ +
+

++	+++ I	+ + +	4+ +	+ + +

196

2-{[(4-{[(2- fluoroethyl)amino]methyl}pyridin-2yl)methyl]amino}-N,Ndimethylacetamide	2-{[(4- <[(cyanomethyl)amino]rnethyl}pyri din-2-yl)methyl]amino}-N,Ndimethylacetamide	N-({2- [(propylamino)methyl]pyridin-4yl}methyl)cyclopropanamine	N -{[2 -({[3-(2 -methylpiperidin-1 yl)propyl]amino}methyl)pyridin-4yl] methyl}· cyclopropanamine	N-{[2-({[4- (dimethylamino)butyl]amino}methy l)pyridin-4- yl]methyl}cyclopropanamine
14	13	t-* NJ	I-* h*	h* o
+	+	+	+	+
	++

+	++	+	+

2-[«4[(cyclopropylamino)methyljpyridin2-yljmethyl)amino]-N-{l-[(2methoxyphenyl)methyl]piperidin-4yljacetamide	benzyl(3-{[(4-{[(2methoxyethyl)amino]methyl}pyridin -2yl)methyl]amino}propyl)methylami ne	benzyl(methyl){3-[({4- [(methylamino)methyl]pyridin-2yl}methyl)amino]propyl}amine	{[(2S)-l-benzylpyrrolidin-2- yl]methyl}[(4{[(cyclopropylmethyl)amino]methyl }pyridin-2-yl)methyl]amine	2-«[4-«[2- (dimethylamino)ethyl]amino}methyl )pyridin-2-yl]methyl}amino)-N,Ndimethylacetamide
20	19	F* M	f-* CD	15
4-	4-	4-		4-
+				4-

+ +	4-	4-	4-	4- 4-

198

N-[(2-{[«[2- (dimethylamino)ethyl](ethyl)carbam oyl}methyl)amino]methyl}pyridin4-yl)methyl]-2,2,2trifluoroacetamide	2-[2-«[3- (dimethylamino)propyl]amino}meth yl)pyridin-4-yl]-2(methylamino)acetonitrile	2-[«2-[«4[benzyl(cyclopropyl)amino]butyl}a mino)methyl]pyridin-4yl}methyl)amino]acetonitrile	2-«[2-«[3- (dimethylamino)propyl]amino}meth yl)pyridin-4- yl]methyl}amino)propanenitrile	2-cyclopropyl-2-({[2-«[2(dimethylamino)ethyl]amino}methyl )pyridin-4yl]methyljamino)acetonitrile
25	24	23	22	N) f—¹
	+	+		+
+ +
+	+
+ + +	+ + +	+ +	+++	+ +
+

199

2-[({4-[[(2cyclohexylethyl)imino]methyl]pyridi n-2-yl}methyl)amino]-N,Ndimethylacetamide	N,N-dimethyl-2-[({4-[N-(2methylcyclopropyl)carboximidoyl]py ridin-2-yl}methyl)amino]acetamide	N,N-dimethyl-2-[({4-[[(3phenylpropyl)imino]methyl]pyridin2-yl}methyl)amino]acetamide	cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]-N,Ndimethylacetamide	NJ 1 r*-i A 1 Z 1	Ν-[(2-{[Ν-«[2(dimethylamino)ethyl](ethyl)carbam oyl}methyl)-2,2,2trifluoroacetamidojmethyljpyridin- 4-yl)methyl]-2,2,2trifluoroacetamide
ω	ω	GJ	GJ		NJ
σ*	en	A	Lü		σ»
+	4- 4-	4-	4· 4-	4- 4-
4-

4-	4-	4-	4-		4-
4-	4-	4-	4-		4- 4-

200

N-«2-[«3- [benzyl(methyl)amino]propyl}amino )methyl]pyridin-4yl}methylidene)cyclopropanamine	N-{[2-({[2-(l-methylpyrrc>lidin-2- yl)ethyl]amino}methyl)pyridin-4- yl]methylidene}cyclopropanamine	yljmethylidenejcyclopropanamine	N-{[2-({[2- (ethylsulfanyl)ethyl]amino}methyl)p yridin-4-	«4-[{[2- (dimethylamino)ethyl]imino}methyl ]pyridin-2-yl}methyl)[3(dimethylamino)propyl]amine	[3-(dimethylamino)propyl]({4-[{[3- (dimethylamino)propyl]imino}meth yl]pyridin-2-yl}methyl)amine
A H*	40	39	38	37
4- 4-	++	4-	4-	4- 4-
4-

4- 4-	4- 4- 4-	4-	+++	4- 4- 4-

201

N-{[2-({[5- (dimethylamino)pentyl]amino}meth yl)pyridin-4- yl]methylidene}cyclopropanamine	N-[(2-{[«4[(dimethylamino)methyl]cyclohexyl }methyl)amino]methyl}pyridin-4yl)methylidene]cyclopropanamine	N-{[2-({[4- (dimethylamino)butyl]amino}methy l)pyridin-4- yl]methylidene}cyclopropanamine	N-{[2-«[(2E)-4(dimethylamino)but-2-en-lyl]amino}methyl)pyridin-4yl]methylidene}cyclopropanamine	N-{[2-(i[3-(pyrrolidin-lyl)propyl]amino}methyl)pyridin-4yl]methylidene}cyclopropanamine
47	46	45	43	A NJ
+ +	+ +	++	+ +	++
	+ + +			+
				+
+ + +	+++	+ + +	+++	+ + +

202

□A Q. ,30 •o 5 t> Ço QJ NI îSxC tê-S _M oTq t o 2 ÉA •Q J, CL Z < 3 O ' 1__1 (T> _ n 3 ~O (D rT l -5 s* z a 3 Λ 5' cl ω ' œ '	2-[({4-[N- cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]-N-[(lethylpyrrolidin-2yl)methyl]acetamide	N-(2-cyanoethyl)-2-[«4-[Ncyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]-N-ethylacetamide	2-[({4-[N- cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]-l-[(2R)-2(pyrrolidin-l-ylmethyl)pyrrolidin-lyl]ethan-l-one	2-[({4-[N- cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]-N-[4(diethylamino)butyl]acetamide
52	ui w	50	49	48
+	+	+	+ +	+


+ +	+ +	+ +	+ + +	+

203

methyl 2-[({4-[N- cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]acetate	2-[({4-[N- cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]-N-methyl-N(prop-2-yn-l-yl)acetamide	l-(4-benzylpiperidin-l-yl)-2-[({4- [N- cyclopropylcarboximidoyl]pyridin-2yljmethyl)amino]ethan-l-one	2-[«4-[N- cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]-l-(4methylpiperazin-l-yl)ethan-l-one	N-(l-benzylpyrrolidin-3-yl)-2-[({4- [N- cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]acetamide
59	56	55	54	53
+	+	+	+	+
				+

+	+	+	+ +	++

204

[3-(dimethylamino)propyl]({4- [(methoxyimino)methyl]pyridin-2yl}methyl)amine	2-[«4-[[(2cyclohexylethyl)imino]methyl]pyridi n-2-yl}methyl)amino]-N-[2(dimethylamino)ethyl]-Nethylacetamide	<[2-«[4- (diethylamino)butyl]amino}methyl) pyridin-4- yl]methylidene}(2,2,3,3,3pentafluoropropyl)amine	2-[<[2-({[4- (diethylamino)butyl]amino}methyl) pyridin-4- yl]methylidene}amino]ethan-l-ol	[4-(diethylamino)butyl]({4-[[(2methoxyethyl)imino]methyl]pyridin2-yl}methyl)amine
64	63	62	h-¹	— 60
+	+ +	+ +	+ +
				+ +

+	+ + +	+++	+++

205

2-[({4-[5-benzyl-3-(trifluoroacetyl)- l,3-oxazinan-2-yl]pyridin-2yl}methyl)amino]-N-[2(dimethylamino)ethylJ-Nethylacetamide	3 It T& ι-¹ Φ - rt 3- ω στ g* ' ·< 3 ô. (D SB □ rt N = T Œ g 'ys. □ O<—. œ -o S? < i-4 ât ? NJ ' t	(2-cyclohexylethyl)({[2-({[4- (diethylamino)butyl]amino}methyl) pyridin-4-yl]methylidene})amine	N-[2-(dimethylamino)ethyl]-Nethyl-2-[({4-[([(2hydroxyethyl)imino]methyl]pyridin2-yl}methyl)amino]acetamide	[4-(diethylamino)butyl]({[4-(lmethylimidazolidin-2-yl)pyridin-2yl]methyl})amine
90	89	67	66	65
	+ +	++	+ +	+
+ + +
+
+ + +	+ + +	+ + +	+ + +	+++

206

(2S)-2-[«4-[[(2hydroxyethyl)imino]methyl]pyridin2-yl}methyl)amino]-4-methyl-l(piperidin-l-yl)pentan-l-one	3· ~< Z NJ Q- A .< O FJ ή 3 S- * (D ΖΓ D îl 2 < 2O zj’ =r i O NJ ' D ' « Z S i ώ sf < h ά œ 3. c; ro o. ·£ ZJ t	2-[«2-[({2-[2- (benzyloxy)phenyl]ethyl}amino)met hyl]pyridin-4yl}methylidene)amino]ethan-l-ol	N-[(2-fluorophenyl)methyl]-2-[({4- [[(2- hydroxyethyl)imino]methyl]pyridin2-yl}methyl)amino]-Nmethylacetamide	N-[2-(dimethylamino)ethyl]-Nethyl-2-[({4-[7-(trifluoroacetyl)-5oxa-7-azaspiro[2.5]octan-6- yl]pyridin-2- yl}methyl)amino]acetamide
95	94	93	92	kO
4-	4-	4-	4-
				+++
				4-
4-	4- 4-	4-	4-	4- 4- 4-
4-	+	4-	4-	4-

207

2-(<[(l-methylpiperîdin-4- yl)methyl]amino}methyl)pyridine-4carbaldehyde	2-({[(2Z)-4-(dimethylamino)but-2en-l-yl]amino}methyl)pyridine-4carbaldehyde	2-({[(2E)-4-(dimethylamino)but-2en-l-yl]amino}methyl)pyridine-4carbaldehyde	2-{[«4- [(dimethylamino)methyl]cyclohexyl }methyl)amino]methyl}pyridine-4carbaldehyde	2-[{4-[([(2hydroxyethyl)imino]methyl]pyridin2-yl}methyl)amino]-N-methyl-N-(2phenylethyl)acetamide
100	99	98	97	96
++	4-	+ +	+	4-
		+++

+++	+	+++	+++	+
				4-

208

N,N-diethyl-2-{[(4-formylpyridin-2yl)methyl]amino}acetamide	N-[(l-ethylpyrrolidin-2-yl)methyl]- 2-{[(4-formylpyridin-2- yl)methyl]amino}acetamide	2-({[2-(4-methylpiperazin-l-yl)-2oxoethyl]amino}methyl)pyridine-4carbaldehyde	2-[({2-oxo-2-[(2R)-2-(pyrrolidin-lylmethyl)pyrrolidin-lyl]ethyl}amino)methyl]pyridine-4carbaldehyde	! N-[2-(dimethylamino)ethyl]-Nethyl-2-{[(4-formylpyridin-2yl)methyl]amino}acetamide
105	104	103	102	TOT
+	+	+	+ +	+ +
			+ +	+ +

+ +	++	++	+ +	+ + +

209

2-«[2(dimethylamino)ethyl]amino}methyl )pyridine-4-carbaldehyde	2-[«4- [benzyl(cyclopropyl)amino]butyl}a mino)methyl]pyridine-4carbaldehyde	2-({[4(dimethylamino)butyl]amino}methy l)pyridine-4-carbaldehyde	2-«[4(diethylamino)butyl]amino}methyl) pyridine-4-carbaldehyde	2-({[2-(4-benzylpiperidin-l-yl)-2oxoethyl]amino}methyl)pyridine-4carbaldehyde
110	109	108	107	106
+	+	+ +	++	+

			+
++	+ +	+++	+++	+

N-[4-(diethylamino)butyl]-2,2,2trifluoro-N-[(4-formylpyridin-2yl)methyl]acetamide	2-«[5- (dimethylamino)pentyl]amino}meth yl)pyridine-4-carbaldehyde	yl)methyl]amino}acetamide	N-(l-benzylpyrrolidin-3-yl)-2-{[(4- formylpyridin-2-	! N-[4-(diethylamino)butyl]-2-{[(4formylpyridin-2yl)methyl]amino}acetamide	2-({[3-(pyrrolidin-l- yl)propyl]amino}methyl)pyridine-4carbaldehyde
115	114	113	112	111
+ +	+	+	+	+
				+

+ + +	+ + +	+	+	+++

Example 5: Cell prolifération Assays for EC50 value Détermination

This example demonstrates the ability of the compounds of the invention to inhibit the prolifération of a human breast cancer cell line.

General method

MCF7 cells were seeded in multi well plates at a density optimized to give approximately 90% confluent cells at the time of harvest. Cells were incubated for 24 hours before addition of compound. Compounds were diluted in complété medium and added to the plates in duplicates. The final concentration of DMSO was maximum 0.5 %. Complété medium used was DMEM with GlutaMAX contaîning 10 % FBS and pen/strep.

120 hours after addition of compounds, the plates were harvested and analyzed by ATPIite 1 Step (Perkin Elmer, cat no 6016739) according to the manufactures recommendation.

212

Compound Name	Compound #	EC50
N-{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4- yl]methyl}-2,2,2-trifluoroacetamide	1	+++
[2-({[4-(dimethylamîno)butyl]amino}methyl)pyridin-4yljmethanamine	2	+++
[2-({[3-(dimethylamino)propyl]amino}methyl)pyridin-4yljmethanamine	3	+++
2-({[4-(aminomethyl)pyridin-2-yl]methyl}arnino)-N-[2(dimethylamino)ethylJ-N-ethylacetamide	4	+++
[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methanamine	5	+++
N-[4-(diethylamino)butyl]-2,2_z2-trifluoro-N-({4- [(trifluoroacetamido)methyl]pyridin-2-yl}methyl)acetannide	6	+++

213

[2-({[4-(azetidin-l-yl)butyl]amino}rnethyl)pyridin-4yl]methanamine	7	++
[2-({[5-(dimethylamino)pentyl]amino}methyl)pyridin-4yljmethanamine	8	+++
2-({[4-(aminornethyl)pyridin-2-yl]methyl}amino)-N-{l-[(2methoxyphenyl)methyl]piperidin-4-yl}acetamide	9	+
2-({[2-({[3-(dimethylamino)propyl]amino}methyl)pyridin-4yl]methyl}amino)propanenitrile	22	+++
N-[(2-{[(£[2(dimethylamino)ethyl](ethyl)carbamoyl)-methyl)amino]methyl}py ridin-4-yl)methyl]-2,2,2-trifluoroacetamide	25	+++
N-[(2-{[N-({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)2_/2,2-trifluoroacetamido]methyl}pyridin-4-yl)methyl]-2,2,2trifluoroacetamide	26	+++
({[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methyl}carbamoyl)formic acid	27	++

214

tert-butyl (<[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methyl}carbamoyl)formate	28	++
ethyl 2-«[(2-{[«[2- (dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}py ridin-4-yl)methyl]carbamoyl}oxy)benzoate	29	++
N-[(2-{[({[2-(azetidin-l- yl)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridin-4yl)methyl]-2,2,2-trifluoroacetamide	30	+++
N-[(2-{[({[2- (dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}py ridin-4-yl)methyl]-2,2,3,3,4_/4,4-heptafluorobutanamide	31	++
N-[(2-{[({[2(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}py ridin-4-yl)methyl]-2,2-difluorobutanamide	32	+
N,N-dimethyl-2-[({4-[[(3-phenylpropyl)imino]methyl]pyridin-2yl}methyl)amino]acetamide	34	+
2-[({4-[[(2-cyclohexylethyl)imino]methyl]pyridin-2yl}methyl)amino]-N,N-dimethylacetamide	36	++

215

[3-(dimethylamino)propyl]({4-[{[3- (dimethylamino)propyl]imino}methyl]pyridin-2-yl}methyl)amine	37	+++
({4-[{[2-(dimethylamino)ethyl]imino}methyl]pyridin-2yl}methyl)[3-(dimethylamino)propyl]amine	38	+++
N-{[2-({[2-(l-methylpyrrolidin-2-yl)ethyl]amino}methyl)pyridin- 4-yl]methylidene}cyclopropanamine	40	++
N-{[2-({[3-(pyrrolidin-l-yl)propyl]amino}methyl)pyridin-4yljmethylidenejcyclopropanamine	42	+++
N-{[2-({[(2E)-4-(dimethylamino)but-2-en-l- yl]amino}methyl)pyridin-4-yl]methylidene}cyclopropanamine	43	+++
N-{[2-({[4-(azetidin-l-yl)butyl]amino}methyl)pyridin-4yljmethylidenejcyclopropanamine	44	+++
N-[(2-{[«4- [(dimethylamino)methyl]cyclohexyl}methyl)amino]methyl}pyridi n-4-yl)methylidene]cyclopropanamine	46	+++

216

2-[({4-[[(2-cyclohexylethyl)imino]rnethyl]pyridin-2yl}methyl)amino]-N,N-diethylacetamide	57	+
N,N-diethyl-2-[({4-[(octylimino)methyl]pyridin-2yl}methyl)amino]acetamide	58	+
[4-(diethylamino)butyl]({4-[[(2- methoxyethyl)imino]methyl]pyridin-2-yl}methyl)amine	60	+++
2-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}amino]ethan-l-ol	61	+++
{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}(2,2,3,3,3-pentafluoropropyl)amine	62	+++
2-[({4-[[(2-cyclohexylethyl)imino]methyl]pyridin-2- yl}methyl)amino]-N-[2-(dimethylamino)ethyl]-N-ethylacetamide	63	+++
[3-(dimethylamino)propyl]({4-[(methoxyimino)methyl]pyridin-2yl}methyl)amine	64	+

217

[4-(diethylamino)butyl]({[4-(l-methylimidazolidin-2-yl)pyridin-2yl]methyl})amine	65	+++
N-[2-(dimethylamino)ethyl]-N-ethyl-2-[({4-[([(2- hydroxyethyl)imino]methyl]pyridin-2-yl}methyl)amino]acetamide	66	+++
(2-cyclohexylethyl)({[2-({[4- (diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene})amine	67	+++
[4-(diethylamino)butyl]({[4-(l-methyl-l,3-diazinan-2-yl)pyridin2-yl]methyl})amine	68	+++
N,N-diethyl-2-[({4-[{[2-(4methylphenyl)ethyl]imino}-methyl]pyridin-2yl}methyl)amino]acetamide	69	+
4-[2-{[2-({[4-(diethylamino)butyl]amino}rnethyl)pyridin-4yl]methylidene}hydrazin-l-yl]benzonitrile	70	++
3-[{[2-({[4-(diethylamino)butyl]amino}rnethyl)pyridin-4yl]methylidene}amino]propan-l-ol	71	+++

218

[4-(diethylamino)butyl][(4-{7-oxa-9-azaspiro[4.5]decan-8yl}pyridin-2-yI)methyl]amine	72	+++
2-[{[2-({[4-(diethylamino)butyl]amino}rnethyl)pyridin-4yl]methylidene}amino]propan-l-ol	73	+++
l-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4- yl]methylidene}amino]propan-2-ol	74	+++
2-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}amino]-2-phenylethan-l-ol	75	+++
3-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}amino]-2,2-dimethylpropan-l-ol	76	+++
(l-{[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}amino]methyl}cyclopropyl)methanol	77	+++
N-[2-(dimethylamino)ethyl]-N-ethyl-2-[({4-[[(3hydroxypropyl)imino]methyl]pyridin-2yl}methyl)amino]acetamide	78	+++

219

N-ethyl-2-[({4-[[(2-hydroxyethyl)imino]methyl]pyridin-2yl}methyl)amino]-N-[(l-methylpyrrolidin-2-yl)methyl]acetamide	79	+++
2-{[{[2-({[4-(diethylamino)butyl]amino}rnethyl)pyridin-4yl]methylidene}amino]methyl}-3-phenylpropan-l-ol	80	++
2-[«4-[[(2-cyclohexyl-3-hydroxypropyl)imino]methyl]pyridin-2yl}methyl)amino]-N-[2-(dimethylamino)ethyl]-N-ethylacetamide	81	+++
N-[3-(dimethylamino)propyl]-N-ethyl-2-[({4-[[(2- hydroxyethyl)imino]methyl]pyridin-2-yl}methyl)amino]acetamide	82	+++
N-[2-(dirnethylamino)propyl]-N-ethyl-2-[({4-[[(2- hydroxyethyl)imino]methyl]pyridin-2-yl}methyl)amino]acetamide	83	+++
l-[<[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}amino]-3-phenylpropan-2-ol	84	+++
N-{[(lS,2S)-2-(dimethylamino)cyclopentyl]rnethy!}-N-ethyl-2[({4-[[(2-hydroxyethyl)imino]methyl]pyridin-2yl}methyl)amino]acetamide	85	++

220

2-[({4-[{[3-(dimethylamino)-2- hydroxypropyl]imino}methyl]pyridin-2-yl}methyl)amino]-N-[2(dimethylamino)ethyl]-N-ethylacetamide	86	+++
2-({[4-(5,5-dimethyl-l,3-oxazinan-2-yl)pyridin-2- yl]methyl}amino)-N-[2-(dimethylamino)ethyl]-N-ethylacetamide	87	+++
N-[2-(dimethylamino)ethyl]-N-ethyl-2-[({4-[({[l(hydroxymethyl)cyclopropyl]methyl)imino)methyl]pyridin-2yl}methyl)amino]acetamide	88	+++
2-[({4-[[(2-benzyl-3-hydroxypropyl)imino]methyl]pyridin-2yl}methyl)amino]-N-[2-(dimethylamino)ethyl]-N-ethylacetamide	89	+++
2-[({4-[5-benzyl-3-(trifluoroacetyl)-l,3-oxazinan-2-yl]pyridin-2- yl}methyl)amino]-N-[2-(dimethylamino)ethyl]-N-ethylacetamide	90	+++
N-[2-(dimethylamino)ethyl]-N-ethyl-2-[({4-[7-(trifluoroacetyl)-5oxa-7-azaspiro[2.5]octan-6-yl]pyridin-2yl}methyl)amino]acetamide	91	+++
N-[(2-fluorophenyl)methyl]-2-[({4-[[(2hydroxyethyl)imino]methyl]pyridin-2-yl}methyl)amino]-Nmethylacetamide	92	+

221

2-[({2-[({2-[2-(benzyloxy)phenyl]ethyl}arnino)methyl]pyridin-4yl}methylidene)amino]ethan-l-ol	93	+
N-(2-cyanoethyl)-N-ethyl-2-[({4-[[(2- hydroxyethyl)imino]methyl]pyridin-2-yl}methyl)amino]acetamide	94	+
(2S)-2-[({4-[[(2-hydroxyethyl)imino]methyl]pyridin-2yl}methyl)amino]-4-methyl-l-(piperidin-l-yl)pentan-l-one	95	+
2-{[({4[(dimethylamino)methyl]cyclohexyl}methyl)amino]methyl}pyridi ne-4-carbaldehyde	97	++
2-({[(2E)-4-(dimethylamino)but-2-en-lyl]amino}methyl)pyridine-4-carbaldehyde	98	+++
2-({[(2Z)-4-(dimethylamino)but-2-en-lyl]amino}methyl)pyridine-4-carbaldehyde	99	+
2-({[(l-methylpiperidin-4-yl)methyl]amino}methyl)pyridine-4carbaldehyde	100	+++

222

N-[2-(dimethylamino)ethyl]-N-ethyl-2-{[(4-formylpyridin-2yl)methyl]amino}acetamide	101	+++
2-[({2-oxo-2-[(2R)-2-(pyrrolidin-l-ylmethyl)pyrrolidin-lyl]ethyl}amino)methyl]pyridine-4-carbaldehyde	102	++
2-({[4-(diethylamino)butyl]amino}methyl)pyridine-4carbaldehyde	107	+++
2-({[3-(pyrrolidin-l-yl)propyl]amino}methyl)pyridine-4- carbaldehyde	111	+++
N-[4-(diethylamino)butyl]-2,2,2-trifluoro-N-[(4-formylpyridin-2yl)methyl]acetamide	115	+++
N-[2-(diethylamino)ethyl]-N-ethyl-2-{[(4-forrnylpyridin-2yl)methyl]amino}acetamide	116	+++
2-[«[3(dimethylamino)cyclopentyl]methyl}amino)methyl]pyridine-4carbaldehyde	117	++

223

(a) +++: ECso <250 nM; ++: 250 nM < ECso < 2500 nM; +: ECso > 2500 nM

Example 6: Cell prolifération Assays for EC50 value Détermination

This example demonstrates the ability of the compounds of the invention to inhibit the prolifération of a human cancer cell lines.

The assays were performed by the method of Example 5 by seeding the relevant cell line at a density optimized to give approximately 90% confluent cells at the time of harvest.

224

225

Jurkat	i—i l—l H ÜJ	HEPG2	HCC1954	m t_i 3	BT474	ARPE19	AMOl	A375	Cell Line
Acute T cell	Plasma cell leukemia	Hepatocellular carcinoma	Breast dutal carcinoma	Myeloma	Mammary ductal carcinoma	Retinal pigmented epithelium	Plasmacytoma	Melanoma	Cell Type
+		+	4-	4-				++	Compound #25
		4-			++	4-			Compound #42
	+	+		4-	+++	4-	+++		Compound #61
									Compound #81
									Compound #90
		4-			+++	4-			Compound #107

INHIBITION OF CELL PROLIFERATION

226

M0LP2	Z Z Mω	MM1R	MIA PACA2	MDA MB 231	LP1	L363	L1236	KMS 12 BM	KARPAS620	K562	Clone E6-1
Myeloma	Myeloma	Myeloma	Pancréas épithélial carcinoma	Breast carcinoma	Myeloma	Plasma cell leukemia	Hodgkin's lymphoma	Myeloma	Plasma cell leukemia	Chronic myelogenous leukemia	lymphoma
++	+++			4-		4-	4-	+++		4- 4-
			+	4-					4·
			4-		+	4-	4-		+++
									+++
		+++							+++
+			4-	+

(a) +++: ECso <250 nM; ++: 250 nM < ECso £ 2500 nM; +: ECso > 2500 nM

UH01

U20S

U266

SU DHL6

SK-MEL-28

SK MM2

RPMI8226

RAJI

OVCAR-3

0PM2

NCIH929

NALM6

M0LP8

Hodgkin's lymphoma

Osteosarcoma

Myeloma

B cell lymphoma

Melanoma

Plasma cell leukemia

Myeloma

Burkitt's lymphoma

Ovary

Myeloma

Lymphoblastic leukemia

Myeloma

+++

4-

+ 4-

4- 4-

+

4-

+

4-

+++

+

4-

4· 4-

4-

+++

4- 4-

+++

4·

4-

4- 4-

+++

Example 7 Inhibition of Tumor Growth in Mouse Xenoqraft Model

This example demonstrates ability of compounds of the invention to inhibit tumor growth in vivo in the OPM-2 subcutaneous mouse xenograft model of multiple myeloma.

Method

Briefly, NOD/SCID mice γ-irradiated with ⁶⁰Co (200 rad) (12 animals/group) were inoculated subcutaneously with 8 x 106 OPM-2 cells assisted with Matrigel.

Dosing according to the table below started when tumors reached an average size of ~100 mm³ (day 15). Dosing continued until the average size of tumors in the vehicle group reached ~2000 mm³ (day 31).

Animais were 7 weeks old female NOD/SCID mice (Mus Musculus), supplied by Beijing HFK Bio-Technology Co. Ltd. (Beijing, china). Body welght was approx. 16-23 g. Before commencement of treatment, ail animais were weighed and tumor volumes were measured, and mice were assigned into groups using randomized block design based upon their tumor volumes.

OPM-2 tumor cells were maintained in vitro in RPMI1640 medium supplemented with 20% fêtai bovine sérum at 37°C in an atmosphère of 5% CO₂ in air. The tumor cells were routinely subcultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.

Tumor sizes were measured three times weekly in two dimensions using a caliper, and the volume was expressed in mm³ using the formula: V = 0.5 a x b²where a and b were the long and short diameters of the tumor, respectively.

Vehicle	Positive control	Compound #61	Compound #61	Compound #61
BID x	QDx4/week	BID x 14	BID x 14	BID x 14
14	x 2	i.p. 20	i.p. 10	i.p. 1 mg/kg

109924581 vl

Days after inoculation	Tumor Volume (mm³)
15	101+11	101+12	101+12	101+11	101+12
17	276+19	156+26	188+25	198+28	249+32
19	406+36	178+36	292+50	276+44	320+45
21	643+59	266+56	440+77	519+67	577+85
24	1047+86	395+92	766+143	694+92	951+124
26	1313+10 8	509+116	1029+196	928+136	1259+169
28	1776+14 2	767+169	1298+236	1289+178	1800+202
31	2473+21 3	1148+175	1573+261	1996+302	2864+334

229

LIST OF REFERENCES

Catchpole S et al., Int. J. Oncol. 38, 1267-77, 2011

Cloos, P.a.C. et al. (2008), Genes. Dev. 22; 115-1140

Cloos, P. Et al., Nature 442, 307-11, 2006

Fischle, W., et. Al., Curr. Opinion Cell Biol. 15, 172-83, 2003

Hayami S. et al. (2010) Mol. Cancer 9

He J et al., Blood 117 (14), 3869-80, 2011

He J et al. Nat Struct Mol Biol 15(11), 2008

Kelly, T.K. et al. (2010), Epigenetic modifications as therapeutic targets, Nat. Biotechnol. 28; 1069-1078

Klose, RJ. et al., Nature 442, 312-16, 2006

Liu, G. Et al., Oncogene 28, 4491-500, 2009

Margueron, R., et al., Curr. Opinion Genet. Dev. 15, 163-76, 2005

Morton and Houghton, Establishment of human tumor xenografts in immunodeficient mice, Nature Protocols, 2 (2) 247-250, 2007

Pfau R et al., PNAS 105(6), 1907-12, 2008

Queguiner, G. and Pastour, P., Comptes Rendus des Séances de l'Académie des Sciences, Série C: Sciences Chimiques, 268(2) 182-5, 1969.

Quina, A.S. et al. (2006), Chromatin structure and epigenetics, Biochem. Pharmacol. 72; 1563-1569

Roy et al. PerkinElmer Technical Note: AlphaLISA #12, Apr. 2011

Tzatsos A et al., PNAS 106 (8), 2641-6, 2009

Yamane K. et al., Mol. Cell 25, 801-12, 2007

Xiang Y. et al. (2007) PNAS 104

Claims

1. A compound ofthe Formula (I)

Q ·: R¹

I

... N, ...Y ”· _N·· '•fi'' wherein

Q is selected from -CH=NR¹², -W, -CH2NHR¹³, -CH=O and -CH(OR¹⁷)2;

n

A is selected from -CHR C(O)-, C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, C3-10 cycloalkylene, heterocyclylene, heteroarylene and arylene, which alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene O may optionally be substituted with one or more R ,· with the proviso that when Q is -CH=O, A is not alkynylene;

Y is selected from -H, -NR⁶R⁷, -OR⁷, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C310 cycloalkyl, heterocyclyl, heteroaryl and aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with ο n one or more R and may form a cyclic structure with R , with the proviso that when Q is -CH=O, Y is not alkynyl;

R¹ is selected from -H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl; or more preferably is selected from -H and C1-4 alkyl; or with -A-Y forms a nitrogen containing optionally substituted heterocyclic group where the optional substitution may be Cl-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally

231 substituted with one or more selected from -OH, aryl, Ci-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl;

T

R is selected from -H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, and C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl, and may form a cyclic structure with Y;

O each R is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Zaryl, -Z- heteroaryl, -Z-NR⁶R⁷, -Z-C(=O)-NR⁶R⁷, -Z-NR⁶-C(=O)-R⁷, -Z-C(=O)R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO2NR⁶R⁷ and -ZCOOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

each R⁴ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-10 cycloalkyl, -N(R¹)2/ carbamoyl, and -OH;

each R⁵ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-6 cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and -OH; each of R⁶ and R⁷ is independently selected from C1-8 alkyl, C1-4 fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl and -Z-aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R ; or, altematively, R° and R' may together with the N-atom to which they are attached form an N-heterocyclic ring

O optionally substituted with one or more independently selected R ;

232

Q each R is independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Zheteroaryl, -Z-aryl, -Z-NR¹⁰R¹³·, -Z-C(=O)-NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -ZSR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C3-6 cycloalkyl, -Zheterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR^⁹R^^, -Z-C(=O)-Nr1⁹r1\ -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defined above, and each R⁹ is independently selected from -H, C1-8 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Zaryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above;

each of R^⁹ and R^ is independently selected from -H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above, or, altematively, R¹⁰and R¹¹ may together with the N-atom to which they are attached form an Nheterocyclic ring optionally substituted with one or more R⁴ as defined above; with the proviso that Y is not H when A is -CH2-;

when Q is -CH=NR¹², R¹² is selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-iocycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z-heteroaryl, -Z-NR^R²,

233

-Z-C(=O)-NR⁶R⁷, -Z-NR⁶-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷ and -Z-COOR⁷, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R³;

When Q is -CH2NHR¹³ , R¹³ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, C(O)C(O)OR⁷, C1-8 alkyl, Ci-4fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, and Z-monocyclic-heteroaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl may optionally be substituted with one or more independently selected R⁸, or is -CR¹⁴R¹⁵-NR⁶R⁷, -CR¹⁴R¹⁵CN, or -CR¹⁴R¹⁵OR⁷, wherein each of rA⁴ and R·*·³ is independently selected from -H, Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, and wherein R¹⁴ and R¹⁵ together with the intervening carbon atom may designate a C3-10 cycloalkyl or C5-io-cycloalkenyl ring, which alkyl, alkenyl, alkynyl, cycloalkyl (ring), cycloalkenyl ring, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R ;

when Q is W, W is selected from an l,3-diaza-C5-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally contaîning one or two oxo groups; a l,3-thiaza-C5-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³ and optionally contaîning one or two oxo groups; an l,3-oxaza-C5-7cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally contaîning one or two oxo groups, wherein in ail three instances two R^3,s on the same carbon atom may together form a spiro group;

R¹⁶ is selected from hydrogen, -C(O)R⁷, and -C(O)C(O)R⁷, and -C(O)C(O)R⁷;

234 when Q is -CH(OR¹⁷)2, each R¹⁷ independently is R³, or wherein two R¹⁷substituents together with the intervening -O-CH(-)-O- may form a heterocyclyl optionally substituted with one or more R³ and containing up to two oxo groups; or an isomer or a mixture of isomers thereof, or a pharmaceutically acceptable sait, or solvaté or prodrug thereof.

n

2. A compound according to claim 1, whereln A Is selected from -CHR C(O), or Ci-8 alkylene, or heterocyclylene.

3. A compound according to claim 1 or claim 2, wherein Y is -NR⁶R⁷.

4. A compound according to claim 3, wherein A is -CHR C(O)-.

5. A compound according to daim 4, wherein A is -CH2-C(O)-.

6. A compound according to any one of claims 2 to 5, wherein Yis

R¹⁰ \ /.N.

\ / ''I-.11

N (CH₂)_n'R” wherein n is from 1 to 3 and each of Rio and Ru independently is as defined in claim 1.

7. A compound as elaimed in claim 6, wherein Y is

R¹⁰ \ \

N \CH₂)/ R¹¹ ch₂ch₃

235 wherein n is from 1 to 3 and each of Rio and Ru independently is as defined in claim 1.

8. A compound according to claim 6, wherein Y is (CH₂)_m—CH₃ ,z\ ,. N,

N (CH₂)_n-· ''(CH₂)_m—CH₃ 'ch₃ wherein n is from 1 to 3 and each m independently is from 0 to 2.

9. A compound according to claim 1 or claim 2, wherein Y is selected from heterocyclyl, heteroaryl and aryl, which may be optionally substituted with one or more R³.

1 *3

10. A compound according to any ofthe preceding claims, wherein R is H.

11. A compound as claimed in any preceding claim, wherein Q is ofthe formula

R¹⁹

R¹⁸.. , N CF₃

-··· \ ·O wherein R¹⁸ and R¹⁹ are hydrogen, or together form a l,3-diaza-C5-7-cycloalk-2yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups; a 1,3-thiazaC5-7-cycloalk-2-yl group which is N-substituted with R¹⁶ and optionally further substituted with one or more R³ and optionally containing one or two oxo groups; an l,3-oxaza-C5-7-cycloalk-2-yl group which is N- substituted with R¹⁶

236

Ο and optionally further substituted with one or more R , and optionally containing O one or two oxo groups, wherein in ail three instances two R s on the same carbon atom may together form a spiro group.

12. A compound according to any one of the preceding claims, wherein the moiety -A-Y includes 1-3 cyclic moieties selected from monocylic cycloalkyl, monocyclic heterocyclyl, monocylic heteroaryl, dicyclic heteroaryl and monocyclic aryl.

13. A compound as shown in the following table:

237

Name N-{[2-«[4-(diethylamino)butyl]amino}methyl)pyridin-4-yl]methyl}-2,2,2trifluoroacetamide [2-({[4-(dimethylamino)butyl]amino}methyl)pyridin-4-yl]methanamine [2-({[3-(dimethylamino)propyl]amino}methyl)pyridin-4-yl]methanamine 2-({[4-(aminomethyl)pyridin-2-yl]methyl}amino)-N-[2-(dimethylamino)ethyl]N-ethylacetamide [2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4-yl]methanamine N-[4-(diethylamino)butyl]-2,2,2-trifluoro-N-({4- [(trifluoroacetamido)methyl]pyridin-2- yl}methyl)acetamide [2-({[4-(azetidin-l-yl)butyl]amino}methyl)pyridin-4-yl]methanamine [2-({[5-(dimethylamino)pentyl]amino}methyl)pyridin-4-yl]methanamine 2-({[4-(aminomethyl)pyridin-2-yl]methyl}amino)-N-{l-[(2- methoxyphenyl)methyl]piperidin-4-yl}acetamide N-{[2-({[4-(dimethylamino)butyl]amino}methyl)pyridin-4- yl]methyl}cyclopropanamine N-{[2-({[3-(2-methylpiperidin-l-yl)propyl]amino}methyl)pyridin-4yljmethyljcyclopropanamine N-({2-[(propylamino)methyl]pyridin-4-yl}methyl) cyclopropanamine 2-{[(4-{[(cyanomethyl)amino]methyl}pyridin-2-yl)methyl]amino}-N_/Ndimethylacetamide 2-{[(4-{[(2-fluoroethyl)amino]methyl}pyridin-2-yl)methyl]amino}-N,Ndimethylacetamide 2-({[4-({[2-(dimethylamino)ethyl]amino}methyl)pyridin-2-yl]methyl}amino)- N,N- dimethylacetamide <[(2S)-l-benzylpyrrolidin-2-yl]methyl}[(4- {[(cyclopropylmethyl)amino]methyl}pyridin-2- yl)methyl]amine benzyl(methyl){3-[({4-[(methylamino)methyl]pyridin-2yl}methyl)amino]propyl)-amine benzyl[3-({[4-({[2-(dimethylamino)ethyl]amino}methyl)pyridin-2- yl]methyl}amino)propyl]methylamine benzyl(3-{[(4-{[(2-methoxyethyl)amino]methyl}pyridin-2-

238

yl)methyl]amino}propyl)methylamine 2-[({4-[(cyclopropylamino)methyl]pyridin-2-yl}methyl)amino]-N-{l-[(2- methoxyphenyl)methyl]piperidin-4-yl}acetamide 2-cyclopropyl-2-({[2-({[2-(dimethylarnino)ethyl]amino}methyl)pyridin-4yl]methyl}amino)acetonltrile 2-({[2-({[3-(dimethylamino)propyl]amino}methyl)pyridin-4- yl]methyl}amino)propanenitrile 2-[({2-[({4-[benzyl(cyclopropyl)amino]butyl}amino)methyl]pyridin-4- yl}methyl)amino]acetonitrile 2-[2-«[3-(dimethylamino)propyl]amino}methyl)pyridin-4-yl]-2- (methylamino)acetonitrile N-[(2-{[({[2(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridin-4yl)methyl]-2,2,2-trîfluoroacetamide N-[(2-{[N-({[2-(dimethylamino)ethyl](ethyl)carbarnoyl}methyl)-2,2,2trifluoroacetamido]methyl}pyridin-4-yl)methyl]-2,2,2-trifluoroacetamide ({[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methyl}carbamoyl)formic acid tert-butyl ({[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methyl}carbamoyl)formate ethyl 2-({[(2-{[({[2(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridin-4yl)methyl]carbamoyl}oxy)benzoate N-[(2-{[({[2-(azetidin-l- yl)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridin-4-yl)methyl]-2,2,2trifluoroacetamide N-[(2-<[«[2- (dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridin-4yl)methyl]-2,2_/3,3,4,4,4-heptafluorobutanamide N-[(2-<[«[2- (dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridin-4yl)methyl]-2,2-difluorobutanamide 2-[({4-[(N-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)amino]-N,Ndimethylacetamide

239

N,N-dimethyl-2-[({4-[[(3-phenylpropyl)imino]methyl]pyridin-2yl}methyl)amino]acetamide Ν,Ν-άΐωβΐΚνΙ-2-[({4-[Ν-(2-ωβΐΚνΙενεΙορΓοργΙ)ε3Γ0οχΐΓηΐάονΙ]ρνπΰΐη-2- yl}methyl)amino]acetamide 2-[({4-[[(2-cyclohexylethyl)imino]methyl]pyridln-2-yl}methyl)amino]-N,Ndimethylacetamide [3-(dimethylamino)propyl]({4-[{[3- (dimethylamino)propyl]imino}methyl]pyridin-2- yl}methyl)amine «4-[{[2-(dimethylamino)ethyl]imino)-methyl]pyridin-2-yl}methyl)[3- (dimethylamino)propyl]amine N-{[2-({[2-(ethylsulfanyl)ethyl]amino}methyl)pyridin-4- yl]methylidene}cyclopropanamine N-{[2-«[2-(l-methylpyrrolidin-2-yl)ethyl]amino}methyl)pyridin-4- yl]methylidene}cyclopropanamine N-«2-[«3-[benzyl(methyl)amino]propyl}amino)methyl]pyridin-4- yl}methylidene)cyclopropanamine N-{[2-«[3-(pyrrolidin-l-yl)propyl]amino}methyl)pyridin-4yljmethylidenejcyclopropanamine ^N-{[2-({[(2E)-4-(dimethylamino)but-2-en-l-yl]amino}methyl)pyridin-4yljmethylidenejcyclopropanamine N-{[2-«[4-(azetidin-l-yl)butyl]amino}methyl)pyridin-4yl] methyl idenejcyclopropa na mi ne N-{[2-({[4-(dimethylamino)butyl]amino}methyl)pyridin-4- yl]methylidene}cyclopropanamine N-[(2-{[({4- [(dimethy!amino)methyl]cyclohexyl}-methyl)amino]methyl}-pyridin-4- yl)methylidene]cyclopropanamine l\l-{[2-({[5-(dimethylamino)pentyl]amino}methyl)pyridin-4- yl]methylidene}cyclopropanamine 2-[({4-[N-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)amino]-N-[4- (diethylamino)butyljacetamide 2-[({4-[N-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)amino]-l-[(2R)-2- (pyrrolidin-1- ylmethyl)pyrrolidin-l-yl]ethan-l-one

240

N-(2-cyanoethyl)-2-[({4-[N-cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]-N- ethylacetamide 2-[({4-[N-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)amino]-N-[(lethylpyrrolidin-2- yl)methyl]acetamide 2-[({4-[N-cyclopropylcarboxlmidoyl]pyrldin-2-yl}methyl)amino]-N-methyl-N[3-(lH-pyrazol-l- yl)propyl]acetamide N-(l-benzylpyrrolidin-3-yl)-2-[«4-[N-cyclopropylcarboximidoyl]pyridin-2yl}methyl)amino]acetamide 2-[({4-[N-cydopropylcarboximidoyl]pyridin-2-yl}methyl)amino]-l-(4methyl piperazin-l-yl)ethan-l-one l-(4-benzylpiperidin-l-yl)-2-[({4-[N-cyclopropylcarboximidoyl]pyridin-2- yl}methyl)amino]ethan-l-one 2-[({4-[N-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)amino]-N-methyl-N(prop-2-yn-l- yl)acetamide 2-[({4-[[(2-cyclohexylethyl)imino]methyl]pyridin-2-yl}methyl)amino]-N,Ndiethylacetamide N,N-diethyl-2-[({4-[(octylimino)methyl]pyridin-2-yl}rnethyl)amino]acetamide methyl 2-[({4-[l\l-cyclopropylcarboximidoyl]pyridin-2-yl}methyl)amino]acetate [4-(diethylamino)butyl]({4-[[(2-methoxyethyl)imino]methyl]pyridin-2yl}methyl)amine 2-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4- yl]methylidene}amino]ethan-l-ol {[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}(2,2,3,3,3- pentafluoropropyl)amine 2-[({4-[[(2-cyclohexylethyl)imino]methyl]pyridin-2-yl}methyl)amino]-N-[2- (dimethylamino)ethyl]-N-ethylacetamide [3-(dimethylamino)propyl]({4-[(methoxyimino)methyl]pyridin-2yl>methyl)amine [4-(diethylamino)butyl]({[4-(l-methylimidazolidin-2-yl)pyridin-2yl]methyl})amine N-[2-(dimethylamino)ethyl]-N-ethyl-2-[({4-[([(2- hydroxyethyl)imino]methyl]pyridin-2- yl}methyl)amino]acetamide (2-cyclohexylethyl)({[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4-

241

yl]methylidene})amine [4-(diethylamino)butyl]({[4-(l-methyl-l,3-diazinan-2-yl)pyridin-2yl]methyl})amine N_/N-diethyl-2-[({4-[{[2-(4-methylphenyl)ethyl]imino}methyl]pyridin-2yl}methyl)amino]acetamjde 4-[2-{[2-({[4-(diethylamino)butyl]amino}rnethyl)pyridin-4yl]methylidene}hydrazin-l- yljbenzonitrile 3-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4- yl]methylidene}amino]propan-l-ol [4-(diethylamino)butyl][(4-{7-oxa-9-azaspiro[4.5]decan-8-yl}pyridin-2- yl)methyl]amine 2-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}amino]propan-l-ol l-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4- yl]methylidene}amino]propan-2-ol 2-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4- yl]methylidene}amino]-2-phenylethan-l-ol 3-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4- yl]methylidene}amino]-2,2- dimethylpropan-l-ol (l-{[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4yl]methylidene}amino]methyl}cyclopropyl)methanol N-[2-(dîmethylamino)ethyl]-N-ethyl-2-[({4-[[(3- hydroxypropyl)imino]methyl]pyridin-2- yl}methyl)amino]acetamide N-ethyl^-fCÎ^H^-hydroxyethyOiminoJmethylJpyridin^-y^methyOaminoJ-N- [(1- methylpyrrolidin-2-yl)methyl]acetamide 2-{[{[2-({[4-(diethylamino)butyl]amino}rnethyl)pyridin-4- yl]methylidene}amino]methyl}-3- phenylpropan-l-ol 2-[({4-[[(2-cyclohexyl-3-hydroxypropyl)imino]methyl]pyridin-2- yl}methyl)amino]-N-[2- (dimethylamino)ethyl]-N-ethylacetamide N-[3-(dimethylamino)propyl]-N-ethyl-2-[({4-[[(2- hydroxyethyl)imino]methyl]pyridin-2- yl}methyl)amino]acetamide N-[2-(dimethylamino)propyl]-N-ethyl-2-[({4-[[(2- hydroxyethyl)imino]rnethyl]pyridin-2- yl}methyl)amino]acetamide

242

l-[{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4- yl]methylidene}amino]-3-phenylpropan-2-ol N-{[(lS,2S)-2-(dimethylamino)cyclopentyl]methyl}-N-ethyl-2-[({4-[[(2hydroxyethyl)imino]methyl]pyridin-2-yl}methyl)amino]acetamide 2-[({4-[{[3-(dimethylamino)-2-hydroxypropyl]imino}-methyl]pyridin-2- yl}methyl)amino]-N-[2- (dimethylamino)ethyl]-N-ethylacetamide 2-«[4-(5,5-dimethyl-l,3-oxazinan-2-yl)pyridin-2-yl]methyl}amino)-N-[2- (dimethylamino)ethylj- N-ethylacetamide N-[2-(dimethylamino)ethyl]-N-ethyl-2-[«4-[({[l(hydroxymethyl)cyclopropyl]methyl}imino)methyl]pyridin-2yl}methyl)amino]acetamide 2-[({4-[[(2-benzyl-3-hydroxypropyl)irnino]rnethyl]pyridin-2-yl}rnethyl)arnino]- N-[2- (dimethylamino)ethyl]-N-ethylacetamide 2-[({4-[5-benzyl-3-(trifluoroacetyl)-l,3-oxazinan-2-yl]pyridin-2- yl}methyl)amino]-N-[2- (dimethylamino)ethylJ-N-ethylacetamide N-[2-(dimethylamino)ethyl]-N-ethyl-2-[({4-[7-(trifluoroacetyl)-5-oxa-7azaspiro[2.5]octan-6- yl]pyridin-2-yl}methyl)amino]acetamide N-[(2-fluorophenyl)methyl]-2-[({4-[[(2-hydroxyethyl)imino]methyl]pyridin-2yl}methyl)amino]- N-methylacetamide 2-[({2-[({2-[2-(benzyloxy)phenyl]ethyl}amino)methyl]pyridin-4- yl}methylidene)amino]ethan-l-ol N-(2-cyanoethyl)-N-ethyl-2-[({4-[[(2-hydroxyethyl)imino]methyl]pyridin-2yl}methyl)amino]acetamide (2S)-2-[({4-[[(2-hydroxyethyl)lmino]methyl]pyridln-2-yl}methyl)amlno]-4methyl-l-(piperidin-l- yl)pentan-l-one 2-[{4-[([(2-hydroxyethyl)imino]methyl]pyridin-2-yl}methy!)amino]-N-methyl- N-(2- phenylethyl)acetamide 2-{[({4-[(dimethylamino)methyl]cyclohexyl}methyl)amino]methyl}-pyridine-4carbaldehyde 2-({[(2E)-4-(dimethylamino)but-2-en-l-yl]amino}methyl)pyridine-4carbaldehyde 2-({[(2Z)-4-(dimethylamino)but-2-en-l-yl]amino}methyl)pyridine-4carbaldehyde

243

2-({[(l-methylpiperidin-4-yl)methyl]amino}methyl)pyridine-4-carbaldehyde N-[2-(dimethylamino)ethyl]-N-ethyl-2-{[(4-formylpyridin-2- yl)methyl]amino}acetamide 2-[({2-oxo-2-[(2R)-2-(pyrrolidin-l-ylmethyl)pyrrolidin-l- yl]ethyl}amlno)methyl]pyridlne-4- carbaldehyde 2-({[2-(4-methylpiperazin-l-yl)-2-oxoethyl]amino}methyl)pyridine-4carbaldehyde N-[(l-ethylpyrrolidin-2-yl)methyl]-2-{[(4-forrnylpyridin-2- yl)methyl]amino}acetamide N_/N-diethyl-2-{[(4-formylpyridin-2-yl)methyl]amino}acetamide 2-«[2-(4-benzylpiperidin-l-yl)-2-oxoethyl]amino}methyl)pyridine-4carbaldehyde 2-({[4-(diethylamino)butyl]amino}methyl)pyridine-4-carbaldehyde 2-({[4-(dimethylamino)butyl]amino}methyl)pyridine-4-carbaldehyde 2-[({4-[benzyl(cyclopropyl)amino]butyl}amino)methyl]pyridine-4carbaldehyde 2-({[2-(dimethylamino)ethyl]amino}methyl)pyridine-4-carbaldehyde 2-«[3-(pyrrolidin-l-yl)propyl]amino}methyl)pyridine-4-carbaldehyde N-[4-(diethylamino)butyl]-2-{[(4-formylpyridin-2-yl)methyl]amino}acetamide N-(l-benzylpyrrolidin-3-yl)-2-{[(4-formylpyridin-2-yl)methyl]amino}acetamide 2-({[5-(dimethylamino)pentyl]amino}methyl)pyridine-4-carbaldehyde N-[4-(diethylamino)butyl]-2,2,2-trifluoro-N-[(4-formylpyridin-2- yl)methyl]acetamide N-[2-(diethylamino)ethyl]-N-ethyl-2-{[(4-formylpyridin-2yl)methyl]amino}acetamide 2-[({[3-(dimethylamino)cyclopentyl]methyl}amino)methyl]pyridine-4carbaldehyde N-[2-(dimethylamino)-2-methylpropyl]-N-ethyl-2-{[(4-formylpyridin-2yl)methyl]amino}acetamide N-ethyl-2-{[(4-formylpyridin-2-yl)methyl]amino}-N-[(l-methylpyrrolidin-2- yl)methyl]acetamlde 2-({methyl[2-oxo-2-(piperidin-l-yl)ethyl]amino}methyl)pyridine-4-

244 carbaldehyde

14. A compound according to claim 12, in the form of an oxalate sait.

15. A compound according to claim 12, in the form of a citrate sait.

16. A compound according to claim 12, in the form of a fumarate sait.

17. A compound according to claim 12, in the form of an ascorbate sait.

18. A compound according to any one ofthe preceding claims, which has a molecular weight of 130-1,000 g/mol, such as 180-800 g/mol, e.g. 225-600 g/mol or 250-500 g/mol.

19. A pharmaceutical composition comprising at least one compound of Formula (I) as defîned in any one of the claims 1-18 and optionally one or more pharmaceutically acceptable excipients, diluents or carriers.

20. A pharmaceutical composition according to claim 19, which comprises one or more further active substances.

21. A compound for use as a médicament which is a compound of the Formula (I)

Q

R¹

I

,.N., ,-^Y ’A' wherein

Q is selected from -CH=NR¹², -W, -CH2NHR¹³, -CH=O and -CH(OR¹⁷)2;

A is selected from -CHR²C(O)-, C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, C3-10 cycloalkylene, heterocyclylene, heteroarylene and arylene, which alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene may optionally be

O substituted with one or more R ; with the proviso that when Q is -CH=O, A is not alkynylene;

Y is selected from -H, -NR⁶R⁷, -OR⁷, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, which alkyl, alkenyl, alkynyl, cycloalkyl,

O heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R and may form a cyclic structure with R²; with the proviso that when Q is -CH=O, Y is not alkynyl; R¹ is selected from -H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl; or more

245 preferably is selected from -H and C1-4 alkyl; or with -A-Y forms a nitrogen containing optionally substituted heterocyclic group where the optional substitution may be C1-8 alkyl,

C2-8 alkenyl, C2-8 alkynyl, orC3-io cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl;

O each R is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, Z-C(=O)-NR⁶R⁷, -Z-NR⁶-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -ZSO2R⁷, -Z-SO2NR⁶R⁷ and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

each R⁴ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-10 cycloalkyl, -N(R¹)2, carbamoyl, and -OH;

each R⁵ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-6 cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and -OH;

each of R⁶ and R⁷ is independently selected from C1-8 alkyl, C1-4 fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Zheterocyclyl, -Z-heteroaryl and -Z-aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R⁸; or, altematively, R⁶ and R⁷ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R⁸;

each R⁸ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰R^1:L, -Z-C(=O)-NR¹⁰R^1:l, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl,

246

C3-6 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰R¹¹, -Z-C(=O)-NR¹⁸R¹¹, Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defined above, and

Q each R is independently selected from -H, Ci-8 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above;

each of R¹⁰ and R¹¹ is independently selected from -H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defined above, or, altematively, R¹⁰ and R¹¹ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more R⁴ as defined above;

with the proviso that Y is not H when A is -CH2-;

when Q is -CH=NR¹², R¹² is selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-iocycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z-heteroaryl, -Z-NR⁶R⁷,

-Z-C(=O)-NR⁶R⁷, -Z-NR⁶-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -ZSO2R⁷ and -Z-COOR⁷, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R ;

When Q is -CH2NHR¹³ , R¹³ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, C(O)C(O)OR⁷, C1-8 alkyl, Ci-4fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, and -Z-monocyclic-heteroaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl may optionally be substituted with one or more independently selected R⁸, or is -CR¹⁴R¹⁵-NR⁶R⁷, -CR¹⁴R¹⁵CN, or CR¹⁴R¹⁵OR⁷, wherein each of R¹⁴ and R¹⁵ is independently selected from -H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, and wherein R¹⁴ and R¹⁵ together with the intervening carbon atom may designate a C3-10 cycloalkyl or

247

C5-10~cycloall<enyl ring, which alkyl, alkenyl, alkynyl, cycloalkyl (ring), cycloalkenyl ring,

O heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R ;

when Q is W, W is selected from an l,3-diaza-C5-7-cycloalk-2-yl group which is N1 fi substituted with R and optionally further substituted with one or more R , and optionally contaîning one or two oxo groups; a l,3-thiaza-C5-7-cycloalk-2-yl group which is N1 fi 3 substituted with R and optionally further substituted with one or more R and optionally contaîning one or two oxo groups; an l,3-oxaza-C5-7-cycloalk-2-yl group which is N1 fi substituted with R and optionally further substituted with one or more R , and optionally

O contaîning one or two oxo groups, wherein in ail three instances two R s on the same carbon atom may together form a spiro group;

r!6 is selected from hydrogen, -C(O)R⁷, and -C(O)C(O)R⁷, and -C(O)C(O)R⁷;

when Q is -CH(OR¹⁷)2, each R¹⁷ independently is R³, or wherein two R¹⁷ substituents together with the intervening -O-CH(-)-O- may form a heterocyclyl optionally substituted

O with one or more R and contaîning up to two oxo groups;

22. A compound for use in the treatment of a HDME dépendent disease which is of the

Formula (I)

Q wherein

Q is selected from -CH=NR¹², -W, -CH2NHR¹³, -CH=O and -CH(OR¹⁷)2;

248

Ο heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R and may o form a cyclic structure with R ; with the proviso that when Q is -CH=O, Y is not alkynyl;

R¹ is selected from -H, Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl; or more preferably is selected from -H and C1-4 alkyl; or with -A-Y forms a nitrogen containing optionally substituted heterocyclic group where the optional substitution may be C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl;

each R³ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR⁶R⁷, Z-C(=O)-NR⁶R⁷, -Z-NR⁶-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -ZSO2R⁷, -Z-SO2NR⁶R⁷ and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

Z is selected from a single bond, C1-4 alkylene, heterocyclylene and C3-6 cycloalkylene; each R⁴ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-10 cycloalkyl, -N(R¹)2, carbamoyl, and -OH;

each of R⁶ and R⁷ is independently selected from C1-8 alkyl, C1-4 fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Zheterocyclyl, -Z-heteroaryl and -Z-aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected R³; or, altematively, R^ and R⁷ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected

249 each R⁸ is independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰R¹¹, -Z-C(=O)-NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C3-6 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰R·¹¹, -Z-C(=O)-NR¹⁰R^1:l, Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defined above, and each R⁹ is independently selected from -H, C1-8 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁸ as defined above;

with the proviso that Y is not H when A is -CH2-;

When Q is -CH2NHR¹³ , R¹³ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, C(O)C(O)OR⁷, C1-8 alkyl, Ci-4fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, and -Z-monocyclic-heteroaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl may optionally be substituted

250 with one or more independently selected R⁸, or is -CR¹⁴R¹⁵-NR⁸R⁷, -CR¹⁴R¹⁵CN, or CR¹⁴R¹⁸OR⁷, wherein each of R¹⁴ and R¹⁸ is independently selected from -H, Ci-8 alkyl,

C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, and wherein

R¹⁴ and R¹⁵ together with the intervening carbon atom may designate a C3-10 cycloalkyl or

C5-10-cycloalkenyl ring, which alkyl, alkenyl, alkynyl, cycloalkyl (ring), cycloalkenyl ring,

Q heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R ; when Q is W, W is selected from an l,3-diaza-C5-7-cycloalk-2-yl group which is N16 3 substituted with R and optionally further substituted with one or more R , and optionally containing one or two oxo groups; a l,3-thiaza-C5-7-cycloalk-2-yl group which is Nsubstituted with R·*·⁸ and optionally further substituted with one or more R⁸ and optionally containing one or two oxo groups; an l,3-oxaza-C5-7-cycloalk-2-yl group which is Nsubstituted with R¹⁶ and optionally further substituted with one or more R³, and optionally

O containing one or two oxo groups, wherein in ail three instances two R s on the same carbon atom may together form a spiro group;

R·*·⁸ is selected from hydrogen, -C(O)R⁷, and -C(O)C(O)R⁷, and -C(O)C(O)R⁷;

when Q is -CH(OR^⁷)2, each R*⁷ independently is R³, or wherein two R·*·⁷ substituents together with the intervening -O-CH(-)-O- may form a heterocyclyl optionally substituted with one or more R and containing up to two oxo groups;

23. Use of a compound for the préparation of a pharmaceutical composition for the treatment of a HDME dépendent disease, which compound is of the Formula (I)

Q .-^r'* X? ·.

'·· _R1 wherein

Q is selected from -CH=NR¹², -W, -CH2NHR¹³, -CH=O and -CH(OR¹⁷)2;

A is selected from -CHR²C(O)-, C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, C3-10 cycloalkylene, heterocyclylene, heteroarylene and arylene, which alkylene, alkenylene,

251 alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene may optionally be substituted with one or more R³; with the proviso that when Q is -CH=O, A is not alkynylene;

Y is selected from -H, -NR⁶R⁷, -OR⁷, Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, O heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R and may form a cyclic structure with R , with the proviso that when Q is -CH=O, Y is not alkynyl;

R¹ is selected from -H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl; or more preferably is selected from -H and C1-4 alkyl; or with -A-Y forms a nitrogen containing optionally substituted heterocyclic group where the optional substitution may be C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C3-10 cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more selected from -OH, aryl, Ci-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, and C3-6 cycloalkyl;

each R³ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 fi 7 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z- heteroaryl, -Z-NR R , Z-C(=O)-NR⁶R⁷, -Z-NR⁶-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -ZSO2R⁷, -Z-SO2NR⁶R⁷ and -Z-COOR⁷, wherein any heterocyclyl may be substituted with one or more R⁴, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵;

each of R⁶ and R⁷ is independently selected from C1-8 alkyl, C1-4 fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z252 heterocyclyl, -Z-heteroaryl and -Z-aryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected o A 7

R ; or, alternatively, R and R may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R⁸;

O each R is independently selected from Ci-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR^R¹¹, -Z-C(=O)-NR¹⁰R^1:L, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclics, heteroaryl and aryl may optionally be substituted with one or more selected from C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C3-6 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR^R¹¹, -Z-C(=O)-NR¹⁰R¹¹, Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein any heterocyclyl may be further substituted with one or more R⁴ as defîned above, and wherein any heteroaryl and any aryl may be further substituted with one or more R⁵ as defîned above, and each R⁹ is independently selected from -H, C1-8 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, -Z-aryl, and -Z- heteroaryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defîned above, and wherein any heteroaryl and any aryl may be substituted with one or more R⁵ as defîned above;

each of R¹⁰ and R¹¹ is independently selected from -H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein any heterocyclyl may be substituted with one or more R⁴ as defîned above, and wherein any heteroaryl and any aryl may be substituted with one or more R³ as defîned above, or, alternatively, R¹⁰ and R¹¹ may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more R⁴ as defîned above;

with the proviso that Y is not H when A is -CH2^-;

when Q is -CH=NR¹², R¹² is selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-I0cycloalkyl, -Z-heterocyclyl, -Z-aryl, -Z-heteroaryl, -Z-NR⁶R⁷,

253

-Z-C(=O)-NR⁸R⁷, -Z-NR⁸-C(=O)-R⁷, -Z-C(=O)-R⁷, -Z-OR⁷, halogen, -Z-SR⁷, -Z-SOR⁷, -ZSO2R⁷ and -Z-COOR⁷, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and

O aryl may optionally be substituted with one or more R ;

When Q is -CH2NHR¹³ , R¹³ is selected from hydrogen, -C(O)R⁷, -C(O)C(O)R⁷, C(O)C(O)OR⁷, C1-8 alkyl, Ci-4fluoroalkyl, C1-4 perfluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Z-heterocyclyl, and -Z-monocyclic-heteroaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl may optionally be substituted with one or more independently selected R⁸, or is -CR¹⁴R¹⁵-NR⁸R⁷, -CR¹⁴R¹⁵CN, or CR¹⁴R¹⁵OR⁷, wherein each of R¹⁴ and R¹⁵ is independently selected from -H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, and wherein R¹⁴ and R¹⁵ together with the intervening carbon atom may deslgnate a C3-10 cycloalkyl or C5-i0-cycloalkenyl ring, which alkyl, alkenyl, alkynyl, cycloalkyl (ring), cycloalkenyl ring,

3 heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more R ; when Q is W, W is selected from an l,3-diaza-C5-7-cycloalk-2-yl group which is Nsubstituted with R·*·⁸ and optionally further substituted with one or more R³, and optionally containing one or two oxo groups; a l,3-thiaza-C5-7-cycloalk-2-yl group which is Nsubstituted with R¹⁸ and optionally further substituted with one or more R³ and optionally containing one or two oxo groups; an l,3-oxaza-C5-7-cycloalk-2-yl group which is N1 fi 3 substituted with R and optionally further substituted with one or more R , and optionally

O containing one or two oxo groups, wherein in ali three instances two R s on the same carbon atom may together form a spiro group;

R¹⁸ is selected from hydrogen, -C(O)R⁷, and -C(O)C(O)R⁷, and -C(O)C(O)R⁷; when Q is -CH(OR¹⁷)2, each R¹⁷ independently is R³, or wherein two R¹⁷ substituents together with the intervening -O-CH(-)-O- may form a heterocyclyl optionally substituted O with one or more R and containing up to two oxo groups;

24. A method of treating a HDME dépendent disease in a subject, said method comprises administering to said subject a therapeutically effective amount of at least one compound of Formula (I) as defined in claim 22.