Inhibitors of histone demethylases

The present invention relates to compounds capable of modulating histone demethylase (HDME) activity, which compounds are useful in the prevention and / or treatment of diseases in the pathogenesis of which are involved genomic regulation disorders, such as, for example, cancer.

BACKGROUND OF THE INVENTION [0002] Eucaryotic cell DNA is packed in chromatin by winding DNA around histone proteins leading to the formation of nucleosomes, the basic chromatin unit. One of the important functions of chromatin is to identify areas of active and silent transcription by changing the ordered chromatin structure. These changes have a significant impact on cell function because they affect basic processes like differentiation, proliferation and apoptosis and are often referred to collectively as "epigenetic" because they can lead to hereditary changes that do not require changes in genomic sequences (Quina, AS et al., (2006), Biochem. Pharmacol. 72; 15631569).

[0003] In these tightly controlled chromatin changes mediated modifications of histone proteins bound to DNA in the nucleosome. In particular, such covalent changes, which include changes in methylation, acetylation, phosphorylation and ubiquitination, are subject to the N-terminal histone tail in histone H3 and histone H4. The addition or removal of such groups from histones is mediated by certain enzymes, e.g. histone methyltransferases and histone demetylases in the case of methyl groups, histone acetyltransferases and histone deacetylases in the case of acetyl groups, etc. Where the activity or expression of these "epigenetic" enzymes is not properly controlled and regulated, it can lead to disease. In particular, neoplasm is an area of ​​great importance for the dysregulated activity of epigenetic enzymes due to the role of epigenetics in cell differentiation, proliferation and apoptosis, but epigenetics may also play a role in other diseases such as metabolic, inflammatory, neurodegenerative and cardiovascular diseases. Accordingly, selective modulation of abnormalities of epigenetic enzymes can be very promising in the context of treating a human disease (Kelly, TK et al., (2010), Nat. Biotechnol. 28; 10691078 and Cloos, PaC et al., (2008) , Genes, Dev 22, 115-1140).

[0004] Methylation and demethylation of lysine residues of the histone tail in H3 are important epigenetic markers that determine transcriptionally active and inactive chromatin. For example, the methylation of lysine 9 in 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. Opnion Genet. Dev 15, 163-76), while the methylation of lysine 4 in histone 3 is associated with transcriptionally active chromatin. Similarly, the labeling of lysine 27 in histone H3 (H3K27) is repressive for its di- and trimethylated states, while the labeling of lysine 36 in histone H3 is found in the case of gene activation (Barski, A. et al (2007), Cell, 129, 823-37; Vakoc, C. et al., (2006), Mol. Cell. Biol. 26, 91852

95; Wagner, EJ and Carpenter, PB, (2012), Nature Mol. Cell. Biol.). There are, however, many exceptions to these general rules regarding the relationship between methylated states of epigenetic markers and their effect on transcription.

[0005] As documented in studies in mice with suppressed SUV39H1, the loss of the tri-methylated variant of the H3K9 marker leads to chromosomal aberrations and predisposes to the cancer (Peters, AH et al., Cell 107, 323-37, 2001). The JMJD2C protein (KDM4C, GASC1) has been identified as a marker removal tool in H3K9 (histone demethylase), and thus can promote tumor formation if its expression and activity are not tightly controlled (Cloos, P. et al., (2006), Nature 442, 307-11; Klose, RJ et al (2006), Nature 442, 312-16; Liu, G. et al. (2009), Oncogene 28, 4491-500). For example, it has been shown that if JMJD2C is overexpressed in cells, it induces transformed phenotypes, such as growth independent of growth factor, anchorage independent growth, and mammosfer formation (Liu, G. et al., (2009), Oncogene 28, 4491-500 ). Oncogene 28, 4491-500; Wissmann, M. et al. (2007), Nat. Cell. Biol. 9, 34753), which indicates the potential importance of JMJD2C as an oncogene. Oncogene 28, 4491-500; Wissmann, M. et al. (2007), Nat. Cell. Biol. 9, 34753), which indicates the potential importance of JMJD2C as an oncogene.

[0006] The JMJD2A protein (KDM4A, JHDM3A) has similar properties to JMJD2C. JMJD2A shows high sequence identity with JMJD2C in its JmjC catalytic domain, is a marker removal tool in H3K9, and has also been shown to be overexpressed in the prostate tumor (Cloos, P. et al., Nature 442, 307-11, 2006). JMJD2A has been shown to interact with the estrogen receptor alpha (ER-alpha), and the overexpression of JMJD2A increases estrogen-dependent transcription, and the down-regulated JMJD2A reduces the transcription of the target gene for seminal ER-alpha, cyclin D1 (Kawazu et al., (2011), PLoS One 6; Berry et al., (2012), Int. J. Oncol. 41). In addition, it has been shown that in the case of catalytically inactive JMJD2A, its ability to stimulate ER-alpha-mediated transcription is impaired, which suggests

[0007] Similarly, JARID1B (KDM5B, PLU1), a tool to remove the tri-methylated variant of the H3K4 marker, has also been identified as a potential oncogene. In the case of cancer, JARID1B is most likely to act as a repressor of tumor repressor genes, by removing H3K4 trimethylation, leading to reduced activation of transcription in the affected chromatin regions. The oncogenic potential of JARID1B is demonstrated by stimulation of its proliferation in cell lines, then confirmed by studies of silencing expression of JARID1B by shRNA, showing inhibition of proliferation in vitro in human MCF7 cells of breast cancer, in SW780 and RT4 cells of bladder cancer in A549 and LC319 cells lung tumors and in mouse 4T1 tumor cells and / or xenograft mouse 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 the prostate tumor and is associated with malignancies and poor prognosis (Xiang Y. et al., (2007), PNAS, 104).

[0008] JARID1A (KDM5A, RBP2) is also a tool to remove tri- and di-methylated variants of the H3K4 tag. JARID1A is overexpressed in the stomach tumor (Zeng et al., (2010), Gastroenterology, 138), and its gene is amplified in the cervix tumor (Hidalgo et al., (2005),

BMC Cancer 5). It has been suggested that JARID1A is a regulator of estrogen receptor progesterone expression control (Stratmann and Haendler (2011), FEBS J. 278). Together with JARID1B, JARID1A plays a role in maintaining the slowly growing populations of tumor cells that are necessary for continuous tumor growth and that are resistant to cytotoxic and targeted treatment (Roesch et al., (2010), Cell 141, Sharma et al., 2010), Cell 141). JARID1A is required for tumor initiation and growth in Rb +/- and malignant Men1 mice (Lin et al., (2011), PNAS, 108). Pasini's data show that JARID1A binds to target genes for the group of Polycomb proteins that are involved in the regulation of important cellular processes such as embryogenesis, cell proliferation and stem cell self-renewal mediated by transcriptional gene repression that determines the cell's intended use (Pasini et al., (2008), Genes & Dev 22). In addition, JARID1A has also been shown to bind to the PRC2 complex and is a target gene regulator for PRC2 (Pasini et al., (2008) Genes & Dev 22). It was shown that another potential oncogene, a tool removing the di-methylated variant of the H3K36 marker, JHDM1B (KDM2B, FBXL10), was strongly expressed in human tumors (Tzatsos A. et al., (2009), PNAS 106 (8), 2641-6 He, J. et al. (2011), Blood 117 (14), 3869-80). Silencing FBXL10 causes the aging of mouse embryonic fibroblasts (MEF) that can be saved by expressing catalytically active (but not, catalytically inactive) JHDM1B (Pfau R. et al., (2008), PNAS 105 (6), 1907-12, He J and others, (2008), Nat. Struct. Moth. Biol. 15, 1169-75.). JHDM1B demethylates H3K36me2 in the tumor suppressor gene of Ink4b (p15^Ink4b), thus silencing the expression of this mediating gene aging in MEF cells and leukemic cells (He, J. et al. (2008), Nat. Struct. Mol. Biol. 15, 1169-75; He, J. and in, (2011), Blood 117 (14), 3869-80). The dependency of JHDM1B was also demonstrated by He et al., As catalytic activity is essential for the development of leukemia in the acute myeloid leukemia model (AML) in mice.

[0009] Inhibitors of the histone demethylase class of epigenetic enzymes, in particular the potential oncogenes JARID1B, JARID1A, JMJD2C, JMJD2A and JHDM1B, would be a new approach to interventions in the case of tumors and other proliferative diseases. Being one of the most debilitating diseases affecting millions of people around the world, there is a great need for effective and specific anti-cancer compounds.

[0010] WO2012 / 007007 describes pyrido [1,2-a] indole derivatives for the treatment of diseases mediated by HDME. [0011] Embodiments of the present invention provide a new series of compounds that can modulate histone demethylase (HDME) activity, at least some of which are useful in the prevention and / or treatment of diseases in the pathogenesis of which genomic regulation disorder is involved, such as for example tumor. As another example, it is believed that malnutrition or poor nutrition has an unfavorable epigenetic effect and the compounds of the invention are expected to exert a beneficial effect in the treatment of the effects of such malnutrition. In addition, epigenetic changes have been shown to be related to behavior. Accordingly, the compounds of the invention may be useful in changing behavior. Alternatively or additionally

SUMMARY OF THE INVENTION [0012] The invention is defined by the scope of the claims. Accordingly, the present invention provides a compound having a structure

<img file="PL2903968T3_D0001.tif" />

or a pharmaceutically acceptable salt thereof. Also provided is a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients, diluents and / or carriers. Also provided are the uses of the above compound or a pharmaceutically acceptable salt thereof as set forth in claims 7-12. Aspects disclosed in this document, which do not relate to the scope of the claims, are given for information purposes.

Compounds of Formula (I) [0013] The disclosure also provides compounds of General Formula (I),

<img file="PL2903968T3_D0002.tif" />

wherein ₂

A is selected from -CHR²C (O) -, C 1-8 alkylene, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkylene, heterocyclyl, heteroarylene and arylene, wherein alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, ₃ The heteroarylene and arylene may be optionally substituted with one or more R groups³;

Y is selected from -H, -NR⁶R⁷, -OR⁷, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl ₃ may optionally be substituted with one or more R groups³ and can create a structure ₂ cyclical with R²;

₁

R¹ is selected from -H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more groups selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F and C3-6 cycloalkyl; or more preferably is selected from -H and C1-4alkyl; or z -AY forms a nitrogen-containing, optionally substituted heterocyclic group, wherein the optional substitution may be C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl or C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted substituted with one or more groups selected from -OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F and C 3-6 cycloalkyl;

₂

R² is selected from -H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl and C3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more groups selected from -OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F and C3-6 cycloalkyl and can form a cyclic structure of Y;

₃ every 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, -ZC (= O) -NR⁶R⁷, -Z-NR⁶-C (= O) -R⁷, -ZC (= O) -R⁷, -Z-OR⁷, halogen atom, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO2NR⁶R⁷ and

-Z-COOR⁷wherein each heterocyclyl may be optionally substituted with one or more R groups⁴ and where each heteroaryl and each aryl may be optionally substituted with one or more R groups⁵;

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

every R⁴ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 ₁ alkoxy, C3-10 cycloalkyl, -N (R.¹) 2, carbamoyl and -OH;

₅ every 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; every R⁶ and R⁷ is independently selected from -H, 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, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may be optionally substituted with one or more independently selected R groups⁸; or, alternatively, R⁶ and R⁷ together with the N atom to which they are attached, they can form an N-heterocyclic ring optionally substituted with one or more independently selected R groups⁸;

every 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-NR¹⁰R¹¹.

-ZC (= O) -NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, heteroaryl and aryl may be optionally substituted with one or more substituents selected from C1-4 alkyl, C1-4 fluoroalkyl, C1-410 hydroxyalkyl, C3-6 cycloalkyl, -Z-heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰R¹¹, -ZC (= O) NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein each heterocyclyl may be further substituted with one or more groups as defined above

R⁴ and where each aryl and each heteroaryl may be further substituted with one or more ₅ R groups defined above⁵and every 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 each heterocyclyl may be substituted with one or more R groups as defined above⁴wherein each heteroaryl and each aryl may be substituted with one or more defined ones ₅ above R groups;

11 each R¹⁰ and R¹¹ is independently selected from -H, C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl,

C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein each heterocyclyl may be optionally substituted with one or more R groups as defined above⁴wherein each heteroaryl and each aryl may be optionally substituted with one or more R groups as defined above⁵ or alternatively, R¹⁰ and R¹¹ together with the N atom to which they are attached may form an N-heterocyclic ring optionally substituted with one or more R groups as defined above⁴;

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

or an isomer or mixture of isomers, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

₁ [0014] If R represents an -AY-substituted heterocyclic group, it is preferably optionally C3-7, for example a C3-6 or C5-6 substituted heterocyclic group. [0015] If R forms a cyclic structure from Y, R is preferably C1-C2 alkylene. Cyclic structure₃ is preferably an optionally substituted (one or more R group) 5- or 6-membered, optionally heterocyclic ring.

[0016] Another aspect of the disclosure is a compound of Formula (I)

<img file="PL2903968T3_D0003.tif" />

wherein ₂

A is selected from -CHR (O) -, C 1-8 alkylene, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkylene, heterocyclyl, heteroarylene and arylene, wherein alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, ₃ heteroarylene and arylene may be optionally substituted with one or more R groups;

Y is selected from -H, -NR⁶R⁷, -OR⁷, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl ₃ it may be optionally substituted with one or more R groups;

₁

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

₂

R is selected from -H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, wherein alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more groups selected from -OH, aryl , C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F and C3-6 cycloalkyl;

₃ 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, -ZC (= O) NR⁶R⁷, -Z-NR⁶-C (= O) -R⁷, -ZC (= O) -R⁷, -Z-OR⁷, halogen atom, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO2NR⁶R⁷ and -Z-COOR⁷wherein each heterocyclyl may be optionally substituted with one or more R groups⁴ and where each heteroaryl and each aryl may be optionally substituted with one or more R groups⁵;

Z is selected from a single bond, C 1-4 alkylene, heterocyclylene and C 3-6 cycloalkylene;

every R⁴ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 ₁ alkoxy, C3-10 cycloalkyl, -N (R) 2, carbamoyl and -OH;

every 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;

every R⁶ and R⁷ is independently selected from -H, 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, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may be optionally substituted with one or more independently selected R groups⁸; or alternatively, R⁶ and R⁷ together with the N atom to which they are attached, they can form an N-heterocyclic ring optionally substituted with one or more independently selected R groups⁸;

every 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-NR¹⁰R¹¹, -ZC (= O) -NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, heteroaryl and aryl may be optionally substituted with one or more groups selected from C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C3-6 cycloalkyl, -Z -heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰R¹¹, -ZC (= O) -NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein each heterocyclyl may be further substituted with one or more R groups as defined above⁴ and where each heteroaryl and each aryl may be further substituted with one or more defined ones ₅ above groups R, 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 each heterocyclyl may be substituted with one or more R groups as defined above⁴ and where each heteroaryl and each aryl may be substituted with one or more R groups as defined above⁵;

11 each 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 each heterocyclyl may be substituted by one or more or more R groups as defined above⁴ and where each heteroaryl and each aryl may be substituted with one or more R groups as defined above⁵ or

11 alternatively, R¹⁰ and R¹¹ together with the N atom to which they are attached, they may form a Ntero cyclic ring optionally substituted with one or more defined above₄ R groups⁴;

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

or an isomer or mixture of isomers or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0017] The disclosure also relates to a compound of Formula 1, wherein ₂

A is selected from -CHR²C (O) -, C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 3-10 cycloalkylene, heterocyclyl, heteroarylene and arylene, wherein alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene may be optionally substituted substituted with one or more groups _R³;

Y is selected from -H, -NR⁶R⁷, -OR⁷, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl ₃ may optionally be substituted with one or more R groups³;

₁

R¹ is selected from -H and C1-4alkyl;

₂

R² is selected from -H, C 1-4 alkyl and C 1-4 hydroxyalkyl;

₃ every 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, -ZC (= O) NR⁶R⁷, -Z-OR⁷, halogen atom, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷ and -Z-COOR⁷wherein each heterocyclyl may be substituted with one or more R groups⁴ and where each heteroaryl and each aryl may be ₅ substituted with one or more R groups⁵;

Z is selected from a single bond, C1-4 alkylene, heterocyclylene and C3-6 cycloalkylene, each R9⁴ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 ₁ alkoxy, C3-10 cycloalkyl, -N (R.¹) 2, carbamoyl and -OH;

₅ every 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; every R⁶ and R⁷ 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-heteroaryl and -Z- aryl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may be optionally substituted with one or more independently selected R groups⁸; or alternatively, R⁶ and R⁷ together with the N atom to which they are attached, they can form an N-heterocyclic ring optionally substituted with one or more independently selected R groups⁸;

every 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-NR¹⁰R¹¹, -ZC (= O) NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, heteroaryl and aryl may be optionally substituted with one or more groups selected from C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C3-6 cycloalkyl, -Z -heterocyclyl, -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰R¹¹, -ZC (= O) -NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein each heterocyclyl may be further substituted with one or more R groups as defined above⁴, and where each heteroaryl and each aryl may be further substituted with one or more R groups as defined above⁵and every R⁹ is independently selected from -H, C1-8 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, -Y-heterocyclyl, -Z-aryl and -Z- heteroaryl, wherein each heterocyclyl may be substituted with one or more R groups as defined above⁴ and where each heteroaryl and each aryl may be substituted with one or more R groups as defined above⁵;

11 each R¹⁰ and R¹¹ is independently selected from -H, C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl,

C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein each heterocyclyl may be substituted with one or more R groups as defined above⁴ and where each heteroaryl and each aryl may be substituted with one or more R groups as defined above⁵ or alternatively, R¹⁰ and R¹¹ together with the N atom to which they are attached, they may form a Ntero cyclic ring optionally substituted with one or more defined above₄ R groups⁴;

with the proviso that Y is not H when A is -CH2-; or an isomer or mixture of isomers, or a pharmaceutically acceptable salt, solvate or prodrug thereof. [0018] A further aspect relates to pharmaceutical compositions comprising at least one compound of Formula (I) as defined herein and optionally one or more pharmaceutically acceptable excipients, diluents and / or carriers.

[0019] A further aspect relates to a compound of Formula (I) as defined herein for use as a medicament.

[0020] A further aspect relates to a compound of Formula (I) as defined herein for use in the treatment of a disease mediated by HDME, for example in the treatment of cancer.

[0021] A further aspect relates to a compound of Formula (I) as defined herein for use in the preparation of a pharmaceutical composition for treating a HDME-mediated disease, such as a cancer.

[0022] The application further provides a method of treating an HDME-dependent disease in a patient, said method comprising administering to said patient a therapeutically effective amount of at least one compound of Formula (I) as herein defined.

[0023] Compounds of Formula (I) as defined herein may be used in the treatment of HDME dependent diseases by inhibiting HDME. Inhibition of HDME would provide a new approach to the prevention and treatment of cancer and other proliferative diseases. When administered alone or in combination with antitumor compounds, the compounds of the invention increase the effectiveness of the treatment of HDME-dependent diseases. As will be shown below, the compounds of the invention show cytostatic and antiproliferative activity against tumor cells.

DETAILED DESCRIPTION OF THE INVENTION [0024] As mentioned above, the invention is defined by the scope of the claims.

Compounds of Formula (I) [0025] The present disclosure generally relates to compounds of Formula (I),

<img file="PL2903968T3_D0004.tif" />

The above definition of compounds of Formula (I) refers herein to the expression "compounds of Formula (I)" as defined herein, "a compound of Formula (I) as defined herein" or simply "compounds of Formula (I) &amp; quot; etc. It is to be understood that these references are intended to include not only the above general formula, but also each of the embodiments, etc. discussed above or hereinafter. It is also to be understood that, unless otherwise stated, references also include isomers, isomer mixtures, pharmaceutically acceptable salts, solvates and prodrugs of the compounds of Formula (I).

[0027] Without wishing to be bound by any particular theory, recent results and X-ray crystallography studies give reason to believe that the HOOC-pyridine-CH2-N &lt;in the compound of Formula (I) plays an important role in the design of compounds capable of for modulating the activity of histone demethylases (HDME). Furthermore, it is believed that the combination of -AY substituents plays a role in obtaining affinity for said histone demethylases. Histone demetylates contain an iron atom, which determines their activity. It is further believed that the pyridine nitrogen and the nitrogen atom in Formula (I) also play a role in the binding of a particular well of histone demetlasses in which the iron atom is located, probably by chelating the iron itself.

[0028] It is also believed that the AY chain, itself and through its substituents, interacts with the area of ​​the demethylase, which is known to house the substrate's lysine chain. As the experimental results presented below in the examples clearly show, there is a wide array of -AY group options that modulate the activity of various demethylases, allowing for selective inhibition. Some demethylase have a lysine chain-binding surface lined with acidic residues and compounds with basic groups in Y show increased potency relative to these enzymes. Similarly, some demethylases are better inhibited by compounds with non-polar groups in the Y chain. Still other demethylases are better inhibited by compounds with uncharged polar groups in the Y chain.

₂ [0029] A is usually selected from -CHR²C (O) -, C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, C3-10 cycloalkylene, heterocyclylene, heteroarylene and arylene.

[0030] Alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene and arylene as A may be ₃ optionally substituted with one or more R's³ (see below).

₂ [0031] In one embodiment, A is selected from -CHR²C (O) -, C1-8 alkylene, C3-10 cycloalkylene, ₂ heterocyclyl, heteroarylene and arylene, in particular from -CHR²C (O) -, C 1-8 alkylene and heterocyclylene, such as -CHR²C (O) - or C 1-8 alkylene or heterocyclylene. In this context, R² it can have any of the sets of values ​​given above or below it.

[0032] In particular, A may be -CH2C (O) - or -CH2-CH2-.

[0033] Y is usually selected from -H, -NR⁶R⁷, -OR⁷, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl. Favorable values ​​for R⁶ and R⁷ are defined below.

[0034] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl as Y may be optionally ₃ substituted with one or more R's³ (look below);

In one embodiment, Y is -NR⁶R⁷. In one embodiment, A is -CHR²C (O) -, especially -CH 2 C (O) -, and Y is -NR⁶R⁷.

[0035] In particular, -AY may have any of the values ​​shown in the compounds of Table 1 below, and each value for -Y can be combined with any of the values ​​shown for A.

[0036] In another variant, A is C1-8 alkyl and Y is -NR⁶R⁷. In one scenario, this embodiment and these variants, -NR⁶R⁷ is an N-heterocyclic ring optionally substituted with one or more independently selected R groups⁸, preferably substituted with one or two independently selected R groups⁸. In another scenario of this embodiment and those variants in which Y is -NR⁶R⁷one of R⁶ and R⁷ is -H or C 1-6 alkyl. In yet another scenario of this embodiment and those variants in which Y is -NR⁶R⁷, R⁶ and R⁷ are independently selected from C1-8 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl and C2-8 alkynyl, e.g.⁶ and R⁷ they are the same. In yet another scenario of this embodiment and those variants in which Y is -NR⁶R⁷one of R⁶ and R⁷ is selected from heterocyclyl, heteroaryl and aryl.

[0037] In another embodiment, Y is -H. In one embodiment, A is selected from C 1-8 alkylene, C 28 alkenylene, C 2-8 alkynylene, and C 3-10 cycloalkylene. In another embodiment, A is selected from heterocyclyl.

[0038] In yet another embodiment, Y is selected from heterocyclyl, heteroaryl and aryl. In one embodiment, A is selected from C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, in particular from C1-8 alkylene, for example from C1-6 alkylene, in particular C1-4 alkylene.

₁ [0039] R¹ is usually selected from -H and C1-4 alkyl (such as methyl, ethyl, propyl and butyl), in particular from -H and methyl, with H. being preferred.

₂ [0040] R² is usually selected from -H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, wherein alkyl, alkenyl, alkynyl and cycloalkyl may be optionally substituted with one or more substituents selected from -OH, aryl , C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F 1 ₂

C3-6 cycloalkyl. In some embodiments, R² is selected from -H, C1-4 alkyl (such as methyl, ethyl, propyl and butyl) and C1-4 hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl), in particular from -H, methyl and hydroxymethyl, wherein the H atom is preferred.

₃ [0041] R³ (optional substituents of some of the meanings A and Y) is typically independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl,

-Z-heterocyclyl, -Z-aryl, -Z-heteroaryl, -Z-NR⁶R⁷, -ZC (= O) -NR⁶R⁷, -Z-NR⁶-C (= O) -R⁷, -ZC (= O) -R⁷.

-Z-OR⁷, halogen atom, -Z-SR⁷, -Z-SOR⁷, -Z-SO2R⁷, -Z-SO2NR⁶R⁷ and -Z-COOR⁷wherein each heterocyclyl may be substituted with one or more R groups⁴wherein each heteroaryl and each aryl may be substituted with one or more R groups⁵. In another embodiment R³ is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl,

-Z-aryl, -Z-heteroaryl, -Z-NR⁶R⁷, -ZC (= O) -NR⁶R⁷, -Z-OR⁷, halogen atom, -Z-SR⁷, -Z-SOR⁷.

-Z-SO 2 R⁷ and -Z-COOR⁷wherein each heterocyclyl may be substituted with one or more R groups⁴ and ₅ wherein each heteroaryl and each aryl may be substituted with one or more R groups⁵.

[0042] Z is usually selected from a single bond, C1-4 alkylene, heterocyclylene and C3-6 cycloalkylene. In one embodiment, Z is selected from C 1-4 alkylene. In another embodiment, Z is selected from a single bond. It should be understood that group Z may appear repeatedly in

Formula (I), and that such Z groups are chosen independently.

[0043] Each R⁴ (optional substituents on heterocyclyl) is independently selected from C 1-6 alkyl, C 1-4 ₁ fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, -N (R¹) 2, carbamoyl and -OH, ₅

Each R⁵ (optional heteroaryl and aryl substituents) is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -CN, -F, -Cl, -Br, carbamoyl and OH.

[0044] Each of R⁶ and R⁷ (e.g., in the -NR group⁶R⁷) is independently selected from -H, 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, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may be optionally substituted with one or more independently selected R groups⁸; or alternatively, R⁶ and R⁷ together with the N atom to which they are attached, they may form a Ntero cyclic ring optionally substituted with one or more independently selected R groups⁸.

[0045] 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-NR¹⁰R¹¹, -ZC (= O) -NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, heteroaryl and aryl may be optionally substituted with one or more substituents selected from C1-4 alkyl, C1-4 fluoroalkyl C1-4 hydroxyalkyl, C3-6 cycloalkyl, -Z-heterocyclyl; , -Z-heteroaryl, -Z-aryl, -Z-NR¹⁰R¹¹, -ZC (= O) -NR¹⁰R¹¹, -Z-OR⁹, halogen, -CN, -Z-SR⁹, -Z-SOR⁹, -Z-SO2R⁹ and -Z-COOR⁹; wherein each heterocyclyl may be further substituted with one or more R groups as defined above⁴ and where each heteroaryl and each ₅ The aryl may be further substituted with one or more R groups as defined above⁵.

[0046] 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 each heterocyclyl may be substituted with one or more R groups⁴ and wherein each heteroaryl and each aryl may be substituted with one or more R groups as defined above⁵. In one embodiment, 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-aryl and -Z-heteroaryl, wherein each heterocyclyl group is independently it may be substituted with one or more R groups defined above⁴ and where each heteroaryl and each aryl may be ₅ substituted with one or more R groups defined above⁵.

11 10 11 [0047] Each of R¹⁰ and R¹¹ (-NR groups¹⁰R¹¹) 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 each heterocyclyl may be substituted one or more R groups defined above⁴ and where each heteroaryl and each aryl may be substituted with one or more R groups as defined above⁵ or alternatively, R¹⁰ and R¹¹ together with the N atom to which they are attached, they may form an N-heterocyclic ring optionally substituted with one or more R groups as defined above⁴.

[0048] It should be understood that in Formula (I), Y is not H when A is -CH2-. In general terms, it is believed that it is preferred that the -AY group has a certain "size" with respect to the number of atoms (excluding hydrogen atoms) and / or molecular weight. It also seems that the limited flexibility of the -AY group plays a role.

[0049] Accordingly, it is believed that the -AY group should preferably consist of at most 40 heavy atoms, e.g., at most 30 heavy atoms or at most 25 heavy atoms or at most 20 heavy atoms. Preferably, the -AY group consists of at least 3 or at least 4 or at least 8 or at least 10 heavy atoms. In some embodiments, the -AY group preferably consists of 3-40 heavy atoms, e.g. 4-30 heavy atoms or 4-25 heavy atoms or 4-20 or 830 or 8-20 or 8-15 heavy atoms. Under the term "heavy atom" is meant all atoms in the group except hydrogen atom (s).

[0050] Furthermore, it is believed that the compounds of Formula (I) should preferably have a molecular weight of at least 130 or at least 150 or at least 180 or at least 250, but no more than 1000 or not more than 800 or no more. than 500 or no more than 400 and may be in any range formed from these preferred upper and lower limits, e.g. 130-1000 g / mol or 150-1000 g / mol, e.g. 180-800 g / mol, e.g. 225-600 g / mol or 250-500 g / mol or 250 to 400.

[0051] In some embodiments, to introduce a group flexibility constitution -AY, this group contains 1-4 rings, i.e. rings derived from cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl and / or aryl. In a certain variant, the -AY group contains 1-3 cyclic groups selected from monocyclic cycloalkyl, monocyclic heterocyclyl, monocyclic heteroaryl, dicyclic heteroaryl and monocyclic aryl. Small substituents such as alkyl or hydroxyl groups in alkyl chains also reduce flexibility and favor some conformations.

It may be advantageous that if -AY does not contain a ring, it contains at least one, e.g. from 1 to 3, branching, each of which independently can have from one to six heavy atoms, e.g. from one to three. heavy atoms or from one to two heavy atoms. -AY preferably should contain at least one heteroatom, preferably at least one nitrogen atom or at least one oxygen atom.

[0053] The options independently suitable for use include that:

Y means

<img file="PL2903968T3_D0005.tif" />

where n is a number from 1 to 3, and each of R10 and R11 independently is as defined above. Y means

<img file="PL2903968T3_D0006.tif" />

where n is a number from 1 to 3, and m each independently represents a number from 0 to 2.

[0054] Y is selected from heterocyclyl, heteroaryl and aryl, which may be optionally substituted ₃ one or more R groups³.

[0055] Based on the tests carried out and the results achieved to date, it is believed that the following compounds are particularly interesting (numbered from 1 to 45), including isomers, mixtures of isomers, as well as pharmaceutically acceptable salts, solvates and prodrugs thereof:

2 - ({[3- (1H-imidazol-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid 2 - ({[2- (dimethylamino) ethyl] amino} methyl) pyridine-4-carboxylic acid 2 - ({[(2R) -2,3-dihydroxypropyl] amino} methyl) pyridine-4-carboxylic acid 2 - {[(cyclopropylmethyl) amino] methyl} pyridine-4-carboxylic acid 2 - {[(cyclopropylmethyl) amino] methyl} pyridine-4-carboxylic acid 2 - ({[2- (dimethylamino) ethyl] (methyl) amino} methyl) pyridine-4-carboxylic acid 2 - {[methyl (prop-2-yn-1-yl) ) amino] methyl} pyridine-4-carboxylic acid 2 - {[(2-fluoroethyl) amino] methyl} pyridine-4-carboxylic acid 2 - {[(furan-2-ylmethyl) amino] methyl} pyridine-4-carboxylic acid 2 - ({[(5-phenylfuran-2-yl) methyl] amino} methyl) pyridine-4-carboxylic acid 2 - ({[(2,4-dimethoxyphenyl) methyl] amino} methyl) pyridine-4-carboxylic acid 2 - ({[2- (methylsulfanyl) ethyl] amino} methyl) pyridine-4-carboxylic acid 2 - ({[2-oxo-2-yl) pyrrolidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid 2 - [({[butyl (methyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid 2 - ({[(1-) methyl-1 H-13-benzodiazol-2-yl) methyl] amino} methyl) pyridine-4-carboxylic acid 2 - [({2- [4- (2-methoxyethyl) piperazin-1-yl] -2-oxoethyl} amino) methyl] pyridine-4-carboxylic acid 2 - [({[bis (prop-2-en-1-yl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid 2 - [({2-oxo-2- [ (2R) -2- (pyrrolidin-1-ylmethyl) pyrrolidin-1-yl] ethyl} amino) methyl] pyridine-4-carboxylic acid 2 - ({[(3R) -1 - [(tert-butoxy) carbonyl] pyrrolidine 3-yl] amino} methyl) pyridine-4-carboxylic acid 2 - ({[(3R) -1 - [(tert-butoxy) carbonyl] pyrrolidin-3-yl] amino} methyl) pyridine-4-carboxylic acid - {[(3 - {[3- (pyrrolidin-1-yl) propyl] amino} propyl) amino] methyl} pyridine-4-carboxylic acid 2 - {[(3-methylbutyl) amino] methyl} pyridine-4 2 - [({[(2-carbamoyl-ethyl) (methyl) carbamoyl] methyl} amino) methyl] pirdin-4-carboxylic acid carboxylic acid2 - [({2- {2- (hydroxymethyl) piperidin-1-yl-] - 2-oxoethyl} amino) methyl] pyridine-4-carboxylic acid 2 - {[({methyl [3- (1-methyl) -1H-imidazol-2-yl) propyl] carbamoyl} methyl} amino] methyl} -pyridine-4-carboxylic acid 2 - {[({[(1-ethylpyrrolidin-2-yl) methyl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid 2 - {[({methyl [(1-methyl-1H-pyrazol-5-yl) methyl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid 2 - ({[(3R) ) -1- (3-phenylpropyl) pyrrolidin-3-yl] amino} methyl) pyridine-4-carboxylic acid 2 - ({[({1 - [(2-methoxyphenyl) methyl] piperidin-4-yl} carbamoyl ) methyl] amino} -methyl) pyridine-4-carboxylic acid 2 - {[({[1- (3-phenylpropyl) piperidin-4-yl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid 2 - {[({ [1- (Furan-2-ylmethyl) piperidin-4-yl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid2 - ({[({1 - [(5-phenylfuran-2-yl) methyl] piperidin-4-yl} carbamoyl) methyl] amino} methyl) pyridine-4-carboxylic acid 2 - [({[(2- cyanoethyl) (ethyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid 2 - ({[2- (1-butylpyrrolidin-2-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid 2- { [({[1- (3,7-Dimethyloct-6-en-1-yl) pyrrolidin-3-yl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid 2 - {[(3 - {[( 2-fluorophenyl) methyl] (methyl) amino} propyl) amino] methyl} pyridine-4-carboxylic acid 2 - ({[(1 R) -2-hydroxy-1- {methyl [3- (1-methyl-1H-) imidazol-2-yl) propyl] carbamoyl} ethyl] amino} methyl) pyridine-4-carboxylic acid 2 - [({2- [3- (1H-1,3-Benzodiazol-2-ylmethyl) piperidin-1-yl] -2-oxoethyl} amino) methyl] pyridine-4-carboxylic acid 2 - {[({[1- (2-phenylethyl) pyrrolidin-3-yl] carbamoyl} methyl ) amino] methyl} pyridine-4-carboxylic acid 2 - ({[3- (4-benzylpiperidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid 41 - [({3 - [( 2-phenoxyethyl) amino] propyl} amino) methyl] pyridine-4-carboxylic acid 2 - [({[methyl ({4 - [(4-methylpiperazin-1-yl) methyl] phenyl} methyl) carbamoyl] methyl} amino ) methyl] pyridine-4-carboxylic acid 2 - ({[2- (2-benzylpyrrolidin-1-yl) -2-oxoethyl] amino} methyl) pyridine-4-carboxylic acid 2 - ({[({4- [ benzyl (cyclopropyl) amino] butyl} (methyl) carbamoyl) methyl] amino} methyl) pyridine-4-carboxylic acid [({2 - [(2S) -1-benzylpyrrolidin-2-yl] ethyl} amino) methyl] pyridine -4-carboxylic acid 2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid2 - [({[methyl ({4 - [(4-methylpiperazin-1-yl) methyl] phenyl} methyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid 2 - ({[2- (2) -benzylpyrrolidin-1-yl) -2-oxoethyl] amino} methyl) pyridine-4-carboxylic acid 2 - ({[({4- [benzyl (cyclopropyl) amino] butyl} (methyl) carbamoyl) methyl] amino} methyl ) Pyridine-4-carboxylic acid [({2 - [(2S) -1-benzylpyrrolidin-2-yl] ethyl} amino) methyl] pyridine-4-carboxylic acid 2 - ({[3- (pyrrolidin-1-yl) ) propyl] amino} methyl) pyridine-4-carboxylic acid2 - [({[methyl ({4 - [(4-methylpiperazin-1-yl) methyl] phenyl} methyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid 2 - ({[2- (2) -benzylpyrrolidin-1-yl) -2-oxoethyl] amino} methyl) pyridine-4-carboxylic acid 2 - ({[({4- [benzyl (cyclopropyl) amino] butyl} (methyl) carbamoyl) methyl] amino} methyl ) Pyridine-4-carboxylic acid [({2 - [(2S) -1-benzylpyrrolidin-2-yl] ethyl} amino) methyl] pyridine-4-carboxylic acid 2 - ({[3- (pyrrolidin-1-yl) ) propyl] amino} methyl) pyridine-4-carboxylic acid2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid

Methyl 2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylate 2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylic acid 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic 2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate (5-methyl-2-oxo-2H-1,3-dioxol-4-yl) methyl

2-Methyl-4-methoxyphenyl [4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 2- (ethoxycarbonyl) phenyl 2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 2 (dimethylamino) ethyl 2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 3- (dimethylamino) propyl 2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4 {4 {[(ethoxycarbonyl) amino] phenyl} methyl carboxylate

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate, 2,6-dimethoxyphenyl

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate, 2,6-dimethylphenyl

2-methoxyphenyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2 (ethoxycarbonyl) phenyl)

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate {4 [(ethoxycarbonyl) (methyl) amino] phenyl} methyl

2-tert-butylphenyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate

2-oxopentan-2-yl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 4 (trifluoroacetamido) butan-2-yl

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 4 (2,2,2-trifluoro-N-methylacetamido) butan-2-yl

Ethyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate (trifluoroacetamido) pent-1-en-3-yl

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate (2,2,2-trifluoro-N-methylacetamido) pent-1-ene 3-yl 2- (2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) -3- (hexadecanoyloxy) propyl hexadecanoate hexadecanoate 1- (2- { [({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4karbonyloksy) -3- (heksadekanoiloksy) propan-2-yl

Methyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N-methanesulfonyl-Nmetylopirydyno-4-carboxamide

N- [2- (dimethylamino) ethyl] -N-ethyl-2 - ({[4- (2-oxo-1,3-oxazolidin-3-carbonyl) pyridin-2-yl] methyl} amino) acetamide

3- (2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) -4 (trifluoroacetamido) propan-2-yl butanoate

3- (2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) -5 (trifluoroacetamido) propan-2-yl} pentanoate

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (pyridin-4-yl) pyridine-4-carboxamide

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (5-methyl-1,3,4-oxadiazol-2-yl) pyridine-4-carboxamide

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (1-methyl-1H-pyrazol-5-yl) pyridine-4-carboxamide 2- (piperidine) acid 1-ylmethyl) pyridine-4-carboxylic acid 2- (azetidin-1-ylmethyl) pyridine-4-carboxylic acid

2 - {{ethyl- [2-oxo-2-yl) {2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,2,2-trifluoroethyl piperidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid 2 - ({butyl [2-oxo-2- (piperidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid - ({benzyl [2-oxo-2- (piperidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (1,3-oxazol-2-yl) pyridine-4-carboxamide

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,6-bis (propan-2-yloxy) phenyl 2 - {[(2-methylpropyl) ) [2-oxo-2- (piperidin-1-yl) ethyl] amino] methyl} pyridine-4-carboxylic acid 2 - ({[2-oxo-2- (piperidin-1-yl) ethyl] (propyl) amino} methyl) pyridine-4-carboxylic acid 2 - ({[2-oxo-2- (piperidin-1-yl) ethyl] (propan-2-yl) amino} methyl) pyridine-4-carboxylic acid

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (1-methyl-1H-imidazol-2-yl) pyridine-4-carboxamide

2-fluoroethyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,2-difluoroethyl 2 - ({[(1S) -1- (tert-butylcarbamoyl)) -3-methylbutyl] amino} methyl) pyridine-4-carboxylic acid 2 - ({methyl [(2S) -4-methyl-1-oxo-1- (piperidin-1-yl) pentan-2-yl] amino} methyl) pyridine-4-carboxylic acid [0056] Further compounds of particular interest are set forth in the following Table 1 and other examples.

Definitions [0057] As used herein, the term "alkyl" refers to a saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to eight carbon atoms (C 1-8 alkyl), more preferably from one to six carbon atoms (C 1-6 alkyl), in particular from one to four carbon atoms (C 1-4 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" means a C 1-4 alkyl group, which may in particular include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl and tertiary butyl. Accordingly, the term "alkylene" means a suitable diradical (-alkyl-).

The term &amp; quot; cycloalkyl &amp; quot; as used herein refers to a cyclic alkyl group, preferably containing from three to ten carbon atoms (C 3-10 cycloalkyl), e.g. from three to eight carbon atoms (C 3-8 cycloalkyl), preferably from three to six carbon atoms (C 3-6 cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In addition, 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. Accordingly, the term "cycloalkylene" means a suitable diradical (-cycloalkyl-).

[0059] As used herein, the term "alkenyl" 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, an alkenyl group contains from two to eight carbon atoms (C 2-8 alkenyl), e.g. from two to six carbon atoms (C 2-6 alkenyl), in particular from two to four carbon atoms (C 2-4 alkenyl), including least one double bond. Examples of alkenyl groups include ethenyl; 1- or 2-propenyl; 1-, 2- or 3-butenyl or 1,3-butadienyl; 1-, 2-, 3-, 4- or 5-hexenyl or 1,3-hexadienyl or 1,3,5-hexatrienyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-octenyl or 1,3-octadienyl or 1,3,5-octatrienyl or 1,3,5,7-octatetraenyl or cyclohexenyl. Accordingly, the term "alkenylene"

[0060] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds, including di-na-tri, tri-ol and poly-yne. Typically, an alkynyl group contains from two to eight carbon atoms (C 2-8 alkynyl), e.g. from two to six carbon atoms (C 2-6 alkynyl), in particular from two to four carbon atoms (C 2-4 alkynyl), including at least one triple bond. Examples of preferred alkynyl groups include ethynyl; 1- or 2-propynyl; 1-, 2- or 3-butynyl or 1,3-butadiynyl; 1-, 2-, 3-, 4- or 5hexinyl or 1,3-hexadiynyl or 1,3,5-hexatriynyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-octynyl or 1,3-octa-diynyl or 1,3,5-octatriynyl or 1,3,5,7-octatetrainyl. Accordingly, the term "alkynylene" means a suitable diradical (-alkynyl).

[0061] As used herein, the term "halo" or "halogen" refers to a fluorine, chlorine, bromine or iodine atom. Thus, the trihalomethyl group is e.g. a trifluoromethyl group or a trichloromethyl group. Preferably, the terms "halo" or "halogen" indicate fluorine or chlorine.

[0062] As used herein, the term "fluoroalkyl" refers to an alkyl group as defined herein, which is substituted one or more times with one or more fluorine atoms, preferably it is perfluorinated. As used herein, the term "perfluoroalkyl" refers to an alkyl group as defined herein, in which all of the hydrogen atoms have been replaced with fluorine atoms. Preferred fluoroalkyl groups include trifluoromethyl, pentafluoroethyl, etc. [0063] As used herein, the term "alkoxy" refers to the group "alkyl-O-" wherein the alkyl is as defined above.

[0064] As used herein, the term "hydroxyalkyl" refers to an alkyl group (as defined above), which alkyl group is substituted one or more times by a hydroxyl group. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2- and CH3-CH (OH) -. [0065] As used herein, the term "oxy" refers to the group "-O-".

[0066] As used herein, the term "oxo" refers to the group "= O".

[0067] As used herein, the term "amine" refers to primary amines (RNH₂, R ϊ H), secondary (R.₂-NH, R₂ ϊ H) and tertiary (R.₃-N, R ϊ H). The substituted amine is intended to mean an amine in which at least one of the hydrogen atoms has been replaced by a substituent.

[0068] As used herein, the term "carbamoyl" refers to the group "H2N (C = O) -".

[0069] As used herein, the term "aryl", unless otherwise indicated, includes carbocyclic aromatic ring systems derived from an aromatic hydrocarbon by the removal of a hydrogen atom. In addition, aryl includes bi-, tri- and polycyclic ring systems. Examples of preferred aryl groups include phenyl, naphthyl, indenyl, indanyl, fluorenyl, indenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, pentalenyl, azulenyl and biphenylenyl. Preferred "aryl" means phenyl, naphthyl or indanyl, in particular phenyl, unless otherwise indicated. Each aryl used may be optionally substituted. Accordingly, the term "arylene" means the corresponding diradical (-aryl-).

[0070] As used herein, the term "heteroaryl" 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 further includes a group of bi-, tri- and polycyclic, 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 includes ring systems substituted with one or more oxo moieties. Examples of preferred heteroaryl groups include N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, furanyl, triazolyl, pyranyl, thiadiazinyl, benzothiophenyl, dihydrobenzo [b] thiophenyl, xantenyl, isoindanyl, acridinyl, benzisoxazolyl, quinolinyl, isoquinolinyl, pteridinyl, azepinyl, diazepinyl, imidazolyl, thiazolyl, carbazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazine, 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 derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and 1-octalline. Accordingly, the term "heteroarylene"

[0071] As used herein, the term "heterocyclyl" refers to cyclic, non-aromatic groups containing one or more heteroatoms selected from O, S and N, preferably from one to four heteroatoms, preferably from one to three heteroatoms. The heterocyclyl further comprises bi-, tri- and polycyclic non-aromatic groups and at least one of the rings contains a heteroatom selected from O, S and N. Heterocyclyl also includes ring systems substituted with one or more oxo groups. Examples of heterocyclic groups are oxetane, pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2- thiazolyl, 1,3-thiazolyl, 1,2,5-oxadiazolyl, piperidinyl, pyridinyl, oxanyl, 2H-pyranyl, 4-H-pyranyl, tianyl, 2H-thiopyranyl, pyridazinyl, 1,2-diazynanyl, pyrimidinyl, 1,3-diazynanyl, pyrazinyl, piperazinyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-diazynanyl, 1,4oksazynyl, morpholinyl, thiomorpholinyl, 1,4-oxathianyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, chromayl, isochromanyl, 4H-chromenyl, 1H-izochromenyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, purinyl, naphthyridinyl, pteridinyl, indolizinyl, 1H-pyrrolizinyl, 4H-quinolizinyl and aza-8-bicyclo [3.2.1] octane. Accordingly, the term "heterocyclylene" means a suitable diradical (heterocyclyl-). benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, chromayl, isochromanyl, 4H-chromenyl, 1H-isochromenyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, purinyl, naphthyridinyl, pteridinyl, indolizinyl, 1H-pyrrolizinyl, 4H-quinolizinyl and aza-8- bicyclo [3.2.1] octane. Accordingly, the term "heterocyclylene" means a suitable diradical (heterocyclyl-). benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, chromayl, isochromanyl, 4H-chromenyl, 1H-isochromenyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, purinyl, naphthyridinyl, pteridinyl, indolizinyl, 1H-pyrrolizinyl, 4H-quinolizinyl and aza-8- bicyclo [3.2.1] octane. Accordingly, the term "heterocyclylene" means a suitable diradical (heterocyclyl-).

[0072] As used herein, the term "N-heterocyclic ring" means a heterocyclyl or heteroaryl as defined above, having at least one nitrogen atom and bonded 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.

Izomery [0073] Związki o Wzorze (I) mogą istnieć w postaci izomerów geometrycznych (tzn. izomerów cis-trans), izomerów optycznych i stereoizomerów, takich jak diastereomery, jak również w postaci tautomerów. Zgodnie z tym, należy rozumieć, że definicja związków o Wzorze (I) obejmuje poszczególne indywidualne izomery odpowiadające wzorowi strukturalnemu Wzoru (I), w tym izomery cis-trans, stereoizomery i tautomery, a także ich mieszaniny racemiczne i ich farmaceutycznie dopuszczalne sole. W związku z tym, definicja związków o Wzorze (I) ma również obejmować wszystkie izomery R i S struktury chemicznej w dowolnym stosunku, np. ze wzbogaceniem (tzn. nadmiarem enancjomerycznym i nadmiarem diastereoizomerycznym) jednego z możliwych izomerów i odpowiednio mniejszą proporcją innych izomerów.

[0074] Diastereoisomers, i.e. non-overlapping stereochemical isomers, can be separated by conventional methods such as chromatography, distillation, crystallization or sublimation. Optical isomers can be obtained by resolution of racemic mixtures in accordance with conventional methods, e.g. by formation of diastereomeric salts by reaction with an optically active acid or base. Examples of suitable acids include, without limitation, tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulphonic acid. The mixture of diastereoisomers can be separated by crystallization followed by separation of optically active bases from these salts. An alternative method for the resolution of optical isomers includes the use of a chiral chromatographic column, optimally selected to maximize the separation of enantiomers. Yet another available method involves the synthesis of covalent diastereoisomeric molecules by reacting compounds of Formula (I) with an optically pure acid in an activated or optically pure isocyanate form. The synthesized diastereoisomers can be separated by conventional methods, such as chromatography, distillation, crystallization or sublimation, followed by hydrolysis to obtain an enantiomerically pure compound. The optically active compounds of Formula (I) can also be obtained using optically active substrates and / or using a chiral catalyst. These isomers may be in the form of the free acid, in the form of the free base, ester or salt. Examples of chiral separation techniques are given in Chiral Separation Techniques, A Practical Approach, second edition, G. Subramanian,

Pharmaceutically acceptable salts [0075] A compound of Formula (I) may be provided in any form suitable for the intended administration, including in particular as pharmaceutically acceptable salts, solvates and prodrugs of the compounds of Formula (I).

[0076] Pharmaceutically acceptable salts refer to salts of compounds of Formula (I) that are acceptable for clinical and / or veterinary use. Typical pharmaceutically acceptable salts include salts obtained by reacting compounds of Formula (I) with a mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition salts and base addition salts. It should be recognized that the particular counterion forming part of any salt is not critical if the salt as a whole is pharmaceutically acceptable and provided that the counterion does not contribute to the undesirable properties of the salt as a whole. These salts can be obtained by means known to those skilled in the art. Pharmaceutically acceptable salts are e.g. those described and discussed in Remington's Pharmaceutical Sciences, 17th edition.

[0077] Examples of pharmaceutically acceptable addition salts include acid addition salts formed with inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric or phosphoric acids; and organic acids, e.g. succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, malt extract, glycolic acid, glucose, camphor sulfur, isotonic, mucin, gentian, isonicotin, sugar, glucuronic, fumed oil , glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, pamoic, ethanesulphonic, pantotenic, stearic, sulfinyl, alginic and galacturonic; and arylsulfonic, e.g. benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic and naphthalenesulfonic acid; and base addition salts formed with alkali and alkaline earth metals and organic bases such as N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and internal salts.

Solvates [0078] The compound of Formula (I) may be provided in soluble or insoluble form together with a pharmaceutically acceptable solvent such as water, ethanol and the like. Soluble forms may also include hydrated forms, such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like.

Prodrugs [0079] The compound of Formula (I) may be provided in the form of a prodrug. As used herein, the term "prodrug" is intended to mean a compound that, when exposed to certain physiological conditions, releases the compound of Formula (I), which then will be able to demonstrate the desired biological effect. A typical example is a labile carboxylic acid ester, in particular a carboxylic acid in the pyridine group of a compound of Formula (I), which, e.g., is able to release the hidden carboxylic group.

[0080] Illustrative examples of carboxylic esters (especially pyridine carboxylic acid) are C1-6 alkyl esters, e.g. methyl esters, ethyl esters, 2-propyl esters, phenyl esters, 2aminoethyl esters, etc., including (5-methyl-ester) esters. 2-oxo-2H-1,3-dioxol-4-yl) methyl, 4-methoxyphenyl esters, 2- (ethoxycarbonyl) phenyl esters, {4 [(ethoxycarbonyl) (methyl) amino] phenyl} methyl esters, 2- (dimethylamino) esters ) ethyl, 3 (dimethylamino) propyl esters, [(ethoxycarbonyl) amino] phenylmethyl esters, 2,6-dimethoxyphenyl esters, 2,6-dimethylphenyl esters, 4-tert-butylphenyl esters, 4-oxopentan-2-yl esters, esters 4 (trifluoroacetamido) butan-2-yl, 4- (2,2,2-trifluoro-N-methylacetamido) butan-2-yl esters, (trifluoroacetamido) pent-1-en-3-yl esters, esters 5- (2,2,2-trifluoro-N-methylacetamido) pent-1-en-3-yl, esters 1,3-bis (hexadecanoyloxy) propan-2-yl, 2,3-bis (hexadecanoyloxy) propyl esters, 4-oxo-4- (propan-2-yloxy) -1- (trifluoroacetamido) butan-2-yl esters, esters 1- oxo-1- (propan-2-yloxy) -5 (trifluoroacetamido) pentan-3-yl, 2,2,2-trifluethyl esters, 2,6-bis (propan-2-yloxy) phenyl esters, 2-fluoroethyl esters , 2,2-difluoroethyl esters, etc.

[0081] In particular, the prodrug may be in the form

<img file="PL2903968T3_D0007.tif" />

13 13 13 where R¹² it has a form (R.¹³) 2N- or the R form¹³O-, where every R¹³ independently of one another may be in accordance with any of the examples of the prodrugs given above or set out below. In particular, 13 each R¹³ may be independently selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl and aryloxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryloxy may be optionally substituted with one or more substituents selected from - OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, F, sulfonamide and C 3-6 cycloalkyl; and one group R¹³ in (R¹³) 2N can be, and preferably is -H.

Processes for Preparing Compounds of Formula (I) [0082] Compounds of Formula (I) as defined herein can be prepared by conventional chemical synthesis methods, e.g. those described in working examples, starting from readily available starting materials. The substrates in the processes described in this application are known or can be readily prepared using conventional methods from commercially available chemicals.

[0083] The final products of the reactions described herein can be isolated by conventional techniques, e.g. by extraction, crystallization, distillation, chromatography, etc.

[0084] Hereinafter, some of the possible routes to compounds of Formula (I) are described.

[0085] The compounds of Formula (I) can be obtained as described below. Suitable steps that can be used in the preparation steps of the compounds will be known to those skilled in the art. The following methods are given as non-limiting examples of how compounds can be prepared.

[0086] Process A to C represents a process for the preparation of compounds of the present invention. Suitable methods for the preparation of intermediates are described later.

Preparation of compounds of Formula (I) [0087]

Scheme 1

<img file="PL2903968T3_D0008.tif" />

Method A [0088] The compound of Formula (I) can be obtained according to Scheme 1 at room temperature or by heating for up to several hours using a solvent such as DMSO, alcohol or tetrahydrofuran and a base such as LiOH, KOH or NaOH. If necessary, purification using, for example, silica gel chromatography is used.

Method B [0089] The compound of Formula (I) can be obtained according to Scheme 1 at room temperature or by heating for up to several hours using a solvent such as water, DMSO, alcohol or tetrahydrofuran and an aqueous acid solution. If necessary, purification using, for example, chromium atography on silica gel is used.

<img file="PL2903968T3_D0009.tif" />

Method C [0090] The compound of Formula (I) can be obtained from halides or triflates (X = halogen, OTf) according to Scheme 2 at room temperature or by heating for up to several hours using a solvent such as toluene or tetrahydrofuran, a base such as cesium carbonate or potassium t-butoxide, a catalyst such as a Pd complex, optionally a salt such as lithium chloride and carbon monoxide. If necessary, purification using, for example, silica gel chromatography is used.

Preparation of intermediates for Compounds of Formula (I) [0091]

<img file="PL2903968T3_D0010.tif" />

Method D Intermediates (i) can be prepared from 2-formylpyridines according to Scheme 3 in a one-pot reaction or by a multistep procedure by mixing with an amine, optionally containing orthogonally protected reactive groups and a reducing agent such as NaBH 4, NaBH (OAc) ) 3, NaCNBH3 or Et3SiH at room temperature or by heating for up to several hours using a solvent such as an alcohol, DCE, DCM, water or toluene, optionally adding a catalyst such as an acid or a Lewis acid. Optionally, the protecting groups may be removed and, if necessary, purified by, for example, silica gel chromatography.

<img file="PL2903968T3_D0011.tif" />

Method E [0093] Intermediates (ii) can be obtained from 2-formylpyridines according to Scheme 4, analogously to method D.

<img file="PL2903968T3_D0012.tif" />

Process F Intermediates (iv) can be prepared from compounds (iii) according to Scheme 5, wherein R 'is a suitable protecting group or a R 1 group, using a solvent such as DMF or THF, a base such as a tertiary amine. with a steric hindrance, a dehydrating agent such as EDCI or DCC and an amine and stirring at or above room temperature for up to several hours. Optionally, said protecting group can be removed and, if necessary, purified by, for example, silica gel chromatography.

Diagram 6 xx

<img file="PL2903968T3_D0013.tif" />

(v) (vi)

Method G [0095] Intermediates (vi) can be obtained from compound (v) according to Scheme 6 in analogy to method F.

<img file="PL2903968T3_D0014.tif" />

Process H Intermediates (viii) can be prepared according to Scheme 7 from compound (vii), wherein R 'is a suitable protecting group or a group R1 and R "is an orthogonal protecting group that can be selectively removed, such as removal of R ": ^tBu in the presence of R ': CF 3 CO by treatment with trifluoroacetic acid in a solvent such as dichloromethane at room temperature for several hours. If necessary, purification using, for example, silica gel chromatography is used.

<img file="PL2903968T3_D0015.tif" />

Method I [0097] Intermediates (x) can be obtained from compound (ix) according to Scheme 8 in a manner analogous to method H.

<img file="PL2903968T3_D0016.tif" />

Method J Intermediates (xii) can be prepared from aldehydes and intermediates (xi) according to Scheme 9 in a one-pot reaction or by a multistep procedure by stirring with an amine (R ': R1 or a suitable protecting group) and agent with a reducing agent such as NaBH4, NaBH (OAc) 3, NaCNBH3 or Et3SiH at room temperature or by heating for up to several hours using a solvent such as alcohol, DCE, DCM, water or toluene, optionally adding a catalyst such as acid or acid Lewis. Optionally, the protecting groups can be removed and, if necessary, purified by, for example, silica gel chromatography.

Method K [0099] Intermediates (xii) can be obtained from compound (xi) according to Scheme 9, using a solvent such as DMF or THF, optionally a base and a suitable electrophile, such as an epoxide, bromide, aliphatic chloride or sulfonate, allyl or benzyl. If necessary, purification using, for example, silica gel chromatography is used.

Diagram 10%

<img file="PL2903968T3_D0017.tif" />

Method L [0100] Intermediates (xiv) can be obtained from compound (xiii) according to Scheme 10, analogously to method J.

Method M [0101] Intermediates (xiv) can be obtained from compound (xiii) according to Scheme 10, analogously to Method K

<img file="PL2903968T3_D0018.tif" />

Process N [0102] Intermediates (xvi) can be obtained from intermediate (xv) according to Scheme 11, in a one-pot reaction or by a multistage process, by stirring with an amine, optionally containing orthogonally protected reactive groups and a reducing agent such as as NaBH 4, NaBH (OAc) 3, NaCNBH 3 or Et 3 SiH at room temperature or with heating for up to several hours, using a solvent such as alcohol, DCE, DCM, water or toluene, optionally adding a catalyst such as acid or Lewis acid. Optionally, the protecting groups can be removed and, if necessary, purified by, for example, silica gel chromatography.

Diagram 12 x

<img file="PL2903968T3_D0019.tif" />

&lt;^xvii&gt; (xviii)

Process O [0103] Intermediates (xviii) can be prepared from intermediate (xvii) according to Scheme 12 analogously to method N.

Inhibitory Effect [0104] The inventors have surprisingly found that the compounds of Formula (I) as defined herein have an inhibitory effect on the activity of one or more HDMEs. Therefore, said one or more HDMEs may be any HDME, but preferably one or more HDME is selected from the JmjC (Jumonji) family, and more preferably said one or more HDMEs are HDME from the human JmjC family, and even more preferably HDME. belonging to families KDM6, KDM5, KDM4 or KDM2. The present invention also relates to the use of a compound of Formula (I) as defined herein in a method of inhibiting HDME. The method comprises contacting the cell with a compound of Formula (I). In connection with this embodiment, the method further provides for

[0105] Thus, preferably in the histone substrate demethylation assay for said HDME, preferred compounds of Formula (I) are compounds capable of reducing or preferably inhibiting said demethylation by said HDMEs. Said histone substrate may be any histone, but preferably it is histone H3 or a fragment thereof, and even more preferably: a fragment containing K4, K9, K27 or K36 with H3. Preferably, said inhibition is determined as the IC50 of said compound of Formula (I) with respect to said demethylation assay.

[0106] Preferred compounds of Formula (I) are those having an IC₅₀ of 1 μM or less, more preferably less than 300 nM, e.g. less than 100 nM, e.g. less than 50 nM, with respect to demethylation of any said histone substrate by any of said HDMEs. Thus, the very preferred compounds of Formula (I) are those that have an IC₅₀ of 1 μM or less, more preferably less than 500 nM, e.g. less than 100 nM, e.g. less than 50 nM, relative to the demethylation of histone H3 methylated on at least one lysine.

[0107] In a preferred embodiment, the IC50 is determined as described in Example 2 below. Thus, compounds of Formula (I) that have IC values ​​are particularly preferred.₅₀ of 1 μM or less, more preferably less than 500 nM, e.g. less than 100 nM, e.g. less than 50 nM, when said IC 50 is determined as described in any of the Examples below.

[0108] Particularly preferred compounds of Formula (I) are compounds that lead to a reduction in tumor size and / or a reduction in the number of metastases in a xenograft model (Morton and Houghton, Nature Protocols, 2 (2), 247-250, 2007). ).

Pharmaceutical compositions [0109] In one aspect, there is provided a pharmaceutical composition comprising, as an active ingredient, 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 a single or in multiple doses. Suitable pharmaceutically acceptable carriers, diluents and excipients include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.

[0110] The pharmaceutical compositions may be formulated with pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients, according to conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 21nd edition, 2000, Lippincott Williams &amp; Wilkins.

[0111] Pharmaceutical compositions formed by combining a compound of Formula (I) as defined herein with pharmaceutically acceptable carriers, diluents or excipients can be easily 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 substance. In tablets, the active ingredient is mixed in appropriate proportions with a carrier having the necessary binding properties and compacted to the desired shape and size.

[0112] The pharmaceutical compositions may be specifically formulated for administration by any suitable route, for example orally and parenterally (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal). It will be understood that the preferred route of administration will depend on the general condition and age of the patient being treated, the nature of the condition being treated and the active ingredient selected.

[0113] Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they may be prepared with coatings such as enteric coatings or they may be prepared in a manner to provide controlled release of the active ingredient, such as sustained or sustained release, according to methods well known in the art.

[0114] For oral administration in the form of a tablet or capsule, the compound of Formula (I) as defined herein can be suitably combined with an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water and the like. In addition, suitable binders, lubricants, disintegrating agents, flavoring and coloring agents may be added to the mixture as desired. Suitable binders include, e.g., lactose, glucose, starch, gelatin, gum arabic, gum tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants include, e.g., sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, e.g., starch, methylcellulose, agar, bentonite, xanthan gum, starchy sodium glycolate, crospovidone, croscarmellose sodium or the like. Additional excipients for capsules include macrogols or lipids.

[0115] For the preparation of solid compositions such as tablets, the active compound of Formula (I) is mixed with one or more excipients, such as those described above, and other pharmaceutical diluents, such as water, to give a solid preformulation composition containing a homogeneous mixture. a compound of Formula (I). The term "homogeneous" should be understood to mean that the compound of Formula (I) is uniformly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets or capsules.

[0116] Liquid compositions for oral or parenteral administration of a compound of Formula (I) include, for example, aqueous solutions, syrups, elixirs, aqueous or oily suspensions and emulsions with edible oils, such as cottonseed oil, sesame oil, coconut oil or oil with peanuts. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinylpyrrolidone.

[0117] Pharmaceutical compositions for parenteral administration include sterile, aqueous and nonaqueous injection solutions, dispersions, suspensions or emulsions, as well as sterile powders intended to be dissolved prior to use in sterile injectable solutions or dispersions. For parenteral administration, solutions containing a compound of Formula (I) in sesame or peanut oil, aqueous propylene glycol, or in a sterile aqueous solution may be used. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent should first be rendered isotonic with the appropriate amount of salt or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.

[0118] The preparation of all these solutions under sterile conditions can easily be carried out using standard pharmaceutical techniques well known to those skilled in the art.

[0119] Depot injectable compositions are also contemplated as being within the scope of the present invention.

[0120] In addition to the above-mentioned components, the compositions of the compound of Formula (I) may contain one or more additional ingredients such as diluents, buffers, flavorings, coloring agents, surfactants, thickeners, preservatives, e.g. methyl hydroxybenzoate. (including antioxidants), emulsifying agents and the like.

[0121] A suitable dose of the compound of Formula (I) will depend on the age and condition of the patient, the severity of the disease being treated, and other factors well known to the practicing physician. The compound may be administered, e.g. orally, parenterally or topically according to various dosage regimens, e.g. daily or intermittently, e.g. at weekly intervals. In general, a single dose will range from 0.01 to 100 mg / kg body weight, preferably from about 0.05 to 75 mg / kg body weight, more preferably from 0.1 to 50 mg / kg body weight, and most preferably from 0 to 100 mg / kg body weight. , 1 to 25 mg / kg body weight. The compound can be administered as a bolus (i.e., the entire daily dose is administered immediately) or in divided doses two or more times a day. The specialist doctor may make changes based on the above-mentioned dose ranges, including known factors such as weight,

[0122] The compounds of Formula (I) may also be prepared in the form of a pharmaceutical composition containing one or more other active substances, alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in a single or in multiple doses. Suitable pharmaceutically acceptable carriers, diluents and excipients are as described above, and the one or more further active ingredients may be any of the active compounds or preferably active agents described in the following section "combination therapy".

Clinical Conditions and Other Uses of Compounds [0123] Compounds of Formula (I) as defined herein are useful in the treatment of an HDME dependent disease, disorder or condition. Treatment may involve administering to a mammal, preferably a human, more preferably a human suffering from a HDME-mediated disease, a therapeutically effective amount, as defined herein, a compound of Formula (I).

[0124] Said HDME may be any HDME, however, preferably HDME according to the method is selected from the JmjC (Jumonji) family as described in Cloos et al., Genes &amp; Development 22, 1115-1140, 2008. More preferably, said HDME is HDME belonging to human family JmjC.

[0125] The present invention also relates to a compound or a pharmaceutically acceptable salt thereof, as defined in claim 1, for use in the treatment of a disease dependent on HDME, for example for the treatment of cancer.

[0126] By the term "HDME dependent disease" is meant any disease characterized by an increased expression and / or activity of HDME in at least some cases of the disease or disease that can be ameliorated by a decrease in HDME activity. Thus, a disease treated with HDME inhibitors, i.e. compounds of Formula (I), may be a proliferative or hyperproliferative disease that includes benign and malignant neoplasia, for example a proliferative or hyperproliferative disease selected from the group consisting of brain, kidney, or neoplastic cancer. liver, adrenal, bladder, breast, stomach (for example, tumors of the stomach), ovaries, esophagus, large intestine, rectum, prostate, pancreas, lung, vagina, thyroid, sarcoma, glioma, multiple myeloma or gastrointestinal cancer, for example,

[0127] In one embodiment, the compounds of Formula (I) as defined herein are useful in the treatment of one or more tumors. The term "cancer" refers to any cancer caused by the proliferation of cancer cells, such as solid tumors, tumors, cancers, sarcomas, leukemias, lymphomas and the like. In particular, cancers that can be treated with the compounds and compositions of the invention include, without limitation: Hearts: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; Lung: bronchopulmonary carcinoma (squamous cell carcinoma, from undifferentiated small cells, from undifferentiated large cells, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, chondroma hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (adenocarcinoma, islet cell, islet cell, glucagonomes, gastrinomas, carcinoids, VIP secreting tumors), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, haemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, adenoma, hamartoma, leiomyoma); The genitourinary system: kidneys (adenocarcinoma, Wilms tumor, sarcoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicles (seminoma, teratoma, embryonal cancer, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, haemangioma; Bones: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibroid sarcoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (retinal cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral bone gland), mildew, chondrosarcinoma, fibroma chondrichoma, osteochondroma and giant cell tumors; Nervous system: skull (osteoma, angioma, granuloma, jaundice, Paget's disease), meningiomas (meningioma, meningioma, glioblastoma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, pinealoma], glioblastoma multiforme, oligodendroglioma, neuroblastoma , retinal glioma, congenital tumors), spinal cord (neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial cancer), cervix (cervical cancer, premalignant cervical dysplasia), ovaries (ovarian cancer, serous cystadenoma, mucous cystadenoma, unclassified types of cancer, granulomatous cells of the ovarian follicle, tumors of Sertoli cells) Leydig, procreator, teratocarcinoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fallopian tubes (cancer); Hematological: blood (acute myelogenous 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, Kaposi's sarcoma, dysplastic lesions, lipoma, hemangioma, skin fibroma, keloids, psoriasis; and adrenal: neuroblastoma. fallopian tubes (cancer); Hematological: blood (acute myelogenous 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, Kaposi's sarcoma, dysplastic lesions, lipoma, hemangioma, skin fibroma, keloids, psoriasis; and adrenal: neuroblastoma. basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic lesions, lipoma, hemangioma, skin fibroma, keloids, psoriasis; and adrenal: neuroblastoma. basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic lesions, lipoma, hemangioma, skin fibroma, keloids, psoriasis; and adrenal: neuroblastoma.

[0128] In one embodiment, the compounds of Formula (I) as defined herein are useful in the treatment of one or more cancers selected from the group consisting of: leukemias including acute leukemias and chronic leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and leukocyte leukemia; lymphomas such as cutaneous T-cell lymphomas (CTCLs), non-cutaneous lymphomas from peripheral T cells, lymphomas associated with human T-cell leukemia virus (HTLV), such as adult cell leukemia / T cell lymphoma (ATLL), Hodgkin's disease and lymphomas, -Hodgkin, large cell lymphomas, diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mesothelioma, primary central nervous system (CNS) lymphoma; multiple myeloma; solid pediatric tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms tumor, bone tumors, and soft tissue sarcomas; common solid tumors of adults, such as head and neck cancers (eg mouth, larynx and esophagus), cancers of the genitourinary system (eg prostate, bladder, kidneys, uterus, ovaries, testicles, rectum and colon), lung cancer, breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, liver cancer and thyroid cancer.

[0129] In another highly preferred embodiment, the compounds of Formula (I) as defined herein are useful in the treatment of squamous cell carcinomas. Preferably, said squamous cell carcinomas are squamous epithelial cancers that may be present in a variety of organs, including the skin, lips, oral cavity, esophagus, bladder, prostate gland, lung, vagina and cervix; brain cancer, such as neuroblastoma, glioma and other malignant and benign brain tumors; breast cancer, pancreatic cancer and multiple myeloma.

[0130] In yet another embodiment, the compounds of Formula (I) as defined herein are useful in the treatment of brain tumors, adult tumors such as head and neck tumors (e.g., mouth, larynx and esophagus), urogenital tract tumors. (eg prostate, bladder, kidneys, uterus, ovaries, testicles, rectum and colon) and breast cancer.

[0131] Other forms of cancer for which compounds of Formula (I) are useful can be found in the Stedman's Medical Dictionary (Lippincott Williams &amp; amp; Wilkins, 28th ed., 2005).

[0132] In yet another related embodiment, the disease that can be treated with compounds of Formula (I) defined herein is selected from existing proliferative or hyperproliferative disease states, such as angiogenesis, such as psoriasis; Kaposi's sarcoma; restenosis, e.g. restenosis caused by a stent; endometriosis; Hodgkin's disease; leukemia; hemangioma; angiofibroma; eye diseases such as neovascular glaucoma; kidney diseases such as glomerulonephritis; malignant cirrhosis of the kidneys; thrombotic microangiopathy syndromes; transplant rejection and glomerulonephritis; fibrotic diseases, such as cirrhosis of the liver; proliferative diseases of mesangial cells; injuries to nervous tissue; and inhibition of re-vascular occlusion after balloon catheterization,

[0133] The compounds of Formula (I) are suitable as active ingredients in pharmaceutical compositions that are effective especially in the treatment of proliferative or hyperproliferative disorders and / or conditions associated with dysregulation of gene expression. Such pharmaceutical compositions have a therapeutically effective amount of a compound of Formula (I) together with other pharmaceutically acceptable excipients, carriers and diluents. As used herein, the phrase "therapeutically effective amount" indicates the amount necessary for administration to a host or host, tissue or host to obtain a therapeutic effect, such as a mitigating or alternatively therapeutic effect, e.g. antitumor effect, e.g. preferably,

[0134] Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, in combination with at least one other anti-cancer compound and a pharmaceutically acceptable adjuvant, carrier or diluent.

Method of treatment [0135] In a further aspect, the present invention relates to a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease in a patient. The disease may be any disease or disorder referred to herein, such as those listed in the "HDME dependent diseases" section, and the compound may be administered alone or in the form of a pharmaceutical composition such as, for example, listed in the "Pharmaceutical Compositions" section. ".

[0136] Therefore, the invention also relates to a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0137] As used herein, the terms "treatment" and "therapy", unless otherwise indicated, refer to reversing, alleviating, inhibiting a process, or preventing a disease, disorder or condition to which such a term applies, or to one or more symptoms. such a disease, disorder or condition and comprises administering a compound of Formula (I) to prevent the onset of symptoms or complications or alleviate the symptoms or complications or eliminate the disease, condition or disorder. The therapy is preferably curative or symptom alleviating.

[0138] In a preferred embodiment of this aspect of the present invention, the compound of claim 1 or a pharmaceutically acceptable salt thereof is used in a method of treating an HDME dependent disorder in a patient. The HDME-dependent disease may be any HDME-dependent disease described above. Preferably, the HDME dependent disease is squamous cell carcinoma or any of the cancerous diseases listed above.

[0139] Accordingly, the invention also relates to a compound or a pharmaceutically acceptable salt according to claim 1 for use in the treatment of a disease dependent on HDME, for example in the treatment of cancer.

[0140] Also disclosed is the use of a compound of Formula (I) as defined herein for the preparation of a pharmaceutical composition intended for the treatment of HDME dependent disease. [0141] In the treatment of an HDME dependent disease, a compound of Formula (I) as defined herein can be used in combination with one or more additional active ingredients. The active substances can be any active substances, and preferably the active substance described above in the section "combination therapy." More preferably, the one or more additional active ingredients are selected from the group consisting of antiproliferative and anti-cancer agents.

Combination therapy [0142] A compound of Formula (I) may also be used advantageously in combination with one or more other anti-proliferative or anti-cancer agents. Such anti-proliferative agents include, without limitation, other HDME inhibitors, proteasome inhibitors, including bortezomib (Valcade) and Carfilzomib, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; compounds targeting / decreasing protein or lipid kinase activity and further anti-angiogenic compounds; compounds that are targeted at reduce or inhibit protein or lipid phosphatase activity; gonadorelin agonists; antiandrogens; angiostatic steroids; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; agents used in the treatment of hematologic malignancies; compounds that are directed to, downregulate or inhibit Flt-3 activity; Hsp90 inhibitors; temozolomide (TEMOD Al (R)); leucovorin; immune stimulating agents such as BCG, IL-2 and IFN-α, antibodies such as rituximab or herceptin and cancer vaccines. bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; agents used in the treatment of hematologic malignancies; compounds that are directed to, downregulate or inhibit Flt-3 activity; Hsp90 inhibitors; temozolomide (TEMOD Al (R)); leucovorin; immune stimulating agents such as BCG, IL-2 and IFN-α, antibodies such as rituximab or herceptin and cancer vaccines. bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; agents used in the treatment of hematologic malignancies; compounds that are directed to, downregulate or inhibit Flt-3 activity; Hsp90 inhibitors; temozolomide (TEMOD Al (R)); leucovorin; immune stimulating agents such as BCG, IL-2 and IFN-α, antibodies such as rituximab or herceptin and cancer vaccines. reduce or inhibit the activity of Flt-3; Hsp90 inhibitors; temozolomide (TEMOD Al (R)); leucovorin; immune stimulating agents such as BCG, IL-2 and IFN-α, antibodies such as rituximab or herceptin and cancer vaccines. reduce or inhibit the activity of Flt-3; Hsp90 inhibitors; temozolomide (TEMOD Al (R)); leucovorin; immune stimulating agents such as BCG, IL-2 and IFN-α, antibodies such as rituximab or herceptin and cancer vaccines.

[0143] The compound of Formula (I) as defined herein can also be advantageously used in combination with known therapeutic methods, e.g., administration of hormones or agents that cause damage to tumor cells, particularly ionizing radiation.

[0144] A compound of Formula (I) as defined herein can be used as a radioactivator, including, for example, in the treatment of cancers that have low sensitivity to radiotherapy.

[0145] By "conjugate" is meant either a fixed combination in one unit dosage form or a combination of components for co-administration, wherein the compound of Formula (I) and associated partner can be administered independently at the same time or separately at a specified time interval, which in particular allows co-operative effects to be shown to the associated partners, e.g. a synergistic effect or any combination thereof.

[0146] As used herein, the phrase "aromatase inhibitor" refers to compounds that inhibit the production of estrogens, i.e. the conversion of substrates, androstenedione and testosterone, respectively to oestrone and estradiol. The term includes, without limitation, steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, in particular aminoglutethimide, rogletimid, pyridoglutethimide, trilostane, testolactone, ketoconazole, 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. Fadrozol 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 of in which it is sold e.g. under the trade name ARIMIDEX. Letrozole can be administered, e.g., in the form as it is marketed e.g. under the trademark FEMARA or FEMAR. Aminoglutethimide can be administered, e.g., in the form as it is marketed e.g. under the trademark ORIMETEN. The combination of the invention containing a chemotherapeutic agent which is an aromatase inhibitor is particularly useful in the treatment of tumors with positive hormone receptors, e.g. breast tumors.

[0147] As used herein, the term "anti-estrogen" refers to compounds that antagonize the action of estrogens at the level of the estrogen receptor. The term includes, without limitation, 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 may be formulated as described in US 4,659,516 or may be administered e.g. in the form as it is marketed e.g. under the trademark FASLODEX. The combination of the invention containing a chemotherapeutic agent which is an antiestrogen is particularly useful in the treatment of tumors with a positive estrogen receptor, e.g. breast tumors.

[0148] As used herein, the term "antiandrogen" refers to a substance that is capable of inhibiting the biological action of androgen hormones and includes, without limitation, bicalutamide (CASODEX), which can be obtained e.g. as disclosed in US 4,636,505.

[0149] As used herein, the expression "a gonadorelin agonist" includes, without limitation, abarelix, goserelin and goserelin acetate. Goserelin is described in US 4,100,274 and can be administered e.g. in the form in which it is sold e.g. under the trademark ZOLADEX. Abarelix can be formulated, for example, as described in US 5,843,901.

[0150] As used herein, the expression "topoisomerase I inhibitor" includes, without limitation, topotecan, gimatecan, irinotecan, camptotecan and its analogues, 9-nitrocamptothecin and camptothecin-macromolecular conjugate PNU-166148 (compound AI 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 trade name

HYCAMTIN.

The expression "topoisomerase II inhibitor" as used herein includes, without limitation, anthracyclines, such as doxorubicin (including liposomal formulation, e.g. CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, anthraquinones, mitoxantrone and losoxantrone and podophyllotoxins, etoposide and teniposide. Etoposide can be administered, e.g., in the form as it is marketed e.g. under the trade name 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 in which it is sold e.g. under the trade name ZAVEDOS. Mitoxantrone can be administered, e.g., in the form as it is marketed e.g. under the trademark NOVANTRON.

[0152] The expression "microtubule active agent" refers to microtubule stabilizing agents, microtubule destabilizing agents and microtubule polymerization inhibitors including, without limitation, taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g. vinblastine, including vinblastine sulfate, vincristine including vincristine sulfate and vinorelbine, disododolides, kochicin and epothilones and their derivatives, e.g. epothilone B and D or derivatives thereof. Paclitaxel can be administered, e.g., in the form in which it is sold 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 RP. Vincristine sulfate can be administered, e.g. under the trade name FARMISTIN. Diskodermolide can be obtained, e.g. as described in US 5,010,099. It also includes Epothilone derivatives which are disclosed 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 Epotilon A and / or B.

[0153] As used herein, the expression "alkylating agent" includes, without limitation, 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.

[0154] The expression "histone deacetylase inhibitors" or "HDAC inhibitors" refers to compounds that inhibit, for example, at least one class of enzymes known as histone deacetylases, and which compounds generally have anti-proliferative activity. Previously disclosed HDAC inhibitors include compounds disclosed e.g. in WO 02/22577, including N-hydroxy-3- [4 - {[(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl] amino] methyl] phenyl ] -2E-2-propenoamide, N-hydroxy-3- [4 - [[[2- (2-methyl-1H-indol-3-yl) -ethylamino] -methyl] -phenyl] -2-2-propenoicamide and their pharmaceutically acceptable salts. It also includes hydroxamic acid suberoylanilide (SAHA). Other commonly disclosed HDAC inhibitors include butyric acid and its derivatives, including sodium phenylbutyrate, thalidomide, trichostatin A and trapoxin.

[0155] The term "antitumour anti-cancer" includes, without limitation, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating agents such as 5-azacytidine and decitabine, methotrexate and edatrexat, and folic 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 in which it is sold e.g. under the trademark HERCEPTIN.

[0156] As used herein, the expression "platinum compound" includes, without limitation, carboplatin, cisplatin, cisplatin 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.

[0157] Strategies that damage cancer cells refer to methods such as ionizing radiation. The expression "ionizing radiation" referred to above and below means the use of ionizing radiation, which occurs both as electromagnetic radiation (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided, without limitation, in radiation therapy and is known in the art. See, e.g., Hellman, Principles of Radiation Therapy, Cancer, Principles and Practice of Oncology, Devita et al., Eds., Ed. 4th, volume 1, pp. 248-275 (1993).

[0158] As used herein, the expression "angiostatic steroids" refers to agents that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11 - ^ - epihydrocortisol, cortexolone, W - ^ - hydroxyprogesterone, corticosterone , deoxycorticosterone, testosterone, estrone and dexamethasone.

[0159] Other chemotherapeutic agents include, without limitation, plant alkaloids, agents and hormonal antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or derivatives of oligonucleotides; or other means or means with a different or unknown mechanism of action.

[0160] The structure of active substances identified by code numbers, generic or trade names can be taken from the current edition of the standard compilation "The Merck Index" or from databases, e.g. Patents International (e.g., IMS World Publications).

[0161] The above-mentioned compounds, which can be used in combination with a compound of Formula (I), can be obtained and administered as described in the art, as in the above-mentioned documents. In addition, the compounds of the invention may be used in a method of profiling the functional and structural similarity of histone demetlasses, comprising taking a set of at least two histone demetlass and a set of at least two compounds of Formula 1 and determining to what extent each compound of Formula 1 inhibits the activity of each of these histone demethylases and the generation of a similarity parity reflecting the degree of similarity of histone demetlasses with respect to their inhibition by these compounds.

EXAMPLES [0163] In general, the invention relates to a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof. Other exemplary compounds are given for informational purposes.

Example 1: Examples of Compounds of Formula (I)

General Methods and Materials [0164] The following Table 1 shows examples of compounds of Formula (I) and indicates routes that can be used in their synthesis. All chemicals were purchased from Sigma-Aldrich, Alfa Aesar, Matrix, Combiblock Oakwood and Chembridge. Anhydrous solvents were from Aldrich Sure / Seal ™. All reactions were carried out under dry nitrogen using dry solvents. The reactions were monitored by thin layer chromatography on Sigma-Aldrich silica gel plates 0.25 mm (60 A, fluorescent indicator). The spots were visualized under UV light (254 nm). Flash column chromatography was performed on a Biotage SNAP Flash System or silica gel 60 (particle size 0.032-0.063 mm) obtained from Silicycle Inc.₁ positive (ES +) or negative (ES-). spectrum¹H-NMR were recorded on a Bruker AM-300 spectrometer and calibrated using the undeuterated residual solvent as an internal standard. The spectra were processed using the Spinworks version 2.5 program (developed by Dr. Kirk Marat, Faculty of Chemistry, University of Manitoba). Preparative HPLC was performed on a Waters 2996 with a Fotodiode Array Detector detector, a Waters 600 Controller, a Waters 100 pump and an automatic Waters 717 sample dispenser, with UV detection at 254 and 280 nm. Flow: 15 ml / minute, working time 30 minutes. Solvents: 0-100% (H 2 O-MeOH) with or without TFA (0.1%). A C18 Supelco column, 25 cm x 21.2 mm, particle size 10 microns was used.

Ethyl 2-formylpyridine-4-carboxylate was obtained analogously to Queguiner, G. and Pastour, P. (Comptes Rendus des seans of the Academie des Sciences, Serie C: Chimiąues Sciences (1969), 268 (2), 182 -5).

Table 1

<td>Structure</td><td>#</td><td>Name</td><td>Road synthesis</td><td>NMR</td>

<td>OH Η Ί Η © a ν Ά. Χ \ Ν / Ν Ν χΧ¹'¹</td><td>1</td><td>2 - ({[3- (1H-imidazol-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 8.10 (s, 1H), 7.98 (dd, 1H), 7.80 (t, 1H), 7.65 (t, 1H), 4, 58 (s, 2H); 4.50 (t, 2H).</td>

<td>Ο ^ΟΗίΐ Ί η ί! χλ Ν CH, Ν Ν ³1 ch₃</td><td>2</td><td>2 - ({[2 (dimethylamino) ethyl] amino} methyl) pyridine -4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 8.03 (s, 1H), 4.58 (s, 2H), 3.63 (m, 4H), 3.0 (s, 6H).</td>

<td>HO 0 A Η °^Hΐί χΐ Ν Λ ΟΗ</td><td>3</td><td>2 - ({[(2R) -2,3-dihydroxypropyl] amino} methyl) pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 8.12 (s, 1H), 4.04 (m, 1H), 3.62 (m, 2H), 3.35 (m, 1H), 3, 18 (dd, 1H).</td>

<td>° Ϊ^ΟΗΓί r '^Ν' ΝΗ χ</td><td>4</td><td>2 {[(cyclopropylmethyl) amino] methyl} pyridine o-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 4.56 (s, 2H), 3.08 (d, 2H), 1.21 (m, 1H), 0.75 (m, 2H), 0, 47 (m, 2H).</td>

<td>ΗΟ Ο ίΐ Ί η X Χ \ Ν CH, ch₃</td><td>5</td><td>2 {[(cyclopropylmethyl) amino] methyl} pyridine o-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 8.0 (s, 1H), 4.42 (s, 2H), 2.80 (s, 6H).</td>

<td>OH ίΐΊ ^CH3J CH Ν N ³ch₃</td><td>6</td><td>2 - ({[2 (dimethylamino) ethyl] (methyl) amino} methyl) pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 8.16 (s, 1H), 4.76 (s, 2H), 3.80 (s, 4H).</td>

<td>HO Y ° A, ch₃1 / CH JZ Ν Z N</td><td>7</td><td>2 - {[methyl (prop-2-yn-1-yl) amino] methyl} pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 7.93 (s, 1H), 3.77 (s, 2H), 3.39 (s, 2H).</td>

<td>HO /&gt; ° ί Ί H YY \ N YY ^ F</td><td>8</td><td>2 - {[(2-fluoro-ethyl) amino] methyl} pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 7.85 (s, 1H), 4.65 (t, 1H), 4.49 (t, 1H), 4.02 (s, 2H).</td>

<td>HO O / /&gt; / Ν Y HN, ^ θνγ</td><td>9</td><td>2 - {[(furan-2-ylmethyl) amino] methyl} pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 7.72 (s, 1H), 6.30 (d, 1H), 6.22 (d, 1H), 3.78 (s, 2H).</td>

<td>^ΗΟ °</td><td></td><td></td><td></td><td></td>

<td rowspan="2">'Υ ΗΝ</td><td></td><td>2 - ({[(5-phenylfuran-2-acid)</td><td></td><td>¹H NMR (300 MHz, CD3OD), δ ppm:</td>

<td>10</td><td>yl) methyl] amino} methyl) pyridine-4-</td><td>AND</td><td>7.75 (s, 1 H), 6.68 (s, 1H), 6.38 (s, 1H),</td>

<td>Ο</td><td></td><td>carboxylic acid</td><td></td><td>3.85 (s, 2H).</td>

<td>IN</td><td></td><td></td><td></td><td></td>

<td>0 ΟΗ</td><td></td><td></td><td></td><td></td>

<td rowspan="3">'Υ .....^NHch₃</td><td></td><td>2 - ({[(2,4-</td><td></td><td>¹H NMR (300 MHz, CD3OD), δ ppm:</td>

<td>11</td><td>dimethoxyphenyl) methyl] amino} methyl) pyridine</td><td>AND</td><td>7.84 (s, 1H), 7.15 (s, 1H), 3.85 (s, 2H),</td>

<td></td><td>no-4-carboxylic acid</td><td></td><td>3.70 (s, 2H).</td>

<td>h₃c</td><td></td><td></td><td></td><td></td>

<td>0 ΟΗ</td><td></td><td>acid 2 - ({[2-</td><td></td><td>¹H NMR (300 MHz, CD3OD), δ ppm:</td>

<td>ίΐ Ί η</td><td>12</td><td>(Methylsulfanyl) ethyl] amino} methyl) pyridine</td><td>AND</td><td>7.85 (s, 1H), 3.96 (s, 2H), 2.82 (t, 2H),</td>

<td>ΥΛ Ν / χ CHO</td><td></td><td>o-4-carboxylic acid</td><td></td><td>2.67 (t, 2H).</td>

<td>ο οη</td><td></td><td>2 - ({[2-oxo-2- (pyrrolidin-1) acid</td><td></td><td>¹H NMR (300 MHz, MeOH-d4): δ ppm:</td>

<td rowspan="2">r 'Υ Ο Η ,, U &lt;Υ Ν Λ Ν-'Λ</td><td>13</td><td>yl) ethyl] amino} methyl) pyridin-4-</td><td>B</td><td>7.70 (s, 1H), 3.70 (s, 2H), 4.0 (s, 2H),</td>

<td></td><td>carboxylic acid</td><td></td><td>3.40 (m, 6H).</td>

<td>HO, Ο \AND CU N</td><td>H ° ON N _CH₃ch₃</td><td>14</td><td>2 - [({[butyl (methyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid</td><td>B</td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm: 7.7 (s, 1H), 3.7 (s, 2H), 3.4 (s, 2H), 3.2 (m, 2H).</td>

<td>HO °</td><td>n νΑ</td><td></td><td>2 - ({[(1-methyl-1H-1,3-benzodiazole-2-acid)</td><td></td><td>¹H NMR (300 MHz, CD3OD), δ ppm:</td>

<td>AT</td><td>NH Ν 'Υχ</td><td>15</td><td>yl) methyl] amino} methyl) pyridine-4-</td><td>AND</td><td>7.84 (s, 1H), 4.16 (s, 2H), 4.02 (s, 2H),</td>

<td></td><td>h₃c</td><td></td><td>carboxylic acid</td><td></td><td>3.90 (s, 3H).</td>

<td>HO</td><td>about</td><td></td><td>2 - [({2- [4- (2-methoxyethyl) piperazin-1-acid</td><td></td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm:</td>

<td>[li H U Jl N N ""</td><td>II LN CH.,</td><td>16</td><td>yl] -2-oxoethyl} amino) methyl] pyridine-4-carboxylic acid</td><td>B</td><td>7.7 (s, 1H), 3.7 (s, 2H), 3.3 (s, 3H), 1.8 (m, 8H).</td>

<td>HO O AT</td><td>ABOUT H ii</td><td></td><td>2 - [({[bis (prop-2-en-1) acid</td><td></td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm:</td>

<td></td><td>1</td><td>17</td><td>yl) carbamoyl] methyl} amino) methyl] pyridine</td><td>B</td><td>7.7 (s, 1H), 5.6 (m, 2H), 4.9 (m, 4H), 3.5</td>

<td></td><td>loam ch₂</td><td></td><td>o-4-carboxylic acid</td><td></td><td>(s, 2H).</td>

<td>HO 0 Jl N</td><td>cn about \ H u NA Λ "~ x '^ /" Ν'Α</td><td>18</td><td>2 - [({2-oxo-2 - [(2R) -2- (pyrrolidin-1-ylmethyl) pyrrolidin-1-yl] ethyl} amino) methyl] pyridine-4-carboxylic acid</td><td>B</td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm: 7.7 (s, 1H), 4.2 (m, 1H), 3.4 (m, 6H), 3.0 (m, 1H).</td>

<td>ο ^0Ηfl Ί η 1 ν</td><td></td><td>Ν - /</td><td>ch₃Ο --CHj 4 ^CH3 0</td><td>19</td><td>2 - ({[(3R) -1 - [(tertbutoxy) carbonyl] pyrrolidin-3-yl] amino} methyl) pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, MeOH-d 4), δ ppm: 7.75 (s, 1H), 3.85 (s, 1H), 1.50 (s, 9H).</td>

<td>ΗΟ Ο</td><td></td><td>ο</td><td></td><td></td><td>2 - ({[(3R) -1 - [(tert)</td><td></td><td>¹H NMR (300 MHz, CD3OD), δ ppm:</td>

<td>11 "Ν</td><td>Η Ν</td><td>Ν</td><td>Ο η \</td><td>20</td><td>butoxy) carbonyl] pyrrolidin-3-</td><td>B</td><td>7.72 (s, 1H), 6.32 (d, 1H), 6.20 (d, 1H),</td>

<td></td><td>Η</td><td>0</td><td>υ</td><td></td><td>yl] amino} methyl) pyridine-4-carboxylic acid</td><td></td><td>4.00 (s, 2H), 3.84 (s, 2H).</td>

<td>ΗΟ 0 ll Ί η 1 Ν Ν</td><td></td><td>Η Ν</td><td></td><td>21</td><td>2 - {[(3 - {[3- (pyrrolidin-1-yl) propyl] amino} propyl) amino] methyl} pyrimidine-4-carboxylic acid</td><td>C</td><td>¹H NMR (300 MHz, D2O), δ ppm: 7.96 (s, 1H), 4.48 (s, 2H), 2.92-3.25 (m, 8H).</td>

<td>0 ΟΗ 11 ρ&gt; 1 Ν</td><td>Η Ν</td><td></td><td>ch₃ch₃</td><td>22</td><td>2 - {[(3-methylbutyl) amino] methyl} pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 7.80 (s, 1H), 3.90 (s, 2H), 2.60 (m, 2H), 0.92 (d, 6H).</td>

<td>ΗΟ ^ Ο</td><td></td><td>ο</td><td>νη₂Χ ^ Ο</td><td></td><td>acid 2 - [({[(2-</td><td></td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm:</td>

<td rowspan="2"></td><td>Η Ν</td><td>Η</td><td rowspan="2">Ν ch₃</td><td>23</td><td>carbamoylethyl) (methyl) carbamoyl] methyl}</td><td>B</td><td>7.9 (s, 1H), 3.8 (s, 2H), 3.5 (m, 4H), 2.3</td>

<td></td><td></td><td></td><td>amino) methyl] pyridine-4-carboxylic acid</td><td></td><td>(m, 2H).</td>

<td>HO O N Γιΐ h ° k 1 ν Λ N k / '' k Ν η HO - ^ Akk</td><td>24</td><td>2 - [({2- [2- (hydroxymethyl) piperidin-1-yl] -2-oxoethyl} amino) methyl] pyridine-4-carboxylic acid</td><td>B</td><td>¹1 H NMR (300 MHz, MeOH-d 4), δ ppm: 7.9 (s, 1H), 3.9 (s, 2H), 3.5 (m, 2H).</td>

<td>H ° ° H₃C^NNfil ^h ! and k AN 1 J N k / '-k N 1 ch₃</td><td>25</td><td>2 - {[({methyl [3- (1-methyl-1H-imidazol-2-yl) propyl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>B</td><td>¹H NMR (300 MHz, MeOH-d4): δ 7.7 (s, 1H), 6.7 (d, 1H), 6.6 (d, 1H), 3.7 (s, 2H), 3, 5 (s, 3H).</td>

<td>HO A⁾kk 0^H II k- A, NA N k / N^WITHV \^H N_ / H₃cX ^</td><td>26</td><td>2 - {[({[(1-ethylpyrrolidin-2-yl) methyl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>B</td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm: 7.7 (s, 1H), 3.7 (s, 2H), 3.4 (m, 2H), 3.3 (m, 3H), 1.0 (t, 3H).</td>

<td>ho A A 0 Η, AA n A N k / '-k N AA ch₃ n__nh₃c</td><td>27</td><td>2 - {[({methyl [(1-methyl-1H-pyrazol-5-yl) methyl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>B</td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm: 7.7 (s, 1H), 7.6 (d, 1H), 7.3 (d, 1H), 6.3 (d, 1H), 4.6 (s, 2H) 4.0 (s, 2H).</td>

<td>0. OH "k rk H kk N.</td><td>28</td><td>2 - ({[(3R) -1- (3-phenylpropyl) pyrrolidin-3-yl] amino} methyl) pyridine-4-carboxylic acid</td><td>D</td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm: 7.80 (s, 1H), 7.20 (m, 5H), 3.85 (s, 2H).</td>

<td>0, OH CH, about ³77 θ Η II 7 &lt;7. ν Λ Λ) 7 7 Ν _ΝΗ</td><td>29</td><td>2 - ({[({1 - [(2-methoxyphenyl) methyl] piperidin-4-yl} carbamoyl) methyl] amino} methyl) pyridines o-4-carboxylic acid</td><td>E</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 7.82 (s, 1H), 7.26 (m, 2 H), 6.94 (m, 2 H), 3.90 (s, 2 H), 3, 85 (s, 3H), 3.62 (s, 2H), 3.24 (s, 2H).</td>

<td>Ο ΟΗ ιό ^η θ Ρι ^^ ΤΊ 7 7 ν 7 7 7 7 7 Η</td><td>thirty</td><td>2 - {[({[1- (3-phenylpropyl)] piperidin-4-yl] carbamoyl} methyl) amino] methyl} pyridine o-4-carboxylic acid</td><td>E</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 7.84 (s, 1H), 3.92 (s, 2H), 3.78 (m, 2H), 3.24 (s, 2H), 2, 96 (m, 2H).</td>

<td>Ο ΟΗ Ιι '· Ί ° ί' '"^Ν'' 'Ti' ° \ 77 ..... ............ κ .....- χ.7¹ X Η</td><td>31</td><td>2 - {[({[1- (furan-2-ylmethyl) piperidin-4-yl] carbamoyl} methyl) amino] methyl} pyridine o-4-carboxylic acid</td><td>E</td><td>¹H NMR (300 MHz, CD₃OD), δ ppm: 7.82 (s, 1H), 7.64 (d, 1H), 7.42 (s, 1H), 6.38 (d, 1H), 6.30 (d, 1H), 3.92 (s, 2H), 3.56 (s, 2H).</td>

<td>° &lt;Λ ^ΟΗο ί ^ ν ^ ίΑ_ / Ί 77a, j7j ίλν Η</td><td>32</td><td>2 - ({[({1 - [(5-phenylfuran-2-yl) methyl] piperidin-4-yl} acid carbamoyl) methyl] amino} methyl) pyridine-4-carboxylic acid</td><td>E</td><td>¹H NMR (300 MHz, CD3OD), δ ppm: 7.82 (s, 1H), 6.70 (s, 1H), 6.40 (d, 1H), 3.92 (s, 2H).</td>

<td>ΗΟ ^, Ο 7 &lt;J^N71 κ 7 J ..... h₃C</td><td>33</td><td>2 - [({[(2-cyanoethyl) (ethyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid</td><td>B</td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm: 7.7 (s, 1H), 4.0 (s, 2H), 3.6 (m, 4H), 1.2 (t, 3H).</td>

<td>0 ^0Η"ΐΥ</td><td colspan="2">Η Ν - /</td><td>Ν</td><td>ΥΥ</td><td>34</td><td>2 - ({[2- (1-butylpyrrolidin-2-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid</td><td>D</td><td colspan="2">¹H NMR (300 MHz, methanol-d4), δ ppm: 8.00 (s, 1H), 4.53 (s, 2H), 3.58-3.13 (m, 6H), 1.01 (t , 3H).</td>

<td>ο ^ΟΗϊϊ Υ Η '• 1 ak, Ν Ν '</td><td>ο Ν "Η</td><td>Η^Ν</td><td>³° \</td><td>h₃c ΥθΗ₃</td><td>35</td><td>2 - {[({[1- (3,7-dimethyloct-6-en-1-yl) pyrrolidin-3-yl] carbamoyl} methyl) amino] methyl} pyridines o-4-carboxylic acid</td><td>E</td><td>¹H NMR (300 MHz, CD3OD), δ 7.72 (s, 1H), 5.10 (m, 1H), 4.36 (m, 3.90 (s, 2H), 3.28 (s, 2H); ).</td><td>ppm: 1H),</td>

<td>Ο ΟΗ</td><td></td><td></td><td></td><td></td><td></td><td>2 - {[(3 - {[(2- 2- acid)</td><td></td><td>¹H NMR (300 MHz, CD3OD), δ</td><td>ppm:</td>

<td>ίίΊ</td><td>Η</td><td></td><td>ch₃</td><td></td><td>36</td><td>fluorophenyl) methyl] (methyl) amino} propyl), and</td><td>C</td><td>7.85 (s, 1H), 3.90 (s, 2H), 2.62 (t,</td><td>2H);</td>

<td></td><td>. ^Ν .</td><td></td><td>Ν 0J</td><td>"0 F</td><td></td><td>mino] methyl} pyridine-4-carboxylic acid</td><td></td><td>2.48 (t, 2H).</td><td></td>

<td>ο ^ ^ΟΗ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Η Ν / -</td><td>Ο 'ISG cho ΟΗ</td><td>η₃ο</td><td>Ν Ν Υ</td><td>37</td><td>2 - ({[(1R) -2-hydroxy-1- {methyl [3- (1-methyl-1H-imidazol-2-yl) propyl] carbamoyl} ethyl] amino} methyl) piperidine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ 8.32 (s, 1H), 7.75 (d, 1H), 7.35 (d, 4.20 (s, 2H).</td><td>ppm: 1H),</td>

<td>ΗΟ</td><td>0</td><td></td><td>0</td><td></td><td></td><td>2 - [({2- [3- (1H-1,3-benzodiazole-2-acid)</td><td></td><td></td><td></td>

<td>ν, Ν</td><td>j Η .-^Ν</td><td>0 Υ ( Ν '</td><td>VNH</td><td></td><td>38</td><td>ylmethyl) piperidin-1-yl] -2-oxoethyl} amino) methyl] pyridine-4-</td><td>B</td><td>¹H NMR (300 MHz, MeOH-d4), δ 7.9 (s, 1H), 7.5 (m, 2H), 7.2 (m, 2H)</td><td>ppm: .</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>carboxylic acid</td><td></td><td></td><td></td>

<td>ο Ρ °. ^0Η "/ Ζγ ο γ "^ν1 ^Η II \ X Υ ν Z Ζ / Ν Ν Η</td><td>39</td><td>2 - {[({[1- (2-phenylethyl) pyrrolidin-3-yl] carbamoyl} methyl) amino] methyl} pyridine o-4-carboxylic acid</td><td>E</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 8.52 (d, 1H), 7.80 (s, 1H), 4.36 (m, 1H), 3.92 (m, 1H), 3, 28 (m, 2H).</td>

<td>ΗΟ γ ° γΖ ίΐ Ί η 1 ( X Ζ / Ν Ν J_Ν Υ / / ΥΥ / / Υ</td><td>40</td><td>2 - ({[3- (4-benzylpiperidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid</td><td>C</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 7.85 (s, 1H), 7.20 (m, 5H), 3.92 (s, 2H), 3.35 (s, 2H).</td>

<td>ΗΟ .0 // ί Ζ Η Η \ 1 / Υ Ν Ν Ζ / / Ν - \ / // // // - &lt;0 - //</td><td>41</td><td>2 - [({3 - [(2-phenoxyethyl) amino] propyl} amino) methyl] pyridine-4-carboxylic acid</td><td>C</td><td>¹1 H NMR (300 MHz, CD 3 OD), δ ppm: 7.82 (s, 1H), 4.18 (t, 2H), 2.96 (t, 2H), 2.70 (m, 4 H).</td>

<td>ΗΟ Ο Τ Ζ Ζ, ν ζ, "-,, -, CH, Ν Ν "γ / / Ν ^Jc^h₃ Ζ ^, Ζ ^, ν</td><td>42</td><td>2 - [({[methyl ({4 - [(4-methylpiperazin-1-yl) methyl] phenyl} methyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid</td><td>B</td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm: 7.7 (s, 1H), 4.4 (s, 2H), 4.0 (s, 2H), 3.6 (s, 2H).</td>

<td>ΗΟ Γιΐ ^η ? ζ ^ -υ²Ζ Υ ν Υ ζ - Ν - --- -Υ ^ Ν "Υ</td><td>43</td><td>2 - ({[2- (2-benzylpyrrolidin-1-yl) -2-oxoethyl] amino} methyl) pyridine-4-carboxylic acid</td><td>B</td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm: 7.7 (s, 1H), 7.2 (m, 4H), 4.4 (m, 1H), 3.5 (m, 4H), 3.4 (s, 2H),</td>

<td rowspan="2">0 ^0Η</td><td colspan="2">0</td><td rowspan="2">..._______________________</td><td rowspan="2">44</td><td rowspan="2">2 - ({[({4- [benzyl (cyclopropyl) amino] butyl} (methyl) carbamoyl) methyl] amino} methyl) pir acid ydyno-4-carboxylic acid</td><td rowspan="2">F</td><td rowspan="2">¹1 H NMR (300 MHz, MeOH-d 4), δ ppm: 7.80 (s, 1H), 3.90 (s, 2H), 3.70 (s, 2H), 0.50 (m, 2H), 0.40 (m, 2H),</td>

<td>Μ And Α,</td><td>Ν ch₃</td>

<td>ο X</td><td>, ΟΗ</td><td></td><td rowspan="2">γΌ Ν</td><td></td><td>2 - [({2 - [(2S) -1-benzylpyrrolidin-2-acid)</td><td></td><td>¹H NMR (300 MHz, MeOH-d4), δ ppm:</td>

<td>ιχ</td><td>ll ^Η</td><td></td><td>45</td><td>yl] ethyl} amino) methyl] pyridine-4-</td><td>D</td><td>7.74 (s, 1H), 7.50 (m, 2H), 7.42 (m, 3H),</td>

<td></td><td></td><td></td><td>ο</td><td></td><td>carboxylic acid</td><td></td><td>4.38 (s, 2H).</td>

<td>ΗΟ ' "</td><td>vv χ%^Ν</td><td></td><td></td><td>46</td><td>2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid</td><td>AND</td><td>¹H NMR (300 MHz, CD3OD): δ 8.54 (d, 1 H), 7.86 (s, 1 H), 7.72 (dd, 1H), 3.92 (s, 2H), 3.36 (s, 2H), 2.66 (t, 2H), 2.58-2.50 (m, 4H), 1.90 (s, 2H), 1.83-1.73 (m, 4H).</td>

<td></td><td>ο II</td><td></td><td></td><td></td><td></td><td></td><td>¹H NMR (300 MHz, CD3OD): δ 8.82 (d,</td>

<td>^Η3 '_ο.</td><td></td><td></td><td rowspan="2"></td><td></td><td>2 - ({[3- (pyrrolidin-1-</td><td></td><td>1H), 8.03 (s, 1H), 7.90 (dd, 1H), 4.43 (s,</td>

<td></td><td>Μ</td><td></td><td>47</td><td>yl) propyl] amino} methyl) pyridine-4-</td><td>G</td><td>2H), 3.98 (s, 3H), 3.46-3.36 (m, 6H),</td>

<td></td><td></td><td></td><td></td><td></td><td>methyl carboxylate</td><td></td><td>3.22 (t, 2H), 2.29-2.39 (m, 2H), 2.142.09 (m, 4H).</td>

<td></td><td></td><td>^ Ν.</td><td>^ 00γ^{;, Η}ο</td><td>48</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, δ CD3OD) 8.54 (dd, 1H), 7.85 (s, 1H), 7.72 (dd, 1H), 3.91 (s, 2H), 2.65-2 43 (m, 8H), 1.55-1.48 (m, 4H), 1.03 (t, 6H).</td>

<td>&gt; Η₃f OH ch₃ 0</td><td>49</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl phenyl) amino] methyl} pyridine-4-carboxylic acid</td><td>B</td><td>'Ή NMR (300 MHz, CD3OD): δ 8.55 (d, 1H), 7.88 (s, 1 H), 7.73 (d, 1H), 3.96 (s, 2H), 3.54 (s, 2H), 3.52-3.31 (m, 4H), 2.45-2.51 (m, 2H), 2.27 (m, 6H), 1.111.19 (m, 3H).</td>

<td>^ΗΧ ο^HSC ^</td><td>50</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate (5-methyl-2-oxo-2H-1,3-dioxol-4-yl) methyl</td><td>G</td><td>1 H NMR (300 MHz, CD 3 OD): δ 8.80 (m, 1H), 7.98 (m, 1H), 7.82 (m, 2H), 5.20 (s, 2H), 4.48 (s, 2H), 3.10-3.40 (m, 8H). ), 1.70-1.98 (m, 4H), 1.25-1.40 (m, 6H).</td>

<td>Ν-'Χ ΧΛ-γχ &gt; ° V \_n/^CH= Η₃(Τ ο</td><td>51</td><td>2-methoxyphenyl 2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate</td><td>G</td><td>1 H NMR (300 MHz, CD 3 OD): δ 8.88 (d, 1H), 8.13 (s, 1H), 8.05 (dd, 1H), 7,207.15 (m, 2H), 7.01 -6.96 (m, 2H), 4.53 (s, 2H), 3.81 (s, 3H), 3.27-3.16 (m, 8H), 1.90-1.85 (m , 4H), 1.33 (t, 6H).</td>

<td>Β-_κ^ C ", (^ // ΪΙΝ-V - Ν V ^ CH₃</td><td>52</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 2- (ethoxycarbonyl) phenyl)</td><td>G</td><td>1 H NMR (300 MHz, CD 3 OD) δ 8.93 (dd, 1H), 8.18 (s 1H), 8.15-8.07 (m, 2H), 7.83-7.62 (m, 1 H), 7.49 (dd, 1H), 7.33 ( dd, 1H), 4.57 (s, 2H), 4.22 (q, 2H), 3.47-2.99 (m, 10H), 2.01-1.73 (m, 2H), 1 , 34 (td, 9H).</td>

<td>/^CH3 h₃c- ^ ΝΖ Χ- ^ Χ- ^ [F χ ~~ ^ X] ^ J Ο ch₃H₃cX</td><td>53</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 2- (dimethylamino) ethyl</td><td>G</td><td>1 H NMR (300 MHz, CD 3 OD) δ 8.83 (d, 1H), 8.09 (s, 1H), 7.95 (d, 1H), 4.76 (t, 2H), 4.10 ( s, 2H), 3.65 (t, 2H), 2.25 (m, 8H), 3.02 (s, 6H), 1.85 (m, 4H), 1.36 (t, 6H).</td>

<td>'χ X h₃c ^ Άη</td><td>54</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 3 (dimethylamino) propyl</td><td>G</td><td>¹1 H NMR (300 MHz, CD 3 OD) δ 8.81 (d, 1H), 8.02 (s, 1H), 7.95 (d, 1H), 4.50 (m, 4H), 3.38 (m) , 2H), 3.26 (m, 8H), 2.98 (s, 6H), 2.25 (m, 2H), 1.87 (m, 4H), 1.38 (t, 6H).</td>

<td>ην - \ / Λ ™ Ά Γ "^{CH 3}\ -CH₃</td><td>55</td><td>2 - {{4 (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate {4 {[(ethoxycarbonyl) amino] phenyl} methyl</td><td>G</td><td>¹H NMR (300 MHz, CD3OD): δ 8.70 (d, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.307.50 (m, 4H), 5.35 (s, 2H), 4.50 (s, 2H), 3, 20 (m, 9H), 1.30 (m, 9H).</td>

<td>ΐ^Η· Ά ° ° Ύ ^ "V" k</td><td>56</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) -pyridine-4-carboxylate 2,6-dimethoxyphenyl</td><td>G</td><td>¹1 H NMR (300 MHz, CD 3 OD): δ 8.89 (dd, 1H), 8.15 (d, 1H), 8.05 (dd, 1H), 7.24 (t, 1H), 6.77 (diast. d, 2H), 4.53 (s, 2H), 3.79 (s, 6H), 3.29-3.13 (d, 8H), 1.92- 1.80 (m, 4H), 1 33 (t, 6H).</td>

<td>CH₃., -., '¹χ_Ύ··· χ ^ χ \ ΧΧ</td><td>57</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate, 2,6-dimethylphenyl</td><td>G</td><td>¹1 H NMR (300 MHz, CD 3 OD): δ 8.90 (d, 1H), 8.20 (s, 1H), 8.00 (d, 1H), 7.2 (s, 3H), 4.50 ( s, 2H), 2.20 (s, 6H), 1.80 (m, 4H), 1.30 (m, 6H).</td>

<td>CH₃ 0 Ν ^ Αι "_Cs-^andx ^ NA /^BAAV ° Vik₁k ϊ Χλ ΧΗ₃ cr</td><td>58</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl phenyl) amino] methyl} pyridine-4-carboxylate 4-methoxyphenyl</td><td>G</td><td>¹1 H NMR (300 MHz, CD 3 OD): δ 8.90 (d, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.10 (m, 2H), 7.00 ( m, 2H), 4.50 (s, 2H), 4.30 (s, 2H), 3.80 (s, 3H), 3.30 (m, 6H), 2.95 (s, 6H), 1.20 (t, 3H)</td>

<td>ę ..... ·_τ.₍₀AND₀/ \_CH Vⁿ</td><td>0</td><td>Γ³r A^H1^CH3</td><td>59</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl phenyl) amino] methyl} pyridine-4-carboxylate 2- (ethoxycarbonyl) phenyl</td><td>G</td><td>'Ή NMR (300 MHz, CD3OD): δ 8.90 (d, 1 H), 8.20 (s, 1 H), 8.05 (d, 1H), 7.75 (m, 1H), 7.45 (m, 1H), 7.30 (m, 1H), 4.60 (s, 2H), 4.30 (s, 2H), 3.80 (m, 2H), 3, 00 (s, 6H), 1.25 (m, 6H)</td>

<td>v (Vv^H3^C '-</td><td>0 Cr-x</td><td>^^CH3 X - N \ __ CH₃</td><td>60</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate {4 [(ethoxycarbonyl) (methyl) amino] phenyl} methyl</td><td>G</td><td>¹1 H NMR (300 MHz, CD 3 OD): δ 8.80 (d, 1H), 8.00 (s, 1H), 7.90 (d, 1H), 7.50 (d, 2H), 7.30 (d, 2H), 5.40 (s, 2H), 4, 50 (s, 2H), 4.20 (m, 2H), 1.80 (m, 4 H), 1.30 (m, 6H), 1.20 (t, 3H);</td>

<td>CH, 0 A-AA A</td><td>Uy</td><td>AND:., h₃c ³</td><td>61</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl phenyl) amino] methyl} pyridine-4-carboxylate 4-tert-butylphenyl</td><td>G</td><td>¹1 H NMR (300 MHz, CD 3 OD): δ 8.80 (d, 1H), 8.10 (s, 1H), 8.00 (d, 1H), 7.50 (d, 2H), 7.20 (d, 2H), 4.55 (s, 2H), 4, 30 (s, 2H), 3.80 (m, 3H), 2.99 (s, 6H), 1.40 (s, 9H), 1.20 (t, 3H)</td>

<td>CH₃ 0</td><td>n^/AND</td><td></td><td></td><td>2 - {[({[2-</td><td></td><td>¹H NMR (300 MHz, CD3OD): δ 8.75 (d,</td>

<td>AND</td><td>sCCyCa 0</td><td>ΎΊΓ CH₃ 0</td><td>62</td><td>(Dimethylamino) ethyl] (ethyl) carbamoyl} methyl phenyl) amino] methyl} pyridine-4-carboxylate</td><td>H</td><td>1H), 7.90-8.10 (m, 2H), 5.50 (m, 1H), 4.50 (s, 2H), 4.25 (s, 2H), 3.75 (m, 2H). )</td>

<td>un₃</td><td></td><td></td><td></td><td>4-oxopentan-2-yl</td><td></td><td>1.20-1.50 (m, 6H).</td>

<td>^H3^C\ 77 1 ch₃</td><td>-7 "X^{0 n}7</td><td>F FF HN ^^ O ο-Γχ Τχ)</td><td>63</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl phenyl) amino] methyl} pyridine-4-carboxylate 4- (trifluoroacetamido) butan-2-yl</td><td>G</td><td>¹1 H NMR (300 MHz, CD 3 OD): δ 8.80 (d, 1H), 7.98 (br s, 1H), 7.9 (d, 2H), 5.20 (m, 1H), 4.9 ( s, 2H), 4.5 (s, 2H), 4.3 (s, 2H), 3.8 (m, 2H), 3.5-3.3 (m, 6H), 3.0 (s , 3H), 2.0 (m, 2H), 1.3 (d, 3H), 1.2 (t, 3H).</td>

<td></td><td></td><td>F "" \ Ao</td><td></td><td>2 - {[({[2-</td><td></td><td>¹1 H NMR (300 MHz, CD 3 OD): δ 8.80 (d,</td>

<td></td><td></td><td>J</td><td></td><td>(Dimethylamino) ethyl] (ethyl) carbamoyl} methyl</td><td></td><td>1H), 8.0 (m, 2H), 5.20 (m, 1H), 4.9 (s,</td>

<td></td><td>ch</td><td>X</td><td>64</td><td>lo) amino] methyl} pyridine-4-carboxylate 4-</td><td>G</td><td>2H), 4.5 (s, 2H), 4.3 (s, 2H), 3.8 (m, 2H),</td>

<td></td><td>r</td><td>o ^ 7h₃</td><td></td><td>(2,2,2-trifluoro-N-methylacetamido) butan-2-</td><td></td><td>3.5-3.3 (m, 6H), 3.2 (s, 3H), 3.0 (s, 6H),</td>

<td></td><td>-γγ'Ύ'ϊ</td><td>77</td><td></td><td>yl</td><td></td><td>2.0 (m, 2H), 1.3 (d, 3H), 1.2 (t, 3H).</td>

<td>X</td><td>^{0 N}&lt;x /</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>(</td><td>, ch₃</td><td></td><td></td><td></td><td></td>

<td>h₃X</td><td>77 '' 7 ⁰7</td><td>/ \ /^CH3 x7 ^ | 7 ch₃</td><td>65</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl phenyl) amino] methyl} pyridine-4-carboxylate ethyl</td><td>Procedure general B</td><td>¹1 H NMR (300 MHz, CDCl 3): δ 8.7 (d, 1H), 7.9 (s, 1H), 7.8 (d, 1H), 4.4 (q, 2H), 4.0 ( s, 2H), 3.5-3.3 (m, 4H), 3.2 (m, 2H), 2.5 (m, 4H), 2.3 (s, 6H), 1.3 (t , 3H), 1.1 (t, 3H).</td>

<td>αχ ο _fl, ° °¹</td><td>66</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl phenyl) amino] methyl} pyridine-4-carboxylate 5- (trifluoroacetamido) pent-1-en-3-yl</td><td>G</td><td>'Ή NMR (300 MHz, CD₃OD): δ 8.84 (d, 1H), 8.02 (s, 1H), 7.96 (d, 1H), 6.045,93 (m, 1H), 5.38 (d, 1H), 5.29 (d, 1H), 2, 98 (s, 6H), 1.25 (t, 3H).</td>

<td>CH, 0 CH_{3 F}^ ch₃ ^ ch₂</td><td>67</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate (2,2,2-trifluoro-N-methylacetamido) pent-1ene-3 yl</td><td>G</td><td>¹H NMR (300 MHz, CD3OD): δ 8.85 (d, 1 H), 8.02 (s, 1H), 7.96 (d, 1H), 6.055,93 (m, 1H), 5.39 (d, 1H), 5.29 (d, 1H), 3, 40 (m, 3H), 1.25 (t, 3H).</td>

<td>Below</td><td>68</td><td>2- (2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl hexadecanoate phenyl) amino] methyl} pyridine-4-carbonyloxy) -3- (heksadekanoyloksy) propyl</td><td>G</td><td>"Ή NMR (300 MHz, CD3OD): δ 8.85 (d, 1H), 8.05 (s, 1H), 7.90 (d, 1 H), 5.50 (m, 1H), 4.50 (s, 2H), 3.80 (m, 2H), 2.98 (s, 6H), 1.30 (m, 57h), 0.90 (m, 6H)</td>

<td colspan="5">H₃C "Ί ^ ΥνΥΊ) ch₃ about^ABOUT^^^^S\_INX '' xx^Stewards\ X^Stewardsx *^z&gt;xx^,withXx ^^{, ZX}xx^ZXx. ^^ ^ss|^/WITH\WITH^/\WITH^/\WITH^with\WITH^with\ /^/\ /^/\ /</td>

<td>.at Ί₃ΖΖη₃ch₃</td><td>Until 0 X P ° γ 'Λ</td><td colspan="2">xh₃</td><td>69</td><td>1- (2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) -3 (hexadecanoyloxy) propan-2-yl hexadecanoate</td><td>G</td><td>¹H NMR (300 MHz, CD3OD): δ 8.80 (d, 1H), 8.05 (s, 1H), 7.90 (d, 1H), 4.50 (s, 2H), 4.40 (m, 2H), 4.20 (s , 3H), 3.00 (s, 6H), 1.201,50 (m, 73H).</td>

<td>CH. 1 h₃C</td><td>/.«AA ^ ch₃</td><td>ZZ</td><td>f^xch₃</td><td>70</td><td>Methyl 2 - {[({[(dimethylamino) ethyl] (ethyl) carbamoyl) methyl) amino] methyl} pyridine-4-carboxylate</td><td>G</td><td>¹H NMR (300 MHz, CD3OD): δ 8.80 (d, 1H), 8.10 (s, 1H), 8.00 (d, 1H), 4.70 (s, 2H), 4.40 (s, 2H), 4.00 (s , 3H), 3.00 (s, 6H), 1.25 (t, 3H).</td>

<td>?^H3^C</td><td>^ Λ / χζ /in,</td><td>at H₃lysine-</td><td>6 // Y // Zj about ³</td><td>71</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -Nmetanosulfonylo-N-methylpyridine-4-carboxamide</td><td>G</td><td>¹1 H NMR (300 MHz, D2O) δ 8.71 (d, 1 H), 7.61 (s, 1H), 7.58 (m, 1H), 4.48 (s, 2H), 4.20 (s, 2H), 3.70 (t, 2H), 3.41 (s, 3H), 3.30-3.24 (m, 4H), 3 , 20 (s, 3H), 2.86 (s, 6H), 1.10 (t, 3H).</td>

<td>CH₃ 0 lo F 'Y?</td><td>72</td><td>N- [2- (dimethylamino) ethyl] -N-ethyl-2- ({[4- (2-oxo-1,3-oxazolidine-3-carbonyl) pyridin-2-yl] methyl} amino) acetamide</td><td>G</td><td>¹1 H NMR (300 MHz, D2O) δ 8.66 (d, 1H), 7.58-7.46 (m, 2H), 4.46 (s, 2H), 4.19 (s, 2H), 3.79 (t, 2H), 3.73-3.67 (m, 2H), 3.31-3.25 (m, 2H), 3.17 -3.11 (m, 2H), 3.03-2.94 (m, 2H), 2.86 (s, 6H), 1.12-1.07 (m, 3H).</td>

<td>H₃c ch₃CH, 0 N + Y 1 Y¹ II Η || 0 1 /^N\ Λ / Υ YYyYy⁵ v ° HaC ^ γ ^ NH • Y F</td><td>73</td><td>3- (2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] m ethyl} pyridine-4-carbonyloxy) -4- (trifluoroacetamido) butyrate propan-2-yl</td><td>G</td><td>¹1 H NMR (300 MHz, CD 3 OD): δ 8.83 (d, 1H), 7.96 (s, 1H), 7.90 (d, 1H), 5.65 (m, 1H), 4.56 ( s, 2H), 4.26 (s, 2H), 3.00 (s, 6H), 1.301.16 (m, 9H).</td>

<td>CH₃ 0 _FL o L .oo o ^ ch₃^CH3</td><td>74</td><td>3- (2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) -5 (trifluoroacetamido) propan-2-yl} pentanoate</td><td>G</td><td>¹H NMR (300 MHz, CD3OD): δ 8.83 (m, 1H), 7.99 (s, 1H), 7.93 (d, 1H), 4.95 (m, 1H), 4.56 (d, 2H), 4.38 (d); , 2H), 4.27 (s, 2H), 3.803.69 (m, 4H), 3.00 (s, 6H), 1.401.36 (m, 9H).</td>

<td>ch₃ He ^ Y ._cxy "X / xAYy \ Y ^T V</td><td>75</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (pyridin-4-yl) pyridine-4-carboxamide</td><td>G</td><td>¹H NMR (300 MHz, CD3OD): δ 8.73 (d, 2H), 8.44 (d, 2H), 8.02 (d, 2H), 6.85 (d, 1H), 4.62 (s, 2H), 4.30 (s , 2H), 3.83 (t, 2H), 3.33-3.31 (m, 4H), 2.99 (s, 6H), 1.26 (t, 3H).</td>

<td>7 1 ch₃</td><td>|_Xch₃- • γ-m 0</td><td>0 Χ^ί&gt;Ίτ</td><td>ιινοΗ, H</td><td>76</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (5-metylo1,3,4-oxadiazol-2-yl) pyridine-4-carboxamide</td><td>G</td><td>¹H NMR (300 MHz, CD₃OD): δ 8.84 (d, 1H), 7.99 (s, 1 H), 7.94 (d, 1H), 4.58 (s, 2H), 4.28 (s, 2H), 3.84-3.79 (m, 2H), 3.43-3.36 (m, 2H), 3.32 -3.28 (m, 2H), 2.98 (s, 6H), 2.52 (s, 3H), 1.27-1.22 (m, 3H).</td>

<td>^h3^c\ 1 ch₃</td><td>^ CH₃- · γ- = ' ABOUT</td><td>Ί0</td><td>JO ην ^ '- ν⁷L. CH₃</td><td>77</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (1-methyl-1H-pyrazol-5-yl) pyridine-4-carboxamide</td><td>G</td><td>¹H NMR (300 MHz, CD₃OD): δ 8.84 (d, 1H), 7.96 (s, 1H), 7.91 (d, 1H), 7.56 (d, 1H), 6.40 (d, 1H), 4.59 (s , 2H), 4.28 (s, 2H), 3.843.80 (m, 2H), 3.41-3.35 (m, 4H), 3.82 (s, 3H), 2.98 (s, 6H), 1.261.21 (m, 3H).</td>

<td></td><td>"7</td><td></td><td></td><td></td><td></td><td></td><td>¹H NMR (300 MHz, CD3OD): δ</td>

<td></td><td>(</td><td>Ί 0</td><td></td><td>78</td><td>2- (piperidin-1-ylmethyl) pyridine-4-carboxylic acid</td><td>AND</td><td>8.50 (d, 1H), 7.40 (s, 1H), 7.65 (d, 1H), 3.65 (s, 2H), 2.50 (m, 4H), 1.60 (m , 4H), 1.40 (m, 2H)</td>

<td>ΗΟ ο c Ν ABOUT</td><td>79</td><td>2- (azetidin-1-ylmethyl) pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD): δ 8.25 (d, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 3.50 (s, 2H), 3.10 ( m, 4H), 1.90 (m, 2H) ppm.</td>

<td>CH O '' A _F, .UajJXa '</td><td>80</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,2,2-trifluoroethyl</td><td>G</td><td>¹H NMR (300 MHz, DMSO-d ₆) δ 8.89 (d, 1 H), 8.04 (s, 1H), 7.91 (d, 1H), 5.09 (q, 2H), 4.49 (s, 2H), 4.16 (s, 2H), 3.68 (t, 2H), 3.27 (q, 2H), 2, 85 (s, 6H), 1.13 (t, 3H).</td>

<td>O and ν'γΝ, / γγΑ ° cc</td><td>81</td><td>2 - ({ethyl [2-oxo-2- (piperidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid</td><td>AND</td><td>¹H NMR (300 MHz, CD3OD) δ 8.48 (d, 1H), 7.94 (s, 1H), 7.70 (d, 1H), 3.80 (s, 2H), 3.47 (m, 4H), 3.36 (s, 2H) , 2.63 (q, 2H), 1.54 (m, 6H), 1.10 (t, 3H).</td>

<td>Γ³ Γ</td><td></td><td></td><td></td><td></td><td></td>

<td>ι ° Χ</td><td></td><td></td><td></td><td></td><td>¹H NMR (300 MHz, CD3OD) δ 8.50</td>

<td></td><td></td><td></td><td>2 - ({butyl [2-oxo-2- (piperidin-1-yl) acid</td><td></td><td>(d, 1 H), 7.94 (s, 1 H), 7.71 (d, 1H),</td>

<td></td><td></td><td>82</td><td>yl) ethyl] amino} methyl) pyridin-4-</td><td>AND</td><td>3.80 (s, 2H), 3.46 (m, 4 H), 3.35 (s,</td>

<td></td><td></td><td></td><td>carboxylic acid</td><td></td><td>2H), 2.54 (m, 2H), 1.51 (m, 8H),</td>

<td>γ</td><td></td><td></td><td></td><td></td><td>1.28 (m, 2H), 0.88 (t, 3H).</td>

<td>Ο'Χ ^ 'ΟΗ</td><td></td><td></td><td></td><td></td><td></td>

<td>^Η0 °</td><td></td><td></td><td></td><td></td><td></td>

<td>Λ</td><td></td><td></td><td></td><td></td><td>¹H NMR (300 MHz, CD3OD) δ 8.49</td>

<td></td><td>X</td><td></td><td>2 - ({benzyl [2-oxo-2- (piperidine) acid</td><td></td><td>(d, 1 H), 8.05 (s, 1 H), 7.72 (d, 1H),</td>

<td>1 ίί /^νΧ</td><td>J</td><td>83</td><td>1-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid</td><td>AND</td><td>7.48-7.08 (m, 5H), 3.85 (s, 2 H), 3.71 (s, 2 H), 3.43 (m, 2 H), 3.31 (m,</td>

<td>υ</td><td></td><td></td><td></td><td></td><td>4H), 1.73-1.33 (m, 6H).</td>

<td>JO A HN θ HoC / O Ai ^X .^{/ X}A Ar k 'and U ^H and^CH3 ° ^N AND⁴</td><td>84</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (1,3-oxazol-2-yl) pyridine-4-carboxamide</td><td>G</td><td>¹H NMR (300 MHz, CD3OD): δ 8.76 (d, 1H), 7.94 (s, 1 H), 7.89 (d, 1H), 7.65 (s, 1H), 7.50 (s, 1H), 4.51 (s, 2H), 4.21 (s, 2H), 3.77-3.73 (m, 2H). ), 3.37-3. 23 (m, 4H), 2.92 (s, 6H), 1.21-1.16 (m, 3H).</td>

<td>Γ CH₃ o τΑ okkcH₃_klc-AA ^ &lt;/ ^ x_INx_xk_CH, ° οΆ 1 HGC ^^ CHG</td><td>85</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,6-bis (propan-2-yloxy) phenyl</td><td>G</td><td>¹1 H NMR (300 MHz, CD 3 OD): δ 8.94 (m, 1H), 8.16 (s, 1H), 8.11 (d, 1H), 7.18 (t, 1H), 6.75 ( d, 2H), 4.60 (m, 2H), 4.30 (s, 2H), 3.00 (s, 6H), 1.30- 1.00 (m, 15H).</td>

<td>X j- N^WITH ABOUT h₃c- / \ CH, N - &lt; ABOUT</td><td>86</td><td>2 - {[(2-methylpropyl) [2-oxo-2 (piperidin-1-yl) ethyl] amino] methyl} pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD) δ 8.48 (d, 1H), 7.99 (s, 1H), 7.71 (d, 1H), 3.79 (s, 2H), 3.55-3 37 (m, 4 H), 3.32 (s, 2H), 2.34 (d, 2H), 1.82 (m, 1H), 1.56 (m, 6H), 0.88 (d, 6H).</td>

<td>ΫΛ&gt; Ο ΟΗ</td><td>87</td><td>2 - ({[2-oxo-2- (piperidin-1-yl) ethyl] (propyl) amino} methyl) pyridine o-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD) δ 8.48 (d, 1H), 7.97 (s, 1H), 7.71 (d, 1H), 3.80 (s, 2H), 3.47 (m) , 4H), 3.35 (s, 2H), 2.69-2.26 (m, 2H), 1.75-1.45 (m, 8H), 0.87 (t, 3H).</td>

<td>Ο ι Υ- ^ υυΑ ° "₃Ah₃M</td><td>88</td><td>2 - ({[2-oxo-2- (piperidin-1-yl) ethyl] (propan-2-yl) amino} methyl) pyridine-4-carboxylic acid</td><td>AND</td><td>¹H NMR (300 MHz, CD3OD) δ 8.45 (d, 1 H), 8.00 (s, 1H), 7.69 (d, 1H), 3.76 (s, 2H), 3.45-3.37 (m, 4H), 3.34 (s, 2H), 3.12- 2.93 (m, 1H), 1.73-1, 36 (m, 6H), 1.13 (d, 6H).</td>

<td>J3 Υ ³ ΗΝ ^ γ^CH= ch₃ ο</td><td>89</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (1-methyl-1H-imidazol-2-yl) pyridine-4-carboxamide</td><td>G</td><td>¹H NMR (300 MHz, CD3OD): δ 8.82 (s, 1 H), 7.93 (s, 1 H), 7.34 (s, 1H), 7.29 (s, 1H), 6.76 (s, 1H), 3.82-3 , 73 (m, 4H), 3.46-3.43 (m, 2H), 3.38-3.30 (m, 4H), 3.26 (s, 3H), 2.93 (s, 6H); ), 1.27-1.12 (m, 3H).</td>

<td>Γ χ _FΎ ΥΥ Ζγ ΥΥ ΥΥ Υυ ΥΥ ΥΥ Υ Ζ_ΝΥ ΥΥ ΥΥ Υ_ΝΥ Υγ γ Ύ ΖΥ 1 Η ^Η 1 Τ^CH3 ° ^Νγγ</td><td>90</td><td>2-Fluoroethyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate</td><td>G</td><td>¹H NMR (300 MHz, CDCl3): δ 8.72 (dd, 1 H), 7.96 (d, 1H), 7.73 (td, 1H), 4.45 (td, 1H), 4.04- 4. 03 (m, 2H), 3.95 ( s, 2H), 3.52-3.49 (m, 4H), 3.52-3.49 (m, 4H), 3.47-3.38 (m, 2H), 2.52-2, 39 (m, 3H), 2.30 (s, 6H), 1.17-1.11 (m, 3H).</td>

<td>&gt;^Η3 r rr \ χ γ &lt;cr ι II ^Η ϊ 1^CH3 ⁰ Ν ^ U ^F</td><td>91</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,2-difluoroethyl</td><td>G</td><td>'Ή NMR (300 MHz, CDCl₃): δ 8.72 (d, 1 H), 7.98 (s, 1 H), 7.76 (dd, 1H), 6.09 (m, 1H), 4.82 (m, 1H), 4.684.63 (m, 2H), 4.55 (m, 1H), 4.04 (s, 2H), 3.50 (s , 2H), 3.49-3.38 (m, 2H), 3.31-3.24 (m, 2H), 2.29 (s, 6H), 1.18-1.11 (m, 3H); ).</td>

<td>HoC Ν-, Α ΑΑ h₃c \ ...... \ -ς ΗΝ-Λ \ ΟΗ^H'^CA Ν &lt;/ h₃/ ^^CH3</td><td>92</td><td>2 - ({[(1S) -1- (tert-butylcarbamoyl) -3-methylbutyl] amino} methyl) pyridine-4-carboxylic acid</td><td>b</td><td>¹1 H NMR (300 MHz, CD 3 OD) δ 8.51 (d, 1H), 7.87 (s, 1H), 7.71 (d, 1H), 3.84 (d, 2H), 3.31 (s , 1 H), 3.11 (dd, 1H), 1.82-1.64 (m, 1H), 1.53-1.40 (m, 2H), 1.32 (s, 9H), 0, 90 (dd, 6H).</td>

<td>ΑΟ H, C ( \ / \ CHd, C&gt; - Ν Ρ ΟΗ</td><td>93</td><td>2 - ({methyl [(2S) -4-methyl-1-oxo-1- (piperidin-1-yl) pentan-2-yl] amino} methyl) pyridine-4-carboxylic acid</td><td>AND</td><td>¹1 H NMR (300 MHz, CD 3 OD) δ 8.46 (d, 1H), 7.96 (s, 1H), 7.70 (d, 1H), 3.98-3.65 (m, 3H), 3 57 (m, 3 H), 2.81 (s, 1H), 2.28 (s, 3H), 1.951.79 (m, 1H), 1.76-1.41 (m, 6H), 0, 93 (dd, 6H).</td>

An exemplary preparation of the compounds of Table 1 is as follows.

2 - ({[2- (dimethylamino) ethyl] amino} methyl) pyridine-4-carboxylic acid (# 2) [0166]

<img file="PL2903968T3_D0020.tif" />

<img file="PL2903968T3_D0021.tif" />

General Procedure A (Ester hydrolysis) [0167] Ethyl ester (2 - ({[2- (dimethylamino) ethyl] amino} methyl) pyridine-4-carboxylate (a)) was dissolved in MeOH-THF-H 2 O (1: 1: 1) and LiOH (1.0 eq.) Was added. The reaction mixture was stirred at room temperature and monitored by TLC. The solvents were removed under reduced pressure. Worked up by dissolving in water and extracting with Et2O. The basic aqueous layer was acidified with 1N HCl to pH 1, and the solution was concentrated to dryness, yielding the hydrochloride salt of the title compound as a colorless solid.

¹H NMR (300 MHz, Methanol-d4), δ ppm: 8.82 (dd, 1H), 8.03 (s, 1H), 7.94 (dd, 1H), 4.58 (s, 2H), 3.63 (m, 4 H) 3.0 (s, 6H).

ES-MS: 224 [M + 1].

2 - ({[2-oxo-2- (pyrrolidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid (No. 13)

<img file="PL2903968T3_D0022.tif" />

[0168]

<img file="PL2903968T3_D0023.tif" />

[0169] Prepared according to General Procedure A of ethyl 2 - ({2,2,2-trifluoro-N- [2-oxo-2- (pyrrolidin-1-yl) ethyl] acetamido} methyl) pyridine-4-carboxylate (e) . Worked-up by grinding a solid residue in Et2O to give the hydrochloride salt of the title compound as a white powder.

¹ H-NMR (300 MHz, MeOH-d4): δ 8.4 (d, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 3.7 (s, 2H), 4 , O (2H), 3.4 (m, 6H), 1.5 (m, 4H).

2 - {[(3 - {[3- (pyrrolidin-1-yl) propyl] amino} propyl) amino] methyl} pyridine-4-carboxylic acid (No. 21) [0170]

<img file="PL2903968T3_D0024.tif" />

<img file="PL2903968T3_D0025.tif" />

[0171] Prepared according to General Procedure A of 2 - {[2,2,2-trifluoro-N- (3 - {[3- (pyrrolidin-1-yl) propyl] amino} propyl) acetamido] methyl} pyridine-4-carboxylate ethyl (j). After work up, the hydrochloride salt of the title compound was obtained as a white, sticky solid.

¹1 H NMR (300 MHz, D 2 O): δ 8.72 (d, 1H), 7.96 (s, 1H), 7.90 (d, 1H), 4.48 (s, 2H), 3.60 (1H); m, 4H), 2.92-3.25 (m, 8H), 1.84-2.25 (m, 8H).

ES-MS: 321.40 [M + H].

2 - ({[(3R) -1- (3-phenylpropyl) pyrrolidin-3-yl] amino} methyl) pyridine-4-carboxylic acid (No. 28) [0172]

<img file="PL2903968T3_D0026.tif" />

[0173] Prepared according to General Procedure A from ethyl 2 - ({2,2,2-trifluoro-N - [(3R) -1- (3-phenylpropyl) pyrrolidin-3-yl] acetamido} methyl) pyridine-4-carboxylate ( n). Is isolated as the lithium salt after treatment by dissolving the residue in a minimum amount of water and extraction with DCM. The aqueous phase was evaporated to dryness to give the title compound as a white solid.¹H-NMR (300 MHz, CDCl 3): δ 8.50 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.20 (m, 5H), 3.85 (s, 2H), 3.1-2.4 (m, 8H), 2.25 (m, 1H), 2.20 (m, 1H), 1.90-1.55 (m, 3H).

ES-MS: 340 [M + 1].

2 - ({[({1- [(2-methoxyphenyl) methyl] piperidin-4-yl} carbamoyl) methyl] amino} methyl) pyridine-4-carboxylic acid (# 29) [0174]

<img file="PL2903968T3_D0027.tif" />

<img file="PL2903968T3_D0028.tif" />

[0175] Prepared according to General Procedure A of 2 - ({2,2,2-trifluoro-N - [({1 - [(2-methoxyphenyl) methyl] piperidin-4-yl} carbamoyl) methyl] acetamido} methyl) pyridine Ethyl 4-carboxylate (q) using 2 equivalents of LiOH. Is isolated as the lithium salt after treatment by dissolving the residue in a minimum amount of water and extraction with DCM. The aqueous phase was evaporated to dryness to give the title compound as a white solid.

¹1 H NMR (300 MHz, CD 3 OD): δ 8.54 (d, 1H), 7.82 (s, 1H), 7.65 (d, 1H), 7.26 (m, 2H), 6.94 (diast. m, 2H), 3.90 (s, 2H), 3.85 (s, 3H), 3.72 (m, 3H), 3.62 (s, 2H), 3.24 (s, 2H), 2.94 (m, 2H), 2.24 (m, 2H), 1.90 (m, 3H), 1.60 (m, 2H).

ES-MS: 411 [MH].

2 - ({[({4 [benzyl (cyclopropyl) amino] butyl} (methyl) carbamoyl) methyl] amino} methyl) pyridine-4-carboxylic acid (# 44)

<img file="PL2903968T3_D0029.tif" />

[0176]

Road Synthesis F

<img file="PL2903968T3_D0030.tif" />

about

General Procedure B Procedure General B Procedure General A (s) -► (t) -► (u) -► Title Compound [0177] Obtained according to General Procedure A from 2 - ({N - [({4-benzyl (cyclopropyl) amino] Butyl} (methyl) carbamoyl) methyl] -2,2,2-trifluoroacetamido} methyl) pyridine-4-carboxylate (u) using 2.5 equivalents of LiOH. Is isolated as the lithium salt after treatment by dissolving the residue in a minimum amount of water and extraction with DCM. The aqueous phase was evaporated to dryness to give the title compound as a white solid.

¹1 H NMR (300 MHz, CDCl 3): δ 8.50 (d, 1H), 7.80 (s, 1H), 7.70 (d, 1H), 7.25 (m, 5H), 3.90 (3H); s, 2H), 3.70 s, 2H), 3.50-3.40 (m, 3H), 2.25 (m, 1H), 2.95 (s, 3H), 2.55 (m, 2H), 1.75 (m, 1H), 1.50 (m, 4H), 0.50 (m, 2H), 0.40 (m, 2H).

ES-MS: 425 [M + 1].

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (pyridin-4-yl) pyridine-4-carboxamide (# 75) [0178]

<img file="PL2903968T3_D0031.tif" />

[0179] Obtained according to General Procedure D from N - ({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) N - ({4 - [(pyridin-4-yl) carbamoyl] pyridin-2-yl} methyl tert-butyl carbamate (y) to give the title compound as a yellow oil.

¹1 H NMR (300 MHz, CD 3 OD): δ 8.73 (d, 2H), 8.44 (d, 2H), 8.02 (d, 2H), 6.85 (d, 1H), 4.62 ( s, 2H), 4.30 (s, 2H), 3.83 (t, 2H), 3.33-3.31 (m, 4H), 2.99 (s, 6H), 1.26 (t , 3H).

ES-MS: 486 [M + 1]

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 4-oxopentan-2-yl (62) [0180]

<img file="PL2903968T3_D0032.tif" />

<img file="PL2903968T3_D0033.tif" />

[0181] Prepared according to General Procedure D from 4 - oxopentane - ({[(tert-butoxy) carbonyl] ({[(dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino} methyl) pyridine-4-carboxylate. 2-yl (aa) to give the title compound as a colorless oil.

¹1 H NMR (300 MHz, CD 3 OD): δ 8.75 (d, 1H), 7.90-8.10 (m, 2H), 5.50 (m, 1H), 4.50 (s, 2H), 4.25 (s, 2H), 3.75 (m, 2H), 1.20-1.50 (m, 6H).

ES-MS: 393 [M + 1] 2 - ({ethyl-N- [2-oxo-2- (piperidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid (# 81)

<img file="PL2903968T3_D0034.tif" />

[0182]

<img file="PL2903968T3_D0035.tif" />

ethyl) ethyl] amino} methyl) pyridine-4-carboxylate to give the title compound as a yellow solid.

¹1 H NMR (300 MHz, CD 3 OD) δ 8.48 (d, 1H), 7.94 (s, 1H), 7.70 (d, 1H), 3.80 (s, 2H), 3.47 (m) , 4H), 3.36 (s, 2H), 2.63 (q, 2H), 1.54 (m, 6H), 1.10 (t, 3H).

ES-MS: 306 [M + 1]

Intermediate compounds

Ethyl 2 - ({[2- (dimethylamino) ethyl] amino} methyl) pyridine-4-carboxylate (a)

General Procedure B (Reductive Amination) [0184] To a mixture of ethyl (2-formylpyridine-4-carboxylate) (1.0 eq) and amine (N1, N1-dimethylethane-1,2-diamine) (1.0 eq.) in 1,2-dichloroethane, AcOH (1.0 eq.) was added followed by NaBH (OAc) 3 (2.5 eq.) and the mixture was stirred at room temperature overnight. Work-up with water (ethyl acetate / NaHCO 3) and purification by column chromatography (CH 2 Cl 2 / MeOH / NH 4 OH 90: 10: 1) gave the title compound as a colorless glue.¹H NMR (300 MHz, Methanol-d4): δ 8.68 (dd, 1H), 7.87 (s, 1H), 7.67 (dd, 1H), 4.34 (q, 2H), 3, 87 (s, 2H), 2.58 (t, 2H), 2.33 (t, 2H), 2.11 (s, 6H), 1.32 (t, 3H).

Ethyl 2 - ({[2- (tert-butoxy) -2-oxoethyl] amino} methyl) pyridine-4-carboxylate (b) [0185] Prepared according to General Procedure B from ethyl 2-formylpyridine-4-carboxylate and 2-aminoacetate tert butyl. The title compound was isolated as a yellow oil by column chromatography (EtOAc / hexane).

¹1 H NMR (300 MHz, MeOH-d 4): δ 8.7 (d, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 4.4 (s, 2H), 4, 3 (Q2), 3.8 (s, 2H), 3.3 (s, 2H), 1.4 (s, (H), 1.3 (t, 3H).

ES-MS: 295 [M + 1].

Ethyl 2 - {[(3-hydroxypropyl) amino] methyl} pyridine-4-carboxylate (f) [0186] Prepared according to General Procedure B from ethyl 2-formylpyridine-4-carboxylate and 3-aminopropane-1-ol.

¹1 H NMR (300 MHz, CDCl 3), 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).

Ethyl 2 - ({[(3R) -1 - [(tert -butoxy) carbonyl] pyrrolidin-3-yl] amino} methyl) pyridine-4-carboxylate (k) [0187] Prepared according to General Procedure B from 2-formylpyridine Ethyl-4-carboxylate and tert-butyl (3R) -3-aminopyrrolidine-1-carboxylate. Column chromatography (MeOH / DCM) gave the title compound as a greenish oil.

¹1 H NMR (300 MHz, CDCl 3): δ 8.70 (d, 1H), 7.86 (s, 1H), 7.74 (d, 1H), 4.50 (q, 2H), 4.00 ( s, 2H), 3.60-3.33 (m 4H), 3.25 (m, 1H), 2.09 (m, 1H), 1.90-1.72 (m, 2H), 1, 46 (s, 9H), 1.41 (t, 3H).

ES-MS: 350 [M + 1]

Ethyl 2 - {[2,2,2-trifluoro-N- (3 - {[3- (pyrrolidin-1-yl) propyl] amino} propyl) acetamido] methyl} pyridine-4-carboxylate (j) [0188] Prepared according to General Procedure B from ethyl 2 - {[2,2,2-trifluoro-N- (3-oxopropyl) acetamido] methyl} pyridine-4-carboxylate (i) and 3- (pyrrolidin-1-yl) propan-1-amine. Column chromatography (MeOH / DCM) gave the title compound.

¹1 H NMR (300 MHz, CD 3 OD): δ 8.66 (dd, 1H), 7.95 (s, 1H), 7.78 (dd, 1H), 4.42 (q, 2H), 3.98 ( s, 2H), 3.56 (m, 4H), 2.42-2.75 (m, 8H), 1.86 (m, 8H), 1.40 (t, 3H).

Ethyl 2 - {[N - ({[4- (cyclopropylamino) butyl] (methyl) carbamoyl} methyl) -2,2,2-trifluoroacetamido] methyl} pyridine-4-carboxylate (t) [0189] Obtained according to General Procedure B of 2 - [(2,2-Trifluoro-N - {[methyl (4-oxobutyl) carbamoyl] methyl} acetamido) methyl] pyridine-4-carboxylate (s) and cyclopropylamine. Column chromatography (EtOAc / hexanes) gave the title compound as a yellow oil.

¹1 H NMR (300 MHz, CDCl 3): δ 8.70 (dd, 1H), 7.85 (ss, 1H), 7.74 (dd, 1H), 4.95 (dd, 2H), 4.40 (d: 1H). q, 2H), 4.32 (ss, 2H), 3.31 (m, 1H), 3.25 (m, 1H), 2.90 (s, 3H), 2.73 (m, 1H), 2.50 (m, 1 H), 2.01 (m, 1H), 1.85-1.30 (m, 8H), 0.53-0.34 (m, 4H).

ES-MS: 459 [M + 1]

2 - ({2,2,2-Trifluoro-N - [(3R) -1- (3-phenylpropyl) pyrrolidin-3-yl] acetamido} methyl) pyridine-4-carboxylate (n) [0190] Obtained according to the General Procedure B from 3-phenylpropanal and ethyl 2 - ({2,2,2-trifluoro-N - [(3R) -pyrrolidin-3-yl] acetamido} methyl) pyridine-4-carboxylate (m).

¹1 H NMR (300 MHz, CDCl 3): δ 8.70 (d, 1H), 7.80 (s, 1H), 7.72 (dd, 1H), 7.24 (m, 5H), 4.95 (diast. q, 2H), 4.37 (m, 2H), 3.78 (m, 1H), 2.60 (m, 3H), 2.46 (m, 2H), 2.32 (m, 2H), 2.21 (m, 1H), 2.04 (m, 2H), 1.88 (m, 1 H), 1.73 (m, 1H), 1.43 (t, 3H).

Ethyl 2 - ({2,2,2-trifluoro-N - [({1- {1 - [(2-methoxyphenyl) methyl] piperidin-4-yl} carbamoyl) methyl] acetamido} methyl) pyridine-4-carboxylate (q) ] Obtained according to General Procedure B from 2-methoxybenzaldehyde and ethyl 2 - [(2,2,2-trifluoro-N {[(piperidin-4-yl) carbamoyl] methyl} acetamido) methyl] pyridine-4-carboxylate (p) .

¹1 H NMR (300 MHz, CDCl 3): δ 8.75 and 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 and 4.72 (2s, 2H, rotamer), 4.45 (q, 2H), 4.30 and 4.08 (2s, 2H, rotamer), 3.83 (m, 4 H), 3.60 (m, 2 H), 2.95 (m, 2 H), 2.22 (m, 2 H), 1.90 (m, 2H), 1.60 (m, 2H), 1.40 (t, 3H).

2 - ({N - [({4- [benzyl (cyclopropyl) amino] butyl} (methyl) carbamoyl) methyl] -2,2,2-trifluoroacetamido} methyl) pyridine-4-carboxylate (u) [0192] Obtained according to General Procedure B of benzaldehyde and ethyl 2 - {[N - ({[4 (cyclopropylamino) butyl] (methyl) carbamoyl} methyl) -2,2,2-trifluoroacetamido] methyl} pyridine-4-carboxylate (t).

¹1 H NMR (300 MHz, CD 3 OD): δ 8.70 (m, 1 H), 7.83 (m, 1 H), 7.77 (m, 1 H), 7.30 (m, 5 H), 4.83 ( dd, 2H), 4.40 (m, 3H), 4.23 (m, 1H), 3.65 (m, 1 H), 3.31 (m, 1H), 3.19 (m, 1H), 3.01 (m, 1H), 2.91 (m, 3H), 2.49 (m, 2H), 1.70 (m, 1H), 1.40 (m, 7H), 0.50 (m). , 2H), 0.45 (m, 2H).

Ethyl 2 - ({[2-oxo-2- (piperidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylate (ac) [0193] Prepared according to General Procedure B from 2 - ({ethyl [2- ethyl oxo-2- (piperidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylate and acetaldehyde to give the title compound as a yellow oil.

¹1 H NMR (300 MHz, CDCl 3) δ 8.67 (m, 1H), 8.04 (m, 1H), 7.71 (m, 1H), 4.40 (q, 2H), 3.89 (s , 2H), 3.46 (m, 4H), 2.68 (q, 2H), 1.77-1.33 (m, 6H), 1.40 (t, 3H), 1.08 (t, 3H).

Ethyl 2 - ({ethyl [2-oxo-2- (piperidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylate (ab) [0194] ¹1 H NMR (300 MHz, CDCl 3) δ 8.68 (d, 1H), 7.93 (s, 1H), 7.71 (d, 1H), 4.40 (q, 2H), 4.02 (s , 2H), 3.56 (t, 2H), 3.47 (s, 2H), 3.28 (t, 2H), 1.58 (m, 6H), 1.40 (t, 3H).

Ethyl 2 - ({N- [2- (tert-butoxy) -2-oxoethyl} -2,2,2-trifluoroacetamido} methyl) pyridine-4-carboxylate (c)

General Procedure C (Formation of triflouroacetamide and / or trifluoroacetate) DIPEA (1.5 eq) was added to the amine (or alcohol) solution (2 - ({[2- (tert-butoxy) -2oxoethyl] amino} methyl) pyridine Ethyl-4-carboxylate (b)) in anhydrous DCM. The mixture was stirred at 0 ° C and trifluoroacetic anhydride (1.5 eq.) Was added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and stirring was continued for 2 h. The reaction was quenched with aqueous NaHCO 3 solution. After treatment with water, the title compound was obtained.

¹H NMR (300 MHz, CDCl3) (rotamers): δ 8.7 (dd, 1H), 7.8 (ss, 1H), 7.7 (dd, 1H), 4.8 (ss, 2H), 4 , 3 (q, 2) 4.2 (ss, 2H), 1.4 (s, 9H), 1.3 (t, 3H).

Ethyl 2 - [(2,2,2-trifluoro-N- {3 - [(trifluoroacetyl) oxy] propyl} acetamido) methyl] pyridine-4-carboxylate (g) [0196] Prepared according to General Procedure C from 2- { [(3-Hydroxypropyl) amino] methyl} pyridine-4-carboxylate (f), using 7 equivalents of DIPEA and 5 equivalents of trifluoroacetic anhydride.

¹H NMR (300 MHz, CDCl3) (rotamers) δ: 8.75 (two doublets, 1H), 7.80 (m, 2H), 4.80 (two singlets, 2H), 4.40 (m, 4H) , 3.70 (two t, 2H), 2.20 (m, 2H), 1.45 (m, 3H).

Ethyl 2 - ({N - [(3R) -1 - [(tert-butoxy) carbonyl] pyrrolidin-3-yl] -2,2,2-trifluoroacetamido} methyl) pyridine-4-carboxylate (1) [0197] Prepared according to General Procedure C of ethyl 2 - ({[(3R) -1 - [(tert-butoxy) carbonyl] pyrrolidin-3-yl] amino} methyl) pyridine-4-carboxylate (k). The reaction time is 12 hours. The title compound was isolated as a yellow oil.

¹H NMR (300 MHz, CDCl3): δ 8.70 (d, 1H), 7.76 (m, 2H), 4.74- 4.71 (m, 3H), 4.43 (q, 2H), 3.69-3.27 (m, 4H), 2.19-2.01 (m, 2H), 1.46 (s, 9H), 1.44 (t, 3H).

ES-MS: 446 [M + 1].

2- (N - {[4- (ethoxycarbonyl) pyridin-2-yl] methyl} -2,2,2-trifluoroacetamido) acetic acid (d)

General Procedure D (Acids from tert-butyl esters or amines from tert-butoxy carbamates) [0198] Ester (or carbamate), (2 - ({N- [2- (tert-butoxy) -2-oxoethyl] -2, Ethyl 2,2-trifluoroacetamido} methyl) pyridine-4-carboxylate (c)) was dissolved in DCM and trifluoroacetic acid (0.1-1 equivalent by volume of DCM) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound.

¹H NMR (300 MHz, 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 - ({2,2,2-trifluoro-N - [(3R) -pyrrolidin-3-yl] acetamido} methyl) pyridine-4-carboxylate (m) [0199] Prepared according to General Procedure D from 2- ( Ethyl {N - [(3R) -1 - [(tert-butoxy) carbonyl] pyrrolidin-3-yl] 2,2,2-trifluoroacetamido} methyl) pyridine-4-carboxylate (1).

¹1 H NMR (300 MHz, CDCl 3): δ 8.67 (d, 1H), 7.81 (s, 1H), 7.72 (d, 1H), 4.39 (q, 2H), 3.97 ( d, 2H), 3.84-3.64 (m, 3H), 3.51-3.45 (m, 2H), 2.11 (m, 1H), 1.97 (m, 1H), 1 39 (t, 3H).

ES-MS: 446 [M + 1]

2 - [(2,2,2-Trifluoro-N - {[(piperidin-4-yl) carbamoyl] methyl} acetamido) methyl] pyridine-4-carboxylate (p) [0200] Prepared according to General Procedure D from 2- ( Ethyl {N - [({1 - [(tert-butoxy) carbonyl] piperidin-4-yl} carbamoyl) methyl] -2,2,2-trifluoroacetamido} methyl) pyridine-4-carboxylate (o). Purification by column chromatography (MeOH / DCM and 1% NH 4 OH) gave the title compound as a brown foam.

¹H NMR (300 MHz, CD3OD): δ 8.75 (m, 1H), 7.90 (m, 2H), 5.00 and 4.90 (2s, 2H, rotamer), 4.42 (q, 2H); ), 4.32 and 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- [2-oxo-2- (pyrrolidin-1-yl) ethyl] acetamido} methyl) pyridine-4-carboxylate (e)

General Procedure E (Formation of Esters, Amides and Sulfonamides) [0201] Amine (pyrrolidine) (or alcohol or sulfonamide) (2 equivalents) was added to the acid solution (2- (N - {[4- (ethoxycarbonyl) pyridin-2-acid) ylo] methyl} -2,2,2-trifluoroacetamido) acetic acid (d)) (1 eq) in DMF. The mixture was cooled to 0 ° C, then EDC HCl (1.5 eq) was added and (ethyl hydroxyimino) cyanoacetate (oxime, 1.5 eq) was added. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. Workup with water and purification by column chromatography gave the title compound.

¹1 H NMR (300 MHz, CD 3 OD): δ 8.75 (m, 1H), 7.90 (s, 1H), 7.85 (m, 1H), 4.90- 4.30 (two sets of singlets iq, 6H, rotamer), 3.45 (m, 4H), 2.00-1.80 (m, 4H), 1.38 (t, 3H).

2 - ({tert -butoxy) carbonyl] piperidin-4-yl} carbamoyl) methyl] -2,2,2-trifluoroacetamido} methyl) pyridine-4-carboxylate (o) [delta] - [({1 - [(tert-butoxy) carbonyl] piperidin-4-yl] ethyl ester [0202] Obtained according to General Procedure E from tert-butyl 4-aminopiperidine-1-carboxylate and acid

2- (N - {[4- (ethoxycarbonyl) pyridin-2-yl] methyl} -2,2,2-trifluoroacetamido) acetic acid (d) to give the title compound as a brown foam.

¹H NMR (300 MHz, CDCl3): δ 8.70 and 8.60 (2d, 1H, rotamer), 7.80 (m, 2H), 4.90 and 4.78 (2s, 2H, rotamer), 4.42 (q, 2H), 4.30 and 4.10 (2 s, 2H, rotamer), 4.10 (m, 1H), 2.80 (m, 2H) 2.0 (m, 2H) , 1.48 (s, 9H), 1.40 (t,

3H).

2 - [(2,2-Trifluoro-N - {[(4-hydroxybutyl) (methyl) carbamoyl] methyl} acetamido) methyl] pyridine-4-carboxylate (r) [0203] Prepared according to General Procedure E of 4 (methylamino) butan-1-ol and 2- (N - {[4 (ethoxycarbonyl) pyridin-2-yl] methyl} 2,2,2-trifluoroacetamido) acetic acid (d).

¹1 H NMR (300 MHz, CDCl 3): δ 8.70 (d, 1H), 7.90 (s 1H), 7.8 (m, 1H), 4.95 (d, 1H), 4.85 (d) , 1H), 4.41 (m, 3H), 4.34 (sH), 3.67 (q, 2H), 3.40 (m, 1H), 3.29 (m, 1H), 2, 97 (s, 3H), 1.74-1.52 (m, 5H), 1.43 (t, 3H).

ES-MS: 420 [M + 1].

2 - ({[(tert-butoxy) carbonyl] ({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino} methyl) pyridine-4-carboxylate

4-Hydroxypentan-2-yl (z) [0204] Prepared according to General Procedure E from 2 - ({[(tert-butoxy) carbonyl] ({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino} methyl) pyridine-4-carboxylic (x) and pentane-2,4-diol. Purification by column chromatography (10-15% MeOH / DCM) gave the title compound as a brown oil.

¹1 H NMR (300 MHz, CDCl 3): δ 8.50 (d, 1H), 7.90 (m, 1H), 7.50 (m, 1H), 5.30 (m, 1H), 4.55 ( m, 2H), 4.20, 4.10 (2s, 2H), 2.25 (2s, 6H), 1.40 (m, 12H), 1.20 (m, 6H).

ES-MS: 495 [M + 1]

Ethyl 2 - {[2,2,2-trifluoro-N- (3-oxopropyl) acetamido] methyl} pyridine-4-carboxylate (i)

General Procedure F (Oxidation of Swine Alcohols to Aldehydes and Ketones) [0205] DMSO (4.0 eq) was diluted with DCM and cooled to -78 ° C, oxalyl chloride (2.0 eq) was added and the mixture was stirred for 30 minutes. Then a solution of the alcohol (ethyl 2 - {[2,2,2-trifluoro-N- (3-hydroxypropyl) acetamido] methyl} pyridine-4-carboxylate (h)) in DCM was added and the mixture was stirred for another 1 h. Et 3 N (5.0 eq.) And the mixture was slowly warmed to room temperature. After treatment with water and column chromatography, the title compound was obtained.

¹H NMR (300 MHz, CDCl3) (rotamers): δ 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).

2 - [(2,2-Trifluoro-N - {[methyl (4-oxobutyl) carbamoyl] methyl} acetamido) methyl] pyridine-4-carboxylate (s) [0206] Obtained according to General Procedure F of 2 - [( Ethyl 2,2,2-trifluoro-N - {[(4-hydroxybutyl) (methyl) carbamoyl] methyl} acetamido) methyl] pyridine-4-carboxylate (r). Purified by column chromatography (EtOAc / hexane).

¹1 H NMR (300 MHz, CDCl 3): δ 9.85 (m, 1H), 8.70 (dd, 1H), 7.9 (ss, 1H), 7.80 (dd, 1H), 4.93 (diast. ss, 2H), 4.43 (ss, 2H), 4.35 (q, 2), 3.01 (ss, 3H), 1.44 (t, 3H).

ES-MS: 418 [M + 1].

2 - ({[(tert -butoxy) carbonyl] ({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino} methyl) pyridine-4-carboxylate 4-oxopentan-2-yl (aa) [0207] Prepared according to General Procedure F from 2 - ({[(tert-butoxy) carbonyl] ({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino} methyl) pyridine-4-carboxylate 4-hydroxypentan-2-yl (from ). After concentration by column chromatography (10% MeOH / DCM), the title compound was obtained as a brown oil.

¹1 H NMR (300 MHz, CDCl 3): δ 8.60 (d, 1H), 7.70 (m, 1H), 7.60 (m, 1H), 5.00 (m, 1H), 4.60 ( m, 2H), 4.15, 4.00 (2s, 2H), 2.15 (s, 6H), 1.40 (m, 14H), 1.10 (m, 6H).

ES-MS: 493 [M + 1]

2 - ({[(tert-butoxy) carbonyl] ({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino} methyl) pyridine-4-carboxylate (v) General Procedure G (protection of amines with a Boc group) [0208] Amine (ethyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate (# 65)) (1 eq.) And Boc2O (1.2 eq. ) was dissolved in THF / H2O. Solid NaHCO 3 (4 eq.) Was added. The reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was purified by column chromatography using a gradient of 0-10% MeOH in DCM to afford the title product as a yellow oil.

¹1 H NMR (300 MHz, CDCl 3): δ 8.52 (m, 1H), 7.84 (m, 1H), 7.74 (m, 1H), 4.65 (m, 2H), 4.23 (mp); m, 2H), 3.45 (m, 4H), 2.50 (m, 2H), 2.25 (m, 6H), 1.43 (m, 9H), 1.19 (m, 3H).

N-tert-butyl (N) ({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) -N- ({4 - [(pyridin-4-yl) carbamoyl] pyridin-2 yl} methyl) carbamate

General Procedure H (Formation of Esters, Amides and Sulfonamides) [0209] Et 3 N (3.0 eq) and propanephosphonic anhydride (2.0 eq) were added to the solution of the amine (pyridin-4-amine) (or alcohol or sulfonamide) (1 , 5 eq.) And acid (2 ({[(tert-butoxy) carbonyl] ({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino} methyl) pyridine-4-carboxylic acid (x)) (1, 0 eq.) In DMF. The reaction mixture was stirred for 12 h at room temperature. DMF was removed in vacuo, diluted with DCM and washed with water to give the title compound as a brown oil. Purified by column chromatography or used without further purification.

¹H NMR (300 MHz, D2O) δ 8.59 (d, 2H), 8.21 (d, 2H), 7.88 (d, 2H), 6.75 (d, 1H), 4.35-4 32 (m, 2H), 3.713,66 (m, 2H), 3.38-3.24 (m, 2H), 3.13- 3.06 (m, 4H), 2.90 (s, 6H); ), 1.20-1.15 (m, 12H).

Ethyl 2 - {[2,2,2-trifluoro-N- (3-hydroxypropyl) acetamido] methyl} pyridine-4-carboxylate (h) [0210] Obtained according to General Procedure A of 2 - [(2,2,2 ethyl-trifluoro-N- {3 - [(trifluoroacetyl) oxy] propyl} acetamido) methyl] pyridine-4-carboxylate (g). Purified by flash chromatography to yield the title compound.

¹H NMR (300 MHz, CDCl3) (rotamers): δ 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).

2 - ({[(tert-butoxy) carbonyl] ({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino} methyl) pyridine-4-carboxylic acid (x) [0211] Prepared according to General Procedure A of 2 - ({[(tert-butoxy) carbonyl] ({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino} methyl) pyridine-4-carboxylate to give the title compound as a yellow solid.

¹1 H NMR (300 MHz, CD 3 OD) δ 8.67 (m, 1H), 7.67 (m, 1H), 7.73 (m, 1H), 4.70 (m, 2H), 4.42 (m) , 2H), 4.14 (m, 2H), 3.36 (m, 4H), 2.44 (m, 2H), 2.24 (m, 6H), 1.43 (m, 12H), 1 , 15 (m, 3H).

Amine intermediates

N - [(1R) -2-hydroxy-1- {methyl [3- (1-methyl-1H-imidazol-2-yl) propyl] carbamoyl} ethyl] carbamate benzyl [0212] A reaction mixture containing methyl [3- ( 1-methyl-1H-imidazol-2-yl) propylamine (1.1 eq), (2R) -2 - {[(benzyloxy) carbonyl] amino} -3-hydroxypropionic acid (1.0 eq), HATU (1.2 eq.) And DIPEA (1.4 eq.) In DMF were stirred at room temperature until TLC showed the reaction was complete. The reaction mixture was then partitioned between EtOAc / saturated NaHCO3 solution. The ethyl acetate extract was concentrated to give the title compound.

(2R) -2-Amino-3-hydroxy-N-methyl-N- [3- (1-methyl-1H-imidazol-2-yl) propyl] propanamide [0213] A mixture of N - [(1R) -2- Methyl hydroxy-1- {methyl [3- (1-methyl-1H-imidazol-2-yl) propyl] carbamoyl} ethyl] carbamate and 10% Pd / C (5% w / w) in methanol was stirred under a hydrogen atmosphere (40 psi) ) until TLC indicated the disappearance of the substrate. The mixture was then filtered through a pad of celite and concentrated to give the title compound.

2-amino-N- [2- (dimethylamino) ethyl] -N-ethyl-acetamide [0214] Prepared according to General Procedure E of Boc-glycine and [2- (dimethylamino) ethyl] (ethyl) amine. Further workup with HCl in methanol gave the title product as the hydrochloride salt.

¹1 H NMR (300 MHz, CDCl 3) δ 3.41 (m, 4 H), 3.23 (m, 2 H), 2.39 (m, 2 H), 2.22 (s, 6 H), 1.52 (s (broad), 2H), 1.11 (m, 3H)

Alcoholic intermediates

2,2,2-trifluoro-N- (3-hydroxybutyl) acetamide

Procedure General I (formation of trifluoroacetamides) [0215] 2,2,2-Trifluoroacetic acid was added at 0 ° C to a solution of 4-aminobutan-2-ol in MTBE. The mixture was brought to room temperature and stirred under nitrogen overnight. The solvent was evaporated under reduced pressure to give the title compound as a colorless oil.

¹1 H NMR (300 MHz, CDCl 3), δ 8.0 (broad s, 1H), 3.95 (m, 1H), 3.6 (m, 1H), 3.3 (m, 2H), 1.75 (m, 1H), 1.6 (m, 1H), 1.2 (d, 6H).

Tert-butyl N- (3-hydroxybutyl) carbamate [0216] Prepared according to General Procedure G from 4-aminobutan-2-ol to give the title product as a colorless gum.

¹1 H NMR (300 MHz, CDCl 3), δ ppm: 5.0 (br s, 1H), 3.7 (m, 1H), 3.4 br s, 1H), 3.2 (m, 2 H), 1.6 ( m, 2H), 1.4 (s, 9H), 1.2 (d, 3H).

ES-MS: 224 [M + 1].

4- (methylamino) butan-2-ol [0217] LAH was added at 0 ° C to a solution of tert-butyl 3-hydroxybutylcarbamate in THF. The mixture was brought to room temperature and heated at 70 ° C under stirring under nitrogen for 3 h. The reaction was quenched with a 10% NaOH solution. After treatment with water, the title product is obtained in the form of a colorless oil.

¹1 H NMR (300 MHz, CDCl 3), δ ppm: 3.9 (m, 1H), 3.6 (br s, 2H), 2.9 (m, 1H), 2.6 (m, 1H), 2.4 ( s, 3H), 1.5 (m, 2H), 1.2 (d, 3H).

2,2,2-trifluoro-N- (3-hydroxybutyl) -N-methylacetamide [0218] Prepared according to General Procedure I from 4- (methylamino) butan-2-ol to give the title product as a colorless oil.

¹1 H NMR (300 MHz, CDCl 3) δ 3.8 (m, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 3.2 (s, 3H), 1.7 (m) , 1H), 1.6 (m, 1H), 1.2 (d, 3H).

ES-MS: 200 [M + 1].

2,2,2-trifluoro-N- (3-hydroxypent-4-en-1-yl) acetamide [0219] Prepared according to General Procedure I from 5-aminopent-1-en-3-ol, to give compound title in the form of a brown foam.

¹1 H NMR (300 MHz, CDCl 3): δ 7.50 (br s, 1H), 5.90 (m, 1H), 5.28 (d, 1H), 5.20 (d, 1H), 4.40 (m, 1 H), 3.75 (m, 1H), 3.40 (m, 1H), 2.00-1.60 (m, 2H).

2,2,2-trifluoro-N- (3-oxo-propyl) acetamide [0220] Prepared according to General Procedure I from 3,3-diethoxypropan-1-amine and ethyl trifluoroacetate, yielding N- (3,3-diethoxypropyl) -2,2,2-trifluoroacetamide which was treated with 2M HCl to give the title compound.

¹1 H NMR (300 MHz, CDCl 3): δ 9.81 (s, 1H), 7.15 (br s, 1H), 3.64 (q, 2H), 2.83 (t, 2H).

trimethyl ({[1- (propan-2-yloxy) ethenyl] oxy}) silane [0221] To a solution of propan-2-yl acetate (1 equivalent) in THF was added LDA (1.1 eq.) at -78 ° C. . The reaction mixture was stirred for 30 minutes and TMSCl (1 eq) was added, allowed to warm up to room temperature and stirred for 1 h. Extract with hexane, wash with water, brine and concentrate to give the title compound.

Propan-2-yl 3-hydroxy-5- (trifluoroacetamido) propan-2-yl-pentanoate [0222] To a solution of 2,2,2-trifluoro-N- (3-oxo-propyl) acetamide (1 eq) in DCM was added trimethyl ({1 - (propan-2-yloxy) ethenyl] oxy}) silane (1 eq.) and TiCl4 (1 eq.) at -78 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. Extract with DCM, wash with water, brine and concentrate to obtain the title compound.

¹1 H NMR (300 MHz, CDCl 3): δ 7.65 (br s, 1H), 5.05 (m, 1H), 4.19 (m, 1H), 3.35 (m, 1H), 2.46 (d, 2H), 1.851.61 (m, 2H), 1.25 (d, 6H).

Propan-2-yl 3-hydroxy-4- (trifluoroacetamido) butyrate butyrate. [0223] Prepared according to General Procedure I from propan-2-yl 4-amino-3-hydroxybutyrate.

¹1 H NMR (300 MHz, CDCl 3): δ 6.94 (br s, 1H), 5.06 (m, 1H), 4.18 (m, 1H), 3.65 (d, 1H), 3.60 (m, 1H), 3.29 (m, 1H), 2.57-2.40 (m, 2H), 1.27 (d, 6H).

Example 2: AlphaLISA tests of lignine histone demethylase for the determination of IC 50 values.

[0224] This example demonstrates the ability of compounds of the invention to inhibit the activity of tested enzymes in vitro (Table 2a).

[0225] Assays are performed analogously to the PerkinElmer protocol described (Roy et al. PerkinElmer Technical Note: AlphaLISA 12, April 2011). The results are shown in Table 3.

General Method [0226] The enzymes are dissolved in enzyme reaction buffer and incubated for 10 minutes, after which μΐ is added to 5 μΐ of the compound solution in enzymatic reaction buffer containing 3% DMSO. Incubate for a further 10 minutes, after which 5 μΐ of the substrate solution is added and the reaction mixture is incubated at room temperature for a given period of time. 10 μΐ of the acceptor beads, suspended in specific dilutions of Epigenetic Buffer mother liquor buffer (Perkin Elmer AL008) are added and the suspension is incubated for 60 minutes in the dark at room temperature and then 10 μΐ of the suspension (in given dilutions of the Epigenetic Buffer buffer) is added. donor streptavidin beads (Perkin Elmer 6760002) in Epigenetic Buffer buffer. After incubation at room temperature in the dark, the plates are read.

[0227] Enzymes:

<td colspan="4">Table 2a</td>

<td>The name of the protein</td><td>Seller / Source</td><td>Sequence</td><td>Expressive body</td>

<td>KDM2A (FBXL10)</td><td>BPS, Bioscience, USA</td><td>1-650</td><td>bac</td>

<td>KDM3B (JMJD1B)</td><td>BRIC</td><td>842-1761</td><td>bac</td>

<td>KDM4A (JMJD2A)</td><td>BPS, Bioscience, USA</td><td>1-350</td><td>E. coli</td>

<td>KDM4B (JMJD2B)</td><td>BPS</td><td>2-500</td><td>bac</td>

<td>KDM4C (JMJD2C)</td><td>BRIC, Denmark</td><td>1-349</td><td>E. coli</td>

<td>KDM5 (JARID1C)</td><td>BPS</td><td>2-1560</td><td>bac</td>

<td>KDM5B (OUT-1)</td><td>BRIC</td><td>1-809</td><td>E. coli</td>

<td>KDM6A (UTX)</td><td>BRIC</td><td>919-1401</td><td>E. coli</td>

<td>KDM6B (JMJD3)</td><td>BPS</td><td>1043-end</td><td>bac</td>

<td>KDM7 (PHF8)</td><td>BRIC</td><td>1-1322</td><td>bac</td>

<td>KDM3A (JMJD1A)</td><td>BPS, Bioscience, USA</td><td>2-end</td><td>bac</td>

[0228] Substrates:

BK9M3: Biotin-ARTKQTAR (KMe3) STGGKAPRKQ-NH2 (Caslo, Denmark)

BK9M2: Biotin-ARTKQTAR (KMe2) STGGKAPRKQ-NH2 (AnaSpec 64359)

BK9M1: Biotin-ARTKQTAR (KMe1) STGGKAPRKQ-NH2 (AnaSpec 64358)

H3K4M3B: H-ART (Kme3) QTARKSTGGKAPRKQLA-NH-biotin (Caslo, Denmark)

BK27M3: Biotin-ATKAAR (ME3) SAPATGGVKKPHRY-NH2? (Caslo, Denmark)

BH3K36M2: RKAAPATGGVK (Me2) KPHRYRPGTVK- (BIOTIN)? (Anaspec) [0229] Enzymatic buffer: 50 mM Hepes (pH see table 2b), 0.003% Tween-20, 0.1% BSA; 5 μM (NH4) 2Fe (SO4) 2

Buffer A: 50 mM Hepes (pH see table 2b), 0.003% Tween-20, 0.1% BSA

Reaction conditions [0230]

<td colspan="6">Table 2b</td>

<td>Enzyme</td><td>Enzyme</td><td>Solution substrate</td><td>Acceptor balls</td><td>Donor balls</td><td>Incubation time</td>

<td>KDM2B</td><td>Buffer A, pH 8.0</td><td>Buffer A, pH 8.0 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K36M1 (PerkinElmer Custom 10120327RS)</td><td>diluted 1: 200 from the standard solution</td><td>60 min</td>

<td></td><td>Final enzyme concentration: 2 nM</td><td>Final substrate concentration (BH3K36M2): 50 nM</td><td>diluted 1: 200 from the standard solution</td><td></td><td></td>

<td>KDM3A</td><td>Buffer A, pH 7.4</td><td>Buffer A, pH 7.4 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K9Me1 (self-adhered)</td><td>diluted 1: 200 from the standard solution</td><td>60 min</td>

<td></td><td>Final enzyme concentration: 1.6 nM</td><td>Final substrate concentration (BK9M2): 100 nM</td><td>diluted 1: 200 from the standard solution</td><td></td><td></td>

<td>KDM3B</td><td>Buffer A, pH 7.4</td><td>Buffer A, pH 7.4 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K9Me1 (self-tapped)</td><td>diluted 1: 200 from the standard solution</td><td>60 min</td>

<td></td><td>Final enzyme concentration: 0.1 nM</td><td>Final substrate concentration (BK9M2): 100 nM</td><td>diluted 1: 200 from the standard solution</td><td></td><td></td>

<td>KDM4A</td><td>Buffer A, pH 7.4</td><td>Buffer A, pH 7.4 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K9Me2 (catalog no. AL117, Perkin Elmer)</td><td>diluted 1: 400 from the standard solution</td><td>60 min</td>

<td></td><td>Final concentration enzyme 0.2 nM</td><td>Final substrate concentration (BK9M3): 100 nM</td><td>diluted 1: 400 from the standard solution</td><td></td><td></td>

<td>KDM4B</td><td>Buffer A, pH 7.4</td><td>Buffer A, pH 7.4 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K9Me2 (catalog no. AL117, Perkin Elmer)</td><td>diluted 1: 400 from the standard solution</td><td>60 min</td>

<td></td><td>Final enzyme concentration 1 nM</td><td>Final concentration substrate (BK9M3): 100 nM</td><td>diluted 1: 400 from the standard solution</td><td></td><td></td>

<td>KDM4C</td><td>Buffer A, pH 7.4</td><td>Buffer A, pH 7.4 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K9Me2 (catalog no. AL117, Perkin Elmer)</td><td>diluted 1: 400 from the standard solution</td><td>60 min</td>

<td></td><td>Final enzyme concentration 1 nM</td><td>Final concentration substrate (BK9M3): 200 nM</td><td>diluted 1: 400 from the standard solution</td><td></td><td></td>

<td>KDM5B</td><td>Buffer A, pH 7.4</td><td>Buffer A, pH 7.4 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K4Me2-1 (Perkin Elmer AL116)</td><td>diluted 1: 200 from the standard solution</td><td>20 min</td>

<td></td><td>Final enzyme concentration: 2 nM</td><td>Final concentration substrate (H3K4M3B): 200 nM</td><td>diluted 1: 200 from the standard solution</td><td></td><td></td>

<td>KDM5C</td><td>Buffer A, pH 7.4</td><td>Buffer A, pH 7.4 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K4Me2-1 (Perkin Elmer AL116)</td><td>diluted 1: 200 from the standard solution</td><td>30 minutes</td>

<td></td><td>Final enzyme concentration 1 nM</td><td>Final concentration substrate (H3K4M3B): 100 nM</td><td>diluted 1: 200 from the standard solution</td><td></td><td></td>

<td>KDM6A</td><td>Buffer A, pH 7.4</td><td>Buffer A, pH 7.4 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K27me2-1 (Perkin Elmer AL121)</td><td>diluted 1: 200 from the standard solution</td><td>60 min</td>

<td></td><td>Final enzyme concentration: 2 nM</td><td>Final substrate concentration (BK27M3): 100 nM</td><td>diluted 1: 200 from the standard solution</td><td></td><td></td>

<td>KDM6B</td><td>Buffer A, pH 7.4</td><td>Buffer A, pH 7.4 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K27me2 (Perkin Elmer AL121)</td><td>diluted 1: 200 from the standard solution</td><td>60 min</td>

<td></td><td>Final enzyme concentration of 1 nM</td><td>Final substrate concentration (BK27M3): 50 nM</td><td>diluted 1: 200 from the standard solution</td><td></td><td></td>

<td>KDM7</td><td>Buffer A, pH 7.4</td><td>Buffer A, pH 7.4 + 25 μM L-Asc, 10 μM α-KG.</td><td>H3K9Me1 (self-adhered)</td><td>diluted 1: 200 from the standard solution</td><td>60 min</td>

<td></td><td>Final enzyme concentration: 2.5 nM</td><td>Final substrate concentration (BK9M2): 100 nM</td><td>diluted 1: 200 from the standard solution</td><td></td><td></td>

HDME BRAKING [0231]

<td colspan="12">Table 3</td>

<td>Structure</td><td>Name</td><td>GASC1</td><td>FBXL10</td><td>JARID1C</td><td>JMJD1B</td><td>JMJD2A</td><td>JMJD2B</td><td>JMJD3</td><td>PHF8</td><td>UTX</td><td>PLU1</td>

<td>OH (l Ί H / Y / k / Z // Z / N NZ / / YY / \ Y</td><td>2 - ({[3- (1H-imidazol-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid</td><td>++</td><td>+</td><td>+++</td><td></td><td>+++</td><td></td><td>+</td><td></td><td>+</td><td></td>

<td>° χ ^OH[Γ and ^h^ N ^ A / N / Y ^ nZHs AND ch₃</td><td>2 - ({[(2-dimethylamino) ethyl] acid no} methyl) pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td>+</td><td>+++</td><td>+++</td><td>+</td><td></td><td>+</td><td></td>

<td>HO 0 AH °^HΙί ANA OH NZ / / YY /</td><td>2 - ({[(2R) -2,3-dihydroxypropyl] amino} methyl) pyridine-4-carboxylic acid</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>0 ° OH and / V NH</td><td>2 {[(cyclopropylmethyl) acid no] methyl} pyridine-4-carboxylic acid</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>ΗΟ Z [| Ί η X χΖ Ν CH, 0Η₃</td><td>2 {[(cyclopropylmethyl) acid no] methyl} pyridine-4-carboxylic acid</td><td>+++</td><td></td><td>+++</td><td></td><td>+++</td><td>+++</td><td></td><td></td><td>+</td><td>+++</td>

<td>° ^0ΗΖζ ^CH31 χΐ Ν CH, Ν ' ³ch₃</td><td>2 - ({[2 (dimethylamino) ethyl] acid (met yl) amino} methyl) pyridine o-4-carboxylic acid</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>++</td>

<td>ΗΟ χ&gt; ° ΖΖ&gt; ch₃1 / CH X χΧ Ν&gt; Ζ Ν</td><td>2 - {[methyl (prop-2yn-1-yl) amino] methyl} pyridine o-4-carboxylic acid</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>++</td>

<td>ΗΟ ^Οίΐ Ί η X Ν Ν F</td><td>2 - {[(2-fluoro-ethyl) amino] methyl} acid pyridine-4-carboxylic acid</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>++</td>

<td>ΗΟ Ο ^ k ΗΝ. crkx.</td><td>2 - {[(furan-2-ylmethyl) amino] methyl} piridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td></td>

<td>^η° Ύ ° ICT ν 'η ΗΝ ύ / ο</td><td>2 - ({[(5-phenylfuran-2-yl) methyl] amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>++</td>

<td>0 ΟΗ X ....... 1 and'^NHCH= ° C ° h₃c ⁰</td><td>2 - ({[(2,4-dimethoxyphenyl) methyl] a-methyl} methyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td></td><td>+</td><td>+</td><td>+</td><td>+</td><td></td><td>+</td><td>+++</td>

<td>0 ^0Ηίΐ Ί η LA Ν CH, Ν S ' ³</td><td>2 - ({[2 (methylsulfanyl) ethyl] amic acid ino} methyl) pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>Ο ΟΗ ΑΑ ο Η ι ΰ Α Ν Α</td><td>2 - ({[2-oxo-2 (pyrrolidin-1-yl) ethyl] amino} methyl) py ydyno-4-carboxylic acid</td><td>+++</td><td>+++</td><td>+++</td><td>+</td><td>+++</td><td>+++</td><td>+</td><td>++</td><td>+</td><td>+++</td>

<td>ΗΟ Ο OjJ '' Ύ Ν CH₃ch₃</td><td>2 [({[butyl (methyl) carbam. acid yl] methyl} amino) methyl] p irydyno-4-carboxylic acid</td><td>+++</td><td>+++</td><td>+++</td><td>+</td><td></td><td>+++</td><td>+</td><td>++</td><td>+</td><td>+++</td>

<td>HO Ο Τ ^ν"" "' Ν Η₃Ο</td><td>2 - ({[(1-methyl-1H1,3-benzodiazol-2-yl) methyl] amino} methyl) p acid irydyno-4-carboxylic acid</td><td>++</td><td></td><td>+++</td><td></td><td>+++</td><td>+++</td><td>+</td><td></td><td>+</td><td>+++</td>

<td>ηο ο ΓΊ ^η ί k 1 Ν Υ^νk ^Ν Υ^Η3</td><td>2 - [({2- [4- (2-methoxyethyl) piperazin-1-yl] -2-oxoethyl} amino) methyl] p acid irydyno-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>ΗΟ, Ο 0 Γ 0 Η? Υ Υ ν Υ, ch₉Ν Υ "Ν Υ ^ L 0 ch₂</td><td>2 - [({[bis (prop-2-enyl) carbamoyl] methyl} am acid amino) methyl] pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>^ηου ° Υ 1 0Ν 00 ο \ 0Υ0000,</td><td>2 - [({2-oxo-2 - [(2R) 2- (pyrrolidin-1-ylmethyl) pyrrolidin-1-yl] ethyl} amino) methyl] py ydyno-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>OH 77 ^CH3 ί. Λ. Β 7^C"³^Ν Ϊ ν7 \ ^CH3 7 ο</td><td>2 - ({[(3R) -1 - [(tert-butoxy) carbonyl] pyrrole yn-3-yl] amino} methyl) pyridine o-4-carboxylic acid</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+</td>

<td>ΗΟ 7&gt; 77 ο Η ι LL 7 ν 7 ο Ν Ν X \ J XX H₃c</td><td>2 - ({[(3R) -1 - [(tert-butoxy) carbonyl] pyrrole yn-3-yl] amino} methyl) pyridine o-4-carboxylic acid</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+</td>

<td>ΗΟ, Ο X Ί -X Ν Ν XX Ν ~</td><td>2 - {[(3 - {[3- (pyrrolidin-1-yl) propyl] amino} propyl ) Amino] methyl} pyridin-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>Ο ^ΟΗίι X Η 1 7 Ν CH, Ν 7 / ^ 77ch₃</td><td>2 - {[(3-methylbutyl) amino] methyl o} pyridine-4-carboxylic acid</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>++</td>

<td>ΗΟ 0 7 νη₂77 ο 77 Η ιι Υ 7 ν 7 J οη₃</td><td>2 - [({[(2-carbamoyl-ethyl) (methyl) -carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>HO 0 χχ Pil Η ° k 1 Ν k χ Ν X "Ν k ΗΟ χΧχΧ</td><td>2 - [({2- [2 (hydroxymethyl) piperidic acid n-1-yl] -2-oxoethyl} amino) methyl] p irydyno-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>ho ο h₃c ^{Ν Ν}2 | ΐ η? | k 1 Ν k J Ν ^ΖΧ^Ζ Ν ch₃</td><td>2 - {[({methyl [3- (1-methyl-1H-imidazol-2-yl) propyl] carbamoyl} acid ylmethyl) amino] methyl} pyridin o-4-carboxylic acid</td><td>++++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>ΗΟ ° X ο Η ι k JY Ν kk χχ Ν Ν Υ - ^ \^Η Ν X * h₃Cⁿ^</td><td>2 - {[({{(1-ethylpyrrolidin-2-yl) methyl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>ΗΟ ° Xk Ο Η ι k JY Ν kk χ-χ XX Ν k / Ν γγ ch₃ νΧ h₃c</td><td>2 - {[({methyl [(1-methyl-1H-pyrazol-5-yl) methyl] carbamoyl} methyl) amino] methyl} pyridine o-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>Οχ ΟΗ γ-'Χχ 1 Η^Λ"ϊΥ</td><td>2 - ({[(3R) -1- (3-phenylpropyl) -pyrrolidin-3-yl] amino} methyl) pyridines o-4-carboxylic acid</td><td>+</td><td>+</td><td></td><td>+</td><td>++</td><td>++</td><td>+</td><td>+</td><td>+</td><td></td>

<td>0. OH CH ' X _aboutabout XnX &lt;a^H II 1 J X. ν AAJJJ NA ^ \ A _N N H</td><td>2 - ({[({1 - [(2-methoxyphenyl) methyl] pip erydyn-4-yl} carbamoyl) methyl] am ino} methyl) pyridine-4-carboxylic acid</td><td>+++</td><td>+++</td><td>+++</td><td>++</td><td>+++</td><td>+++</td><td></td><td>+++</td><td></td><td>+++</td>

<td>O. OH Ύ li '1 a ° f T "" 1' 1 H</td><td>2 - {[({[1- (3-phenylpropyl)] piperidin-4-yl] carbamoyl} methyl) amine ino] methyl} pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>OH Ϊ .................. ..... of (XI Λ 1 JV N k ^ "k ^ N kH</td><td>2 - {[({[1- (furan-2-ylmethyl) piperidin-4-yl] carbamoyl} methyl) amine ino] methyl} pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>++</td><td>+++</td>

<td>K&gt; ^OH[Jx ^h ? Γ ^^Ν^ ΧΧγΧΤΧ_N k - ^N_N kk H</td><td>2 - ({[({1 - [(5-phenyl-furan-2-yl) methyl] piperidin-4-yl} carbamoyl) methyl] amine ino} methyl) pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>ΗΟ Υ&gt; \ / Ν : r Ν Ν h₃cC</td><td>2 - [({[{2-ethylenyl) (ethyl) carbam oil] methyl} amino) methyl] pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>^0ΗX A "\ /^CH3 II Ί ^η ν Li Α ν ^ΝΝ)</td><td>2 - ({[2- (1-butylpyrrolidin-2-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid</td><td>+++</td><td></td><td>+++</td><td>+</td><td>+++</td><td>+++</td><td>+</td><td>+</td><td>+</td><td>+++</td>

<td>H₃^cΟ ΟΙΙ Η, Ο Xch₃ιί '1 κ ϊ. Γ^Ν'^Γ ~ Ν Ν ' Η</td><td>2 - {[({[1- (3,7-dimethyloct-6-en-1-yl) pyrrolidin-3-yl] carbamoyl} methyl) amine ino] methyl} pyridine-4-carboxylic acid</td><td>+++</td><td>++</td><td>+++</td><td>+</td><td>+++</td><td>+++</td><td>++</td><td>++</td><td>+</td><td>+++</td>

<td>Ο ΟΗ ίΧ ^ Χ "· χ F</td><td>2 - {[(3 - {[(2-fluorophenyl) methyl] (methyl o) amino} propyl) amino] m ethyl} pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>Ο. OH AND Ο, Κ ° ..................... Ν Ν - 'Ύ Ν ΤΎ ί ch₃ νΖ OH H₃C "</td><td>2 - ({[(1 R) -2-hydroxy-1- {methyl [3- (1-methyl-1H-imidazol-2-yl) propyl] carbamoyl} acid yl] amino} methyl) pyridine-4-carboxylic acid</td><td>+++</td><td>+</td><td>++</td><td>+</td><td>+++</td><td>+++</td><td>+</td><td>+</td><td>+</td><td></td>

<td>^η° ₀ zc A! And Η o N 'him N- \ j «Z^NHn-YJ</td><td>2 - [({2- [3- (1H-1,3-benzodiazol-2-ylmethyl) piperidin-1-yl] -2-oxoethyl} amino) methyl] p acid irydyno-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>ABOUT 0. ^OHZY O - ^N1 H || \ XZ n Z Z. Z. NY / Υγ / H</td><td>2 - {[({[1- (2-phenylethyl) pyrrolidin-3-yl] carbamoyl} methyl) amine ino] methyl} pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>HO y ° YY il Ί η 1 T XZ Ν NJ N // / YY / zY</td><td>2 - ({[3- (4-benzylpiperidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>HO O il Ί η η Γ ll XZ / ν N Zz Z N // z /// z / _about //</td><td>2 - [({3 - [(2-phenoxyethyl) amino] propane yl} amino) methyl] pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>HO / O AND Γ jl H? UK n XL ch₃^N Ν V "|| r Ν ' ³CH, ίχΧ NJ</td><td>2 - [({[methyl ({4 - [(4-methylpiperazin-1-yl) methyl] phenyl} methyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>++</td><td>+++</td>

<td>HO 0 κ 1 ^;nn</td><td>2 - ({[2- (2-benzyl-pyrrolidin-1-yl) -2-oxo-ethyl] -amino} -methyl) -pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>OH. 'T and II I 'Ί h and ........' X -ZN z. N NN '-_ηch₃</td><td>2 - ({[({4 [benzyl (cyclopropyl) amo] butyl} (methyl) carbonyl) methyl) methyl] amino} methyl o) pyridine-4-carboxylic acid</td><td>+++</td><td>+++</td><td>+++</td><td>+</td><td>+++</td><td>+++</td><td></td><td>++</td><td></td><td></td>

<td>° H AND ^H r- ^ O</td><td>2 - [({2 - [(2S) -1-benzylpyrrolidin-2-yl] ethyl} amino) methyl] pyridine-4-carboxylic acid</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>HO ° CZA ^ ZO</td><td>2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid</td><td>++</td><td></td><td>+++</td><td></td><td>++</td><td>+++</td><td>+</td><td>+</td><td>+</td><td>+++</td>

<td>CH, γ</td><td>2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridin-4-carboxylate methyl</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>++</td>

<td>k</td><td>2 - ({[4- (diethylamino) butyl] amino acid o} methyl) pyridine-4-carboxylic acid</td><td>+++</td><td></td><td>+++</td><td></td><td>+</td><td>+++</td><td>+</td><td>+</td><td>+</td><td>+++</td>

<td>^H0 0 Ok ⁰ ? ' X J-LOkO / \ k^N\ ^ lk k k "k ^ \._CHk CH₃</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl o) carbamoyl} methyl) amino no] methyl} pyridine-4-carboxylic acid</td><td>+++</td><td>++</td><td>+++</td><td>+</td><td>+++</td><td>+++</td><td>+</td><td>++</td><td>+</td><td>+++</td>

<td>\ h ^ JX ku-k-Λ ^ "'"' \ -CH,</td><td>2 - ({[4 (diethylamino) butyl] amino} 4-methoxyphenyl} 4-methyl} pyridine-4-carboxylate</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<img file="PL2903968T3_D0036.tif" />

2 - ({[4 (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 2 (ethoxycarbonyl) phenyl) ++ +++

<img file="PL2903968T3_D0037.tif" />

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 2 (dimethylamino) ethyl +++ +++

<img file="PL2903968T3_D0038.tif" />

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 3 (dimethylamino) propyl ++ +++

<td>ΧΗ, - "^CH3 '^CH3</td><td>2 - ({[4 (diethylamino) butyl] amino} methyl} pyridine-4-carboxylate {4 {[(ethoxycarbonyl) amino] phenyl} methyl sulfamate</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>Υ V ΧΖ ΥΤ YŻHg ^ CH,</td><td>2 - ({[4- (diethylamino) butyl] amine}} methyl) pyridine-4-carboxylate 2,6-dimethoxyphenyl</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>, .- 00, 'Γ " Ίϊα,</td><td>2 - ({[4- (diethylamino) butyl] amine} methyl} pyridine-4-carboxylate, 2,6-dimethylphenyl</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>-Ογ^ογ ^ 7 ° w *</td><td>2-Methoxyphenyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl o) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>ΓΧ ° Ο Αο-7 7^ν ° ^CH=</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl o) carbamoyl} methyl) amino] methyl} pyridin-4carboxylate 2 (ethoxycarbonyl) phenyl)</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>+++</td>

<td>'ΎΥ7 7 ίΥ- ^ γ \ ^^ch3</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl} pyridine-4-carboxylate {4 [(ethoxycarbonyl) (methyl) amino] phenyl} methyl</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>+++</td>

<td>- · ........ 7.</td><td>2-tertbuthyl 2 - {[({[(dimethylamino) ethyl] (ethyl o) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td>

<td>^CH3 ° (ί^μ II ι Ύ ΐΧ X '' 'CH</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl o) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate, 4-oxopentan-2-yl</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td>

<td>F Χχ ^ S * ™</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl o) carbamoyl} methyl) amino} methyl} pyridine-4-carboxylate 4 (trifluoroacetamido) butan-2-yl</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>++</td>

<td>Υύυ⁴Οχχ X '</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl o) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 4- (2,2,2-trifluoro-N-methylacetamido) butan-2-yl</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>++</td>

<td>Ύ ^ CH</td><td>Ethyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl o) carbamoyl} methyl) amino} methyl} pyridine-4-carboxylate</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>++</td>

<td>F fAAj Q CH,⁰ Hj &lt;T ° TH,</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl o) carbamoyl} methyl) amino} methyl} pyridine-4-carboxylate (trifluoroacetamido) pent1-en-3-yl</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>++</td>

<td>F CHj f / '0 CH₃⁰ H &lt;TUj</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl o) carbamoylmethyl) amino] methyl} pyridine-4carboxylate 5- (2,2,2-trifluoro-N-methylacetamido) pent-1-ene-3-yl</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>++</td>

<td>Below</td><td>2- (2 {[({[2- (dimethylamino) ethyl] hexanoate (ethyl o) carbamoyl} methyl) amino no] methyl} pyridine-4karbonyloksy) -3- (heksadekanoyloksy) prop yl</td><td colspan="2">++</td><td colspan="2">+</td><td colspan="2"></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td colspan="2">++</td>

<td colspan="16">H₃C ^^ * 0 ^ T</td>

<td>Αγ f A h₃part of kj ^θ^ '' A Ah₃ch₃</td><td colspan="2">1- (2 - {[({[2 (dimethylamino) ethyl] (ethyl) hexanoate carbamoyl} methyl) amino] m ethyl} pyridine-4karbonyloksy) -3- (heksadekanoiloksy) propan-2-yl</td><td colspan="2">++</td><td colspan="2"></td><td></td><td></td><td></td><td></td><td></td><td></td><td colspan="2">+++</td><td>++</td>

<td>ch₃γ ° ^CH 3 0</td><td>Methyl 2 - {[({[(dimethylamino) ethyl] (ethyl) carbamoyl) methyl) amino] methyl} pyridine-4-carboxylate</td><td>+++</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>+++</td>

<td>^ΗΥ AH₃CH₃ 0 Ν ^ Χ-Ι Y | Y_HSCkx ^_NX /^Kx0VY ° V J γ ^ NH Y F</td><td>3- (2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl phenyl) amino] methyl} pyridine-4karbonyloksy) -4- (trifluoroacetamido) butyrate propan-2-yl</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>++</td>

<td>T 0 ^ 00 &lt;Γ Ύ \ = o £ 0</td><td>3- (2 - {[{{[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridin-4-carbonyloxy) -5- (trifluoroacetamido) pentanine propan-2-yl</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td>

100

<td>⁰_0ΗΑ ο</td><td>2- (piperidin-1-ylmethyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td>

<td>Υ%^0Η(ξ Ν Ο</td><td>2- (azetidin-1-ylmethyl) pyridine-4-carboxylic acid</td><td>+</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td>

<td>Α X η χ ο ch₃LZkŹ / Busy k ι</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,2,2-trifluoroethyl</td><td>+++</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td>

101

<td>Ο ° Η όαλ₀</td><td>2 - ({ethyl [2-oxo-2 (piperidin-1-yl) ethyl] amino} methyl) pyridic acid yn-4-carboxylic acid</td><td>++</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>++</td>

<td></td><td>2 - ({butyl [2-oxo-2 (piperidin-1-yl) ethyl] amino} methyl) pyridic acid yn-4-carboxylic acid</td><td>+</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td>

<td>X ..... g</td><td>2 - ({benzyl [2-oxo-2 (piperidin-1-yl) ethyl] amino} methyl) pyridic acid yn-4-carboxylic acid</td><td>+</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td>

<td>X (Τ '^ CHj γΧ' ^ 'Ν 0 CHa Χ ^ ^ ^ ° χγΧ2χχ^Νχ.Χχ, χ ^ χχ-^Νχ₍,,, XX ° Theirs, ιι.Χ, ιι</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,6-Bis (propan-2-yloxy) phenyl</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>++</td>

102

<td>° γ^0Η Γ ό7.₀</td><td>2 - {[(2-methylpropyl) [2-oxo-2 (piperidin-1-yl) ethyl] amino] methyl} pyridic acid yn-4-carboxylic acid</td><td>+</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>+</td>

<td>° ° υ^η Γ ' ΑΛΛθ</td><td>2 - ({[2-oxo-2 (piperidin-1-yl) ethyl] (propyl) amino} metric acid yl) pyridine-4-carboxylic acid</td><td>+</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>+</td>

<td>0. ΟΗ | H₃C .ch_andί ^&gt; ΊΓ ° CULa.0</td><td>2 - ({[oxo-2 (piperidin-1-yl) ethyl] propan-2-yl) amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>+</td>

<td>7 | 7^CH?_ΟΧ ch₃ 0 ^N7A</td><td>2-Fluoroethyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate</td><td>++</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>+++</td>

<td>F_r J '' 7777 ch₃ 0 n ^ J</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,2-difluoroethyl</td><td>+++</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td><td>+++</td>

103

<td>about him όυΛΛτ £ H CH_andch₃</td><td>2 - ({[(1S) -1- (tert-butylcarbamoyl) -3-methyl-butyl] amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td>++</td><td>+</td>

<td>° °^HLA ch₅</td><td>2 - ({methyl [(2S) -4-methyl-1-oxo-1- (piperidin-1-yl) pentan-2-yl] amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td>

<td>CH, 1 RAS ' / ¼ O CH,^H II ¹WITH \ &gt; &lt;\ H, with</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] m ethyl} -N-methanesulfonyl-4-carboxamide-Nmetylopirydyno</td><td>+++</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

<td>r \ ΎΎ (From "With ^ f \ T CH, k ^ OH,</td><td>N- [2- (dimethylamino) ethyl] -N-ethyl-2 - ({[4- (2-oxo-1,3oksazolidyno-3-carbonyl) pyridin-2-yl] methyl} amino) acetamide</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+</td><td>+++</td>

104

<td>9 CK NH X Cu A yr xh, k CH,</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl yl) amino] methyl} -N- (pyridin-4-yl) pyridine-4-carboxamide</td><td>++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td>

<td>gZ ^^ N 0 CH, j&gt; Yu \ AA / \ ,, A • &lt;· r ^^x ς, '</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] m ethyl} -N- (5-methyl-1,3,4-oxadiazol-2-yl) pyridine-4-carboxamide</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td>

<td>HC Ο CH, \ JTL Αχ</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] m ethyl} -N- (1-methyl-1H-pyrazol-5-yl) pyridine-4-carboxamide</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td>

<td>0 CH, UT &lt; ^ Cl 1 ..</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] m ethyl} -N- (1,3-oxazol-2-yl) pyridine-4-carboxamide</td><td>+++</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>+++</td>

<img file="PL2903968T3_D0039.tif" />

(a) +++: IC50 &amp; lt; 100 nM;

2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (1-methyl-1H-imidazol-2-yl) pyridine-4-carboxamide ++: 100 nM &lt;IC50 &lt; 1000 nM;

++ +:

IC50&gt; 1000 nM +++ +++

106

Example 3: Immunofluorescence tests of lysine histone demethylase for the determination of IC50 values ​​in a cell

Immunofluorescence assays of histone lysine demethylase for the determination of IC 50 values, untransfected cells [0232] This example demonstrates the ability of compounds of the invention to inhibit H3K4 demethylation in a human osteosarcoma cell line.

General Method [0233] U2OS cells were harvested and plated in multi-well plates on media containing the compound. The medium used was DMEM containing 5% FBS and penicillin / streptomycin. After 20 hours of incubation of the cells with the compounds, the cells were washed once in PBS, harvested with 4% aqueous formaldehyde solution and washed twice in PBS. The cells were then permeabilized in PBS with 0.2% Triton X-100 for 10 minutes at room temperature. Blocking was performed in PBS with 0.2% Triton X-100 and 5% FBS for 45 minutes at room temperature. The cells were incubated with the primary antibody aH3K4me3 (Cell Signaling, No. 9751S) diluted in blocking solution in the ratio 1: 1000 w overnight at 4 ° C. After incubation with the primary antibody, the cells were washed 3 times with PBS, incubated with the secondary antibody diluted 1: 1000 (Alexa Fluor 594 goat anti-rabbit IgG, Invitrogen, A11012) and Hoechst, 20 μg / ml (Sigma, 33342) in the blocking solution and again washed 3 times with PBS. Finally, PBS was added and high-throughput imaging and analysis was performed using IN Cell Analyzer 1000 (GE Healthcare). The IC50 values ​​shown in Table 4 are based on the average measurement of the H3K4me3 staining in cells.

107

Inhibition of lysine histone demethylase

<td colspan="3">Table 4</td>

<td>Structure</td><td>Name</td><td>IC50</td>

<td>° K^OHχ, λοχχΧο XX Η</td><td>2 - {[({[1- (3-phenylpropyl) piperidin-4-yl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>+</td>

<td>CH, 1 ° γ ° όζ - ^. 0</td><td>Methyl 2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylate</td><td>++</td>

<td>ΗΟ Ο δ ................... ΎΤ k ^ \ Ζ k ^ ^ | \ Γ CH " Α</td><td>2 - ({[4 (diethylamino) butyl] amino} methyl) pyridine-4-carboxylic acid</td><td>++</td>

<td>Η ° Ο ον °?³C / \ ζ \ kT k ^ k ^ χ k ^ k k ch₃</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>++</td>

<td>₀/ ". Φ δ, γΑ \ / γ / Υ / Α Χγ ^ ς Αη₃</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 4-methoxyphenyl</td><td>+++</td>

108

<td colspan="2">φ ο ο ο</td><td>Ζ '- ^' Ζ / X</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 2- (ethoxycarbonyl) phenyl)</td><td>+++</td>

<td colspan="2">γγ - / -</td><td>'Ζ ^^' Χι-ι. AND</td><td>2- ({[4- (diethylamino) butyl] amino} methyl) pyridin-4-carboxylate 2- (dimethylamino) ethyl</td><td>++</td>

<td></td><td></td><td>ΥΗ₃</td><td></td><td></td>

<td>X?</td><td>UHL 1 , Υ Υ</td><td>Ζι ΖΥ._ΟΗX</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 3- (dimethylamino) propyl</td><td>++</td>

<td>° Ζ / ° · ί</td><td>X</td><td>γ-γργγ</td><td>2 - {{[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate {4 [(ethoxycarbonyl) amino] phenyl} methyl</td><td>+++</td>

<td>yJyX X &lt;_νΛ / \</td><td>ch₃</td><td>^ζ"\^{/ Λ}\ η_!</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 2,6-dimethoxyphenyl</td><td>+++</td>

<td></td><td></td><td>Α: η₃</td><td></td><td></td>

<td>fk Η 3 C Η 3 ° γ ζ</td><td>"" Ζ /</td><td>ι</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate, 2,6-dimethylphenyl</td><td>+++</td>

<td></td><td></td><td>Ζ; η₃</td><td></td><td></td>

109

<td>h₃c φ X</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 4-methoxyphenyl</td><td>+++</td>

<td>coo f &lt;X | About CH₃Φ, ΧΥ'χΧχ / Χ'Χοη, X</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2 (ethoxycarbonyl) phenyl)</td><td>+++</td>

<td>"k i" · 'Weaves. Y X &lt;2X / "/ \ CH₃1</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate {4 [(ethoxycarbonyl) (methyl) amino] phenyl} methyl</td><td>+++</td>

<td>ch₃H₃C ^^ CH₃° γ ° fjX 0 ch₃V &lt;ΥΧ '· χχΧ \ Ν Υ- ΥΤ V- '' CHs ^ ΌΗ₃</td><td>2-tert-butylphenyl 2 - {[({[(2-dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate</td><td>+++</td>

<td>^{of &lt;}y "y y yt"^{ch 3}JL ch₃ about (Ί * ^ T ° CH₃tL NN CH₃^ Ch.</td><td>2-Oxopentan-2-yl 2 - {[({[(2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate</td><td>+++</td>

<td>F k^vYY ° ch, A. yX ° ^ck ΦΑ γΙ ^ ,, χχχΥ II</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 4- (trifluoroacetamido) butan-2-yl</td><td>+++</td>

110

<td>F ^CH3^:yy ABOUT ^CH3 Yk. Ο.γ, γ ,,. / Γ ,,</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 4- (2,2,2-trifluoro-N-methylacetamido) butan-2-yl}</td><td>+++</td>

<td>γ Υ | Ί ^{0 CH}3 ΓΑυαΛν-υΑοη. k^CH3</td><td>Ethyl 2 - {[({[(dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate</td><td>+++</td>

<td>F | ZY 0 CH₃h₂T Γη₃</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate (trifluoroacetamido) pent-1-en-3-yl</td><td>+++</td>

<td>F CH₃ 0 CH₃° "0 ° k".</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 5- (2,2,2-trifluoro-N-methylacetamido) pent-1-en-3 yl</td><td>+++</td>

<td>\\ Jy η ch₃ oh ° x ° rfY] about ch₃γ γΓΓ γγγΓ V YZ Y / Y ^ Y / Yh₃^ ch₃</td><td>2- (2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] hexadecanoate] methyl} pyridine-4-carbonyloxy) -3- (heksadekanoiloksy) propyl</td><td>+++</td>

111

<td>° &lt;γ ° 77 0 CH₃L7^K7 ^ 7_C" ^ ch₃</td><td>1- (2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] hexadecanoic] methyl} pyridine-4-carbonyloxy) -3- (heksadekanoiloksy) propan-2-yl</td><td>+++</td>

<td>ch₃Y Clute, ^ ch₃</td><td>Methyl 2 - {[({[(dimethylamino) ethyl] (ethyl) carbamoyl) methyl) amino] methyl} pyridine-4-carboxylate</td><td>+++</td>

<td>CH, 1 7 ° /^N7 /^CH3 1 ° ^^%ίΐΊ ° ^CH3 ΊΑυΧΊτΑοη, k 7h₃</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N-methanesulfonyl-N-methylpyridine-4-carboxamide</td><td>++</td>

<td>Γ7 YX Cl-fe</td><td>N- [2- (dimethylamino) ethyl] -N-ethyl-2 - ({[4- (2-oxo-1,3oksazolidyno-3-carbonyl) pyridin-2-yl] methyl} amino) acetamide</td><td>++</td>

<td>ch₃_ABOUTX-s₃77 77 °&gt; 7³X χ F</td><td>Methyl 3- (2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) -4- (trifluoroacetamido) propan-2-yl butanoate</td><td>+++</td>

112

<td>F^F4a ° F 1 HN H₃C ^^ CH₃vy 0 0 o ffkj About ch₃kU k ^ k ^ kr k ^ Yh. AND,</td><td>3- (2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) -5 (trifluoroacetamido) propan-2-yl} pentanoate</td><td>+++</td>

<td>F J X nA about ch₃LXxAX / kX_aijAND ch₃</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,2,2-trifluoroethyl</td><td>+++</td>

<td>&lt;Άν about ch₃Y ^ AAA / A V ^ -NOL ah₃</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (1,3-oxazol-2-yl) pyridine-4-carboxamide</td><td>++</td>

<td>ch₃O ^ CH-j 0 CH₃AzYoUVo \, UJ L, - .. U C ..</td><td>2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,6-bis (propan-2-yloxy) phenyl</td><td>++</td>

<td>_H3c A ° Χ³Yauk&gt; ,, Ash₃</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (1-methyl-1H-imidazol-2-yl) pyridine-4-carboxamide</td><td>++</td>

<td>^Η!^ ^ Γγγγ ch₃ about</td><td>2-Fluoroethyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate</td><td>+++</td>

<td>F AND_ABOUTAND ch₃ about</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,2-difluoroethyl</td><td>+++</td>

<td colspan="3">(a) +++: IC50 &lt;1 μΜ; ++: 1 μΜ IC50 &lt;&lt;50 μΜ; +: IC50&gt; 50 μΜ</td>

<td colspan="3"></td>

113

Example 4: Cell proliferation assays for determining EC50 values ​​[0234] This example demonstrates the ability of compounds of the invention to inhibit the proliferation of a human breast cancer cell line.

General Method [0235] MCF7 cells were seeded at 1250 cells / well in 50 μl medium / well in 96-well black plates. Cells were incubated for 24 hours before compound addition. Compounds were diluted in complete medium (50 μl / well) and added to the plates in duplicate. The total volume of medium in the wells was 100 μl, and the final DMSO concentration was 0.5%. The full medium used was DMEM with GlutaMAX containing 10% FBS and penicillin / streptomycin.

[0236] 120 hours after the addition of the compounds, the plates were collected and analyzed using a 1-stage ATPlite (Perkin Elmer, catalog no. 6016739) according to the manufacturer's instructions. In summary, 100 μl ATPlite solution was added to each well, the plates were shaken at 700 rpm for 2 minutes, then incubated for 20 minutes in the dark and then analyzed for luminescence using an EnSpire 2300 Mulitilabel reader (Perkin Elmer). EC 50 values ​​were calculated using GraphPad Prism 6 software. The results are shown in Table 5.

114

<td colspan="3">Table 5</td>

<td>Structure</td><td>Name</td><td>E C5 0</td>

<td>° °^HAND NH AND</td><td>2 - {[(cyclopropylmethyl) amino] methyl} pyridine-4-carboxylic acid</td><td>++</td>

<td>° °^hfl ^H</td><td>2 - ({[2- (methylsulfanyl) ethyl] amino} methyl) pyridine-4-carboxylic acid</td><td>++</td>

<td>Ύ Λ aaj</td><td>2 - ({[(1-methyl-1H-1,3-benzodiazol-2-yl) methyl] amino} methyl) pyridine-4-carboxylic acid</td><td>++</td>

115

<td>^H0-X ^</td><td>0</td><td></td><td></td>

<td>ί</td><td>A-^ nA_n^^^ch:</td><td>2 - [({[bis (prop-2-en-1-yl) carbamoyl] methyl} amino) methyl] pyridine-4 acid</td><td rowspan="2">++</td>

<td></td><td>s ch₂</td><td>carboxylic acid</td>

<td>^HO&gt;</td><td>γ- ° h₃C</td><td></td><td></td>

<td></td><td>01? ||</td><td>2 - {[({methyl [3- (1-methyl-1H-imidazol-2-acid)</td><td>++</td>

<td>with</td><td>I^KAA AND ch₃</td><td>yl) propyl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td></td>

<td>^0H</td><td>ABOUT</td><td></td><td></td>

<td>ΙίΊ</td><td>ii O '^ xS</td><td>2 - ({[({1 - [(2-methoxyphenyl) methyl] piperidine-4-acid</td><td rowspan="2">++</td>

<td>AA</td><td>^ ALAj lA H</td><td>yl} carbamoyl) methyl] amino} methyl) pyridine-4-carboxylic acid</td>

<td>HO _</td><td>&gt; °</td><td></td><td></td>

<td>L</td><td>h₃C</td><td>2 - [({[(2-cyanoethyl) (ethyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid</td><td>++</td>

<td>° ^ X^0H</td><td></td><td></td><td></td>

<td>M</td><td>hr Π</td><td>2 - {[(3 - {[(2-fluorophenyl) methyl] (methyl) amino} propyl) amino] methyl} pyridine-4-</td><td rowspan="2">++</td>

<td>N</td><td>^ /ⁿ\ ^^ⁿAA F</td><td>carboxylic acid</td>

116

<td colspan="2">-'γ ' And with</td><td rowspan="2"></td><td rowspan="2">2 - ({[3- (4-benzylpiperidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid</td><td rowspan="2">++</td>

<td>Υ Ί Ν</td><td>Ν Ń</td>

<td>^Η° -</td><td></td><td></td><td></td><td></td>

<td>η</td><td></td><td>π</td><td>2 - [({3 - [(2-phenoxyethyl) amino] propyl} amino) methyl] pyridine-4-carboxylic acid</td><td>++</td>

<td></td><td>χ^Ν γΥ / \ Υ</td><td>-aj</td><td></td><td></td>

<td>° °_Η</td><td></td><td>RGI</td><td></td><td></td>

<td></td><td>Ο</td><td>AJ</td><td>acid 2 - ({[({4-</td><td></td>

<td></td><td rowspan="2">1 CHs</td><td>1 N</td><td>[Benzyl (cyclopropyl) amino] butyl} (methyl) carbamoyl) methyl] amino} methyl) pyridine</td><td>+</td>

<td>Yr Υ '</td><td>07</td><td>4-carboxylic acid</td><td></td>

<td>^Η° 0</td><td></td><td></td><td></td><td></td>

<td></td><td>ο</td><td>ch₃</td><td></td><td></td>

<td>G Ν</td><td>KJA 1</td><td>AND X^NY ch₃</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>++</td>

<td></td><td>^ ch₃</td><td></td><td></td><td></td>

117

<img file="PL2903968T3_D0040.tif" />

2-Methyl-4-methoxyphenyl [4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate

2- (ethoxycarbonyl) phenyl ++ +

++ +

118

<img file="PL2903968T3_D0041.tif" />

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate

3- (dimethylamino) propyl ++

<img file="PL2903968T3_D0042.tif" />

2 - ({4 - [(ethoxycarbonyl) amino] phenyl} methyl 2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate ++

<img file="PL2903968T3_D0043.tif" />

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate, 2,6-dimethoxyphenyl ++

119

<img file="PL2903968T3_D0044.tif" />

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate, 2,6-dimethylphenyl +++

<img file="PL2903968T3_D0045.tif" />

<img file="PL2903968T3_D0046.tif" />

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 4-methoxyphenyl ++

120

<img file="PL2903968T3_D0047.tif" />

<img file="PL2903968T3_D0048.tif" />

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2- (ethoxycarbonyl) phenyl)

2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate {4 - [(ethoxycarbonyl) (methyl) amino] phenyl} methyl ++ ++ ++

121

<td colspan="3">ch₃h₃c ^^ ch₃</td><td rowspan="3">2-tert-butylphenyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate</td><td rowspan="3">++ +</td>

<td colspan="2">about</td><td rowspan="2">ch₃_WITHN ch₃</td>

<td>° Y ° ZN</td><td>\ h₃</td>

<td></td><td></td><td></td><td></td><td></td>

<td rowspan="2">nX ³ ° Tears / Z</td><td></td><td>ch₃AND</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridin-4-</td><td>++</td>

<td>- Ah₃</td><td>sⁿ\ Y Zh₃</td><td>4-oxopentan-2-yl carboxylate</td><td>+</td>

<td>F , Α / Ζγ'ζ ° "Ά</td><td>0</td><td>oh₃</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridin-4-</td><td>++</td>

<td>N / k /</td><td colspan="2">Xh₃</td><td>4- (trifluoroacetamido) butan-2-yl carboxylate</td><td>+</td>

122

<td>F CH₃° "A</td><td>0</td><td>ch₃</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridin-4-</td><td>++</td>

<td>kA</td><td>^ \ H₃</td><td>Ά,</td><td>4- (2,2,2-trifluoro-N-methylacetamido) butan-2-yl carboxylate</td><td>+</td>

<td>^ CH₃ABOUT</td><td></td><td></td><td></td><td></td>

<td colspan="3">r ^ il ° U k_NAA^Juk_N- ^ XX_CH3^ CH.</td><td>Ethyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4 carboxylate</td><td>++ +</td>

<td>; Α^Β^ Γ ° γ9Α</td><td>AT-</td><td>ch₃Ά ch₃</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridin-4-</td><td>++</td>

<td>s J ϊ H₂(&lt;</td><td>9_CH₃</td><td></td><td>5- (trifluoroacetamido) pent-1-en-3-yl carboxylate</td><td>+</td>

<td>F CH₃ | ^ N</td><td>0</td><td>ch₃</td><td></td><td></td>

<td>^f A ^ y "ffAk</td><td>ΑΛζχ</td><td>AND ch₃</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridin-4-</td><td>++</td>

<td>II II⁰ h / ° H2C</td><td>^ οη₃</td><td></td><td>5 (2,2,2-trifluoro-N-methylacetamido) pent-1-en-3-yl carboxylate carboxylate</td><td>+</td>

123

<img file="PL2903968T3_D0049.tif" />

2- (2 - {[({[2 ++ (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy hexadecanoate) -3₊ (Heksadekanoiloksy) propyl

124

<img file="PL2903968T3_D0050.tif" />

<img file="PL2903968T3_D0051.tif" />

1- (2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) 3- (hexadecanoyloxy) propan-2-yl hexadecanoate

Methyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate ++

++ +

125

<td>CH, 1 Ύ Zo ί / Ά about ch₃AZ \ Z ^ Z AZ Zh₃^ ch₃</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -Nmetanosulfonylo-N-methylpyridine-4-carboxamide</td><td>++ +</td>

<td>r \ ΎΎ AA] about ch₃LA Al ^ A ^ ch₃lh₃</td><td>N- [2- (dimethylamino) ethyl] -N-ethyl-2 - ({[4- (2-oxo-1,3-oxazolidine-3-carbonyl) pyridin-2-yl] methyl} amino) acetamide</td><td>++</td>

<td>CH, 1 τ_Η. A o [/ " and ^aboutAzz '^!!Zf^tl/ (X NH N ⁰ ZZ^H3 xZ x 1^CH3 VF F</td><td>3- (2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) -4- (trifluoroacetamido) propan-2-yl butanoate</td><td>++</td>

126

<td>F Y ° HN HC -CH * IN 0 0 0 rfY ° ^CHs Y</td><td>3- (2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) -5- (trifluoroacetamido) propan-2-yl} pentanoate</td><td>++</td>

<td>F Y Ύ ° ^CH3 XX /^k\ X_n- ^ - X '₃Their 3</td><td>2, 2, 2-trifluoroethyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate</td><td>++</td>

<td>jf ^ N ^{0 CH}3 V Ϊ &lt; ^^CH3</td><td>2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} -N- (1,3-oxazol-2-yl) pyridine-4-carboxamide</td><td>++</td>

127

<img file="PL2903968T3_D0052.tif" />

<img file="PL2903968T3_D0053.tif" />

2-Fluoroethyl 2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate ++ ++

2 - {[({[2- (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylate 2,2-difluoroethyl ++ +

(a) +++: EC50 &lt;1 pM; ++: 1 pM &lt;EC50 &lt;50 pM; +: EC50&gt; 50 pM

128

Example 5: Ligorous immunon fluorescence assays for determination of IC50 values ​​in a cell [0237] This example demonstrates the ability of compounds of the invention to inhibit the demethylation of a particular H3 lysine in a human osteosarcoma cell line transfected to express lysine-specific histone demethylase.

General Method [0238] U2OS cells were seeded 24 hours prior to transfection. Transfection was performed using the Fugene HD transfection reagent, as recommended by the manufacturer. Six hours after transfection, the cells were harvested and plated in multi-well plates into medium containing the compound. The medium used was DMEM containing 5% FBS and penicillin / streptomycin. After 20 hours of incubation of the cells with the compounds, the cells were washed once in PBS, collected by fixing with a 4% aqueous solution of formaldehyde and washed twice with PBS. The cells were then permeabilized in PBS with 0.2% Triton X-100 for 10 minutes at room temperature. Blocking was performed in PBS with 0.2% Triton X-100 and 5% FBS for 45 minutes at room temperatureof that. The cells were incubated with primary antibodies diluted to 1 μg / ml in the blocking solution overnight at 4 ° C. The primary antibodies used in the assays were HA.11 (Covance, MMS 101P) and the label-sensing antibodies given in the following Table 6. After incubation with primary antibodies, cells were washed 3 times with PBS, incubated with secondary antibodies diluted 1: 1000 (Alexa Fluor 594 goat anti-rabbit IgG, Invitrogen, A11012, Alexa Flour 488 donkey anti-mouse IgG, Invitrogen, A21202) and Hoechst 20 μg / ml (Sigma, 33342) in blocking solution and again washed 3 times with PBS. Finally, PBS was added and high-throughput imaging and analysis was performed using IN Cell Analyzer 1000 (GE Healthcare).⁺ (transfected cells) and HA^-(untransfected cells). The IC 50 values ​​shown in the following Table 7 are based on the average measurement of the marker staining identified in Table 6 below in the transfected cells.

129

<td colspan="6">Table 6</td>

<td>The name of the construct</td><td>Seller / Source</td><td>Sequence</td><td>Detected tag</td><td>Primary antibody for tracer detection</td><td>Plasmid NCBI ID</td>

<td>pCMVHAJMJD2C</td><td>BRIC</td><td>Full length</td><td>H3K9me3</td><td>Abcam Ab8898</td><td>NM_014663</td>

<td>pCMVHAJMJD2A</td><td>BRIC</td><td>Full length</td><td>H3K9me3</td><td>Abcam Ab8898</td><td>NM_015061</td>

<td>pCMVHA PLU1</td><td>BRIC</td><td>Fragment (1-752)</td><td>H3K4me2</td><td>Millipore 07-030</td><td>NM_006618</td>

<td colspan="5">Table 7</td>

<td>Structure</td><td>Name</td><td>GASC1 (KDM4C)</td><td>JMJD2A (KDM4A)</td><td>PLU1 (KDM5B)</td>

<td>° °_HAND ^H ag 1A /ⁿYZ \ 0v</td><td>2 - ({[3- (1H-imidazol-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td>++</td>

<td>° ^OH(l ^HY YZ γγ γζ 1 ch₃</td><td>2 - ({[2- (dimethylamino) ethyl] amino} methyl) pyridine-4-carboxylic acid</td><td>++</td><td></td><td>++</td>

130

<td>Η ° °</td><td>2 - ({[(2R) -2,3-dihydroxypropyl] amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td>+</td>

<td>τγ fi) ΝΗ AND</td><td>2 - {[(cyclopropylmethyl) amino] methyl} pyridine-4-carboxylic acid</td><td>+</td><td></td><td>++</td>

<td>^ΗΟγ ° ίι ^Η^ 7 77 1 ch₃</td><td>2 - ({[4- (dimethylamino) butyl] amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td>++</td>

<td>^{0 0Η}77 ο, ι ch₃</td><td>2 - ({[2- (dimethylamino) ethyl] (methyl) amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td>+</td>

131

<td>^Η0 ° ό · ζ ^</td><td>CH,</td><td>2 - {[methyl (prop-2-yn-1-yl) amino] methyl} pyridine-4-carboxylic acid</td><td>+</td><td></td><td>+</td>

<td>Ζ</td><td>Α</td><td></td><td></td><td></td><td></td>

<td>f</td><td>Ί</td><td></td><td></td><td></td><td></td>

<td>LOAM</td><td>Άζ</td><td></td><td></td><td></td><td></td>

<td></td><td>ι ΗΝ</td><td>2 - {[(furan-2-ylmethyl) amino] methyl} pyridine-4-carboxylic acid</td><td>++</td><td>++</td><td>++</td>

<td></td><td>AT</td><td></td><td></td><td></td><td></td>

<td>° °^η</td><td></td><td></td><td></td><td></td><td></td>

<td>Α</td><td rowspan="2"></td><td>2 - ({[2- (methylsulfanyl) ethyl] amino} methyl) pyridine-4-carboxylic acid</td><td></td><td>++</td><td></td>

<td>ζΑ</td><td></td><td></td><td></td><td></td>

<td>0 υ "</td><td></td><td></td><td></td><td></td><td></td>

<td>Α</td><td>0</td><td></td><td></td><td></td><td></td>

<td>LA</td><td>ζΑθ</td><td>2 - ({[2-oxo-2- (pyrrolidin-1-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid</td><td>++</td><td></td><td>+</td>

132

<td>^ΗΟ °</td><td></td><td></td><td></td><td></td><td></td>

<td>ΆΧχ 1 ch₃</td><td></td><td>2 - [({[butyl (methyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid</td><td>++</td><td></td><td>+</td>

<td>ΗΟ, Ο 0 Α »^Ν h₃c</td><td>AND &lt;0</td><td>2 - ({[(1-methyl-1H-1,3-benzodiazol-2-yl) methyl] amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td>++</td>

<td>ΗΟ °</td><td></td><td></td><td></td><td></td><td></td>

<td>αΑ</td><td>X \ /^CH3 zr</td><td>2 - [({2- [4- (2-methoxyethyl) piperazin-1-yl -] - 2-oxoethyl} amino) methyl] pyridine-4-carboxylic acid</td><td>+</td><td></td><td>+</td>

<td>Η ° °</td><td></td><td></td><td></td><td></td><td></td>

<td>ÓvJk S ch₂</td><td>X&gt;^CH2</td><td>2 - [({[bis (carbamoyl) methyl-prop-2-en-1-yl)} amino) methyl] pyridine-4-carboxylic acid</td><td>++</td><td></td><td>++</td>

<td>HO O</td><td>X</td><td>2 - {[(3 - {[3- (pyrrolidin-1-yl) propyl] amino} propyl) amino] methyl} pyridine-4-carboxylic acid</td><td>+</td><td></td><td>+</td>

133

<td>HO .O γ nh₂1^CH3</td><td>2 - [({[{2-carbamoylethyl) (methyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid</td><td>+</td><td></td><td></td>

<td>f = \^H0\ H_sC--ⁿx ^ⁿUCJA 1^CH3</td><td>2 - {[({methyl [3- (1-methyl-1H-imidazol-2-yl) propyl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>++</td><td></td><td>++</td>

<td>X. θ H 3^C</td><td>2 - {[({[(1-ethylpyrrolidin-2-yl) methyl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>+</td><td></td><td>++</td>

<td>^H0 0^CH3 /^N~~ N h₃c</td><td>2 - {[({methyl [(1-methyl-1H-pyrazol-5-yl) methyl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>+</td><td></td><td>+</td>

134

<td>⁰_ΟΗAl ^η</td><td>2 - ({[(3R) -1- (3-phenylpropyl) pyrrolidin-3-yl] amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td>++</td>

<td>CX OH CH V _aboutwith kuOPÓ H</td><td>2 - ({[({1 - [(2-methoxyphenyl) methyl] piperidin-4-yl} carbamoyl) methyl] amino} methyl) pyridine-4-carboxylic acid</td><td></td><td></td><td>++</td>

<td>0 °^HKiiro H</td><td>2 - {[({[1- (3-phenylpropyl) piperidin-4-yl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>+</td><td></td><td>+</td>

<td>° Y °^HOyOZ¹H</td><td>2 - {[({[1- (furan-2-ylmethyl) piperidin-4-yl] carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>+</td><td></td><td>+</td>

<td>- °_HΥ, Ό'ΌΌ H</td><td>2 - ({[({1 - [(5-phenylfuran-2-yl) methyl] piperidin-4-yl} carbamoyl) methyl] amino} methyl) pyridine-4-carboxylic acid</td><td>+</td><td></td><td>+</td>

135

<td>^{Η0 0}η₃Χ</td><td>2 - [({[(2-cyanoethyl) (ethyl) carbamoyl] methyl} amino) methyl] pyridine-4-carboxylic acid</td><td></td><td></td><td>++</td>

<td>° ^ΟΗΛ _Η</td><td>2 - ({[2- (1-butylpyrrolidin-2-yl) ethyl] amino} methyl) pyridine-4-carboxylic acid</td><td></td><td></td><td>++</td>

<td>0 οπ ___ Οχ γ F</td><td>2 - {[(3 - {[(2-fluorophenyl) methyl] (methyl) amino} propyl) amino] methyl} pyridine-4-carboxylic acid</td><td>+</td><td></td><td>++</td>

<td>ο · «. &lt;3Η - X. r ° γ ν</td><td>2 - ({[({4 [benzyl (cyclopropyl) amino] butyl} (methyl) carbamoyl) methyl] amino} methyl) pyridic acid Dyno-4-carboxylic acid</td><td></td><td></td><td>+</td>

<td>⁰_0Ηλ. Γ-0</td><td>2 - [({2 - [(2S) -1-benzylopyrrolidin-2-yl] ethyl} amino) methyl] pyridine-4-carboxylic acid</td><td>+</td><td></td><td>++</td>

136

<td>^ΗΟ ο ό ΖΓ</td><td></td><td>X</td><td>2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylic acid</td><td>++</td><td></td><td>++</td>

<td>CH, 1 ° γ ° Α</td><td></td><td>Υ</td><td>Methyl 2 - ({[3- (pyrrolidin-1-yl) propyl] amino} methyl) pyridine-4-carboxylate</td><td>++</td><td></td><td>++</td>

<td>_ΗΟ °</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Λ</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>χχ</td><td>-Ζ / Ζ.</td><td>^x"Zi^ZX'' Zh. 1</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylic acid</td><td>++</td><td></td><td>++</td>

<td></td><td></td><td>Ζη₃</td><td></td><td></td><td></td><td></td>

<td>X</td><td></td><td>ch₃</td><td>acid 2 - {[({[2-</td><td></td><td></td><td></td>

<td></td><td>-Χζ L</td><td>^ ΧχΆ CK ,.</td><td>(Dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carboxylic acid</td><td>+</td><td>++</td><td>++</td>

137

<td>&gt; η₃0 φ Ύ</td><td>2-Methyl-4-methoxyphenyl [4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate</td><td>++</td><td></td><td>+++</td>

<td>7 7 Χη₃</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 2- (ethoxycarbonyl) phenyl</td><td>++</td><td></td><td>+++</td>

<td>° γ ° γ / \ /^Η3Ć7Ć__ Ν Τ 'Τ' Ν CH, 7</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 2- (dimethylamino) ethyl</td><td>++</td><td></td><td>++</td>

138

<td>ch₃WITH AZ AZ ^ ch₃Ί \ Γ AZ \ Z \ Z&gt; Z \ h₃^ ch₃</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate 3- (dimethylamino) propyl</td><td>++</td><td></td><td>++</td>

<td>h₃c Ί r · ΎΤ \ Y Οχ /, / ^ χζχ &gt; From XH L_C| _ |₃</td><td>2 - ({[4- (diethylamino) butyl] amino} methyl) pyridine-4-carboxylate {4 - [(ethoxycarbonyl) (methyl) amino] phenyl} methyl</td><td></td><td>+++</td><td></td>

<td>ll b ' X Μζ-χΧ, -Ζχ X</td><td>2- (2 - {[({[2 (dimethylamino) ethyl] (ethyl) carbamoyl} methyl) amino] methyl} pyridine-4-carbonyloxy) -3- (hexadecanoyloxy) propyl hexadecanoate</td><td></td><td>++</td><td></td>

<td colspan="5">(a) +++: IC50 &lt;1 pM; ++: 1 pM IC50 &lt;&lt;50 pM; +: IC50&gt; 50 pM</td>

[0239] Throughout this specification, unless explicitly indicated otherwise, the word "or" is used as an operator that returns the actual value when one or both of the conditions are met, as opposed to the operator "or only" which requires meeting only one of the conditions. The word "comprising" is used in the sense of "in" and not in the sense of "consisting of". The failure to include any previously published document in this document should be considered as admission or representation that its knowledge contained in it was general knowledge in Australia or elsewhere at the time of its publication.

LIST OF REFERENCES [0240]

Catchpole S et al., Int. J. Oncol. 38, 1267-77, 2011 Cloos, PaC 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 TK et al., (2010), "Epigenetic modifications as therapeutic targets", Nat. Biotechnol. 28; 10691078

Klose RJ et al., Nature 442, 312-16, 2006

Liu, G. et al. Oncogene, 28, 4491-500, 2009

Margueron, R., et al., Curr. Opin. 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 Seances de l'Academie de Sciences, Serie C: Sciences Chimiques, 268 (2), 182-5, 1969.

Quina, AS et al. (2006), "Chromatin structure and epigenetics", Biochem. Pharmacol. 72; 1563-1569 Roy et al. PerkinElmer Technical Note: AlphaLISA No. 12, April 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

140

SEQUENCE LIST [0241] &lt;110&gt; EpiTherapeutics ApS &lt;120&gt; histone demethylase inhibitors &lt;130&gt; P18387WO &lt;150&gt; US61 / 708806 &lt;151&gt; 2012-10-02 &lt;150&gt; DK201200599 &lt;151&gt; 2012-10-02 &lt;150&gt; US61 / 770050 &lt;151&gt; 2013-02-27 &lt;150&gt; DK201370112 &lt;151&gt; 2013-02-27 &lt;160&gt; 6 &lt;170&gt; BiSSAP 1.2 &lt;210&gt; 1 &lt;211&gt; 19 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 1 &lt;223&gt; Biotin &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 9 &lt;223&gt; trimethylated &lt;400&gt; 1

Ala Arg Thr Lys Gin Thr Ala Arg Lys Ser Thr Gly Gly Lys Ala Pro 15 10 15

Arg Lys Gin &lt;210&gt; 2 &lt;211&gt; 19 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 1 &lt;223&gt; Biotin &lt;220&gt;

141 &lt;221&gt; MOD_RES &lt;222&gt; 9 &lt;223&gt; dimethylated &lt;400&gt; 2

Ala Arg Thr Lys Gin Thr Ala Arg Lys Ser Thr Gly Gly Lys Ala Pro 15 10 15

Arg Lys Gin &lt;210&gt; 3 &lt;211&gt; 19 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 1 &lt;223&gt; Biotin &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 9 &lt;223&gt; methylation &lt;400&gt; 3

Ala Arg Thr Lys Gin Thr Ala Arg Lys Ser Thr Gly Gly Lys Ala Pro 15 10 15

Arg Lys Gin &lt;210&gt; 4 &lt;211&gt; 21 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 4 &lt;223&gt; trimethylated &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 21 &lt;223&gt; Biotin &lt;400&gt; 4

142

Ala Arg Thr Lys Gin Thr Ala Arg Lys Ser Thr Gly Gly Lys Ala Pro 15 10 15

Arg Lys Gin Leu Ala &lt;210&gt; 5 &lt;211&gt; 21 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 1 &lt;223&gt; Biotin &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 7 &lt;223&gt; trimethylated &lt;400&gt; 5

Ala Thr Lys Ala Ala Arg Lys Ser Ala Pro Ala Thr Gly Gly Val Lys 15 10 15

Lys Pro His Arg Tyr &lt;210&gt; 6 &lt;211&gt; 22 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 11 &lt;223&gt; dimethylated &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; 22 &lt;223&gt; Biotin &lt;400&gt; 6

<td>Arg</td><td>lys</td><td>ala</td><td>ala</td><td>Pro</td><td>ala</td><td>Thr Gly Gly Val</td><td>Lys Lys Pro His Arg Tyr</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td>'' 10</td><td>15</td>

<td>Arg</td><td>Pro</td><td>Gly</td><td>Thr</td><td>val</td><td>lys</td><td></td><td></td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td>

143