Untitled record

Full description Background of the invention

The present invention relates to compounds that can modulate the activity of histone demethylases (HDMEs), whereby said compounds are useful in the prevention and/or treatment of diseases in which genomic dysregulation is involved in the formation of diseases, for example, cancer. cancer.

The nucleic acid (DNA) of eukaryotic cells is packaged into the chromatin by wrapping DNA around histone proteins to form nucleosomes, which are the main unit of chromatin. One of the most important functions of chromatin is to identify regions of active and latent transcription by altering the structure of chromatin organization. 10 such changes have a profound effect on cellular function since they affect basic processes such as differentiation

differentiation, proliferation, and apoptosis, often collectively referred to as 'metagenesis' since it may result in inherited changes that do not include changes in the genetic sequences of Quina et al., Biochem. Pharmacol, 2006, 72 pages, 1563-1569.

15th These strictly controlled changes in chromatin are mediated by alterations of histone proteins bound to DNA in the nucleosome. In particular, the N-terminal histone tail of histone H3 and histone H4 is subjected to the aforementioned covalent changes, which include changes in methylation, acetylation, phosphorylation, and ubiquitination. mediate

20 In the occurrence of addition or removal of these groups in the histones of special enzymes, for example,

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Enzymes of histone methyl transferases, histone demethylases for methyl, histone acetyltransferases, histone deacetylases of the acetyl group, etc. If the activity or expression of these epigenetic enzymes is not adequately controlled

5 Correct and organized may lead to disease. Cancer, in particular, is of particular interest with regard to dysregulated epigenetic enzyme activity due to the role of epigenetics in cell differentiation, proliferation and programmed cell death, but epigenetics may also play a role in other diseases such as metabolic disease, Inflammatory, neurodegenerative and cardiovascular. Therefore, it may

10 Selective inclusion of aberrant effect of epigenetic enzymes in the treatment of human disease by the inventor

<p>-1069 Number 28 pages Nat. Biotechnol. et al. 2010 in Kelly, TK</p>

1078 and Cloos, PaC et al. 2008, No. 22, pp. 115-1140.

Methylation and demethylation of the lysine residues in the histone H3 tail are important epigenetic markers that define transcriptionally repressed and active chromatin.

<p dir="rtl">15th For example, treatment with methylation of lysine 9 on histone H3K9 (H3) is normally associated with epigenetic inactive chromatin by Inventor Fischle, W, et al. 2003 cited in Curr. Opinion Cell Biol No. 15, pages 83-172, and Inventor</p>

, 15 number Curr. Opinion Genet. Dev. et al. 2005 in Margueron, R.

Sqat from 76-163.

20 Whereas, methylation of lysine 4 on histone 3 is bound to transcriptionally active chromatin. Similarly, lysine tagged histone H3K27 (H3) is repressive in di- and tri-methylated conditions while lysine tagged histone H3 is found to correlate with gene activation, Inventor Barski, A. et al. 2007, Cell, No. 129, 37-823, and The Inventor. Vakoc, C et al. 2006 in .Mol.

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General, Wagner, E.J. &amp; Carpenter, PB No. 26 of 95-9185, and , Cell. Biol.

2012 Nature Mall. Cell Biol Count 13 of 26-115.

(There are, however, many exceptions to these general rules for the association between methylation states of sequence epigenetics and their effect on transcription.

5 As documented by studies of the genetically engineered SUV39H1 mouse, it lost the Tri-methyl-tri variant.

The methylation of H3K9 results in chromosomal aberrations and cancer risk (Peters, AH, et al. Cell No. 107 from 37-323 for 2001).

Histone demethylases (H3K9) as scavenger (KDM4C, GASC1) JMJD2C protein identified

histone demethylase (and can thus promote cancer if its expression is not controlled or

10 Tightly Activity, Inventor Cloos, P, et al., 2006, Nature No. 442 of 11307, Klose, RJ et al. 2006, Nature No. 442 of 16-312, Inventor Liu G et al. 2009, Gene Ontology 28, 4491-500 For example, JMJD2C demonstrated the induction of mutant phenotypes such as growth factor-independent growth, stabilization factor-independent growth and mammary scale formation, if overexpressed in cells by the inventor Liu, G.

15th et al. 2009. Oncogene 28, 4491-500. These findings may be supported by overexpression of JMJD2C in a number of human tumours such as squamous cell carcinoma, metastatic lung carcinoma, prostate cancer, breast cancer

39 Issue 60 of Cancer Res 2002 and others for Yang, ZQ and many others for the inventor

20 4735 and Yang, ZQ et al. 2001, Cancer Res, Jpn. J Number 92 of 28-

423, Inventor Hu, N et al. 2005, Cancer Res No. 65 of 46-2542, Liu G et al. 2009, Oncogene 28, 4491-500, Inventor Wissmann, M and

2007 Others for Inventor Nat, in Cell Biol Number 9 of Number 53-347, indicating the potential importance of JMJD2C as an oncogenic gene.

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The KDM4A protein (JMJD2A, and JHDM3A) exhibits properties similar to JMJD2C. JMJD2A demonstrates a high sequence conformation for JMJD2C in the JmjC catalytic domain, and is label-free.

Nature et al. Cloos, P. The overexpression of H3K9 . in prostate cancer also elucidated

Number 442 from 11-307 of 2006.

5 JMJD2A demonstrated interaction with ER-alpha (estrogen-receptor alpha) and overexpression of JMJD2A that improve estrogen-dependent transcription and reduced JMJD2A transcription of an ER-alpha spermatogenic target gene, cyclin D1, by Kawazu et al. 2011 PLoS 6 One, Berry et al. For 2012 41 Int J Oncol . Additionally, it has been shown that catalytically inhibited JMJD2A loses its ability to mimic ER-alpha-mediated transcription, 10 suggesting that JMJD2A inhibitors may be useful in the treatment of ER-alpha-positive breast tumors by Berry et al. 2012 141 Int J Oncol.

In a similar way, the tri-methyl mutant of H3K4, KDM5B, PLU1 (JARID1B) has also been identified as a potential oncogene. In cancer, JARID1B potentially acts as a suppressor of tumor suppressor genes by removing the 15 H3K4 methylated tary. leading to reduced transcriptional activity in affected chromatin regions. The tumorigenic potential of JARID1B by mimicking proliferation in cell lineages is further demonstrated by studies to characterize the shRNA gene expression of JARID1B that shows inhibition of proliferation in MCF7 human breast cancer cells, in SW780 bladder cancer cells and RT4. , and in lung cancer cells 20 A549 and LC319 and in 4T1 mouse tumour cells in the laboratory and/or in

Mouse Outgraft Experiments, Inventor Yamane K et al. (2007) Mol. Cell 25 n. 801-12 and Hayami S et al. (2010) 9 Cancer. Mol. 59. Catchpole S et al. (2011), Int. J. Oncol Issue 38 of 1267-77 Finally, JARID1B is overexpressed in prostate cancer and is tumor-associated.

25 JARID1A (KDM5A, 2007 (104)). 25 Xiang Y represents the malignant and weak predecessor of

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RBP2 is also a heterozygous screening medium for the H3K4 marker. JARID1A is overexpressed in gastric carcinomas (Zeng et al. (2010) 138 for Gastroenterology). Its gene is amplified in cervical cancer (Hidalgo et al. 2005). (5) BMC Cancer. It has been suggested that JARID1A represents the control of expression 5 of a micro-synthesised progesterone receptor by the estrogens of Stratmann and Haendler,

FEBS J in 2011. (278). Besides JARID1B, JARID1A has been included in maintaining slow-growing proliferation of cancer cells that are required for sustained tumor growth and that are resistant to cytotoxicity and targeted therapy by Roesch et al. (2010) for 141 Cell, Inventor Sharma and others for Cell 141 (2010). JARID1A is the inventor of Lin and 10 others for 2011. Required for tumor initiation and progression in Rb-/+-deficient cells and Lin, et al. 2011, 1 Men 108 PNAS. Data from Pasini show that JARID1A binds to Polycomb protein target genes that are involved in the regulation of important cellular processes such as embryonic cell formation, cell proliferation, and stem-cell self-renewal by suppressing transcription of genes that determine cell fate decisions. Pasini, et al.

15th (2008) 22 Genes &amp; Dev. Additionally, JARID1A has also been shown to bind the PRC2 complex.

It is a regulator of target genes and another potential oncogene, representing a heterodimerizer of dimethyl for H3K36 tag, has been shown that JHDM1B (KDM2B, FBXL10) is highly expressed in human cancer tumors, Inventor Tzatsos A et al. (2009) PNAS

106(8), 6–2641, Inventor. He, J et al. 2011, 117(14 Blood),

20 3869-80.

Induction of FBXL10 epigenetic properties causes a sensing in mouse embryonic lymphoblasts (MEFs), which can be rescued by expression of the catalytically active (but not catalytically inactive) factor. Pfau, JHDM1B, et al (2008), 105(6 PNAS), from 12 -1907, He J et al. (2008), 1169-75, 15 Nat Struct Mol Biol.

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The JHDM1B demethylating enzyme of H3K36me2 on the tumor suppressor gene Ink4b (p15Ink4b), thereby suppressing the expression of this gene that mediates downstream signaling in MEFs and leukemic cells.

Inventor He, J and others of 2008 15 Nat Struct Mol Biol from 75-1169, He,

5 J et al. 2011 80-3869, (14) 117 Blood.

As a catalytic activity, He et al. by JHDM1B and further show the catalytic dependence of

Required for leukemogenesis in a mouse AML model.

Histone demethylases inhibitors of the class of epidermal enzymes, and in particular the potential oncogenes JMJD2A, JMJD2C, JARID1A, JARID1B, and JHDM1B, offer a 10 new avenue for intervention in cancers and other proliferative diseases. As the world's deadliest disease, it affects millions of people around the world, and there is still an urgent need for specific, effective compounds against cancer.

The invention models provide a new series of compounds that can modify the activity of histone demethylases (HDMEs), and at least some of their compounds are useful for the prevention and/or treatment of diseases in which genomic dysregulation is involved in the formation of diseases, such as for example Example, cancer. For example, malnutrition or poor nutrition which is believed to have an effect of inadequate epigenetic effect and it can be expected that the compounds of the invention will have a beneficial effect in treating such effects of poor nutrition. In addition to the above, it was found that changes related to epigenetics are related to behaviour. Based on the above, the compounds according to the invention can be useful in behavior modification. Alternatively or additionally it can be

Such compounds are useful for investigating the extent to which different demethylases are inhibited by similar compounds as an investigation of the structure, functions, and mechanism of action of demethylases.

General description of the invention

The invention presents a compound having the following general formula (I):

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where

A is selected from--(C2-8, alkenylene C2-8, alkylene C1-8, CHR2C(O)cycloalkylene C3-10, alkenylene, heterocycline, heterocyclylene)

5 aryl aryl is heteroarylene and aryl arylene, which can be

yen alkynyl alkylene , alkenylene yen alkynyl alkylene , alkylene yen alkyl alkyl

alkenylene , cycloalkyl cycloalkylene , heterocyclylene , heteroarylene aryl heteroarylene and aryl aryl of their own optionally substituted with one or more R3 ;

10 Y is selected from C3-10, C2-8 alkenyl C1-8 alkyl C1-8, OR7, NR6R7, H cycloalkyl, heterocyclyl heterocyclyl, heteroaryl aryl and aryl, which are alkyl, alkenyl, alkynyl , cycloalkyl , heterocyclyl , heteroaryl aryl heteroaryl and their aryl optionally substituted with one or more R3 and can form a cyclic structure with

15th R2;

R1 is selected from C3-10, alkynyl C2-8 alkenyl C1-8 alkyl C1-8,–H cycloalkyl, whose alkyl, alkyl, alkyl and cycloalkyls are optionally substituted with one or more selected OH-,aryl,6- alkoxy C1, aryl heterocyclic, aryloxy aryloxy, aryloxy heterocyclic, F, and 6-C3 cycloalkyls; Or more preferably done

20 Y picking from H and 4-alkyl C1; or so that -AY- forms a nitrogen atom containing a heterocyclic cyclic group having a selective substitution whereby the selective substitution can be C1-8 alkynyl C2-8 alkenyl C1-8 alkyl, or C3-10 cycloalkyl, which is an alkyl,

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Alkenyl, alkenyl and their cycloalkyls optionally substituted with one or more selective OH-, aryl, C1-6 alkoxy, aryl heterocyclic, aryloxy, aryloxy heterocyclic, F, and C3-6

; cycloalkyl

R2 is selected from 8-H, C1 alkyl, 8-alkynyl C2-8, C2 alkenyl, and 10-C3

5 cycloalkyl, whose alkyl, alkenyl, alkenyl and cycloalkyls are optionally substituted by one or more selective OH-,aryl, 6-C1 alkoxy, aryl heterocyclic, aryloxy, aryloxy heterocyclic, F, and 6-C3 cycloalkyls, and may form a toroidal structure with Y;

Each R3 is individually selected from 6-C1-4, fluoroalkyl C1-4, alkyl C1

Z- , C3-10 cycloalkyl , alkynyl C2-6 , alkenyl C2-6 , hydroxyalkyl-cyclyl

10 Heterocyclic Z-, aryl -Z-, heterocyclyl-aryl heterocyclic, -Z-NR6R7, Z

Z SR7, halogen, C(=O)-NR6R7, Z-NR6-C(=O)-R7, ZC(=O)-R7, Z OR7 where any cyclyl is heterogeneous, Z COOR7, Z-SOR7, Z- SO2R7, Z-SO2NR6R7

it may have a replacement with one or more R4, and where any aryl is heterogeneous and any aryl may have one or more R5 substitutions;

15th Z is selected from single ligands, 4-alkylene C1, heterocyclylene and 6-cycloalkylene C3;

Each R4 is individually selected from 6-C1-4 fluoroalkyl C1-4, alkyl C1 N(R1)-2, C3-10 cycloalkyl, alkoxy C1-4, hydroxyalkyl, carbamoyl

carbamoyl, and -;OH

20 Each R5 is individually selected from 6-C1-4, fluoroalkyl C1-4, alkyl C1

CN, -F, -Cl, -Br, cycloalkyl C3-6, alkoxy C1-4, hydroxyalkyl, carbamoyl and -;OH

R6 and R7 are individually selected from 8-C1-4, fluoroalkyl C1-4, alkyl-H, C1

C3-10, alkynyl C2-8, alkenyl C2-8, hydroxyalkyl C1-4, perfluoroalkyl

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Z-, cycloalkyl-cyclyl heterocyclic, -Z-aryl heterocyclic and -Z-aryl, which are alkyl, alkyl, alkyl, cycloalkyl, cyclyl heterocyclic, aryl heterocyclic and aryl-specific optionally substituted with one or more R8s selected on acuity; Or, alternatively, they can form R6 and R7 together with a nitrogen atom to which they are attached to a nitrogen-substituted heterocyclic ring.

5 Optionally with one or more R8s selected separately;

Each R8 is individually selected from C1-4, C1-4 fluoroalkyl, C1-6 alkyl

cyclyl-Z- , C3-10 cycloalkyl , C2-6 alkynyl , C2-6 alkenyl , hydroxyalkyl

heterocyclic, -Z-aryl heterocyclic, -Z NR10R11, -ZC(=O)- , aryl -Z-

Z - CN, Z SR9, Z SOR9, Z SO2R9, halogen halogen, NR10R11, -Z OR9

<p dir="rtl">10 COOR9, which may be alkyl, alkenyl, alkenyl, cycloalkyl, heterocyclic, aryl heterocyclic and aryl groups optionally substituted with one or more selected 4-C1 alkyls, 4-C1 Z-, cycloalkyl C3-6, hydroxyalkyl C1- 4 , fluoroalkyl-heterocyclyl cyclyl, -Z-aryl heterocyclic, -,-Z NR10R11, -ZC(=O)-NR10R11, -Z OR9 , aryl -Z</p>

where any cyclyl other than Z COOR9- and CN, Z SR9, Z SOR9, Z SO2R9, halogen

<p dir="rtl">15th a homolog that can have one or more additional substitutions of R4 as defined earlier, and where any aryl is heterogeneous and any aryl can have one or more additional substitutions of R5 as defined earlier, and</p>

Each R9 is individually selected from -8-C1-4, fluoroalkyl C1-4, alkyl H, C1

cyclyl-Z- , C3-10 cycloalkyl , C2-8 alkynyl , C2-8 alkenyl , hydroxyalkyl

<p dir="rtl">20 heterocyclic, -Z-aryl, and -Z-aryl heterocyclic, where any heterocyclic cyclyl may have one or more R4 substitutions as defined previously, and where any aryl heterocyclic and any aryl may have one or more substitutions of R5 as previously defined;</p>

Both R10 and R11 are individually selected from C1-4, H, C1-6 alkyl fluoroalkyl,

, C3-10 cycloalkyl , alkynyl C2-8 , alkenyl C2-8 , hydroxyalkyl C1-4

<p dir="rtl">25 heterogeneous cyclyls, heteroaryls, and aryls, where any heterocyclic cyclyls may have</p>

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Substitution by one or more R4 as previously defined, and where any aryl is heterogeneous and any aryl may have one or more R5 substitutions as previously defined, or, alternatively, R10

The R11 may form together with a nitrogen atom to which they are bonded to an N heterocyclic ring optionally replaced by one or more R4 as previously defined;

5 Provided that Y is not H when A is CH2–--;

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

where R1 forms with AY– a heterocyclic group that is optionally substituted, preferably optionally replaced by 7-C3 eg 6-C3 or 6-C5 heterocyclic group

where R2 forms a ring structure with Y, and R2 is preferably alkylene C1-C2. Structure

10 The cyclic is preferably optionally replaced (with one or more R3) by 5 or 6 atoms, optionally a heterocyclic ring group.

A preferred aspect of the present invention relates to a compound of formula (I).

where

15th A is selected from (CHR2C(O-), 8-C2-8, alkenylene C2-8, alkylene C1 cycloalkylene C3-10 cycloalkyl, alkenylene, heterocycline, heteroarylene and arylene alkylene, which can be, alkenylene, alkenylene, cycloalkylene, heterocyclylene, heterocyclylene and special arylene optionally substituted with one

20 or more than R3;

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Y is selected from H, NR6R7, OR7, 8-alkynyl C2-8, alkenyl C2-8, alkyl C1, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, which are alkyl, alkenyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl and special aryl optionally replaced by one or more of R3;

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

R2 is selected from H, and 8-C3-10, alkynyl C2-8, alkenyl C2-8, alkyl C1 cycloalkyl, which is a special alkyl, alkenyl, alkyl and cycloalkyls optionally replaced by one or more selective OH-,aryl,6- alkoxy C1, aryl heterocyclic, aryloxy, aryloxy aryl heterocyclic, F, and 6-cycloalkyl C3 ;

10 Each R3 is individually selected from C1-4, C1-4 fluoroalkyl, C1-6 alkyl

cyclyl-Z- , C3-10 cycloalkyl , C2-6 alkynyl , C2-6 alkenyl , hydroxyalkyl

heterocyclic, -Z-aryl, -Z-aryl heterocyclic, Z-NR6R7, and -ZC(=O)-NR6R7, Z NR6-C(=O)-R7, and Z-C(=O)-R7, Z OR7, Halogen, Z SR7, Z-SOR7, Z-SO2R7, Z-SO2NR6R7 and Z COOR7, where any heterocyclic cyclyl may have

<p dir="rtl">15th substitution with one or more R4, and where any aryl is heterogeneous and any aryl may have a replacement with one or more R5;</p>

Z is selected from single ligands, 4-alkylene C1, heterocyclic cyclin and 6-C3

; cycloalkylene

Each R4 is individually selected from C1-4, C1-4 fluoroalkyl, C1-6 alkyl 20 N(R1)2, C3-10 cycloalkyl, C1-4 alkoxy, hydroxyalkyl-, carbamoyl, and OH-;

Each R5 is individually selected from C1-4, C1-4 fluoroalkyl, C1-6 ALKYL.

<p>-Carbamoyl and CN, -F, -Cl, -Br, cycloalkyl C3-6, alkoxy C1-4, hydroxyalkyl</p>

;

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R6 and R7 are separately selected from -8-C1-, fluoroalkyl C1-4, alkyl H, C1

C3-10, alkynyl C2-8, alkenyl C2-8, hydroxyalkyl C1-4, perfluoroalkyl 4

Z-, cycloalkyl-cyclyl heterocyclic, -Z-aryl heterocyclic and -Z-aryl, which are alkyl, alkenyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl and aryl

5 Optionally replace with one or more R8s selected separately; or, alternatively, they may form R6 and R7 together with a nitrogen atom to which they are attached to a heterogeneous nitrogen ring optionally substituted by one or more individually selected R8s;

Each R8 is individually selected from C1-4, C1-4 fluoroalkyl, C1-6 alkyl

cyclyl-Z- , C3-10 cycloalkyl , C2-6 alkynyl , C2-6 alkenyl , hydroxyalkyl

<p dir="rtl">10 Heterocyclic Z-, heterocyclyl-aryl aryl Heterocyclic Z-, heteroaryl-aryl, Z-</p>

CN, Z SR9, Z SOR9, Z ,halogen, NR10R11, -ZC(=O)-NR10R11, -Z OR9

SO2R9 and -Z COOR9, where alkyl, alkenyl, alkenyl, cycloalkyl, heterocyclic, aryl heterocyclic, and aryl groups may be optionally substituted with one or more selected from

<p>-Z- , cycloalkyl C3-6 , hydroxyalkyl C1-4 , fluoroalkyl C1-4 , alkyl C1-4</p>

15th Heterocyclic cyclyl, -Z-aryl heterocyclic, -Z-aryl, -(Z NR10R11, -ZC(=O-

Z COOR9 -CN, Z SR9, Z SOR9, Z SO2R9, Halogen, NR10R11, -Z OR9

where any heterocyclic cyclyl can have one or more additional substitutions of R4 as defined earlier, and where any heterocyclic aryl and any aryl can have one or more additional substitutions of R5 as defined earlier, and

20 Each R9 is individually selected from -8-C1-4, fluoroalkyl C1-4, alkyl H, C1

cyclyl-Z- , C3-10 cycloalkyl , C2-8 alkynyl , C2-8 alkenyl , hydroxyalkyl

heterocyclic, -Z-aryl, and -Z-aryl heterocyclic, where any heterocyclic cyclyl may have one or more R4 substitutions as defined previously, and where any aryl heterocyclic and any aryl may have one or more substitutions of R5 as previously defined;

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5

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Both R10 and R11 are individually selected from C1-4,H, C1-6 alkyl fluoroalkyl,

, C3-10 cycloalkyl , alkynyl C2-8 , alkenyl C2-8 , hydroxyalkyl C1-4

Heterocyclyl, heteroaryl, and aryl, wherein any heterocyclic cyclyl may have one or more R4 substitutions as defined above, and where any heterocyclic aryl and any aryl may have one or more R5 substitutions as defined Previously, or, alternatively, they may form R10 and R11 together with a nitrogen atom to which they are attached to a heterocyclic nitrogen ring having optionally replaced by one or more of R4 as previously defined;

Provided that Y is not H when A is CH2–--;

or isomer or mixture of isomers thereof, or a pharmaceutically acceptable salt, solvate or drug

<p dir="rtl">10 Ole prodrug of it.</p>

In an alternative aspect, the invention relates to a compound of formula 1 where

C2-8, alkenylene C2-8, alkylene -CHR2C(O)-, C1-8 are selected from A

C3-10 cycloalkylene , alkenylene , cycloalkylene heterogeneous , arylene heterogeneous and arylene , wherein the alkylene , alkenylene , alkenylene , cycloalkylene , cyclelene heterogeneous , arylene 15 heterocyclic and arylene are optionally substituted with one or more of R3 ;

, alkynyl C2-8 , alkenyl C2-8 , alkyl H, NR6R7, OR7, C1-8 are selected from Y

<p dir="rtl">C3-10 cycloalkyl, cyclyl heterocyclic, heteroaryl and aryl, of which alkyl, alkenyl, alkenyl, cycloalkyl, cyclyl heterocyclyl, heteroaryl and aryl are optionally substituted with one or more of R3;</p>

<p dir="rtl">20 R1 is selected from H and 4-alkyl C1;</p>

R2 is selected from 4-alkyl H, C1 and 4-hydroxyalkyl C1 ;

Each R3 is individually selected from C1-4, C1-6 fluoroalkyl, C1-6 alkyl.

cyclyl-Z- , C3-10 cycloalkyl , C2-6 alkynyl , C2-6 alkenyl , hydroxyalkyl

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heterocyclic, -Z-aryl Z- , aryl-aryl heterocyclic, -(Z-NR6R7, ZC(=O)

where any, Z COOR7, Z SR7, Z-SOR7, Z-SO2R7, halogen, NR6R7, Z OR7

Heterocyclic cyclyls may have one or more R4 substitutions, and where any aryl is heterogeneous and any aryl may have one or more R5 substitutions;

5 Z is selected from single ligands, 4-alkylene C1, heterocyclic cyclin and 6-C3

, cycloalkylene

Each R4 is individually selected from C1-4, C1-4 fluoroalkyl, C1-6 alkyl

N(R1)2, C3-10 cycloalkyl, alkoxy C1-4, hydroxyalkyl-, carbamoyl, and OH-;

Each R5 is individually selected from C1-4, C1-4 fluoroalkyl, C1-6 alkyl

-Carbamoyl and,CN, -F, -Cl, -Br, cycloalkyl C3-6, alkoxy C1-4, hydroxyalkyl 10 ;

R6 and R7 are separately selected from -8-C1-, fluoroalkyl C1-4, alkyl H, C1

<p>-Z- , C3-10 cycloalkyl , alkynyl C2-8 , alkenyl C2-8 , hydroxyalkyl 4</p>

cyclyl heterocyclic, -Z-aryl heterocyclic and -Z-aryl, which are alkyl, alkyl, alkenyl, 15cycloalkyl, cyclyl heterocyclic, aryl heterocyclic and aryl optionally substituted with one or

More than R8 selected separately; or, alternatively, they may form R6 and R7 together with a nitrogen atom to which they are attached to a nitrogen heterocyclic ring having optionally replaced by one or more separately selected R8s;

Each R8 is individually selected from C1-4, C1-4 fluoroalkyl, C1-6 alkyl 20 C2-6, hydroxyalkyl alkyl, 6-Z-, C3-10 cycloalkyl, C2-cyclyl alkynyl

Homogeneous, -Z-aryl heterocyclic, -Z-aryl, - ,Z NR10R11, -ZC(=O)-NR10R11-Z OR9, Halogen, CN, Z SR9, Z SOR9, Z SO2R9 and -Z COOR9, where it may be alkyl, alkenyl, alkenyl, cycloalkyl, heterocyclic, aryl heterocyclic and aryl groups optionally substituted with one or more of the selected 4-C1-4, fluoroalkyl C1-4, alkyl C1

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5

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Z- , cycloalkyl C3-6 , hydroxyalkyl-cyclyl heterogeneous, -Z-aryl heterocyclic, -

CN, Z SR9, ,halogen ,-Z NR10R11, -ZC(=O)-NR10R11, -Z OR9 ,Aryl-Z

Z SOR9, Z SO2R9 and -Z COOR9; where any heteroaryl cyclyl can have one or more R4 additional substitutions as defined earlier, and where any heteroaryl aryl and any aryl can have one or more R5 additional substitutions as defined earlier, and

Each R9 is individually selected from -8-C1-4, fluoroalkyl C1-4, alkyl H, C1

cyclyl-Z- , C3-10 cycloalkyl , C2-8 alkynyl , C2-8 alkenyl , hydroxyalkyl

heterocyclic, -Z-aryl, and -Z-aryl heterocyclic, where any heterocyclic cyclyl may have

10 substitution with one or more R4 as previously defined, and where any aryl is heterogeneous and any aryl may have one or more R5 substitutions as previously defined;

15

R10 and R11 are separately selected from fluoroalkyl C1-4, H, C1-6 alkyl, C3-10 cycloalkyl, alkynyl C2-8, alkenyl C2-8, hydroxyalkyl C1-4, heterocyclyl, heteroaryl, and aryl , where any heterocyclic cyclyl may have one or more R4 substitutions as defined earlier, and where any heterocyclic aryl and any aryl may have one or more R5 substitutions as defined earlier, or, alternatively, R10 and R11 may form together with a nitrogen atom to which they are attached to a nitrogen heterocyclic ring having optionally replaced by one or more R4 as previously defined;

Provided that Y is not H when A is CH2–--;

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

Another aspect of the present invention relates to pharmaceutical compositions comprising at least one compound of formula (I) as defined in the present application, and optionally one or more of the acceptable excipients.

Pharmaceuticals, diluents and/or carriers.

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Another aspect of the present invention relates to a compound of formula (I) as defined in the present application for use as a drug.

Another aspect of the present invention relates to a compound of formula (I) as defined in the present application for use in the treatment of HDME-dependent disease (histone demethylases), eg for the treatment of cancer. Another aspect of the present invention relates to a compound of formula (I) of As defined in the present application for use in the preparation of a pharmaceutical formulation for the treatment of an HDME-dependent disease, such as cancer.

An additional aspect of the invention relates to a method for treating an HDME-dependent disease in a subject, the said method comprising administering to said subject a therapeutically effective amount of at least one compound of formula (I) as defined in the present application.

10

15

Compounds of formula (I) as defined in the present application may be used in the treatment of HDME-dependent diseases by inhibiting HDMEs. Inhibition of HDMEs provides a new approach for the prevention and treatment of cancer and other metastatic diseases. Administer alone or optional in combination with antiviral compounds For malignant tumours, the compounds of the invention increase the efficiency of disease treatment of HDMEs.As will be shown below, the compounds of the invention have a cell-fixing or anti-proliferative effect against cancer cells.

Detailed description:

Compounds of formula (I)

According to the aforementioned, the present invention relates to compounds of formula (I)

<img file="SA5601B1_D0001.tif" />

٥٦٠١

5

-١٨-

The previous definition of compounds of formula (I) is indicated in the present application by the expressions “compounds of formula (I)” as defined in the present application, “a compound of formula (I) as defined in the present application.”

present application", or simply "compounds of formula (I)", etc. It should be understood that the signs mentioned are intended to include not only all the previous general formulas, but also all forms,

etc., discussed above or below. It should also be recognised that, unless otherwise specified, the references cited also include isomers, mixtures of isomers, pharmaceutically acceptable salts,

Solutes and prodrugs from compounds of formula (I).

Without being bound by any specific theory, the present results and X-ray crystal studies provide reasons to believe that the HOOC catalyst CH2-N&lt;, cf-pyridine. Formula (I), spinner

10 It is important when designing compounds that can modulate the activity of histone demethylases (HDMEs). In addition, the AY- constituent combination is believed to play a role in determining the binding affinity of these histone demethylases. Histone demethylases contain an iron atom on which the enzyme activity depends. Therefore, the pyridine nitrogen and the nitrogen atom of the formula (I) also plays a role in attaching a specific cavity to the histone demethylase enzymes where the iron atom is located.

15th Possibly by chelation of iron itself.

It is also thought that the AY chain, itself and through its components, interacts with the dimethyls space known to accommodate the lysine chain from the substrate. As the experimental results presented below in the examples clearly demonstrate, there is a wide range of possibilities for the AY-group modulating activity in various demethylases to confer selective inhibition. Some dimethylazines include a unit-lined lysine chain space

Acidic structures and compounds with major groups in Y that show the evolution of activity in these enzymes. Similarly, some DimethylAzE is better inhibited by compounds with polar groups in the Y chain. However, other DimethylAzE is better inhibited by compounds with uncharged polar groups in the Y chain. However, other DimethylAzE is better inhibited.

25 By compounds with uncharged polar groups in the Y series.

٥٦٠١

-١٩-

More specifically, the carboxylic acid group of the pyridine ring is thought to play a role in binding to a specific cavity of histone demethylases.

CHR2C(O)-, C1-8 alkylene, C2-8alkenylene, C2-8 - typically selected from A

alkynylene, C3-10 cycloalkylene, heterocyclic arylene, heterocyclic arylene and arylene.

5 Alkylene, alkenylene, alkenylene, cycloalkylene, heterocylene, arylene heterogeneous and an arylene such as A may be optionally substituted with one or more of the R3 (see further below).

CHR2C(O)-, C1-8alkylene, C3-10 - Picked up from A, in one embodiment

cycloalkylene , heterocyclic cyclene, heterocyclic arylene and arylene, in particular of CHR2C(O)-, C1-8 alkylene and heterocyclic cyclene, as -(CHR2C(O, or -C1)

10 8 alkylene , or heterocyclic cycline. In this context, R2 may take any of the sets of values

specified above or below. Specifically, A can be -(CH2C(O–) or --CH2

.-CH2

H, -NR6R7, -OR7, C1-8 ALKYL, C2-8alkenyl, C2-8 - typically selected from Y

alkynyl, C3-10 cycloalkyl , heterocyclyl, heteroaryl and aryl.

15th The preferred values ​​for R6 and R7 are defined in more detail below.

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

In one embodiment, Y is NR6R7–. In one of the variant forms, A is CHR2C(O-), especially -(CH2C(O–), and Y is NR6R7–.

20 In particular, AY- may take any of the values ​​shown in the compounds in the following Table 1 and any Y- values ​​shown here may be combined with any values ​​shown for A-.

٥٦٠١

-٢٠-

In contrast, A is C1-8 alkyl and Y is NR6R7–. In one of the scenarios in this model and these contrast images, NR6R7 represents a heterogeneous N ring having optionally replaced by one or more individually selected R8s, preferably replaced by one or two individually selected R8s. In another scenario for this model and these variants where Y is NR6R7-, one 5 of R6 and R7 represents H- or 6-C1 alkyl. In another scenario as well for this model and these pictures

C1-8 alkyl, C1-4 are selected separately from R7 and -NR6R7, R6 being Y heterotrophs where for example, fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, and C2-8alkynyl

example, so that R6 and R7 are identical. In another scenario as well for this model and these heteroforms where Y is NR6R7, one of R6 and R7 is selected from heterocyclyl, 10-heteroaryl and aryl.

In another embodiment, Y is H-. In one of the variant images, A is picked up from C1-8 alkylene

In contrast, C2-8 alkenylene, C2-8 alkynylene, and C3-10cycloalkylene.

Other, A is picked from heterogeneous cyclyls.

In another embodiment as well, Y is selected from heterogeneous cyclyls, heteroaryls and aryls. in one

C1-8alkylene, C2-8 alkenylene, C2-8 are selected from A,15 variants of which

alkylene, specifically from 8-alkylene C1, exemplified by 6-alkylene C1, specifically from 4-.alkylene C1

R1 is typically selected from H and C1-4 alkyl (eg methyl, ethyl, propyl and butyl), particularly from H- and H-methyl being preferred.

H, C1-8 alkyl, C2-8 alkenyl, C2-8alkynyl, C3-10 - typically selected from R2 20

cycloalkyl , which is a special alkyl, alkenyl, alkyl and cycloalkyls optionally substituted by one or more selective OH-,aryl, C1-6alkoxy, aryl heterocyclic, aryloxy, aryloxy heteroaryloxy, F heteroaryloxy, and 6-cycloalkyl C3. In some embodiments, R2 is selected from H, C1-4 alkyl (as methyl, ethyl, propyl and butyl) and 4-hydroxyalkyl C1

٥٦٠١

-٢١-

(such as hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl), in particular of H-, methyl and hydroxymethyl, with H being preferred.

C1-6 alkyl, typically selected separately from the Y and A (possible components of some meanings) of R3

C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 5

Z-,cycloalkyl-cyclyl heterocyclic, -Z-aryl, -Z-aryl heterocyclic, Z-NR6R7

Z, halogen, ZC(=O)-NR6R7, Z-NR6-C(=O)-R7, ZC(=O)-R7, Z OR7 where any cyclyl other than Z COOR7, SR7, Z-SOR7, Z-SO2R7 , Z-SO2NR6R7

Homogeneous may have one or more R4 substitutions, and where any aryl is heterogeneous and any aryl 10 may have one or more R5 substitutions. In another embodiment, R3 is selected separately from 6-C1

alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl,

Z-,C3-10 cycloalkyl-aryl, -Z-heteroaryl, -(Z-NR6R7, ZC(=O)

where any, Z COOR7, Z SR7, Z-SOR7, Z-SO2R7, halogen, NR6R7, Z OR7

Heterocyclic cyclyls may have one or more R4 substitutions, and where any aryl is heterogeneous 15 and any aryl may have one or more R5 substitutions.

Z is typically selected from single ligands, C1-4 alkylene, heterocyclic cycline and C3-cycloalkylene. In one embodiment, Z is picked up from C1-4 alkylene. In another embodiment, Z is picked from individual ligaments. It should be realized that combination Z may appear several marts in formula (I) and that the said Z's are selected separately.

20 All R4 (probably heterogeneous cyclyl groups) are individually selected from

C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-10

N(R1)2,cycloalkyl-, carbamoyl, and OH-,

٥٦٠١

-٢٢-

All R5 (possibly constituent groups of heteroaryls and aryls) are selected separately.

C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-6 of

.–OHCarbamoyl and,CN, -F, -Cl, -Br cycloalkyl

Both R6 and R7 (for example, from slit–NR6R7) are individually selected from H,

C1-8 alkyl, C1-4 fluoroalkyl, C1-4 perfluoroalkyl, C1-4hydroxyalkyl, C2-5

Aryl-Z-,heterocyclyl-Z-,8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl

heterocyclic and Z-aryl, which are alkyl, alkenyl, alkenyl, cycloalkyl, cyclyl heterocyclic, aryl heterocyclic and aryl-specific optionally substituted with one or more individually selected R8s; Or, alternatively, R6 and R7 may form together with a nitrogen atom to which they are attached to a nitrogen heterocyclic ring having optionally substituted with one or more individually selected R8s.

C1-6 alkyl, C1-4 fluoroalkyl, C1-4 are individually selected from R8 each non-Z-cyclyl, hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl

Homologous, -Z-aryl heterocyclic, -Z-aryl, - ,Z NR10R11, -ZC(=O)-NR10R11-

Where, Z COOR9- and CN, Z SR9, Z SOR9, Z SO2R9, halogen, Z OR9

15th alkyl, alkenyl, alkenyl, cycloalkyl, heterocyclic cyclyl groups, heteroaryl and aryl

C1-6 alkyl, C1-4fluoroalkyl, C1-4 optionally substituted with one or more of the selected

cyclyl non-Z-,hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl

Homologous, -Z-aryl heterocyclic, -Z-aryl, - ,Z NR10R11, -ZC(=O)-NR10R11-

Z OR9, Halogen, CN, Z SR9, Z SOR9, Z SO2R9 and -Z COOR9; where any cyclyl 20 heterocyclic can have one or more additional substitutions of R4 as defined previously, and where any heterocyclic aryl and any aryl may have one or more additional substitutions of R5 as defined above.

H, C1-8 alkyl, C1-4fluoroalkyl, C1-4 - be selected separately from R9 each cyclyl non-Z-,hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl

25 Homologous, -Z-aryl, and -Z-aryl heterocyclic, where any heterocyclic cyclyl may have

٥٦٠١

-٢٣-

Substitution by one or more R4 as defined earlier, and where any aryl is heterogeneous and any aryl may have one or more R5 substitutions as previously defined. In one of the models, each R9

H, C1-8 alkyl, C1-4fluoroalkyl, C1-4 hydroxyalkyl, -selected separately from non-aryl -Z-aryl, and -Z-,C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl

5 Homogeneous, where any heterocyclic cyclyl may have one or more R4 substitutions as previously defined, and where any heterocyclic aryl and any aryl may have one or more R5 substitutions as defined earlier.

H, C1-6 alkyl, - are selected separately from (NR10R11- from the notch) R11 and R10 each of

C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8alkenyl, C2-8 alkynyl, C3-10

10 cycloalkyl, heterocyclyl, heteroaryl, and aryl, where any cyclyl heterocyclic

may have one or more R4 substitutions as previously defined, and where any aryl is heterogeneous and any aryl may have one or more R5 substitutions as previously defined, or, at

Alternatively, R10 and R11 may form together with an N atom to which they are bonded to an N heterocyclic ring having optionally replaced by one or more of the R4 as previously defined.

15th It will be realized that in the formula (Y), I is not H when A is CH2–--. In general, it is thought to be advantageous if the AY-slit has a definite “size” with respect to the number of atoms (not to mention hydrogen atoms) and/or the molecular weight. The limited elasticity of the A-Y-slit also appears, which plays a definite role.

Hence, it is believed that the AY- moiety should preferably consist mostly of 40 heavy atoms, 20 as often of 30 heavy atoms, or mostly of 25 heavy atoms, or mostly of 20 heavy atoms. Preferably, the −AY moiety will consist of at least 3, or at least 4, or at least 8 or at least 10 heavy atoms. In some embodiments, the AY- moiety preferably consists of 340 heavy atoms, such as 4-30 heavy atoms, 4-25 heavy atoms, 4-20, 8-30, 8-20, or 15-8 atoms heavy. The term "heavy atom" means all atoms in the crevice except hydrogen atoms.

٥٦٠١

-٢٤-

In addition, it is believed that 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, and not to exceed 1000, or not to exceed 800 , or does not exceed 500, or does not exceed 400 and may be within any of these upper and lower detailed limits, eg 130-1,000 g/mol, or 1505 1,000 g/mol, eg 180-800 g/mol, for example Example, 225-600 g/mol or 250

500 g/mol, or 250 to 400.

In some embodiments, in order to provide limited flexibility for the A-Y- moiety, the moiety comprises 1-4 cyclos, i.e. cycloalkyls derived from a cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl and/or aryl. In some variants, the AY- radical includes 1-3 cyclic radicals 10 selected from a monocylic cycloalkyl , a monocyclic heterocyclyl , a heteroaryl monocylic heteroaryl , a heterocyclic dicyclic aryl and an aryl heter monocyclic aryl . Small constituent groups such as alkyl or hydroxyl groups on alkyl chains also reduce flexibility and favor specific 15 conformations.

It may be preferable that AY– does not comprise a ring, comprising at least one, eg from 1 to 3, branches, each of which may separately be from one to six heavy atoms, eg from one to three Thirt heavy, or from one to two atoms heavy. It is preferable that the–AY contain at least one heterogeneous atom, preferably at least one nitrogen atom or at least one oxygen.

Individually applicable options include:

Y be

٥٦٠١

-٢٥-

<img file="SA5601B1_D0002.tif" />

R10

where n is from 1 to 3 and R10 and R11 are separately as defined earlier.

Y be

(CH2)m CH3

<img file="SA5601B1_D0003.tif" />

5 where n is from 1 to 3 and m is separately from 0 to 2.

Y is selected from heterocyclyl, heteroaryl and aryl, which may optionally have one or more R3 substitutions.

Based on the ongoing studies and the results obtained so far, it is believed that the following compounds (No. 1 to 45), which include isomers, mixtures of isomers, as well as pharmaceutically acceptable salts, 10 solutes and prodrugs thereof, are of particular interest:

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 15

acid

2-{[(cyclopropylmethyl)amino]methyl}pyridine-4-carboxylic acid

٥٦٠١

-٢٦-

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 5

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 10

2-({[2-(methylsulfanyl)ethyl]amino}methyl)pyridine-4-carboxylic

acid

2-({[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino}methyl)pyridine-4-

carboxylic acid

2-[({[butyl(methyl)carbamoyl]methyl}amino)methyl]pyridine-4-15

carboxylic acid

2-({[(1-methyl-1H-1,3-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 20

٥٦٠١

-٢٧-

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]pyrrolidin-3- 5

yl]amino}methyl)pyridine-4-carboxylic acid

2-({[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3- 20

yl]amino}methyl)pyridine-4-carboxylic acid

2-{[(3-{[3-(pyrrolidin-1-])

yl)propyl]amino}propyl)amino]methyl}pyridine-4-carboxylic acid 10

2-{[(3-methylbutyl)amino]methyl}pyridine-4-carboxylic acid

2-[({[(2-

carbamoylethyl)(methyl)carbamoyl]methyl}amino)methyl]pyridine-4-carboxylic acid

2-[({2-[2-(hydroxymethyl)piperidin-1-yl]-2-15

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 20

2-{[({methyl[(1-methyl-1H-pyrazol-5-

yl)methyl]carbamoyl}methyl)amino]-methyl}pyridine-4-carboxylic acid

٥٦٠١

-٢٨-

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- 5 .)]

yl]carbamoyl}methyl)amino]methyl}pyridine-4-carboxylic acid

2-{[({[1-(furan-2-ylmethyl)piperidin-4-]

yl]carbamoyl}methyl)amino]methyl}pyridine-4-carboxylic acid

2-({[({1-[(5-phenylfuran-2-yl)methyl)]piperidin-4-

yl}carbamoyl(methyl]amino}-methyl)pyridine-4-carboxylic acid 10

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-3-15

yl]carbamoyl}methyl)amino]-methyl}pyridine-4-carboxylic acid

2-{[(3-{[(2-

fluorophenyl)methyl](methyl)amino}propyl)amino]methyl}pyridine-4-

carboxylic acid

2-({[(1R)-2-hydroxy-1-{methyl]3-(1-methyl-1H-imidazol-2-20)

yl)propyl]carbamoyl}-ethyl]amino}methyl)pyridine-4-carboxylic acid

٥٦٠١

-٢٩-

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-4-5

carboxylic acid

2-[({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-4-10

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 15

2-[({2-[(2S)-1-benzylpyrrolidin-2-yl]ethyl}amino)methyl]pyridine-

4-carboxylic acid

2-({[3-(pyrrolidin-1-yl)propyl]amino}methyl)pyridine-4-carboxylic

acid

methyl 2-({[3-(pyrrolidin-1-yl)propyl]amino}methyl)pyridine-4-20

carboxylate

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

٥٦٠١

-٣٠-

2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-carboxylic acid

(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl 2-({[4-

(diethylamino)butyl]amino}methyl)pyridine-4-carboxylate 5

4-methoxyphenyl 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- 10

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

3-(dimethylamino)propyl 2-({[4-

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

{4-{[(ethoxycarbonyl)amino]phenyl}methyl 2-({[4-

(diethylamino)butyl]amino}methyl)pyridine-4-carboxylate 15

2,6-dimethoxyphenyl 2-({[4-

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

2,6-dimethylphenyl 2-({[4-

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

4-methoxyphenyl 2-{[({[2- 20

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-

carboxylate

٥٦٠١

-٣١-

2-(ethoxycarbonyl)phenyl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-carboxylate

{4-[(ethoxycarbonyl)(methyl)amino]phenyl}methyl 2-({[4-

(diethylamino)butyl]amino}methyl)pyridine-4-carboxylate 5

4-tert-butylphenyl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-

carboxylate

4-oxopentan-2-yl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-10 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 2-{[({[2-15])

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-carboxylate

ethyl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-

carboxylate 20

5-(trifluoroacetamido)pent-1-en-3-yl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-carboxylate

٥٦٠١

-٣٢-

5-(2,2,2-trifluoro-N-methylacetamido)pent-1-en-3-yl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-carboxylate

2-(2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-5 carbonyloxy)-3-(hexadecanoyloxy)propyl hexadecanoate

1-(2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-

carbonyloxy)-3-(hexadecanoyloxy)propan-2-yl hexadecanoate

methyl 2-{[({[2- 10

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-carboxylate

2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}-N-methanesulfonyl-N-methylpyridine-4-carboxamide 15

N-[2-(dimethylamino)ethyl]-N-ethyl-2-({[4-(2-oxo-1,3-)

oxazolidine-3-carbonyl)pyridin-2-yl]methyl}amino)acetamide

propan-2-yl 3-(2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-

carbonyloxy)-4-(trifluoroacetamido)butanoate 20

propan-2-yl 3-(2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-

carbonyloxy)-5-(trifluoroacetamido)pentanoate

٥٦٠١

-٣٣-

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-(5-5

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-(piperidin-1-ylmethyl)pyridine-4-carboxylic acid 10

2-(azetidin-1-ylmethyl)pyridine-4-carboxylic acid

2,2,2-trifluoroethyl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-

carboxylate

2-({ethyl[2-oxo-2-(piperidin-1-yl)ethyl]amino}methyl)pyridine-4-15

carboxylic acid

2-({butyl[2-oxo-2-(piperidin-1-yl)ethyl]amino}methyl)pyridine-4-

carboxylic acid

2-({benzyl[2-oxo-2-(piperidin-1-yl)ethyl]amino}methyl)pyridine-4-

carboxylic acid 20

٥٦٠١

-٣٤-

2-{[({[2-

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

2,6-bis(propan-2-yloxy)phenyl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-5 carboxylate

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 10

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 15

2-fluoroethyl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-

carboxylate

2,2-difluoroethyl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-20 carboxylate

2-({[(1S)-1-(tert-butylcarbamoyl)-3-

methylbutyl]amino}methyl)pyridine-4-carboxylic acid

٥٦٠١

-٣٥-

2-({methyl[(2S)-4-methyl-1-oxo-1-(piperidin-1-yl)pentan-2-yl]amino}methyl)pyridine-4-carboxylic acid

Additional compounds of particular interest are shown in the following Table 1 and in other examples.

Tariffs

5 The term “alkyl” as used in the present application refers to a saturated, straight or branched hydrocarbon chain. Preferably one to 8 carbon atoms (C1-8-alkyl) in the hydrocarbon chain, and more preferably one. to six carbon atoms (C1-6-alkyl), and in particular what ranges from one to four carbon atoms (C1-4-alkyl), including, methyl, ethyl, ethyl, propyl, isopropyl, butyl

10 isobutyl, secondary butyl, tertiary butyl,

pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl, isohexyl, heptyl and octyl. In one preferred form the "alkyl" represents a C1-4-alkyl group, which may include in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and secondary butyl

15th butyl, and tert-butyl. Similarly, the term "alkylene" means the corresponding binary moiety (-alkyl-).

The term “cycloalkyl” as used in the present application refers to a cyclic alkyl group, preferably containing from three to ten carbon atoms (-10-C3 cycloalkyl), such as from three to eight carbon atoms (C3-8- cycloalkyl(, preferably from the third

20 to six carbons (C3-6-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl alkyl. For use in the present application it also includes a polycyclic group such as for example octyl[2,2,2] dicyclic, 2,2,1[heptanyl]dicyclic, decalinyl

٥٦٠١

-٣٦-

and adamantyl. Similarly, the expression "cycloalkylene" means the corresponding binary moiety (cycloalkyl).

The term “alkenyl” as used in the present application refers to straight or branched chain hydrocarbons or cyclic hydrocarbons containing one or more double bonds, including 5-enes, trienes and polyenes. Typically, an alkenyl group includes the following From two carbon atoms to eight carbon atoms (C2-8-alkenyl), such as what ranges from two carbon atoms to six carbon atoms (C2-6-alkenyl), and in particular what ranges from two carbon atoms to four carbon atoms (C2- 4-alkenyl(, including at least one double bond. -2,-1;but-dienyl or 5-hexenyl, or 1,3-hex-dienyl, or 1,3,5-hex-trienyl-3,-2,-1;hex-trienyl- , 4-, 5-, 6-, or 7-octenyl, or 1,3-octadienyl, or 1, 3, 5-

or cyclohexenyl, octatetraenyl, or 1, 3, 5, 7- octatrienyl octate arinyl

cyclohexenyl; Similarly, the term “alkenylene” means the corresponding binary moiety (15 alkenyl).

The term “alkenyl” as used in the present application refers to a straight or branched hydrocarbon chain containing one or more triple bonds, including di-enes, tertiary-enes and poly-enes. Typically, the alkenyl group includes the following two atoms Carbon to eight carbon atoms (C2-8-alkynyl), such as what ranges from two carbon atoms to six carbon atoms (C2-6-alkynyl), 20 and in particular what ranges from two carbon atoms to four carbon atoms (C2- 4-alkynyl), including at least one triple ligand. Examples of preferred alkenyl groups include ethynyl; 1- or 2-propenyl; 1-,2- or 3-butenyl, or 1,3-butynyl; 1-, 2-, 3-, 4- or 5-hexenyl, or 1,3-hex-diinyl, or 1,3,5-hex-tarenyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-octenyl, or 1,3-octadenyl, or 1,3,5-octate arynyl, or 1,3,5,7-octate Arenelle.

25 Similarly, the term "alkenylene" means the corresponding binary moiety (alkenyl-).

٥٦٠١

-٣٧-

The expressions “halo” and “halogen” as used in the present application refer to fluoro, chloro, bromo or iodo. Thus the taryhalomethyl group represents for example, a trifluoromethyl group, or a trichloromethyl group. Preferably, the expression should specify "halo" and "halogen" fluoro or chloro.

5 The term “fluoroalkyl” as used in the present application refers to an alkyl group as defined in the present application which is to be replaced once or twice by one or more fluoroalkyls, preferably perfluorinated. The term “perfluoroalkyl” as used in the present application refers to an alkyl group as defined in the present application where all hydrogen atoms are replaced by fluoro atoms. Favorite fluoroalkyl groups include tari fluoro

10 Methyl , pentafluoroethyl, etc.

The term “alkoxy” as used in the present application refers to an “alkyl-O-” group, being an alkyl as defined above.

The term “hydroxyalkyl” as used in the present application refers to an alkyl group (as defined in the present application above), which has its alkyl group substituted

15th One or more times of hydroxyhydroxybutyrate. Examples of hydroxyalkyl groups include -HO-CH2-CH2-,HO-CH2- and -(CH3-CH(OH).

The expression “oxy” as used in the present application refers to the “-O-” group.

The expression “oxo” as used in the present application refers to the “O=” group.

The term “amine” as used in the present application refers to major amines (R-NH, R  H),

By substituting that amine and tert. Amin (R3-N, R  H) means minor (R2-NH, R2  H) 20

means amine where at least one of the hydrogen atoms has been replaced by the substitution group.

The term “carbamoyl” as used in the present application refers to the group “H2N(C=O)-(.

٥٦٠١

-٣٨-

The term "aryl", as used in the present application, unless otherwise indicated, includes carboxylic aromatic ring systems derived from an aromatic hydrocarbon by removing a hydrogen atom. The aryl furthermore includes two-, ternary, and polycyclic ring systems. Examples of preferred aryl radicals include phenyl, naphthyl, indenyl, indanyl, fluoroenyl.

5 Fluorenyl, biphenyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, pentalenyl, azulenyl, and biphenylenyl. The preferred “aryl” is phenyl, naphthyl or indanil, and in particular phenyl, unless otherwise noted. Any Ariel used can be an optional replacement. Similarly, the term "arylene" means the corresponding binary slit (aryl-).

<p dir="rtl">10 The term "heteroaryl aryl", as used in the present application, refers to aromatic groups containing one or more heteroatoms selected from S, O, and N, preferably from one to four heterocyclic atoms, and preferably more than one to three Heterogeneous dart. Heteroaryl furthermore includes binary, ternary and polycyclic groups, where at least one ring of the group is aromatic, and at least one of the rings contains a heterocyclic atom.</p>

<p dir="rtl">15th Selected from S, O, and N. Heterocyclic aryl systems also include substitutions with one or more oxo moieties. Examples of preferred heterocyclic aryl moieties include N-hydroxytetrazolyl, N-hydroxytetrazolyl-hydroxyimidazolyl, hydroxytriazolyl-hydroxyimidazolyl, furanyl, triazolyl, benzyl pyranyl, thiadiaziophenyl, dihydrophenyl, ]b[thiophenyl-dihydro</p>

<p dir="rtl">20 benzo [b] thiophenyl, Azntinil xanthenyl, Oaokayevdanil isoindanyl, Okradinell, acridinyl Benz Oazuksasulal benzisoxazolyl, Kinulinil quinolinyl, Oazukinulinil isoquinolinyl, Ftiradinell phteridinyl, Ozippinil azepinyl, Dai Ozippinil diazepinyl, Aimidasulal imidazolyl, Thiazulal thiazolyl, Carpasulal carbazolyl, Peredinell pyridinyl, Piridazenel pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tet arzolyl</p>

25 tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxazolyl

٥٦٠١

-٣٩-

Oazuthiazulal isothiazolyl, Pirollal pyrrolyl, Andoleel indolyl, Benz Aimidasulal benzimidazolyl, Bnzovioarnnel benzofuranyl, Senaulinel cinnolinyl, Andasulal indazolyl, Andoleezenel indolizinyl, Fetaalzenel phthalazinyl, T. Arazenel triazinyl, Oizoandoleel, isoindolyl Baouril purinyl, Ooxadaizulal oxadiazolyl, Thiadaizulal thiadiazolyl, Vihuaraznal

5 furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinoxalinyl, naphthyridinyl dihydroquinolyl, dihydroquinol, dihydroquinol

dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl

<p dir="rtl">10 benzofuryl, furopyridinyl, pyrolopyrimidinyl, azaindolyl azaindolyl, pyrazolidinyl, and pyrazolidinyl. Examples include other than</p>

<p>-4, 3, 2, 1 hydrogenated bound on partially hydrogenated derivatives</p>

Tetrahydronaphthyl R, 1,4-dihydronaphthyl, and 1-octalin. Similarly, the term "heteroarylene" means the corresponding binary moiety (aryl-heterogeneous).

15th The term “heterogeneous cyclyl” as used in the present application, refers to acyclic aromatic groups containing one or more heterocyclic atoms selected from Oxygen (O), Sulfur, and N (Nitrogen), preferably from one to four heterogeneous atoms, preferably more than one to three heterocyclic atoms Heterogeneous cyclyls furthermore include di, ternary and polycyclic aromatic groups, at least one of

20 The rings contain a heterogeneous atom selected from S, O, and N. Heterocyclic cyclyls also include ring systems that are replaced by one or more oxo moieties. Examples are ring groups

Oxetane, pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, heterocyclic thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolylazylazyl, 1,3 , 1,3-thiazolyl, 1,2,5-

oxadiazolyl, piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, 25

٥٦٠١

-٤٠-

thianyl, 2H-thiopyranyl, pyridazinyl, 1,2-diazinanyl, pyrimidinyl, 1,3-diazinanyl, pyrazinyl, piperazinyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-diazinanyl, 1,4-oxazinyl, morpholinyl, thiomorpholinyl, 1,4-oxathianyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, chromayl, isochromanyl, 4H-chromenyl, 1H-isochromenyl, 5 chlorinyl, phenyl,yl,inridinyl, chlorinyl, phenyl,yl, phenyl,rin,yl,inridinyl, chloride, indazolyl, isobenzofuranyl, indazolyl , 1H-pyrrolizinyl, 4H-quinolizinyl and aza-8-

bicyclo[3.2.1]octane Similarly, the term "heterocyclic cyclilin" means the corresponding binary moiety (cyclyl heterocyclic-).

10 The term “heterocyclic N-ring” as used in the present application, refers to a heterocyclic cyclyl or heteroaryl as defined in the present application above having at least one nitrogen atom, and is bound by a nitrogen atom. Examples of such heterocyclic N-rings include:

pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 15 piperidinyl, pyridinyl, morphyrazinyl, pyridazinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, etc.

Aizum Art

Compounds of formula (I) can exist as geometric isomers (ie, 20 cis-trans isomers), optical isomers, or

stereoisomers, such as diastereomers, as well as clades. Based on the foregoing, it should be understood that the definition of compounds having formula (I) includes each individual isomer corresponding to the structural formula: Formula (I), including cis-trans isomers, isomers and tautomers, as well as Arctic mixtures of

٥٦٠١

-٤١-

These pictures and salts are acceptable in pharmacy. Hence, the definition of compounds of formula (I) is also intended to include all the R- and S-isomers of the chemical formula in any proportion, for example, by enrichment (i.e. enantiomeric or stereoisomeric increase) of one of the possible isomers and ratios The smaller analogue of the other isomers.

5 The dimers, ie, a non-interfering chemical stereoisomerase, can be separated by a conventional method such as chromatografting, distillation, crystallization or sublimation. Optical isomers can be obtained by decomposition of amorphous mixtures according to conventional processes, for example by forming dicotyledonous salts by treatment with a photoactive acid or base. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyl

10 dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. A mixture of stereoisomers can be separated by crystallization followed by liberation of the photoactive bases from these salts. An alternative process for the separation of optical isomers involves the use of an optimally selected Kerley chromatograft column to amplify the isomerization separation. Another method also available involves the synthesis of covalent homodimers by the reaction of formula compounds

15th (I) With an optically pure acid in the form of a dopant or an optically pure isocyanate. The dimers can be separated

The stereotaxes are created by conventional means such as chromatografting, distillation, crystallization or sublimation, and then analyzed with water to obtain the morphologically pure compound. The optically pure compounds of Formula (I) can similarly be obtained using optically pure starting materials and/or using a chiral catalyst. These isomers may be in the form of a free acid, a free base, an ester or a salt.

Chiral Separation Techniques, A 20. Examples of Chiral Separation Techniques are presented in Practical Approach, 2nd ed. by G. Subramanian, Wiley-VCH, 2001

Pharmacologically acceptable salts

A compound of formula (I) may be presented in any form suitable for the intended administration, in particular comprising pharmaceutically acceptable salts, solutes and prodrugs of a compound of formula (I).

٥٦٠١

-٤٢-

Pharmaceutically acceptable salts refer to salts of compounds of formula (I), considered acceptable for clinical and/or veterinary use. Typical pharmaceutically acceptable salts include those salts prepared by the reaction of compounds of formula (I) of a mineral or organic acid or an organic or inorganic base. They are known as These salts are called acid addition salts and base addition salts, respectively

5 The specific antagonist that forms part of any salt is not of a critical nature, as long as the salt as a whole is pharmaceutically acceptable and the antibody does not contribute properties that are not required for the salt as a whole. These salts can be prepared by methods known to an experienced person. The pharmaceutically acceptable salts are, for example,

Remington's Pharmaceutical Sciences, 17. Ed. 10 In those described and annotated in Alfonso R. Gennaro (Ed.), Mack Publishing Company, Easton, PA, Encyclopedia of Pharmaceutical and later editions and in USA, 1985 10

.Technology

Examples of pharmaceutically acceptable acid addition salts include, for example, acid addition salts formed with inorganic acids:

Hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric, or

phosphoric acid; and organic acids eg succinic, maleic, acetic, fumaric, 15 citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccuronic, glutic, fur, , ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinilic, alginic and galacturonic acid; and arylsulfonic 20

eg p-benzenesulfonic, benzenesulfonic-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid; Addition of base salts formed with alkali metals, alkaline earth metals and organic bases such as -N,N

25 Dibenzylethylenediamine, chloroprocaine

٥٦٠١

-٤٣-

chloroprocaine, choline, diethanolamine, ethylenediamine, N meglumine (ethylenediamine, meglumine-methylglucamine), methylglucamine, lysine and procaine; And the salt is an internal problem.

soluble

5 A compound of formula (I) may be presented in soluble or insoluble forms with a pharmaceutically acceptable solvent such as water, ethanol, and the like. The soluble forms may also include hydrated forms such as mono-hydrate and dihydrate , and half hemihydrate, trihydrate, and tetrahydrate

tetrahydrate, and the like.

10 Primary drugs

A compound of formula (I) can be presented as a prodrug.

The term “prodrug” used in the present application is intended to mean a compound when exposed to certain physiological conditions - a compound of formula (I) released when it is able to exhibit the desired biological effect. A typical example of this is a variable ester of a carboxylic acid, in particular special

15th The pyridine carboxylic acid group of a compound of formula (I), can, for example, release the latent carboxylic acid group.

Illustrative examples of esters of a carboxylic acid group (in particular pyridine carboxylic acid) are in C1-6 alkyl esters, for example, methyl esters, ethyl esters, 2-propyl esters.

20 esters, vinyl esters, 2,phenyl esters- aminoethyl esters, etc.,

including :

methyl esters, ethyl esters, 2-propyl esters, phenyl esters, 2-aminoethyl esters, etc., including (5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl

٥٦٠١

5

-٤٤-

10

15

20

esters, 4-methoxyphenyl esters, 2-(ethoxycarbonyl)phenyl esters, {4-[(ethoxycarbonyl)(methyl)amino]phenyl}methyl esters, 2-

(dimethylamino)ethyl esters, 3-(dimethylamino)propyl esters, [(ethoxycarbonyl)amino]phenylmethyl esters, 2,6-dimethoxyphenyl esters, 2,6-dimethylphenyl esters, 4-tert-butylphenyl esters, 4-oxopentan-2- y

esters, 4-(trifluoroacetamido)butan-2-yl esters, 4-(2,2,2-trifluoro-N-methylacetamido)butan-2-yl esters, 5-(trifluoroacetamido)pent-1-en-3-yl

esters, 5-(2,2,2-trifluoro-N-methylacetamido)pent-1-en-3-yl esters,

1,3-bis(hexadecanoyloxy)propan-2-yl esters, 2,3-

bis(hexadecanoyloxy)propyl esters, 4-oxo-4-(propan-2-yloxy)-1-(trifluoroacetamido)butan-2-yl esters, 1-oxo-1-(propan-2-yloxy)-5-

(trifluoroacetamido)pentan-3-yl esters 2,2,2-trifluoethyl esters, 2,6-bis(propan-2-yloxy)phenyl esters, 2-fluoroethyl esters, 2,2-difluoroethyl

esters, etc.

In particular, the image of the primary property according to the invention can be as follows

_R12 _O

R¹

_N NAY

where R12 has the form -R13(2N) or the form -R13O, whereby each individual R13 may be consistent with any of the examples of prodrugs given or described below. In particular, each R13 can be individually selected from C2-8, C2-8 alkenyl, C1-8 alkyl C3-10 cycloalkyl, alkynyl, aryloxy and be alkyl, alkenyl, alkyl, cycloalkyl

٥٦٠١

-٤٥-

its aryloxy is optionally substituted with one or more selective OH-,aryl,C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy,F, and sulfonamide moiety, and C3-6-cycloalkyl cycloalkyl; And one R13 can be in -R13(2N), and preferably, H– .

5 Compounds of formula (I) as defined in the present application may be prepared by conventional methods of chemical synthesis, for example, those described in the operational examples, starting from readily available starting materials. Commercially available chemical agents.

The end products of the reactions described in the present application can be isolated by conventional techniques, for example, by extraction, crystallization, distillation, chromatography, etc.

Possible methods for preparing compounds of formula (I) are described below. Compounds of formula (I) can be prepared as described below. Know the useful steps that can be used in the preparation steps of compounds for an experienced person. The following methods are given as non-limiting examples of how Preparation of compounds.

15th Methods A through C show the preparation of compounds according to this invention.

Useful methods for generating intermediates are described next.

Preparation of compounds of formula (I)

chart 1

<img file="SA5601B1_D0004.tif" />

20 Method A

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-٤٦-

A compound of formula (I) according to reaction scheme 1 can be prepared 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 KOH, LiOH, or NaOH. A purification method such as NaOH, KOH, or LiOH is used. Silica gel chromatograph if needed.

5 way b

A compound of formula (I) according to Reaction Scheme 1 can be prepared at room temperature, or by heating for up to several hours using a solvent such as water, DMSO, alcohol, or tetrahydrofuran, and aqueous acid. Silica if the need arises.

10 chart 2

<img file="SA5601B1_D0005.tif" />

C . method

A compound of formula (I) can be prepared from halides or triflates (X = halogen OTf, halogen) according to reaction scheme 2 either at room temperature or by heating up to several 15 hours with a solvent such as toluene or tetrahydrofuran, a base such as cesium carbonate or potassium t-butoxide, a catalyst such as the Pd complex chosen as a salt such as lithium chloride and carbon monoxide. A purification method such as chromatograft silica gel is used if the need arises.

20 Preparation of intermediates for compounds of formula (I)

٥٦٠١

-٤٧-

chart 3

<img file="SA5601B1_D0006.tif" />

10

method d

The intermediates (1) can be prepared from 2-formyl pyridines according to the reaction scheme 3 in one vessel or by a stepwise procedure with an amine mixture, optionally containing the orthogonal protected reaction sites, and a reducing agent such as NaBH4, NaBH(OAc) 3), NaCNBH3, or Et3SiH, either at room temperature or by heating up to several hours with a solvent such as alcohol, DCE, DCM, water, or toluene, and optionally the addition of a catalyst such as Lewis acid or acid. Optionally, the protective groups can be removed and a purification method such as silica gel chromatography is used if the need arises.

chart 4

<img file="SA5601B1_D0007.tif" />

15

The method is

Intermediates (ii) can be prepared from 2-formylpyridines according to reaction scheme 4 corresponding to Method D.

chart 5

٥٦٠١

-٤٨-

<img file="SA5601B1_D0008.tif" />

way and

Intermediates (iv) can be prepared from (iii) according to reaction scheme 5, where R' represents a suitable protective group or R1, using a solvent such as DMF or THF, a base such as a blocking tertiary amine, a hydrophobic agent such as EDCI or DCC and an amine, By mixing at or above room temperature for a period of up to several hours Optionally, this protective group can be removed, and a purification method such as silica gel chromatograft is used if necessary.

chart 6

<img file="SA5601B1_D0009.tif" />

10

way g

The intermediate compounds (vi) can be prepared from (v) according to the reaction scheme 6 corresponding to the method

And.

chart 7

٥٦٠١

-٤٩-

<img file="SA5601B1_D0010.tif" />

method h

The intermediates (viii) can be prepared according to the reaction diagram 7 of (vii), where R' represents a suitable protective group or R1 and R' is a protective group in the orthagonal position.

5 orthogonal, can be removed selectively, such as removing R':tBu in the presence of R':CF3CO by treating with trifluoroacetic acid in a solvent such as dichloromethane at room temperature for several hours. A purification method such as chromatograft silica gel is used if the need arises.

chart 8

<img file="SA5601B1_D0011.tif" />

10

method i

The intermediates (x) can be prepared from (ix) according to the reaction scheme 8 corresponding to method h.

Scheme 9

٥٦٠١

<img file="SA5601B1_D0012.tif" />

-٥٠-

<img file="SA5601B1_D0013.tif" />

10

15

J way

Intermediates (xii) can be prepared from aldehydes and intermediates (xi) according to the reaction scheme 9 in one vessel or by a step-by-step procedure by mixing with an amine (R': R1 or a suitable protecting group) and a reducing agent such as NaBH3, NaCNBH(OAc) reducing agent 3, NaBH4, or Et3SiH, either at room temperature or by heating up to several hours with a solvent such as alcohol, DCE, DCM, water, or toluene, and optionally the addition of a catalyst such as acid or Lewis acid. Purification method such as chromatograft silica gel if the need arises.

K . method

Intermediates (xii) of (xi) can be prepared according to Reaction Scheme 9 using a solvent such as DMF or THF, optionally a base, and a suitable electrolytic type such as epoxide, aliphatic, allylic, benzylic bromide, chloride, or sulfonate sulfonate A purification method such as silica gel chromatogram is used if the need arises.

chart 10

٥٦٠١

-٥١-

<img file="SA5601B1_D0014.tif" />

way to

The intermediate compounds (xiv) can be prepared from (xiii) according to the reaction scheme 10 in a manner corresponding to method j.

method m

Intermediate compounds (xiv) can be prepared from (xiii) according to the reaction scheme 10 in a manner corresponding to method k.

chart 11

<img file="SA5601B1_D0015.tif" />

10

method n

The intermediates (xvi) can be prepared from the intermediates (xv) according to the reaction scheme 11 in one vessel or by a step-by-step procedure with an amine mixture, optionally containing protected reactive sites at the orthagonal position, and a reducing agent such as NaBH4, NaBH(OAc)3, NaBH(OAc), NaCNBH3, or Et3SiH, either at room temperature or by heating up to several hours with

٥٦٠١

-٥٢-

A solvent such as alcohol, DCE, DCM, water, or toluene, and optionally a catalyst such as an acid or Lewis acid is added.

Optionally, the protecting groups can be removed and a purification method such as silica gel chromatografts can be used if needed.

5 chart 12

<img file="SA5601B1_D0016.tif" />

method s

The intermediates (xviii) can be prepared from the intermediates (xvii) according to the reaction scheme 12 corresponding to the method N.

10 inhibitory effect

The inventors surprisingly found that the compounds of Formula (I) as defined in the present application have an inhibitory effect on the activity of one or more HDMEs. In this regard, one or more of the said HDMEs may be any HDME, however it is preferable that one be selected One or more HDMEs of the Jumonji (JmjC) family, preferably one or more

15th of the HDMEs(s) is an HDME of the human JmjC family and more preferably HDME belonging to the KDM6, KDM5, KDM4 or KDM2 families. The present invention also relates to a compound of Formula (I) as defined in the present application for a method for inhibiting HDMEs. The method includes A cell comes into contact with a compound of formula (I). In a related embodiment, the method is also fair to

٥٦٠١

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The compound is present in an effective quantity to produce a concentration sufficient to inhibit histone demethylation in the cell

.demethylation of a histone in the cell

Thus, preferably in a test for demethylation of histone substrate by the aforementioned HDME, then the compounds of preferred formula (I) are compounds that can reduce or preferably be

5 This demethylation process is inhibited by the said HDME. The histone substrate in question can be any histone, but preferably histone H3 or a fragment thereof, and more preferably also: a fragment comprising K27, K9, K4, or K36 of H3. Preferably, said inhibition shall be determined in the form of an IC50 value of said compound of formula (I) with respect to said demethylation test.

10 Compounds of formula (I) are those having an IC50 at or below 1 μM concentration, more preferably less than 300 nM, eg less than 100 nM, such as less than 50 nM for the demethylation of any The histone substrate mentioned by any of said HDME. Thus compounds of formula (I) highly preferred are those having an IC50 at or below 1 μM, more preferably less than 500 nM, eg less than

15th 100 nm, as less than 50 nm with respect to the demethylation of histone H3

Methylated on at least one lysine.

In one preferred embodiment, IC50 is specified as described in Example 2 below in the present application. Thus, compounds of Formula (I) having an IC50 value at or below 1 mM, and more preferably less than 500 nm, eg less than 20 of 100 nm, such as less than 50 nm when made, are particularly preferred. Determine the stated IC50 value as described in and one of the examples below in the present application.

Especially the preferred formula (I) compounds that result in low tumor volume and/or

Morton and Houghton, (Low number of metastases when tested in an exograft model). Nature Protocols, 2 (2) 247-250, 2007

٥٦٠١

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Pharmaceutical formulations

In one aspect of this invention, a pharmaceutical composition is provided comprising, as an active ingredient, at least one compound of Formula (I) as defined in the present application and optionally one or more excipients, diluents and/or acceptable carriers 5 Pharmaceuticals Compounds of formula (I) may be administered alone or in combination with pharmaceutically acceptable carriers, diluting agents, or excipients, either in a single dose or in multiple doses. Suitable carriers, diluting agents, or excipients include solid diluents or fillers, sterile aqueous solutions and various inert organic solvents.

10

Pharmaceutical formulations may be formulated using pharmaceutically acceptable carriers or diluents as well as any other known adjuvants or excipients according to conventional techniques such as those disclosed

Remington: The Science and Practice of Pharmacy, 21st Edition, 2000, in Lippincott Williams &amp; Wilkins.

Pharmaceutical formulations formed by incorporating a compound of formula (I) can easily be given according to

15th To be defined in the present application with pharmaceutically acceptable carriers, diluting agents or excipients, in a variety of dosage forms such as tablets, powders, emulsions, syrups, suppositories, injectable solutions and the like. In powders, the carrier is broken down into a solid fine volume such as talc or starch which is in a mixture with the active ingredient broken down to a fine volume. In the tablets, the active ingredient is mixed with the carrier having the necessary binding properties in appropriate proportions and incorporated into the

20 Required shape and size.

Pharmaceutical formulations in particular may be prepared for administration by any suitable route such as the oral route and the non-gastrointestinal route (including subcutaneous, intramuscular, intrathecal, and intravenous).

٥٦٠١

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Intravenous and intradermal). We will realize that the preferred course of action depends on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

Oral pharmaceutical formulations include solid dosage forms such as capsules, tablets, lozenges, pills, lozenges, powders and granules. Where 5 is appropriate, it may be prepared by encapsulations such as enteric encapsulations or may be prepared to provide a controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.

For oral administration in tablet or capsule form, a compound of Formula (I) as defined in the present application may be suitably combined with a pharmaceutically acceptable, non-toxic orally acceptable carrier such as ethanol, glycerol, water or the like 10. In addition to the above, binders, lubricants, disintegrating agents, flavouring agents and appropriate colourants may be added to the mixture, as appropriate. Suitable binders include, for example, lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, poly-15 types of ethylene glycol, polyethylene glycol. wax or something like that. Include slippery agents

Lubricants, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like. Dissolving agents include, for example, starch, methyl cellulose R, 20 agar, bentonite, xanthan gum, sodium starch glycolate, crospovidone, croscarmellose sodium or the like. Additional excipients for the capsules include macrogollets or fats.

To prepare solid formulations such as tablets, the active compound of formula (I) is mixed with one or 25 more excipients, such as those described above, and other pharmaceutical dilution agents such as

٥٦٠١

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water to prepare a pre-formulated solid composition containing a homogeneous mixture of a compound of formula (I). The term “homogeneous” should be understood to mean a compound of formula (I) that is evenly dispersed throughout the composition so that the composition can be easily subdivided into effective unit doses Equally as tablets or capsules.

5 Liquid formulations for either oral or non-gastrointestinal administration of a compound of formula (I) include, for example, aqueous solutions, syrups, elixir, aqueous suspensions or oil emulsions with edible oils such as cottonseed oil, Sesame oil, coconut oil or peanut oil. Dispersing agents or suspending agents suitable for aqueous suspensions include synthetic or natural gums such as polysaccharides, alginate, acacia, dextran 10, sodium carboxymethylcellulose, gelatin, methylvinylpyrrolidone or polyvinylpyrrolidone.

Pharmaceutical formulations for non-GI administration include sterile injectable aqueous and non-aqueous solutions, dispersants, suspensions or emulsions as well as sterile powders that are reconstituted into sterile injectable solutions or dispersions prior to use. For non-GI 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 appropriately regulated if necessary and the liquid diluent first converted to isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Oily solutions 20 are suitable for administration into the joints, into the muscles and under the skin.

The preparation of all these solutions under aseptic conditions is easily achieved by standard pharmaceutical techniques well known to those skilled in the art.

The present invention also anticipates injectable depot formulations as being in the scope of its field.

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In addition to the aforementioned ingredients, formulations of a compound of formula (I) may include one or more additional ingredients such as thinning agents, buffer solutions, flavoring agents, colorants, surface active agents, thickening agents, preservatives, for example For example, methyl hydroxybenzoate (including antioxidants), emulsifying agents and the like.

5 The appropriate dose of a compound of formula (I) depends on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practicing physician.

The compound, for example, can be administered either orally, trans-gastrointestinal or topically according to different dosing schedules, eg, daily or at intervals, such as weekly intervals. Generally a single dose will consist in the range of 0.01 to 100 mg/kg bw, preferably about 0.05 to 75 mg/kg bw, more preferably 0.1 to

50 mg/kg body weight, preferably between 0.1 to 25 mg/kg body weight. The compound may be administered as a large dose (i.e., the total dose given once daily) or in divided doses two or more times a day. Variations based on the above-mentioned dosage range values ​​may be made by a physician of ordinary skill in 15 The range taking into account known considerations such as weight, age, condition of the person being treated, severity of the lesion, and specific route of administration.

Compounds of Formula (I) may also be prepared in a pharmaceutical composition comprising one or more other active ingredients alone, or in combination with pharmaceutically acceptable carriers, diluting agents, or excipients either in a single dose or in several doses. The pharmaceutically acceptable excipients are 20, as described above, and one or more of the other active ingredients may be any active ingredients, or preferably an active ingredient as described in the “Combination Therapy” section below in the present application.

Clinical conditions and other uses of the compounds

٥٦٠١

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Compounds of Formula (I) as defined in the present application are useful for the treatment of an HDME-dependent disease, disorder, or condition. Treatment may include administration to a breast, preferably human, and more preferably human suffering from an HDME-dependent disease, a therapeutically effective amount of the compound According to formula (I) as defined in the present application.

5 Said HDME can be any HDME, however HDME is preferred of the method

Clos et. al., as described in JmjC, the present Jumonji are selected from the family

2008 1115-1140, 22 Genes &amp; Development, which is included in the present application as a reference in its entirety. More preferably, the aforementioned HDME is a human JmjC-family HDME.

The present invention also relates to a compound of formula (I) as defined in the present application for use in the treatment of HDME-based disease, eg for the treatment of cancer.

“HDME-dependent disease” means any disease characterized by elevated HDME expression and/or activity in at least some examples of disease, or disease that is mitigated by reduced activity of HDMEs. Thus, the disease to be treated with HDME inhibitors, ie, compounds of formula (I), can be a proliferative or

benign or malignant includes benign or malignant tumors, hyperproliferative disease 15

tumors , for example a proliferative or hyperproliferative disease that is selected from the group consisting of brain, kidney, liver, adrenal gland, bladder, breast, stomach (for example gastric tumors), ovaries, esophagus, colon colon rectum 20, prostate, pancreas, lung, vagina, thyroid

thyroid, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, eg, colon or colorectal cancer, neck and head, and epidermal hyperproliferation eg Example, psoriasis

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psoriasis, prostate hyperplasia, neoplasms, including epithelial neoplasms, including breast cancer, and leukemia.

In one embodiment, compounds of Formula (I) as defined in the present application are useful in the treatment of one or more types of cancer. The term “cancer” refers to any cancer caused by the proliferation of tumor cells.

5 New, such as solid tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. In particular, types of cancer that can be treated by the compounds, formulations and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, 10 rhabdomyosarcoma, liposarcoma), myxoma myxoma,

rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), bronchial adenoma, sarcoma, lymphoma, hamartoma, chondromatosis tumor

middle mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulincarcinoma, 20 glucagonoma, gastrinoma, tumors

large bowel bowel (adenocarcinoma, 25 tubular adenoma, villous adenoma, tumor

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hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilm's nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) prostate (adenocarcinoma,

5 sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcfnoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroadenoma, fibroadenoma, lipoma); liver: hepatoma, hepatocellular carcinoma, cholangiocarcinoma,

<p dir="rtl">10 angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple cell sarcoma, myeloma, multiple myeloma, chondrosarcoma, Ewing's sarcoma chordate</p>

<p dir="rtl">15th malignant giant cell tumor chordoma</p>

osteocartilaginous osteochondrosis (osteochronfroma

exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors

<p dir="rtl">20 Nervous system: skull (bone, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcorna, gliomatosis, astrobrain, gliomatosis), brain medulloblastoma, glioma, tumor</p>

25 ependymoma, germinoma [pinealoma], glioblastoma multiform, glioma

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oligodendroglioma, schwannoma, retinoblastoma, congenital tumors (spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: axis of the uterus

<p dir="rtl">5 endometrial carcinoma, cervix, cervical carcinoma, pre-tumor cervical dysplasia, ovaries (ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, mucinous cystadenocarcinoma) Unclassified carcinoma, unclassified carcinomas</p>

<p dir="rtl">10 granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, vulva (squamous cell carcinoma, intraepithelial carcinoma, fibrosarcoma, fibrosarcoma, sarcoma, fibrosarcoma) melanoma, vagina (clear cell carcinoma</p>

<p dir="rtl">15th clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (acute and chronic myeloid leukemia) acute lymphoblastic leukemia,</p>

<p dir="rtl">20 chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma; Skin: malignant melanoma</p>

25 melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, and dysplastic nevus

٥٦٠١

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moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; Adrenal glands: neuroblastoma.

In one embodiment, compounds of Formula (I) as defined in the present application are in the treatment of one or 5 more cancers selected from the group consisting of:

Acute myeloid (AML) lymphocytic leukemia

leukemia, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (CML) and hair cell leukemia

<p dir="rtl">10 Hairy Cell Leukemia; Cutaneous T-cell lymphomas, non-subcutaneous T-cell lymphomas, cutaneous T-cell lymphomas, human T-cell lymphoma virus-associated lymphomas such as leukemia/lymphoma Adult T-cell leukemia/Iymphoma (ATLL), Hodgkin's lymphoma and non-Hodgkin's disease</p>

<p dir="rtl">15th Hodgkin's, Diffuse large B-cell lymphoma, DLBCL diffuse large B-cell lymphoma; Burkitt's lymphoma; mesothelioma, lymphoma of the main central nervous system ) CNS pri mary central nervous system; multiple myeloma; childhood solid tumors, such as brain tumors</p>

<p dir="rtl">20 neuroblastoma, retinoblastoma, Wilm's tumor, bone tumors, soft-tissue sarcomas, common solid tumors such as head and neck cancers (eg, of the mouth, larynx, esophagus laryngeal and esophageal, genito urinary cancers (for example the prostate)</p>

25 bladder, kidneys, uterus, ovaries, testicles, rectum and colon), lung cancer, breast cancer,

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pancreatic cancer, melanoma and other types of skin cancer, stomach cancer, brain tumors, liver and thyroid cancer.

In a highly preferred embodiment, a compound of formula (I) as defined in the present application is useful in the treatment of squamous cell carcinomas. Preferably squamous cell carcinomas include

5 The types of carcinoma of the squamous epithelium, which may occur in many different organs, including cancer of the skin, lips, mouth, esophagus, urinary bladder, prostate, lungs, vagina and cervix, brain cancer, which is neuroblastoma, glioblastoma and other tumors benign and malignant brain; Breast cancer, pancreatic cancer, and multiple myeloma.

10 In yet another embodiment, compounds of formula (I) as defined in the present application are useful in the treatment of brain cancer, neoplasms in adults such as head and neck cancers (eg, mouth, larynx and esophagus), genitourinary cancers (for example, prostate, bladder, kidney, uterus, ovary, testis, rectum, colon), and breast cancer.

Other forms of cancer may be found for which compounds of formula (I) are useful

Lippincott Williams &amp; Wilkins, 28th Ed., ( Stedman's Medical dictionary 15 in

2005), which are incorporated into the present application for reference in their entirety.

In another embodiment also related, the disease to be treated with compounds of Formula (I) as defined in the present application is selected from persistent or hypermetastatic conditions such as angiogenesis, such as psoriasis, Kaposi's sarcoma, restenosis

20 restenosis, eg, stent-induced restenosis, endometriosis, Hodgkin's disease; leukemia, hemangioma, and angiofibroma; Or the land of the eyes, eye diseases, such as the new awareness. The neovascular glaucoma, or renal diseases, such as glomerulonephritis

٥٦٠١

-٦٤-

malignant nephrosclerosis and glomerulonephritis

thrombotic microangiopathic syndromes, transplant rejections, glomerulopathy; fibrotic diseases, such as cirrhosis of the liver and cirrhosis of the liver, or reproductive diseases

5 cells; injuries to nerve tissue; and inhibition of vascular re-occlusion after balloon catheter therapy, for use in vascular prostheses or after insertion of mechanical devices to stabilize open vessels, eg, stents, and as immune-suppressants, as an aid in the free healing of scar-free wounds -free wound healing, treating age spots and dermatitis

10 contact dermatitis

Compounds of Formula (I) are suitable as active agents in pharmaceutical formulations that are efficient for the treatment of proliferative or hyperproliferative diseases and/or diseases associated with genetic irregularities. These pharmaceutical formulations include a therapeutically effective amount of a compound of Formula (I). In addition to other pharmaceutically acceptable excipients, carriers, and diluents.

15th therapeutically” according to its use in the current application to an amount necessary for administration to a host, or to a cell,

tissue, or organ of the host, to achieve a curative effect, for example mitigating or alternatively a curative effect,

For example anti-tumor effect, for example, reducing or preferably inhibiting proliferation

malignant cancer cells, benign tumor cells or other reproductive cells, or from any

Another HDME-dependent disease.

20 Another aspect of the invention is a pharmaceutical composition comprising a therapeutically active amount of at least one compound of formula (I) as defined in the present application, or a pharmaceutically acceptable salt, soluble or prodrug thereof, in combination with at least one antigen For other tumors, a pharmaceutically acceptable excipient, a carrier or a diluent.

treatment method

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In another aspect, the present invention relates to a method for treating disease in a subject, the said method includes giving the said subject a therapeutically effective amount of at least one compound of formula (I) as defined in the present application. The disease can be any disease or disorder according to For what was mentioned in the present application, for example the example mentioned in the section "HDME-based mothers", and 5 the compound can be given alone or in a pharmaceutical composition, an example of the example mentioned in the section "pharmaceutical formulations".

Hence, the invention also relates to a compound of formula (I) as defined in the present application for use as a medicine.

The terms “cure” and “cure,” as used in the present application, unless otherwise indicated, mean the reversal, elimination, inhibition of a process, or prevention of a disease, disorder or condition to which it applies.

This term, or one or more symptoms of a disease, disorder or condition in question and includes administration of a compound of formula (I) to prevent the onset of a symptom or complication, or to eliminate a symptom or complication, or to eliminate a disease, condition, or Press, preferably, treatment is curative or mitigating.

15th In a preferred embodiment of this aspect of the invention the method is a method for treating an HDME-dependent disease in a subject, the said method comprising administering to said subject a therapeutically effective amount of a compound of formula (I) as defined in the present application to a subject in need of Said treatment HDME disease may be any HDME disease as previously described in the present application Preferably HDME disease that is squamous cell carcinoma or any of the 20 other precancerous conditions previously mentioned.

Hence, the invention also relates to a compound of formula (I) as defined in the present application for use in the treatment of an HDME-dependent disease, such as a treatment for cancer.

Furthermore, the invention relates to the use of a compound of formula (I) as defined in the present application to prepare a pharmaceutical composition for the treatment of HDME-dependent disease.

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In one embodiment of an HDME disease treatment method, a compound of formula (I) as defined in the present application is administered in combination with one or more additional active substances. The active substances may be any active substances, preferably an active substance As described in the present application previously in the section “Combination Therapy.” More preferably one or more of the active substances is selected

5 additional from the group consisting of antiproliferative or antineoplastic agents.

Treat the combination

A compound of formula (I) may also be used for use in combination with one or more other antiproliferative or antineoplastic agents. Antiproliferative agents include, but are not limited to, HDME inhibitors, liposome inhibitors, including bortezomib.

<p dir="rtl">10 Valcade and Carfilzomib, aromatase inhibitors; antiestrogens; I topoisomerase inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone inhibitors that stimulate deacetyla processes; Cell;cyclooxygenase inhibitors;MMP inhibitors;mTOR inhibitors;antagonists of metabolites</p>

<p dir="rtl">15th anti-tumor; platinum compounds; Compounds target/reduce protein or lipid kinase activity as well as antiangiogenic compounds; Compounds that target, reduce, or inhibit the activity of a protein or lipid phosphatase; gonadorelin aids; anti-androgens; angiostatic steroids; methionine aminopeptidase inhibitors; bisphosphonates</p>

<p dir="rtl">20 bisphosphonates ; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; Agents used in the treatment of hematological malignancies</p>

<p dir="rtl">25 hematologic malignancies; Compounds that target, reduce, or inhibit the activity of 3-;Flt</p>

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Hsp90 inhibitors; TEMOD AL(R) temozolomide); leucovorin; immunostimulating agents, such as BCG, IL-2 or IFN-α, antibodies, such as rituximab or herceptin, and cancer vaccines.

A compound of formula (I) as defined in the present application may also be used to improve in combination with

<p dir="rtl">5 Known therapeutic processes, for example, administration of hormones or methods of destroying a tumor cell, especially ionizing radiation.</p>

A compound of formula (I) as defined in the present application may also be used as a radiosensitizing agent, including, for example, in the treatment of tumors showing poor sensitivity to radiotherapy.

<p dir="rtl">10 The term “combination” means either a fixed combination in the form of a single dose unit, or a set of parts for co-administration in which a compound of formula (I) and a combination partner may be administered independently at the same time or separately at intervals allowing in particular that The factors involved in the combination exhibit a synergistic effect, eg, synergistic, or any combination thereof.</p>

The phrase, “an aromatase inhibitor” as used in the present application relates to a compound that inhibits estrogen production

<p dir="rtl">15th estrogen, that is, the conversion of the substrates androstenedione and testosterone into estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane, and in particular, non-steroidal compounds, notably aminoglutethimide and roglethimide,</p>

20 Pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane may be given, for example, in the form in which it is marketed, for example, under the brand name AROMASIN. Formestane may be given, for example, in the form in which it is marketed,

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For example, under the LENTARON brand. Fadrozole, for example, may be given in the form in which it is marketed, for example, under the brand name AFEMA. Anastrozole, for example, may be given in the form in which it is marketed, for example, under the brand name ARIMIDEX. Letrozole can be given

5 Letrozole, for example, is in the form in which it is marketed, for example, under the trademark FEMARA or FEMAR. Aminoglutethimide, for example Aminoglutethimide, may be given in the form in which it is marketed, for example, under the brand name ORIMETEN. A combination of the invention comprising a chemotherapeutic agent representing an aromatase inhibitor is particularly useful for treating hormone receptor-positive tumors, eg, 10 breast tumors.

The term “antiestrogen” as used herein relates to a compound that antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen may be given, for example, in the form that is marketed, for example, under the brand name NOLVADEX. Arloxphene hydrochloride may be given,

For example, in an image that is marketed, for example, under the brand name EVISTA. Fulvest Arnet may be shaped as disclosed in US Pat. No. 4659516 or may be given, for example, in a form that is marketed, eg, under the brand name FASLODEX. The combination of the invention includes a chemotherapeutic agent which is an anti-estrogen specifically useful in the treatment of estrogen receptor-positive tumors, eg, breast tumors. The term “anti-androgen” as used herein relates to any substance which is capable of inhibiting the effects of Biological androgenic hormones including, but not limited to, bicalutamide

25 CASODEX (bicalutamide), which is formed, for example, as disclosed in US Pat. No. 4636505. The phrase, “gonadotropin co-factor” as used herein includes, but is not limited to, abarelix, goserelin

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and goserelin acetate. Goserelin is disclosed in US Patent No. 4100274 and may be administered, for example, in a form marketed, eg, under the brand name ZOLADEX. Aparelix may be formed, for example, as disclosed in US Pat. No. 5843901. The phrase includes, “rice topoisomeric inhibitor I” as used

5 Here, but not limited to topotecan, gematican, irinotecan, camptothecane and their analogues, 9-nitro-nitrocamptothecin and large camptothecin are attached.

PNU-66148-1 (compound Al in I.A. No. 17804-99). Irinotecan, for example, may be given in a form marketed, eg, under the brand name CAMPTOSAR. Topotecan, for example, may be given in

10 Image marketed as, for example, the brand name HYCAMTIN. The term includes, "a rice-II topoisomer inhibitor" as used herein, but is not limited to anthracyclines such as doxorubicin (including formulations

Lipids, eg, CAELYX (, daunorubicin, epirubicin, idarubicin and nemorubicin, antR-quinone compounds mitoxantrone

15th anthraquinones mitoxantrone, losoxantrone, podophyllotoxins etoposide and teniposide. Etoposide may be given, for example, in a form marketed, eg, under the brand name ETOPOPHOS. Tenoposide may be given, eg, in the form marketed, eg, under the brand name VM 26-BRISTOL. Doxorubicin, eg, can be given in

20 An image that is marketed, for example, under the brand name ADRIBLASTIN or ADRIAMYCIN. Iprobicin may be given, for example, in a form marketed, eg, under the brand name FARMORUBICIN. Idarubicin, eg, may be given in a form marketed, eg, under the brand name ZAVEDOS. Mitoxantrone may be given, for example, in a form that is marketed, for example, under the brand name NOVANTRON.

25 The term relates, to "tubular active factor", to microtubule-inducing agents, microtubular non-stabilizing agents and polymerization inhibitors and includes, but is not limited to, taxanes.

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taxanes, such as paclitaxel and docetaxel, vinca alkaloids, such as vinblastine, including vinblastine sulfate

5 discodermolides, cochicine, and epothilones and derivatives thereof, eg, epothilone B or D and derivatives thereof. Paclitaxel may be given as, eg, in pi]n] that is marketed, eg, TAXOL. Docetaxel may be given, for example, in a form marketed as, for example, the brand name TAXOTERE. Vinblastine sulfate may be given, eg, in the form that is marketed, eg,

<p dir="rtl">10 The brand name VINBLASTIN RP may be given vincristine sulfate, for example</p>

Example, in the image being marketed, for example, under the FARMISTIN brand name. Discodermolide may be obtained, eg, as disclosed in US Pat. 5010099. Derivatives of ibutylone which are disclosed in I.A. 10121/98, J.P. 6194181, I.P.N. 25929/98, I.C. are also included here. No. 08849/98,

<p dir="rtl">15th International Application No. 43653/99, International Application No. 22461/98 and International Application No.</p>

31247 00 . They are epoxylon A and/or B.

The phrase, “alkylation agent” as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or BCNU (nitrosourea or Gliadel). Cyclophosphamide may, for example, be given in

<p dir="rtl">20 Image marketed, ie, under the brand name CYCLOSTIN. Ifosfamide, for example, may be given in the form marketed, ie, by the brand name HOLOXAN. The phrase, “histone deacetylases inhibitors” or “HDAC inhibitors” relates to compounds that inhibit at least one example of a class of enzymes known as histone deacetylases, and generally have antiproliferative activity. Previously detected HDAC inhibitors include compounds that have been</p>

25 disclosed, for example, in International Application No. 22577/02, and includes:

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N-hydroxy-3-[4-{[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3- [4-[[[2-(2-methyl-1H-indol-3-yl)-ethylJ-amino]methyl]phenyl]-2E-2-propenamide

And the salts are pharmaceutically acceptable. It also includes Superoyl Anilide Hydroxamic Acid (SAHA).

<p dir="rtl">5 Suberoylanilide hydroxamic acid. HDAC inhibitors are generally detected including butyric acid and its derivatives, including sodium phenylbutyrate.</p>

phenylbutyrate, thalidomide, trichostatin A and trichostatin

trapoxin.

The term "antitumor metabolic" includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine,

DNA demethylating agents, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine, in the marketed form, ie, may be given under the brand name XELODA. Gemcitabine is given, such as,

<p dir="rtl">15th In the image being marketed, i.e., under the brand name GEMZAR. A monoclonal antibody trastuzumab that can be administered is also used, for example, in a form marketed, ie, under the brand name HERCEPTIN.</p>

The expression, "compound platin" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin.

<p dir="rtl">20 oxaliplatin; Carbobaltin, eg, may be given in the form marketed, ie, under the brand name CARBOPLAT. Oxaliplatin may be administered, eg, in the form marketed, ie, under the brand name ELOXATIN.</p>

Tumor cell destruction methods refer to methods such as ionizing radiation. The phrase, “ionization radiation” refers to the above and here means radiation with ions which occurs in the form of any of the electromagnetic radiation (

<p dir="rtl">25 . Radiation provided</p>

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. ion therapy, without limitation, is radiotherapy and is well known in the art

Hellman, Principles of Radiation Therapy, Cancer, in Principles, for example

and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp.

248-275 (1993).

<p dir="rtl">5 The phrase, “angiostatic steroids” as used herein refers to agents that inhibit or inhibit angiogenesis, such as, eg, anecortave, triamcinolone</p>

hydrocortisone, 11-[alpha]-epihydrocotisol, cortexolone, 17[alpha]-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone,

estrone, dexamethasone and n-dexamethasone.

<p dir="rtl">10 Other chemotherapeutic agents include, but are not limited to, plant alkaloids, hormonal agents and antagonists; biological response modifiers, preferably lymphokines or interferons; oligonucleotides against transcription direction oligonucleotide derivatives or oligonucleotides;</p>

<p dir="rtl">15th or various factors or factors with other mechanisms or mechanisms of unknown action. The structure of active agents defined by coding numbers, or generic or trade names can be obtained from the physical version of "The Merck Index" or from databases, eg, international patents (eg, IMS).</p>

The previously mentioned compounds, which can be used in combination with a compound of the formula ., can be prepared

20 (I), given as described in the field such as in the previously mentioned documents.

Furthermore, the compounds of the invention may be used in a method for identifying functionally and structurally similar features of enzymes of histone demethylases comprising a group of at least two histone demethylases and a group of at least two of the compounds of formula 1 and of determining the extent to which a compound of formula 1 By inhibiting the activity of the aforementioned histone methylases,

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The generation of a similarity coefficient reflects the degree of similarity between the enzymes of histone demethylases in relation to their inhibition by the mentioned compounds.

Examples

Example 1: Examples of compounds having formula (I)

5 General methods and materials

The following table 1 shows examples of compounds according to the invention and indicates the methods that can be used in

Sigma-Aldrich, Alfa Aesar, Matrix, Synthesis. All chemicals purchased from Aldrich are Combiblock, Oakwood, and Chembridge anhydrous solvents.

Sure/Seal™. All reactions are carried out in nitrogen atmosphere using dry solvents. The reactions were monitored by means of a thin layer shelf chromatogram performed on silica gel plates of up to 10 mm.

Size 0.25 mm (60 Å Sigma-Aldrich, fluorescent indicator). Spots seen under UV light (254 nanometers).

Biotage SNAP on Flash column chromatography

Flash System, or silica gel 60 silica gel (particle size 0.032–0.063 mm) Obtained from Silicycle, Inc. Low purity ES mass spectra obtained (Spray

Electrospray) using a Micromass Quattro Ultima mass spectrometer in positive (ES+) or negative (ES-) ion mode. The -1H NMR spectra were recorded on a Bruker AM-300 spectrophotometer and calibrated with a calibrated anisotropic solvent as reference. . Internal spectra were processed using Spinworks CC

Dr. Kirk Marat, Department of Chemistry, University of 20 2,5 (Developed by

Manitoba. Preparatory HPLC was performed on 2996 Waters equipped with a photodiode array detector, 600 Waters controller, 100Waters pump, and 717Waters self-sampling unit, with UV detection at 254 and 280 nm. Flow rate: 15ml/min, running time 30 minutes. Solvents: 0-100% (H2O-MeOH), with

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or without adding 0.1% (TFA). The column used is Supelco C18, 25 cm×

21.2 mm, particle size 10 μm.

Queguiner, G. and Ethyl 2-formylpyridine-4-carboxylate was similarly prepared for Pastour, P. (Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques (1969), 268(2), 182-5) 5

Table 1

<tr><td><p>NMR</p></td><td><p dir="rtl">synthesis method</p></td><td><p dir="rtl">name</p></td><td><p>#</p></td><td><p dir="rtl">structural formula</p></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD), δ ppm: 8.10 (s, 1H), 7.98</p><p>(dd, 1H), 7.80 (t, 1H), 7.65 (t, 1H), 4.58 (s, 2H), 4.50 (t, 2H).</p></td><td><p dir="rtl">a</p></td><td><p>2-({[3-(1H-imidazol-1-</p><p>yl)propyl]amine o}methyl)pyrid ine-4-</p><p>carboxylic acid</p></td><td><p>1</p></td><td></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD), δ ppm: 8.03 (s, 1H), 4.58 (s, 2H), 3.63</p></td><td><p dir="rtl">a</p></td><td><p>2-({[2-(dimethylamin o)ethyl]amino}methyl)pyridin e-4-</p><p>carboxylic</p></td><td><p>2</p></td><td></td></tr>

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<tr><td><p>(m, 4Η), 3.0 (s, 6Η).</p></td><td></td><td><p>acid</p></td><td></td><td></td></tr><tr><td><p>1Η NMR (300 MHz, CD30D), δ ppm: 8.12 (s, 1Η), 4.04</p><p>(m, Hi), 3.62 (m, 2Η), 335</p><p>(m, hi),</p><p>3.18 (dd, 1Η).</p></td><td></td><td><p>2-({[(2R)_)</p><p>2,3-dihydroxypropyl]amino}meth yl)pyridine-4-carboxylic</p><p>acid</p></td><td><p dir="rtl">٣</p></td><td><p>HO.o</p></td></tr><tr><td><p>1Η NMR</p><p>(300 MHz, CD30D), δ ppm: 4.56 (s, 2Η), 3.08 (d, 2Η), 1.21</p><p>(m, 1Η), 0.75 (m,</p><p>2Η), 0.47 (m, 2Η).</p></td><td></td><td><p>2-{[(cyclopropyl methyl)amino] methyl}pyridin e-4-carboxylic acid</p></td><td><p dir="rtl">٤</p></td><td><p>Hz</p></td></tr>

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<tr><td><p>1H-NMR</p><p>(300MHz, CD3OD), δ ppm: 8.0 (s, 1H), 4.42(s, 2H), 2.80(s, 6H).</p></td><td><p dir="rtl">a</p></td><td><p>2-{[(cyclopropyl methyl)amino] methyl}pyridin</p><p>e-4-carboxylic acid</p></td><td><p>5</p></td><td></td></tr><tr><td><p>1H NMR</p><p>(300 MHz, CD3OD), δ ppm: 8.16(s, 1H), 4.76 (s, 2H), 3.80 (s, 4H).</p></td><td><p dir="rtl">a</p></td><td><p>2-({[2-(dimethylamin o)ethyl](methy l)amino}methy l)pyridine-4-</p><p>carboxylic acid</p></td><td><p>6</p></td><td></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD), δ ppm: 7.93 (s, 1H), 3.77 (s, 2H), 3.39</p><p>(s, 2h).</p></td><td><p dir="rtl">a</p></td><td><p>2-</p><p>{[methyl(prop</p><p>-2-yn-1-yl)amino]meth yl}pyridine-4-</p><p>carboxylic acid</p></td><td><p>7</p></td><td></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD), δ ppm: 7.85</p></td><td><p dir="rtl">a</p></td><td><p>2-{[(2-fluoroethyl)am ino]methyl}pyr</p><p>idine-4-</p></td><td><p>8</p></td><td></td></tr>

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<tr><td><p>(t, 1Η), 4.49</p><p>(t, 1Η), 4.02</p><p>(s, 2Η).</p></td><td></td><td><p>carboxylic</p><p>acid</p></td><td></td><td></td></tr><tr><td><p>1Η NMR (300 MHz, CD30D), δ ppm: 7072 (s, 1Η), 6.30 (d, 1Η), 6.22 (d, 1Η), 3.78</p><p>(s, 2Η).</p></td><td></td><td><p>2-{[(furan-2-ylmethyl)amin o]methyl}pyrid ine-4-carboxylic acid</p></td><td><p dir="rtl">٩</p></td><td><p dir="rtl">HO MEAT GOLD</p></td></tr><tr><td><p>1Η NMR</p><p>(300 MHz, CD30D), δ ppm: 7.75</p><p>(s, 1Η), 6.68</p><p>(s, 1Η), 6.38</p><p>(s, 1Η), 3.85</p><p>(s, 2Η).</p></td><td></td><td><p dir="rtl">-5)a))-2</p><p>phenylfuran-</p><p>2-</p><p>yl)methyl]ami no}methyl)pyri dine-4-</p><p>carboxylic acid</p></td><td><p dir="rtl">١٠</p></td><td><p>HO m</p><p dir="rtl">NS</p><p dir="rtl">Ji Lou</p></td></tr><tr><td><p>1Η NMR (300 MHz, CD30D), δ ppm: 7.84 (s, 1Η), 7.15</p></td><td></td><td><p dir="rtl">-2,4)a))-2</p><p>dimethoxyphe nyl)methyl]am ino}methyl)pyr idine-4-</p></td><td><p dir="rtl">١١</p></td><td><p>HjC'5</p></td></tr>

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<tr><td><p>(s, 1h), 3.85</p><p>(s, 2H), 3.70</p><p>(s, 2h).</p></td><td></td><td><p>carboxylic</p><p>acid</p></td><td></td><td></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD), δ ppm: 7.85</p><p>(s, 1H), 3.96 (s, 2H), 2.82 (t, 2H), 2.67</p><p>(t, 2h).</p></td><td><p dir="rtl">a</p></td><td><p>2-({[2-(methylsulfan yl)ethyl]amino }methyl)pyridi ne-4-</p><p>carboxylic acid</p></td><td><p>12</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4): δ ppm: 7.70 (s, 1H), 3.70</p><p>(s, 2H), 4.0</p><p>(s, 2H), 3.40</p><p>(m, 6h).</p></td><td><p dir="rtl">NS</p></td><td><p>2-({[2-oxo-2-(pyrrolidin-</p><p>1-yl)ethyl]amino}methyl)pyridi ne-4-</p><p>carboxylic acid</p></td><td><p>13</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ ppm: 7.7 (s,</p></td><td><p dir="rtl">NS</p></td><td><p>2-[({[butyl(methy l)carbamoyl]m ethyl}amino)m</p></td><td><p>14</p></td><td></td></tr>

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<tr><td><p>1h), 3.7 (s,</p><p>2h), 3.4 (s,</p><p>2H) 3.2 (m,</p><p>2h).</p></td><td></td><td><p>ethyl]pyridine</p><p>-4-carboxylic acid</p></td><td></td><td></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD), δ ppm: 7.84 (s, 1H), 4.16 (s, 2H), 4.02 (s, 2H), 3.90</p><p>(s, 3h).</p></td><td><p dir="rtl">a</p></td><td><p>2-({[(1-methyl-1H-</p><p>1,3-benzodiazol-</p><p>2-yl)methyl]ami no}methyl)pyri dine-4-</p><p>carboxylic acid</p></td><td><p>15</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ ppm: 7.7 (s,</p><p>1h), 3.7 (s,</p><p>2h), 3.3 (s,</p><p>3H), 1.8</p></td><td><p dir="rtl">NS</p></td><td><p>2-[({2-[4-(2-methoxyethyl)) piperazin-1-yl]-2-</p><p>oxoethyl}amine o)methyl]pyrid ine-4-</p><p>carboxylic acid</p></td><td><p>16</p></td><td></td></tr>

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<tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ ppm: 7.7 (s,</p><p>1H), 5.6 (m, 2H), 4.9 (m, 4H), 3.5 (s,</p><p>2h).</p></td><td><p dir="rtl">NS</p></td><td><p>2-</p><p>[({[bis(prop-2-en-1-</p><p>yl)carbamoyl]methyl}amino)methyl]pyridin e-4-</p><p>carboxylic acid</p></td><td><p>17</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ</p><p>ppm: 7.7 (s, 1H), 4.2 (m, 1H), 3.4 (m, 6H), 3.0 (m,</p><p>1h).</p></td><td><p dir="rtl">NS</p></td><td><p>2-[({2-oxo-</p><p>2-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrro lidin-1-yl]ethyl}amino (methyl]pyridi ne-4-</p><p>carboxylic acid</p></td><td><p>18</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ</p><p>ppm: 7.75</p><p>(s, 1h), 3.85</p><p>(s, 1h), 1.50</p></td><td><p dir="rtl">a</p></td><td><p>2-({[(3R)-1-[(tert-butoxy)carbon yl]pyrrolidin-3-yl]amino}meth</p></td><td><p>19</p></td><td></td></tr>

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<tr><td><p>(s, 9h).</p></td><td></td><td><p>yl)pyridine-4-carboxylic acid</p></td><td></td><td></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD), δ ppm: 7.72 (s, 1H), 6.32 (d, 1H), 6.20 (d, 1H), 4.00</p><p>(s, 2h), 3.84(s, 2h).</p></td><td><p dir="rtl">NS</p></td><td><p>2-({[(3R)-1-[(tert-butoxy)carbon yl]pyrrolidin-</p><p>3-yl]amino}meth yl)pyridine-4-carboxylic</p><p>acid</p></td><td><p>20</p></td><td></td></tr><tr><td><p>1H NMR</p><p>(300MHz,</p><p>D2O), δ ppm: 7.96</p><p>(s, 1h), 4.48</p><p>(s, 2H), 2.92-3.25</p><p>(m, 8h).</p></td><td><p dir="rtl">NS</p></td><td><p>2-{[(3-{[3-(pyrrolidin-1-yl)propyl]amin o}propyl)amin o]methyl}pyrid ine-4-</p><p>carboxylic acid</p></td><td><p>21</p></td><td></td></tr><tr><td><p>1H-NMR (300MHz, CD3OD), δ ppm: 7.80</p><p>(s, 1h),</p></td><td><p dir="rtl">a</p></td><td><p>2-{[(3-methylbutyl)a mino]methyl}p</p><p>yridine-4-carboxylic</p></td><td><p>22</p></td><td></td></tr>

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<tr><td><p>3.90(s, 2h),</p><p>2.60 (m, 2h), 0.92 (d, 6h).</p></td><td></td><td><p>acid</p></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ ppm: 7.9 (s,</p><p>1h), 3.8 (s,</p><p>2H), 3.5 (m, 4H), 2.3 (m, 2</p></td><td><p dir="rtl">NS</p></td><td><p>2-[({[(2-carbamoyleth yl)(methyl)car bamoyl]methyl }amino)methyl]pyridine-4-</p><p>carboxylic acid</p></td><td><p>23</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ ppm: 7.9 (s,</p><p>1h), 3.9 (s,</p><p>2H), 3.5 (m, 2H).</p></td><td><p dir="rtl">NS</p></td><td><p>2-[({2-[2-(hydroxymeth .)]</p><p>yl)piperidin-</p><p>1-yl]-2-oxoethyl}amin o)methyl]pyrid ine-4-</p><p>carboxylic acid</p></td><td><p>24</p></td><td></td></tr><tr><td><p>1H-NMR (300MHz, MeOH-d4):</p><p>δ 7.7 (s,</p><p>1h), 6.7 (d,</p></td><td><p dir="rtl">NS</p></td><td><p>2-{[({methyl[3-(1-methyl-1H-imidazol-]</p><p>2-</p></td><td><p>25</p></td><td></td></tr>

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-٨٣-

<tr><td><p>1h), 6.6 (d,</p><p>1h), 3.7 (s,</p><p>2h), 3.5 (s,</p><p>3h).</p></td><td></td><td><p>yl)propyl]carb amoyl}methyl)amino]methyl}pyridine-4-carboxylic acid</p></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ ppm: 7.7 (s,</p><p>1h), 3.7 (s,</p><p>2H), 3.4 (m,</p><p>2H), 3.3 (m,</p><p>3H), 1.0 (t, 3H).</p></td><td><p dir="rtl">NS</p></td><td><p>2-{[({[(1-ethylpyrrolidin</p><p>-2-yl)methyl]carb amoyl}methyl)amino]methyl}</p><p>pyridine-4-carboxylic</p><p>acid</p></td><td><p>26</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ ppm: 7.7 (s,</p><p>1h), 7.6 (d,</p><p>1h), 7.3 (d,</p><p>1h), 6.3 (d,</p><p>1h), 4.6 (s,</p><p>2h), 4.0 (s, 2h).</p></td><td><p dir="rtl">NS</p></td><td><p>2-{[({methyl[(1-methyl-1H-pyrazol-5-yl)methyl]carb amoyl}methyl) amino]methyl} pyridine-4-carboxylic acid</p></td><td><p>27</p></td><td></td></tr>

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<tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ</p><p>ppm: 7.80</p><p>(s, 1h), 7.20</p><p>(m, 5h), 3.85 (s, 2h).</p></td><td><p dir="rtl">Dr</p></td><td><p>2-({[(3R)-1-(3-phenylpropyl)pyrrolidin-3-yl]amino}meth yl)pyridine-4-carboxylic acid</p></td><td><p>28</p></td><td></td></tr><tr><td><p>1H-NMR (300MHz,</p><p>CD3OD), δ ppm: 7.82(s, 1H), 7.26(m, 2H), 6.94(m, 2H), 3.90(s, 2H), 3.85(s, 3H), 3.62(s, 2H), 3.24( s,</p><p>2h).</p></td><td><p dir="rtl">h</p></td><td><p>2-({[({1-[(2-methoxyphen yl)methyl]]pipe ridin-4-</p><p>yl}carbamoyl)methyl]amino}methyl)pyridin e-4-</p><p>carboxylic acid</p></td><td><p>29</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, CD3OD), δ ppm: 7.84(s,</p><p>1H), 3.92(s, 2H), 3.78(m,</p></td><td><p dir="rtl">h</p></td><td><p>2-{[({[1-(3-phenylpropyl) piperidin-4-yl]carbamoyl} methyl)amino] methyl}pyridin</p></td><td><p>30</p></td><td></td></tr>

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<tr><td><p>2h), 3.24(s,</p><p>2H), 2.96(m,</p><p>2h).</p></td><td></td><td><p>e-4-carboxylic acid</p></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, CD3OD), δ</p><p>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,</p><p>2h).</p></td><td><p dir="rtl">h</p></td><td><p>2-{[({[1-</p><p>(furan-2-ylmethyl)piper</p><p>idin-4-yl]carbamoyl}methyl)amino]methyl}pyridin</p><p>e-4-</p><p>carboxylic acid</p></td><td><p>31</p></td><td></td></tr><tr><td><p>1H-NMR (300MHz,CD</p><p>3OD), δ ppm: 7.82</p><p>(s,1H),6.70(s,1H),6.40(d,1 H),3.92(s,2H)</p></td><td><p dir="rtl">h</p></td><td><p>2-({[({1-[(5-phenylfuran-</p><p>2-yl)methyl]pipe ridin-4-yl}carbamoyl)methyl]amino}methyl)pyridin e-4-</p><p>carboxylic acid</p></td><td><p>32</p></td><td></td></tr>

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<tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ ppm: 7.7 (s,</p><p>1h), 4.0 (s,</p><p>2H), 3.6 (m,</p><p>4H), 1.2 (t, 3H).</p></td><td><p dir="rtl">NS</p></td><td><p>2-[({[(2-cyanoethyl)(et hyl)carbamoyl]methyl}amino (methyl]pyridi ne-4-</p><p>carboxylic acid</p></td><td><p>33</p></td><td></td></tr><tr><td><p>1H NMR (300 MHz, Methanol-d4), δ ppm: 8.00 (s, 1H), 4.53 (s, 2H), 3.58-3.13</p><p>(m, 6h), 1.01 (t, 3h).</p></td><td><p dir="rtl">Dr</p></td><td><p>2-({[2-(1-butylpyrrolidin .)</p><p>-2-yl)ethyl]amino}methyl)pyridi ne-4-carboxylic</p><p>acid</p></td><td><p>34</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, CD3OD), δ</p><p>ppm: 7.72(s, 1H), 5.10(m, 1H), 4.36(m, 1H), 3.90(s, 2H), 3.28(s,</p></td><td><p dir="rtl">h</p></td><td><p>2-{[({[1-(3,7-dimethyloct-6-en-1-yl))pyrrolidin-3-</p><p>yl]carbamoyl} methyl)amino] methyl}pyridin</p></td><td><p>35</p></td><td></td></tr>

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<tr><td><p>2h).</p></td><td></td><td><p>e-4-carboxylic acid</p></td><td></td><td></td></tr><tr><td><p>1H-NMR (300MHz, CD3OD), δ ppm: 7.85</p><p>(s, 1h), 3.90(s, 2h), 2.62(t, 2h), 2.48 (t, 2h).</p></td><td><p dir="rtl">NS</p></td><td><p>2-{[(3-{[(2-fluorophenyl) methyl](methy l)amino}propyl (amino]methyl)</p><p>} pyridine-4-carboxylic acid</p></td><td><p>36</p></td><td></td></tr><tr><td><p>1H-NMR (300MHz, CD3OD), δ ppm: 8.32</p><p>(s, 1h), 7.75(d, 1h), 7.35(d, 1h), 4.20(s, 2h).</p></td><td><p dir="rtl">a</p></td><td><p>2-({[(1R)-2-hydroxy-1-</p><p>{methyl[3-(1-methyl-1H-imidazol-2-yl)propyl]carb amoyl}ethyl]a mino}methyl)p yridine-4-carboxylic acid</p></td><td><p>37</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ</p></td><td><p dir="rtl">NS</p></td><td><p>2-[({2-[3-</p><p>(1H-1,3-benzodiazol-</p></td><td><p>38</p></td><td></td></tr>

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<tr><td><p>ppm: 7.9 (s, 1H), 7.5 (m, 2H), 7.2 (m, 2H).</p></td><td></td><td><p>2-ylmethyl)piper yl]-2-idin-1-oxoethyl}amin o)methyl]pyrid ine-4-</p><p>carboxylic acid</p></td><td></td><td></td></tr><tr><td><p>1H-NMR (300MHz,</p><p>CD3OD), δ ppm: 8.52(d, 1H), 7.80(s, 1H), 4.36(m, 1H), 3.92(m, 1H), 3.28(m, 2H).</p></td><td><p dir="rtl">h</p></td><td><p>2-{[({[1-(2-phenylethyl)p yrrolidin-3-yl]carbamoyl} methyl)amino] methyl}pyridin e-4-</p><p>carboxylic acid</p></td><td><p>39</p></td><td></td></tr><tr><td><p>1H-NMR (300MHz, CD3OD), δ ppm: 7.85</p><p>(s, 1h), 7.20(m, 5h), 3.92(s, 2h), 3.35 (s, 2h).</p></td><td><p dir="rtl">^NS</p></td><td><p>2-({[3-(4-benzylpiperidi n-1-</p><p>yl)propyl]amine o}methyl)pyrid ine-4-</p><p>carboxylic acid</p></td><td><p>40</p></td><td></td></tr>

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-٨٩-

<tr><td><p>1H-NMR</p><p dir="rtl">12 A 7 A 300)</p><p>CD30D), δ ppm: 7.82</p><p>(s, 1Η), 4.18(4, 2Η), 2.96(4, 2Η), 2.70 (m,</p><p>4Η).</p></td><td><p dir="rtl">Kh</p></td><td><p>2-1(03-1(2-phenoxyethyl)aminojpropyl}amino)methyl]</p><p>pyridine-4-carboxylic acid</p></td><td><p dir="rtl">٤١</p></td><td><p>HO o</p></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, Me0H-d4), δ</p><p dir="rtl">,^606 0AM</p><p>1Η), 4.4 (s,</p><p>2Η), 4.0 (s,</p><p>2Η), 3.6 (s, 2Η).</p></td><td><p dir="rtl">core</p></td><td><p>2-[({[methyl({4-[(4-methylpiperazi .])</p><p>n-1-yl)methyl]phe nyl}methyl)car bamoyljmethyl }amino)methyl]pyridine-4-carboxylic</p><p>acid</p></td><td><p dir="rtl">٤٢</p></td><td><p dir="rtl">ϋ 92 LA</p><p dir="rtl">C m m 8 d mc ml</p></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, Me0H-d4), δ</p><p dir="rtl">,^606 0AM</p></td><td><p dir="rtl">core</p></td><td><p>2-(0[2-(2-benzylpyrroli)</p><p>nl-yl)-2-oxoethyljamin</p></td><td><p dir="rtl">٤٣</p></td><td><p>ΗΟ 0</p><p dir="rtl">so</p></td></tr>

٥٦٠١

-٩٠-

<tr><td><p>1H), 7.2 (m,</p><p>4H), 4.4 (m,</p><p>1H), 3.5 (m,</p><p>4h), 3.4 (s, 2h).</p></td><td></td><td><p>o}methyl)pyrid ine-4-</p><p>carboxylic</p><p>acid</p></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ</p><p>ppm: 7.80</p><p>(s, 1H), 3.90 (s, 2H), 3.70 (s, 2H), 0.50</p><p>(m, 2h),</p><p>0.40 (m,</p><p>2h).</p></td><td><p dir="rtl">^And</p></td><td><p>2-({[({4-[benzyl(cyclop ropyl)amino]b utyl}(methyl)c arbamoyl)met hyl]amino}met</p><p>yl)pyridine-</p><p>4-</p><p>carboxylic acid</p></td><td><p>44</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, MeOH-d4), δ ppm: 7.74</p><p>(s, 1h), 7.50</p><p>(m, 2h),</p><p>7.42 (m,</p><p>3h), 4.38 (s, 2h).</p></td><td><p dir="rtl">Dr</p></td><td><p>2-[({2-[(2S)]-</p><p>1-benzylpyrrolidi n-2-yl]ethyl}amino (methyl]pyridi ne-4-</p><p>carboxylic acid</p></td><td><p>45</p></td><td></td></tr>

٥٦٠١

-٩١-

<tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ 8.54 (d, 1h), 7.86 (s, 1h),</p><p>7.72 (dd,</p><p>1H), 3.92 (s, 2H), 3.36 (s, 2H), 2.66 (t,</p><p>2H), 2.58</p><p>2.50 (m,</p><p>4h), 1.90 (s,</p><p>2H), 1.83</p><p>1.73 (m, 4h).</p></td><td><p dir="rtl">a</p></td><td><p>2-({[3-(pyrrolidin-1-yl)propyl]amine o}methyl)pyrid ine-4-</p><p>carboxylic acid</p></td><td><p>46</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ</p><p>8.82 (d, 1h),</p><p>8.03 (s, 1h),</p><p>7.90 (dd,</p><p>1h), 4.43 (s,</p><p>2h), 3.98 (s,</p><p>3H), 3.46</p><p>3.36 (m,</p></td><td><p dir="rtl">g</p></td><td><p>methyl 2-({[3-</p><p>(pyrrolidin-1-yl)propyl]amin o}methyl)pyrid ine-4-</p><p>carboxylate</p></td><td><p>47</p></td><td></td></tr>

٥٦٠١

-٩٢-

<tr><td><p>6H), 3.22 (t, 2H), 2.292.39 (m, 2H), 2.14</p><p>2.09 (m, 4h).</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>1H NMR (300 MHz,) δ CD3OD 8.54</p><p>(dd, 1h),</p><p>7.85 (s, 1h),</p><p>7.72 (dd,</p><p>1H), 3.91 (s, 2H), 2.65</p><p>2.43 (m,</p><p>8H), 1.55 -</p><p>1.48 (m,</p><p>4H), 1.03 (t, 6H).</p></td><td><p dir="rtl">a</p></td><td><p>2-({[4-(diethylamino)butyl]amino}m ethyl)pyridine-4-carboxylic acid</p></td><td><p>48</p></td><td></td></tr><tr><td><p>1H-NMR (300MHz,</p><p>CD3OD): δ 8.55 (d, 1H</p><p>), 7.88 (s, 1h), 7.73 (d,</p></td><td><p dir="rtl">NS</p></td><td><p>2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-</p></td><td><p>49</p></td><td></td></tr>

٥٦٠١

-٩٣-

<tr><td><p>1h), 3.96 (s,</p><p>2h), 3.54 (s,</p><p>2H), 3.52</p><p>3.31 (m,</p><p>4H), 2.45</p><p>2.51 (m, 2H), 2.27 (m,6H), 1.11</p><p>1.19 (m, 3h).</p></td><td></td><td><p>4-carboxylic</p><p>acid</p></td><td></td><td></td></tr><tr><td><p>1H-NMR (300MHz,</p><p>CD3OD): δ 8.80 (m, 1h), 7.98</p><p>(m, 1h), 7.82 (m, 2h), 5.20 (s, 2h), 4.48 (s,</p><p>2H), 3.10 -3.40 (m, 8H), 1.70</p><p>1.98 (m,</p><p>4H), 1.25</p><p>1.40 (m,</p></td><td><p dir="rtl">g</p></td><td><p>(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl 2-({[4-(diethylamino)butyl]amino}m ethyl)pyridine-4-carboxylate</p></td><td><p>50</p></td><td></td></tr>

٥٦٠١

-٩٤-

<tr><td><p>6h).</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>1H-NMR (300MHz,</p><p>CD3OD): δ 8.88 (d, 1H</p><p>), 8.13 (s, 1H), 8.05 (dd, 1H), 7.20 – 7.15</p><p>(m, 2H), 7.01 - 6.96</p><p>(m, 2h), 4.53 (s, 2h), 3.81 (s, 3h), 3.27 – 3.16</p><p>(m, 8H), 1.90 - 1.85</p><p>(m, 4h), 1.33 (t, 6h).</p></td><td><p dir="rtl">g</p></td><td><p>4-methoxyphen</p><p>yl 2-({[4-(diethylamino) butyl]amino}m ethyl)pyridine</p><p>-4-carboxylate</p></td><td><p>51</p></td><td></td></tr>

٥٦٠١

-٩٥-

<tr><td><p>1H NMR</p><p>(300MHz,</p><p>CD3OD) δ</p><p>8.93 (dd,</p><p>1h), 8.18 (s</p><p>1H), 8.15 –</p><p>8.07 (m,</p><p>2h), 7.83 –</p><p>7.62 (m,</p><p>1H), 7.49</p><p>(dd, 1h),</p><p>7.33 (dd,</p><p>1h), 4.57 (s,</p><p>2H), 4.22 (q,</p><p>2H), 3.47 –</p><p>2.99 (m,</p><p>10h), 2.01 –</p><p>1.73 (m,</p><p>2H), 1.34</p><p>(td, 9h).</p></td><td><p dir="rtl">g</p></td><td><p>2-(ethoxycarbon yl)phenyl 2-(ethoxycarbon yl)phenyl 2-(ethoxycarbon yl)phenyl 2-(ethoxycarbon yl)phenyl 2-(ethoxycarbon yl)phenyl 2-(ethoxycarbon yl)phenyl 2-(ethoxycarbon yl)phenyl 2-(ethoxycarbon yl)phenyl 2-</p><p>({[4-(diethylamino) butyl]amino}m ethyl)pyridine</p><p>-4-carboxylate</p></td><td><p>52</p></td><td></td></tr>

٥٦٠١

-٩٦-

<tr><td><p>1H NMR (300 MHz, CD3OD) 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) ,</p><p>2.25 (m, 8H), 3.02(s,</p><p>6H), 1.85 (m, 4H),</p><p>1.36 (t, 6h).</p></td><td><p dir="rtl">g</p></td><td><p>2-</p><p>(dimethylamine o)ethyl 2-</p><p>({[4-(diethylamino) butyl]amino}m ethyl)pyridine</p><p>-4-</p><p>carboxylate</p></td><td><p>53</p></td><td></td><td></td></tr><tr><td><p>1H NMR</p><p>(300MHz,</p><p>CD3OD) δ 8.81 (d, 1h), 8.02 (s, 1h), 7.95 (d, 1h), 4.50 (m,</p><p>4H), 3.38 (m, 2H), 3.26 (m, 8H), 2.98 (s,</p></td><td><p dir="rtl">g</p></td><td><p>3-(dimethylamine</p><p>o)propyl 2-({[4-</p><p>(diethylamino) butyl]amino}m ethyl)pyridine-4-</p><p>carboxylate</p></td><td><p>54</p></td><td></td><td></td></tr>

٥٦٠١

-٩٧-

<tr><td><p>6H), 2.25 (m, 2H), 1.87 (m,</p><p>4h), 1.38 (t, 6h).</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ</p><p>8.70 (d, 1H</p><p>), 7.90 (s,</p><p>1h), 7.80 (d,</p><p>1h), 7.30</p><p>7.50 (m,</p><p>4h), 5.35 (s,</p><p>2h), 4.50 (s,</p><p>2H), 3.20</p><p>(m, 9h),</p><p>1.30 (m, 9h).</p></td><td><p dir="rtl">g</p></td><td><p>{4-{[(ethoxycarbo nyl)amino]phe nyl}methyl 2-</p><p>({[4-(diethylamino) butyl]amino}m ethyl)pyridine</p><p>-4-carboxylate</p></td><td><p>55</p></td><td></td></tr><tr><td><p>1H NMR</p><p>(300MHz,</p><p>CD3OD): δ</p><p>8.89 (dd,</p><p>1h), 8.15 (d,</p><p>1H), 8.05</p></td><td><p dir="rtl">g</p></td><td><p>2,6-dimethoxyphe</p><p>nyl 2-({[4-(diethylamino) butyl]amino}m ethyl)pyridine</p></td><td><p>56</p></td><td></td></tr>

٥٦٠١

-٩٨-

<tr><td><p>(dd, 1h), 7.24 (t, 1h), 6.77 (d, 2h), 4.53 (s, 2h), 3.79 (s, 6h), 3.29 - 3.13</p><p>(d, 8h), 1.92 - 1.80 (m,</p><p>4h), 1.33 (t, 6h).</p></td><td></td><td><p>-4-carboxylate</p></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ 8.90 (d, 1H</p><p>), 8.20 (s,</p><p>1h), 8.00 (d,</p><p>1H), 7.2 (s, 3H), 4.50 (s, 2H), 2.20 (s,</p><p>6h), 1.80</p><p>(m, 4H), 1.30 (m, 6H)</p></td><td><p dir="rtl">g</p></td><td><p>2,6-dimethylpheny</p><p>l 2-({[4-(diethylamino)butyl]amino}m ethyl)pyridine-4-</p><p>carboxylate</p></td><td><p>57</p></td><td></td></tr>

٥٦٠١

-٩٩-

<tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ</p><p>8.90 (d, 1H</p><p>), 8.10 (s,</p><p>1h), 8.05 (d,</p><p>1H), 7.10</p><p>(m, 2h),</p><p>7.00 (m,</p><p>2h), 4.50 (s,</p><p>2h), 4.30 (s,</p><p>2H), 3.80</p><p>(s, 3H), 3.30</p><p>(m, 6h),</p><p>2.95 (s, 6h),</p><p>1.20 (t, 3h)</p></td><td><p dir="rtl">g</p></td><td><p>4-methoxyphen</p><p>yl 2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td><p>58</p></td><td></td></tr><tr><td><p>1H-NMR (300MHz,</p><p>CD3OD): δ 8.90 (d, 1H</p><p>), 8.20 (s, 1h), 8.05 (d,</p><p>1H), 7.75 (m, 1H), 7.45 (m,</p></td><td><p dir="rtl">g</p></td><td><p>2-(ethoxycarbon</p><p>yl)phenyl 2-</p><p>{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-</p></td><td><p>59</p></td><td></td></tr>

٥٦٠١

١٠٠-

<tr><td><p>1H), 7.30 (m, 1H), 4.60 (s,</p><p>2h), 4.30</p><p>(s, 2h), 3.80 (m, 2h),</p><p>3.00 (s, 6h), 1.25 (m, 6h)</p></td><td></td><td><p>4-carboxylate</p></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, CD3OD): δ 8.80 (d, 1H</p><p>), 8.00 (s, 1H), 7.90 (d, 1H), 7.50 (d, 2H), 7.30 (d, 2H), 5.40 (s, 2H), 4.50 (s,</p><p>2H), 4.20</p><p>(m, 2H), 1.80 (m,</p><p>4h), 1.30 (m, 6h),</p><p>1.20 (t, 3h)</p></td><td><p dir="rtl">g</p></td><td><p>{4-[(ethoxycarbo nyl)(methyl)a mino]phenyl}</p><p>methyl 2-</p><p>({[4-(diethylamino) butyl]amino}m ethyl)pyridine</p><p>-4-carboxylate</p></td><td><p>60</p></td><td></td></tr>

٥٦٠١

-١٠١-

<tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ 8.80 (d, 1H</p><p>), 8.10 (s, 1H), 8.00 (d, 1H), 7.50 (d, 2H), 7.20 (d, 2H), 4.55 (s, 2H), 4.30 (s,</p><p>2H), 3.80</p><p>(m, 3h),</p><p>2.99 (s,</p><p>6H), 1.40 (s, 9H), 1.20 (t, 3H)</p></td><td><p dir="rtl">g</p></td><td><p>4-tert-butylphenyl</p><p>2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td><p>61</p></td><td></td></tr><tr><td><p>1H-NMR (300MHz,</p><p>CD3OD): δ 8.75 (d, 1H ), 7.90-8.10</p><p>(m, 2H), 5.50 (m,</p><p>1H), 4.50 (s, 2H), 4.25</p></td><td><p dir="rtl">^NS</p></td><td><p>4-oxopentan-2-yl 2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td><p>62</p></td><td></td></tr>

٥٦٠١

-١٠٢-

<tr><td><p>(s, 2h),</p><p>3.75 (m,</p><p>2H), 1.20</p><p>1.50 (m, 6h).</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, CD3OD): δ</p><p>8.80 (d, 1h),</p><p>7.98 (brs, 1h), 7.9 (d,</p><p>2H), 5.20 (m, 1H), 4.9 (s, 2H), 4.5 (s, 2H), 4.3 (s, 2H), 3.8</p><p>(m, 2h), 3.5-3.3 (m, 6h), 3.0 (s, 2.0 (m, 2h), 1.3 (d, 3h), 1.2 (t, 3h).</p></td><td><p dir="rtl">g</p></td><td><p>4-(trifluoroaceta mido)butan-</p><p>2-yl 2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td><p>63</p></td><td></td></tr>

٥٦٠١

-١٠٣-

<tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ</p><p>8.80 (d, 1h),</p><p>8.0 (m, 2h),</p><p>5.20 (m,</p><p>1h), 4.9 (s,</p><p>2h), 4.5 (s,</p><p>2h), 4.3 (s,</p><p>2H), 3.8 (m, 2H), 3.5-3.3 (m, 6H), 3.2 (s, 3H), 3.0 (s, 6H), 2.0 (m, 2H), 1.3 (d, 3H), 1.2</p><p>(t, 3h).</p></td><td><p dir="rtl">g</p></td><td><p>4-(2,2,2-trifluoro-N-</p><p>methylacetami do)butan-2-yl</p><p>2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td><p>64</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CDCl3): δ</p><p>8.7 (d, 1h),</p><p>7.9 (s, 1h),</p><p>7.8 (d, 1h),</p><p>4.4 (q, 2h),</p><p>4.0 (s, 2h),</p></td><td><p dir="rtl">General Procedure B</p></td><td><p>ethyl 2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td><p>65</p></td><td></td></tr>

٥٦٠١

-١٠٤-

<tr><td><p>3.5-3.3 (m,</p><p>4H), 3.2 (m,</p><p>2H), 2.5 (m,</p><p>4h), 2.3 (s,</p><p>6H), 1.3 (t,</p><p>3H), 1.1 (t,</p><p>3h).</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ</p><p>8.84 (d, 1H</p><p>), 8.02 (s,</p><p>1h), 7.96 (d,</p><p>1H), 6.04</p><p>5.93 (m,</p><p>1h), 5.38 (d,</p><p>1h), 5.29 (d,</p><p>1H), 2.98</p><p>(s, 6h), 1.25</p><p>(t, 3h).</p></td><td><p dir="rtl">g</p></td><td><p>5-(trifluoroaceta mido)pent-1-</p><p>en-3-yl 2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td><p>66</p></td><td></td></tr>

٥٦٠١

-١٠٥-

<tr><td><p>1H-NMR</p><p>(300MHz, CD3OD): δ</p><p>8.85 (d, 1h),</p><p>8.02 (s, 1h), 7.96 (d, 1h),</p><p>6.05-5.93</p><p>(m, 1h),</p><p>5.39 (d, 1h),</p><p>5.29 (d, 1h),</p><p>3.40 (m,</p><p>3H), 1.25 (t, 3H).</p></td><td><p dir="rtl">g</p></td><td><p>5-(2,2,2-trifluoro-N-</p><p>methylacetami do)pent-1-en-3-yl 2-</p><p>{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td><p>67</p></td><td></td></tr><tr><td><p>1H-NMR (300MHz,</p><p>CD3OD): δ 8.85 (d, 1h), 8.05 (s, 1h), 7.90 (d,</p><p>1H), 5.50</p><p>(m, 1h), 4.50 (s,</p><p>2H), 3.80 (m, 2H), 2.98 (s, 6H),</p></td><td><p dir="rtl">g</p></td><td><p>2-(2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-</p><p>carbonyloxy)-3-</p><p>(hexadecanoy loxy)propyl</p><p>hexadecanoat</p></td><td><p>68</p></td><td><p dir="rtl">less</p></td></tr>

٥٦٠١

-١٠٦-

<tr><td><p>1.30 (m, 57Η), 0.90 (m, 61a)</p></td><td></td><td><p>e</p></td><td></td><td></td></tr>

Hi

<img file="SA5601B1_D0017.tif" />

<tr><td><p>1H-NMR</p></td><td></td><td></td><td></td><td><p dir="rtl">they</p></td></tr><tr><td><p>(300MHz,</p></td><td></td><td><p dir="rtl">-2)) AA-2)-1</p></td><td></td><td></td></tr><tr><td><p>CD30D): δ</p></td><td></td><td><p>(dimethylamino)</p></td><td></td><td></td></tr><tr><td><p dir="rtl">,(111,0) 8.80</p></td><td></td><td><p>ethyl](ethyl)carb</p></td><td></td><td></td></tr><tr><td><p>8.05 (s, 1Η),</p></td><td></td><td><p>amoyl}methyl)a</p></td><td></td><td></td></tr><tr><td><p>7.90 d, 1Η),</p></td><td></td><td><p>mino]methyl}pyri</p></td><td></td><td></td></tr><tr><td></td><td><p dir="rtl">g</p></td><td></td><td><p dir="rtl">٦٩</p></td><td><p>CH,</p></td></tr><tr><td><p>4.50 (s, 2Η),</p></td><td></td><td><p>dine-4-</p></td><td></td><td></td></tr><tr><td><p>4.40 (m, 2Η),</p></td><td></td><td><p>carbonyloxy)-3-</p></td><td></td><td></td></tr><tr><td><p>4.20 (s, 3Η),</p></td><td></td><td><p>(hexadecanoylo</p></td><td></td><td></td></tr><tr><td><p>3.00 (s, 6Η),</p></td><td></td><td><p>xy)propan-2-y0</p></td><td></td><td></td></tr><tr><td><p>1.20-1.50 (m.</p></td><td></td><td><p>hexadecanoate</p></td><td></td><td></td></tr><tr><td><p>73Η).</p></td><td></td><td></td><td></td><td></td></tr>

٥٦٠١

-١٠٧-

<tr><td><p>1H-NMR</p><p>(300MHz,</p><p>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).</p></td><td><p dir="rtl">g</p></td><td><p>methyl 2-{[({[2-(dimethylamino) ethyl](ethyl)carb amoyl}methyl)a mino]methyl}pyri dine-4-</p><p>carboxylate</p></td><td><p>70</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, D2O): δ 8.71 (d, 1H ), 7.61</p><p>(s, 1H), 7.58 (m, 1H), 4.48 (s, 2H), 4.20 (s, 2H), 3.70 (t, 2H), 3.41</p><p>(s, 3H), 3.303.24 (m, 4H), 3.20 (s, 3H), 2.86 (s, 6H), 1.10 (t, 3H).</p></td><td><p dir="rtl">g</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](ethyl)carb amoyl}methyl)a mino]methyl}-</p><p>N-</p><p>methanesulfonyl</p><p>-N-methylpyridine-4-carboxamide</p></td><td><p>71</p></td><td></td></tr>

٥٦٠١

-١٠٨-

<tr><td><p>1H-NMR</p><p>(300MHz, D2O): δ 8.66</p><p>(d, 1H ), 7.58-7.46 (m, 2H), 4.46 (s, 2H ), 4.19 (s,</p><p>2H), 3.79 (t,</p><p>2H), 3.73</p><p>3.67 (m, 2H), 3.31-3.25 (m,</p><p>2H), 3.173.11 (m, 2H), 3.03-2.94 (m, 2H), 2.86 (s,</p><p>6H), 1.12</p><p>1.07 (m, 3h).</p></td><td><p dir="rtl">g</p></td><td><p>N-[2-(dimethylamino)ethyl]-N-ethyl-2-({[4-(2-oxo-1,3-oxazolidine-3-carbonyl)pyridin-2-yl]methyl}amino)acetamide</p></td><td><p>72</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz, CD3OD): δ</p><p>8.83 (d, 1h),</p><p>7.96 (s, 1h),</p><p>7.90 (d, 1h), 5.65 (m, 1h), 4.56 (s, 2h),</p></td><td><p dir="rtl">g</p></td><td><p>propan-2-yl 3-</p><p>(2-{[({[2-(dimethylamino) ethyl](ethyl)carb amoyl}methyl)a mino]methyl}pyri</p><p>dine-4-</p><p>carbonyloxy)-4-</p></td><td><p>73</p></td><td></td></tr>

٥٦٠١

-١٠٩-

<tr><td><p>4.26 (s, 2h),</p><p>3.00 (s, 6h), 1.30 – 1.16</p><p>(m, 9h).</p></td><td></td><td><p>(trifluoroacetami do)butanoate</p></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ 8.83 (m, 1H), 7.99 (s, 1H), 7.93 (d, 1H), 4.95 (4.38(d, 2H), 4.27 (s,</p><p>2H), 3.80 – 3.69 (m, 4h), 3.00 (s, 6h),</p><p>1.40 – 1.36</p><p>(m, 9h).</p></td><td><p dir="rtl">g</p></td><td><p>propan-2-yl 3-</p><p>(2-{[({[2-(dimethylamino) ethyl](ethyl)carb amoyl}methyl)a mino]methyl}pyri</p><p>dine-4-</p><p>carbonyloxy)-5-(trifluoroacetami do)pentanoate</p></td><td><p>74</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ 8.73 (8.02 (d, 2H), 6.85 (d, 1H), 4.62 (s, 2H), 4.30 (s, 2H), 3.83 (t,</p></td><td><p dir="rtl">g</p></td><td><p>2-{[({[2-(dimethylamino) ethyl](ethyl)carb amoyl}methyl)a mino]methyl}-N-(pyridin-4-yl)pyridine-4-carboxamide</p></td><td><p>75</p></td><td></td></tr>

٥٦٠١

-١١٠-

<tr><td><p>2H), 3.33</p><p>3.31 (m, 4h),</p><p>2.99 (s, 6h),</p><p>1.26 (t, 3h).</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>1H-NMR (300MHz,</p><p>CD3OD): δ 8.84 (d, 1h), 7.99 (s, 1h), 7.94 (d, 1h), 4.58 (s, 2h), 4.28 (s, 2h), 3.84-3.79 (m,</p><p>2H), 3.433.36 (m, 2H), 3.32-3.28 (m, 2H), 2.98 (s, 6H), 2.52 (s,</p><p>3H), 1.271.22 (m, 3H).</p></td><td><p dir="rtl">g</p></td><td><p>2-{[({[2-(dimethylamino) ethyl](ethyl)carb amoyl}methyl)a mino]methyl}-N-(5-methyl-</p><p>1,3,4-oxadiazol-2-yl)pyridine-4-carboxamide</p></td><td><p>76</p></td><td></td></tr>

٥٦٠١

-١١١-

<tr><td><p>1H-NMR (300MHz,</p><p>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), 3.84-3.80 (m,</p><p>2H), 3.413.35 (m, 4H), 3.82 (s, 3H), 2.98 (s, 6H), 1.26-1.21 (m,</p><p>3h).</p></td><td><p dir="rtl">g</p></td><td><p>2-{[({[2-(dimethylamino) ethyl](ethyl)carb amoyl}methyl)a mino]methyl}-N-(1-methyl-</p><p>1H-pyrazol-5-yl)pyridine-4-carboxamide</p></td><td><p>77</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ 8.50 (d, 1h), 7.40 (s, 1h), 7.65 (d, 1h), 3.65 (s, 2h),</p></td><td><p dir="rtl">a</p></td><td><p>2-(piperidin-1-ylmethyl)pyridine-4-carboxylic acid</p></td><td><p>78</p></td><td></td></tr>

٥٦٠١

-١١٢-

<tr><td><p>2.50 (m, 4h),</p><p>1.60 (m, 4h),</p><p>1.40 (m, 2h)</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>1H-NMR (300MHz,</p><p>CD3OD): 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.</p></td><td><p dir="rtl">a</p></td><td><p>2-(azetidin-1-ylmethyl)pyridine-4-carboxylic</p><p>acid</p></td><td><p>79</p></td><td></td></tr><tr><td><p>1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, 1H), 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,</p></td><td><p dir="rtl">g</p></td><td><p>2,2,2-trifluoroethyl 2-</p><p>{[({[2-</p><p>(dimethylamino) ethyl](ethyl)carb amoyl}methyl)a mino]methyl}pyri</p><p>dine-4-carboxylate</p></td><td><p>80</p></td><td></td></tr>

٥٦٠١

-١١٣-

<tr><td><p>6H), 1.13 (t, 3H).</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>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).</p></td><td><p dir="rtl">NS</p></td><td><p>2-({ethyl[2-oxo-2-</p><p>(piperidin-1-yl)ethyl]amino}m ethyl)pyridine-</p><p>4-carboxylic acid</p></td><td><p>81</p></td><td></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD) δ 8.50 (d, 1H), 7.94 (s, 1H), 7.71 (d, 1H), 3.80 (s, 2H), 3.46 (m, 4H), 3.35 (s, 2H) , 2.54 (m, 2H), 1.51 (m, 8H), 1.28 (m,</p></td><td><p dir="rtl">NS</p></td><td><p>2-({butyl[2-oxo-2-</p><p>(piperidin-1-yl)ethyl]amino}m ethyl)pyridine-</p><p>4-carboxylic acid</p></td><td><p>82</p></td><td></td></tr>

٥٦٠١

-١١٤-

<tr><td><p>2H), 0.88 (t, 3H).</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD)</p><p>δ 8.49 (1H), 8.05 (s, 1h), 7.72 (d, 1h), 7.48–7.08 (m,</p><p>5H), 3.85 (s, 2H), 3.71 (s, 2H), 3.43 (m, 2H), 3.31 (m,</p><p>4h), 1.73–1.33 (m, 6h).</p></td><td><p dir="rtl">NS</p></td><td><p>2-({benzyl[2-oxo-2-</p><p>(piperidin-1-yl)ethyl]amino}m ethyl)pyridine-</p><p>4-carboxylic acid</p></td><td><p>83</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ 8.76 (d, 1h), 7.94 (s, 1h), 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,</p></td><td><p dir="rtl">g</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](ethyl)carb amoyl}methyl)a mino]methyl}-</p><p>N-(1,3-oxazol-2-yl)pyridine-4-carboxamide</p></td><td><p>84</p></td><td></td></tr>

٥٦٠١

-١١٥-

<tr><td><p>2H), 3.37</p><p>3.23 (m, 4h),</p><p>2.92 (s, 6h),</p><p>1.21-1.16 (m, 3h).</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): 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</p><p>(m, 15h).</p></td><td><p dir="rtl">g</p></td><td><p>2,6-bis(propan-2-yloxy)phenyl 2-{[({[2-(dimethylamino) ethyl](ethyl)carb amoyl}methyl)a mino]methyl}pyri</p><p>dine-4-</p><p>carboxylate</p></td><td><p>85</p></td><td></td></tr><tr><td><p>1H NMR (300</p><p>MHz, CD3OD) δ 8.48 (d, 1H), .71 (d, 1H), 3.79 (s, 2H), 3.55 –</p></td><td><p dir="rtl">NS</p></td><td><p>2-{[(2-methylpropyl)[2-</p><p>oxo-2-</p><p>(piperidin-1-yl)ethyl]amino]m ethyl}pyridine-</p></td><td><p>86</p></td><td></td></tr>

٥٦٠١

-١١٦-

<tr><td><p>3.37 (m, 4h),</p><p>3.32 (s, 2h),</p><p>2.34 (d, 2h),</p><p>1.82 (m, 1h),</p><p>1.56 (m, 6h), 0.88 (d, 6h).</p></td><td></td><td><p>4-carboxylic</p><p>acid</p></td><td></td><td></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD) δ 8.48 (d, 1H), 7.97 (s, 1H), 7.71 (d, 1H), 3.80 (s, 2H), 3.47 (m, 4H), 3.35 (s,</p><p>2h), 2.69 –</p><p>2.26 (m, 2h), 1.75 - 1.45</p><p>(m, 8h), 0.87 (t, 3h).</p></td><td><p dir="rtl">NS</p></td><td><p>2-({[2-oxo-2-</p><p>(piperidin-1-yl)ethyl](propyl)a mino}methyl)pyri dine-4-</p><p>carboxylic acid</p></td><td><p>87</p></td><td></td></tr>

٥٦٠١

-١١٧-

<tr><td><p>1H NMR (300</p><p>MHz, CD3OD) δ 8.45 (d, 1H), 8.00 (s, 1H), 7.69 (d, 1H), 3.76 (s, 2H), 3.45 –</p><p>3.37 (m, 4H), 3.34 (s, 2H), 1.73 - 1.36</p><p>(m, 6h), 1.13 (d, 6h).</p></td><td><p dir="rtl">NS</p></td><td><p>2-({[2-oxo-2-</p><p>(piperidin-1-yl)ethyl](propan-2-</p><p>yl)amino}methyl)pyridine-4-carboxylic acid</p></td><td><p>88</p></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CD3OD): δ 8.82 (s, 1H), 7.93 (s, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 6.76 (s, 1H), 3.82-3.73 (m,</p><p>4H), 3.463.43 (m, 2H), 3.38-3.30 (m, 4H), 3.26 (s,</p></td><td><p dir="rtl">g</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](ethyl)carb amoyl}methyl)a mino]methyl}-N-(1-methyl-1H-imidazol-2-</p><p>yl)pyridine-4-carboxamide</p></td><td><p>89</p></td><td></td></tr>

٥٦٠١

-١١٨-

<tr><td><p>3H), 2.93 (s,</p><p>6h), 1.27</p><p>1.12 (m, 3h).</p></td><td></td><td></td><td></td><td></td></tr><tr><td><p>1H-NMR</p><p>(300MHz,</p><p>CDCl3): δ</p><p>8.72 (dd, 1H</p><p>), 7.96 (d,</p><p>1H), 7.73 (td,</p><p>1h), 4.45 (td,</p><p>1H), 4.04</p><p>4.03 (m, 2h),</p><p>3.95 (s, 2h), 3.52-3.49 (m,</p><p>4H), 3.52</p><p>3.49 (m, 4H), 3.47-3.38 (m,</p><p>2H), 2.52</p><p>2.39 (m, 3h),</p><p>2.30 (s, 6h), 1.17-1.11 (m, 3h).</p></td><td><p dir="rtl">g</p></td><td><p>2-fluoroethyl 2-{[({[2-(dimethylamino)ethyl](ethyl)carb amoyl}methyl)a mino]methyl}pyri dine-4-</p><p>carboxylate</p></td><td><p>90</p></td><td></td></tr>

٥٦٠١

-١١٩-

<tr><td><p>1H-NMR (300MHz,</p><p>CDCl3): δ 8.72 (d, 1H), 7.98 (s, 1H), 7.76 (dd, 1H), 6.09 (m, 1H), 4.82 (m, 1H), 4.68-4.63 (m, 2H), 4.55 ( m, 1h), 4.04 (s, 2h), 3.50 (s,</p><p>2H), 3.493.38 (m, 2H), 3.31-3.24 (m, 2H), 2.29 (s,</p><p>6H), 1.181.11 (m, 3h).</p></td><td><p dir="rtl">g</p></td><td><p>2,2-difluoroethyl</p><p>2-{[({[2-(dimethylamino) ethyl](ethyl)carb amoyl}methyl)a mino]methyl}pyri</p><p>dine-4-</p><p>carboxylate</p></td><td><p>91</p></td><td></td></tr><tr><td><p>1H NMR (300</p><p>MHz, CD3OD) δ 8.51 (d, 1H), 7.87 (s, 1H), 7.71 (d, 1H), 3.84 (d, 2H), 3.31 (s,</p></td><td><p dir="rtl">NS</p></td><td><p>2-({[(1S)-1-(tertbutylcarbamoyl)-3-</p><p>methylbutyl]amine o}methyl)pyridin e-4-carboxylic</p></td><td><p>92</p></td><td></td></tr>

٥٦٠١

-١٢٠-

<tr><td><p>1H), 3.11 (dd,</p><p>1H), 1.82 –</p><p>1.64 (m, 1h), 1.53 - 1.40</p><p>(m, 2H), 1.32</p><p>(s, 9h), 0.90</p><p>(dd, 6h).</p></td><td></td><td><p>acid</p></td><td></td><td></td></tr><tr><td><p>1H NMR (300 MHz, CD3OD) δ 8.46 (d, 1H), 7.96 (s, 1H), 7.70 (d,</p><p>1H), 3.98 - 3.65 (m, 3H), 3.57 (m, 3H), 2.81 (s, 1H), 2.28 (s, 3H),</p><p>1.95 – 1.79</p><p>(m, 1h), 1.76 - 1.41 (m, 6h), 0.93 (dd,</p><p>6h).</p></td><td><p dir="rtl">a</p></td><td><p>2-</p><p>({methyl[(2S)-4-methyl-1-oxo-1-</p><p>(piperidin-1-yl)pentan-2-yl]amino}methyl)</p><p>pyridine-4-carboxylic acid</p></td><td><p>93</p></td><td></td></tr>

Illustrative preparation methods for the compounds in Table 1 are as follows.

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

٥٦٠١

-١٢١-

<img file="SA5601B1_D0018.tif" />

Synthesis method A

<img file="SA5601B1_D0019.tif" />

10

15

General Procedure A (hydrolysis of the ester)

ester (Ethyl 2-({[2-(dimethylamino)ethyl]amino}methyl)pyridine- added

a (4-carboxylate) in 1:1:1 (MeOH-THF-H2O) and 1,0 (LiOH equivalent). The reaction mixture was stirred at room temperature and monitored by TLC. Solvents were removed in vacuo. The treatment is by dissolving in water and extracting with Et2O The aqueous base was converted to acid with 1 N of HCl to pH 1, the solution was concentrated to dry to provide the HCl 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, 4H), 3.0 (s, 6h).

ES-MS: 224 [M+1].

2-({[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino}methyl)pyridine-4-carboxylic (13#) acid

٥٦٠١

-١٢٢-

<img file="SA5601B1_D0020.tif" />

B synthesis method

<img file="SA5601B1_D0021.tif" />

It was prepared by general procedure A from -2-ethyl 2-({2,2,2-trifluoro-N-[2-oxo]

5 pyrrolidin-1-yl(ethyl]acetamido}methyl(pyridine-4-carboxylate)(e). Processed by solid pulverization with Et2O to provide the HCl salt of the title compound as a white powder.

1H-NMR (300MHz, MeOH-d4): δ 8.4 (d, 1H), 7.7 (s, 1H), 7.6 (d, 1H),

3.7 (s, 2h), 4.0 (s, 2h), 3.4 (m, 6h), 1.5 (m, 4h).

2-{[(3-{[3-(pyrrolidin-1-yl)propyl]amino}propyl)amino]methyl}pyridine-4-10 (21#) carboxylic acid

<img file="SA5601B1_D0022.tif" />

synthesis method c

٥٦٠١

-١٢٣-

<img file="SA5601B1_D0023.tif" />

It was prepared by general procedure A of -3]}-3)-ethyl 2-{[2,2,2-trifluoro-N

(pyrrolidin-1-yl)propyl]amino}propyl)acetamido]methyl}pyridine-4-

carboxylate (J). The treatment produces a salt of hydrochloric acid

5 The title compound is in the form of a white sticky solid.

1H NMR (300 MHz, D2O): δ 8.72 (d, 1H), 7.96 (s, 1H), 7.90 (d, 1H), 4.48 (s, 2H), 3.60 (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-

(#28) carboxylic acid 10

<img file="SA5601B1_D0024.tif" />

D . synthesis method

٥٦٠١

-١٢٤-

<img file="SA5601B1_D0025.tif" />

<img file="SA5601B1_D0026.tif" />

<img file="SA5601B1_D0027.tif" />

It was prepared by general procedure A from -3-1-(ethyl 2-({2,2,2-trifluoro-N-[(3R)))

(N(phenylpropyl)pyrrolidin-3-yl]acetamido}methyl)pyridine-4-carboxylate.

Isolate as lithium salt after treatment by dissolving the residue in a minimal amount of water and extracting it with DCM. The aqueous phase was evaporated to dryness to provide the compound mentioned in the title as a white solid.

10

1H-NMR (300MHz, CDCl3): 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-]

29#((yl}carbamoyl)methyl]amino}methyl)pyridine-4-carboxylic acid

<img file="SA5601B1_D0028.tif" />

H . synthesis method

٥٦٠١

-١٢٥-

<img file="SA5601B1_D0029.tif" />

Prepared by General Procedure A of:

ethyl 2-({2,2,2-trifluoro-N-[({1-[(2-methoxyphenyl)methyl])piperidin-4-]

Q) Using (yl}carbamoyl)methyl]acetamido}methyl)pyridine-4-carboxylate

5 2 eq of LiOH. The isolation is carried out as lithium after treatment by dissolving

The residue is in the minimum amount of water and extracted with DCM. The aqueous phase was evaporated to dryness to provide the compound mentioned in the title as a white solid.

1H-NMR (300MHz, CD3OD): δ 8.54(d,1H), 7.82(s, 1H), 7.65(d, 1H),

7.26(m, 2H), 6.94(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). 10

ES-MS: 411 [MH].

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

<img file="SA5601B1_D0030.tif" />

15th Synthesis method and

٥٦٠١

-١٢٦-

<img file="SA5601B1_D0031.tif" />

General Procedure 0 General Procedure 8

h (u) ► Title Compound

General Procedure B

<img file="SA5601B1_D0032.tif" />

Prepared by general procedure from:

ethyl 2-({Ν-[({4-

benzyl(cyclopropyl)amino]butyl}(methyl)carbamoyl)methyl]-2,2,2-

u) using 2.5 equivalents) 5-trifluoroacetamido }methyl)pyridine-4-carboxylate

from LiOH. Isolate as lithium salt after treatment by dissolving the residue in a minimum amount of water and extracting with DCM. The aqueous phase was evaporated to dryness to obtain the compound mentioned in the title in the form of a white solid.

1H-NMR (300MHz, CDCI3): δ 8.50 (d, 1Η), 7.80 (s, 1Η), 7.70 (d, 1Η),

7.25 (m, 5Η), 3.90 (s, 2Η), 3.70 s, 2Η), 3.50-3.40 (m, 3Η), 2.25 (m, 1 0

1Η), 2.95 (s, 3Η), 2.55 (m, 2Η), 1.75 (m, 1Η), 1.50 (m, 4Η), 0.50 (m,

2Η), 0.40 (m, 2Η).

ES-MS: 425 [Μ+1].

2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}-N-(75#)(pyridin-4-yl)py2idine-4-ca2boxamide 15

<img file="SA5601B1_D0033.tif" />

Synthesis method g

٥٦٠١

-١٢٧-

ss sss for

(ί lx - meat - meat 76

L2?a1 Abba.-q02a'2/21a29?z2 ν9;10h1hib.','6a210\e.j0911h1

- (H {7 Title Compound

Prepared by General Procedure D from:

tert-butyl N-({[2-(dimethylamin0)ethyl](ethyl)carbam0yl}methyl)-N-({4-y) to get) [(pyridin-4-yl)carbamoyl]pyridin-2-yl} methyl)carbamate

5 The compound mentioned in the title is in the form of yellow oil.

1H-NMR (300MHz, CD30D): δ 8.73 (d, 2Η), 8.44 (d, 2Η), 8.02 (d, 2Η),

6.85 (d, 1Η), 4.62 (s, 2Η), 4.30 (s, 2Η), 3.83 (t, 2Η), 3.33-3.31 (m, 4Η),

2.99 (s, 61.26, 1a (t, 3Η).

ES-MS: 486 [Μ+1]

4-oxopentan-2-y, 2-0 1 -2]0)

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-carboxylate

(**٦٢)

<img file="SA5601B1_D0034.tif" />

٥٦٠١

-١٢٨-

General Procedure E or General Procedure H

<img file="SA5601B1_D0035.tif" />

4-oxopentan-2-y,

General Procedure D (aa) H Title Compound

Prepared by General Procedure D from:

2-({[(tert-butoxy)carbonyl]({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino}methyl)pyridine-4-

5 40 Ha7>A5300P (aa) to obtain the compound mentioned in the heading in the form of a color oil for it.

-NMR (300MHz, CD30D): δ 8.75 (d, 1Η ), 7.90-8.10 (m, 2Η), 5.50 (m,

1Η), 4.50 (s, 2Η), 4.25 (s, 2Η), 3.75 (m, 2Η), 1.20-1.50 (0, 61a).

Εδ-Μδ: 393 [Μ+1]

2-({ethyl[2-oxo-2-(pipe2idin-l-yl)ethyl]amino}methyl)py2idine-4-;

(#81) carboxylic acid 10

<img file="SA5601B1_D0036.tif" />

Synthesis method

٥٦٠١

-١٢٩-

<img file="SA5601B1_D0037.tif" />

<img file="SA5601B1_D0038.tif" />

It was prepared by general procedure A from -1-ethyl 2-({ethyl[2-oxo-2-(piperidin)).

To obtain the compound mentioned in yl(ethyl]amino}methyl)pyridine-4-carboxylate

The title is in solid form.

1H NMR (300 MHz, CD3OD) δ 8.48 (d, 1H), 7.94 (s, 1H), 7.70 (d, 1H), 5

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

(a) Ethyl 2-({[2-(dimethylamino)ethyl]amino}methyl)pyridine-4-carboxylate 10

General Procedure B (Reductive Secretary)

to a mixture of (1,0)aldehyde (ethyl 2-formylpyridine-4-carboxylate equivalent),

and amine 1,N1,2-dimethylethane-diamine(1,N1)(1,2-dichloroethane equivalent), in 1,2-dichloroethane(1,0 equivalent), followed by

15th 3(2.5) NaBH(OAc equivalent), the mixture was stirred at room temperature, overnight.

Hydrotreatment (NaHCO3/EtOAc) and purification by column chromatograph

(1:10:90, OH4 NH/MeOH/CH2Cl2) to provide the compound mentioned in the title in the form of a colorless gum.

٥٦٠١

-١٣٠-

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).

Ethyl2-({[2-(tert-butoxy)-2-oxoethyl]amino}methyl)pyridine-4-carboxylate

5 )NS(

It was prepared by general procedure B from ethyl 2-formylpyridine-4-carboxylate-2 ethyl

tert-butyl 2-butyl 2-aminoacetate-t-formylpyridine-4-carboxylate

aminoacetate; The compound mentioned in the title was isolated as yellow oil by column chromatogram (EtOAc/hexanes).

1H-NMR (300MHz, MeOH-d4): δ 8.7 (d, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 10

4.4 (s, 2H), 4.3 (q, 2), 3.8 (s, 2H), 3.3 (s, 2H), 1.4 (s, (H), 1.3 (t, 3H)

.ES-MS: 295 [M+1]

(f) Ethyl 2-{[(3-hydroxypropyl)amino]methyl}pyridine-4-carboxylate

It was prepared by general procedure b from ethyl 2-formylpyridine-4-carboxylate-2-ethyl 15-formylpyridine-4-carboxylate and 3-aminopropan-1-ol.

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-

(K) yl]amino}methyl)pyridine-4-carboxylate 20

It was prepared by general procedure b from ethyl 2-formylpyridine-4-carboxylate and tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate. result from column

٥٦٠١

-١٣١-

Chromotope(DCM/MeOH) to provide the compound mentioned in the title as liquefied oil

for the color green.

1H-NMR (300MHz, CDCl3): 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). 5

ES-MS: 350 [M+1]

Ethyl 2-{[2,2,2-trifluoro-N-(3-{[3-(pyrrolidin-1-])

(j) yl)propyl]amino}propyl)acetamido]methyl}pyridine-4-carboxylate

It was prepared by general procedure b from -3)-ethyl 2-{[2,2,2-trifluoro-N

(i) and 3-)pyridine-1-yl (oxopropyl)acetamido [methyl}pyridine-4-carboxylate 10

3 Provides a column-(pyrrolidin-1-yl)propan-1-amine.propan-1-amine

Chromotograph (DCM/MeOH) is the compound mentioned in the title.

1H NMR (300 MHz, CD3OD): 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). 15th

Ethyl 2-{[N-({[4-(cyclopropylamino)butyl](methyl)carbamoyl}methyl)-)2,2,2(t-trifluoroacetamido]methyl}pyridine-4-carboxylate

It was prepared by general procedure B from -4 ethyl 2-[(2,2,2-trifluoro-N-{[methyl]).

(s) oxobutyl(carbamoyl]methyl}acetamido)methyl]pyridine-4-carboxylate

20 and cyclopropylamine. cyclopropylamine provides the column chromatophoresis (EtOAc/hexanes).

hexanes (the compound mentioned in the title is in the form of a yellow oil.

1H-NMR (300MHz, CDCl3): δ 8.70 (dd, 1H), 7.85 (ss, 1H), 7.74 (dd, 1H), 4.95 (dd, 2H), 4.40 (q, 2H), 4.32 (ss, 2H) ), 3.31 (m, 1H), 3.25 (m,

٥٦٠١

-١٣٢-

1H), 2.90 (s, 3H), 2.73 (m, 1H), 2.50 (m, 1H), 2.01 (m, 1H), 1.85-1.30 (m, 8H), 0.53.034 (m, 4H).

ES-MS: 459 [M+1]

5 Ethyl 2-({2,2,2-trifluoro-N-[(3R)-1-(3-phenylpropyl)pyrrolidin-3-(N)yl]acetamido}methyl)pyridine-4-carboxylate 5

It was prepared by general procedure B from (ethyl 2-({2,2,2-trifluoro-N-[(3R))).

pyrrolidin-3-

(M) yl]acetamido}methyl)pyridine-4-carboxylate .

1H-NMR (300MHz, CDCl3): δ 8.70 (d, 1H), 7.80 (s, 1H), 7.72 (dd,1H),

7.24 (m, 5H), 4.95 (q, 2H), 4.37 (m, 2H), 3.78 (m, 1H), 2.60 (m, 3H), 10

2.46 (m, 2H), 2.32 (m, 2H), 2.21 (m, 1H), 2.04 (m, 2H), 1.88 (m,1H),

1.73 (m, 1h), 1.43 (t, 3h).

Ethyl 2-({2,2,2-trifluoro-N-[({1-[(2-methoxyphenyl)methyl]piperidin-4-)ph(yl}carbamoyl)methyl]acetamido}methyl)pyridine-4-carboxylate

15th It was prepared by general procedure b from -4-ethyl 2-[(2,2,2-trifluoro-N-{[(piperidin)]).

(P(yl)carbamoyl]methyl}acetamido)methyl]pyridine-4-carboxylate.

1H-NMR (300MHz, CDCl3): δ 8.75 &amp; 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 &amp;

4.72 (2s, 2H, rotamer), 4.45 (q, 2H), 4.30 &amp; 4.08 (2s, 2H; rotamer), 3.83 (m, 4H), 3.60 (m, 2H) 2.95 (m, 2H), 2.22 (m) , 2H), 1.90 (m, 2H), 1.60 20

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

٥٦٠١

-١٣٣-

Ethyl 2-({N-[({4-

[benzyl(cyclopropyl)amino]butyl}(methyl)carbamoyl)methyl]-2,2,2-)u(trifluoroacetamido}methyl)pyridine-4-carboxylate

It was prepared by general procedure B from -4]})-ethyl 2-{[N

(cyclopropylamino)butyl](methyl)carbamoyl}methyl)-2,2,2- 5

(t) trifluoroacetamido]methyl}pyridine-4-carboxylate .

1H NMR (300 MHz, CD3OD): δ 8.70 (m, 1H), 7.83 (m, 1H), 7.77 (m,

1H), 7.30 (m, 5H), 4.83 (dd, 2H), 4.40 (m, 3H), 4.23 (m, 1H), 3.65 (m,

1H), 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) 10

Ethyl 2-({[2-oxo-2-(piperidin-1-yl)ethyl]amino}methyl)pyridine-4-(Ag) carboxylate

It was prepared by general procedure b from -1-ethyl 2-({ethyl[2-oxo-2-(piperidin)]).

acetaldehyde and acetyl aldehyde (yl(ethyl]amino}methyl)pyridine-4-carboxylate

15th To obtain the compound mentioned in the title in the form of yellow oil.

1H NMR (300 MHz, CDCl3) 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-(AB) carboxylate 20

1H NMR (300 MHz, CDCl3) 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).

٥٦٠١

-١٣٤-

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

General procedure c) formation of trifluoroacetamide and/or trifluoroacetate

(trifluoroacetate .)

5 DIPEA (1.5 equivalent) was added to a solution of amine (or alcohol)

(Ethyl 2-({[2-(tert-butoxy)-2-oxoethyl]amino}methyl)pyridine-4-

carboxylate (b)) in anhydrous DCM. The mixture was stirred at 0°C and tetrafluoroacetic anhydride (1,5 equiv.) was added dropwise. After addition, the reaction was allowed to warm to room temperature and stirring continued for 2 hours. Quench the reaction with an aqueous solution of

10 NaHCO3. Hydrotherapy provides the compound mentioned in the title.

1H-NMR (300MHz, 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})

(g) acetamido)methyl]pyridine-4-carboxylate

15th It was prepared by general procedure C from -3)]}-2 ethyl

and (using 7 equivalents of (hydroxypropyl)amino]methyl}pyridine-4-carboxylate

DIPEA and its equivalent 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) 20

Ethyl 2-({N-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-2,2,2-

(i) trifluoroacetamido}methyl)pyridine-4-carboxylate

٥٦٠١

-١٣٥-

It was prepared by general procedure C from -ethyl 2-({[(3R)-1-[(tert)]

(K) (butoxy)carbonyl]pyrrolidin-3-yl]amino}methyl)pyridine-4-carboxylate.

The reaction time is 12 hours. The compound mentioned in the title has been isolated as yellow oil.

1H-NMR (300MHz, 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), 5

1.44 (t, 3h).

.ES-MS: 446 [M+1]

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

10 General procedure d) acids obtained from t-butyl esters or amines

) tert butoxy carbamates butoxy carbamate t from amines

ester (or carbamate) (Ethyl 2-({N-[2-(tert-butoxy))-2-oxoethyl]- dissolved)

Pre-DCM a2,2,2(c))-trifluoroacetamido}methyl)pyridine-4-carboxylate

Tar-fluoroacetic acid (0,1-1 volume equivalent of DCM) was added. The mixture was stirred at

15th Room temperature throughout the night. The solvent was evaporated at reduced pressure to obtain the compound mentioned in the title.

1H-NMR (300MHz, CD3OD): δ 8.75 (m, 1H), 7.8 8.00 (m, 2H), 5.45, .4.99 (2s, 2H; rotamer), 4.20 - 4.40 (m, 4H), 1.40 (t, 3h)

Ethyl 2-({2,2,2-trifluoro-N-[(3R)-pyrrolidin-3-(m)yl]acetamido}methyl)pyridine-4-carboxylate 20

It was prepared by general procedure D from -ethyl 2-({N-[(3R)-1-[(tert)]

butoxy)carbonyl]pyrrolidin-3-yl]-2,2,2-trifluoroacetamido}methyl)pyridine-

4-carboxylate (i).

٥٦٠١

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1H-NMR (300MHz, CDCl3): 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]

Ethyl 2-[(2,2,2-trifluoro-N-{[(piperidin-4- 5 .)]

(p) yl)carbamoyl]methyl}acetamido)methyl]pyridine-4-carboxylate

It was prepared by general procedure d from -ethyl 2-({N-[({1-[(tert))]

butoxy)carbonyl]piperidin-4-yl}carbamoyl)methyl]-2,2,2-

. The purification is performed by trifluoroacetamido}methyl)pyridine-4-carboxylate (Q).

10 Column chromatography (DCM/MeOH and 1% NH4OH) provides the compound mentioned in the title in the form of a brown foam.

1H-NMR (300MHz, CD3OD): δ 8.75 (m, 1H ), 7.90 (m, 2H), 5.00 &amp;

4.90 (2s, 2H, rotamer), 4.42 (q, 2H), 4.32 &amp; 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) 15

Ethyl 2-({2,2,2-trifluoro-N-[2-oxo-2-(pyrrolidin-1-)]e(yl)ethyl]acetamido}methyl)pyridine-4-carboxylate

General Procedure e) Formation of esters, amides, and sulfonamides

sulfonamides

20 Pyrrolidine amine, alcohol or sulfonamide has been added

acid (2-(N-{[4-(ethoxycarbonyl)pyridin-2 equivalent) to a solution of ()sulfonamide)

2-yl]methyl}-2,2,2-trifluoroacetamido (acetic acid (d)) (1 equivalent) in DMF.

Cooling to 0°C before adding 1,5 (EDC HCl equivalent) hydroxyl

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ethyl(hydroxyl iminocyanoaectate) oxyma; 1.5 equiv.). The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. Hydrotreatment and purification by column chromatogenesis yielded the compound mentioned in the title.

1H-NMR (300MHz, CD3OD): δ 8.75 (m, 1H), 7.90 (s, 1H), 7.85(m, 1H),

4.90 -4.30 (two set of singlet &amp; q , 6H, rotamer), 3.45 (m, 4H), 2.00-5

1.80 (m, 4H), 1.38 (t, 3H)

Ethyl 2-({N-[({1-[(tert-butoxy)carbonyl]piperidin-4-yl}carbamoyl)methyl]-)2,2,2 (O-trifluoroacetamido}methyl)pyridine-4-carboxylate

It was prepared by general procedure E from -1-tert-butyl 4-aminopiperidine

carboxylate and 2-(N-{[4-(ethoxycarbonyl)pyridin-2-yl]methyl}-2,2,2-10

trifluoroacetamido (acetic acid) (d) to provide the compound mentioned in the title in the form of a brown foam.

1H-NMR (300MHz, CDCl3): δ 8.70 &amp; 8.60 (2d, 1H; rotamer ), 7.80 (m,

2H), 4.90 &amp; 4.78 (2s, 2H, rotamer), 4.42 (q, 2H), 4.30 &amp; 4.10 (2s, 2H;

rotamer), 4.10 (m, 1H), 2.80 (m, 2H) 2.0 (m, 2H), 1.48 (s, 9H), 1.40 (t, 15

3h)

Ethyl 2-[(2,2,2-trifluoro-N-{[(4-)]

hydroxybutyl)(methyl)carbamoyl]methyl}acetamido)methyl]pyridine-4-

(r) carboxylate

20 It was prepared by general procedure E from -4-(methylamino)butan-1-ol and 2-(N).

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

acid (d).

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1H-NMR (300MHz, CDCl3): 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 (s 1h), 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]

4-hydroxypentan-2-yl 2-({[(tert-butoxy)carbonyl])({[2- 5

(dimethylamino)ethyl](ethyl)carbamoyl} methyl)amino}methyl)pyridine-4-)z(carboxylate

from 2-({[(tert-butoxy)carbonyl]){[2(dimethylamino)ethyl] General Procedure E from

K) and ((ethyl)carbamoyl}methyl)amino}methyl)pyridine-4-carboxylic acid

10 pentane-2,4-diol. The purification is performed by column chromatogenesis (10-15%).

DCM /MeOH) to provide the compound mentioned in the title as brown oil.

1H-NMR (300MHz, CDCl3): 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] 15

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

General procedure f (Swern oxidation of alcohols to aldehydes and ketones)

DMSO (4,0 equivalent) was diluted with DCM and cooled to -78 °C, 2.0 oxalyl chloride equivalent (2.0 oxalyl chloride) was added and the mixture was stirred for 30 minutes. Then

alcohol (ethyl 2-{[2,2,2-trifluoro-N-(3- a solution of H DCM)) was added in (hydroxypropyl)acetamido]methyl}pyridine-4-carboxylate

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Stir the mixture for another hour. Then, 5,0 Et3N (equivalent) was added and the mixtures were warmed to room temperature. Hydrotherapy The chromatophoresis column provides the elevation of the compound mentioned in the title.

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) 5

Ethyl 2-[(2,2,2-trifluoro-N-{[methyl(4-)]

(s) oxobutyl(carbamoyl]methyl}acetamido)methyl]pyridine-4-carboxylate

It was prepared by general procedure F from -4]}-ethyl 2-[(2,2,2-trifluoro-N).

hydroxybutyl)(methyl)carbamoyl]methyl}acetamido)methyl]pyridine-4-

r. and purification by carboxylate (r). Purified by column chromatography 10

Column chromatids (EtOAc/hexanes).

1H-NMR (300MHz, CDCl3): δ 9.85 (m, 1H), 8.70 (dd, 1H), 7.9 (ss, 1H),

7.80 (dd, 1H), 4.93 (ss, 2H), 4.43 (ss, 2H), 4.35 (q, 2), 3.01 (ss, 3H),

1.44 (t, 3h).

.ES-MS: 418 [M+1] 15

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

It was prepared by general procedure F from 4-hydroxypentane-2-yl 2-(}](t-butoxy) 20 carbonyl[)}[2-(dimethylamino)ethyl](ethyl)carbamoyl{methyl)amino{ Methyl(pyridine-4-

Carboxylate (Z). Column chromatography (10% DCM/MeOH) purification provides the compound mentioned in the title as brown oil.

٥٦٠١

-١٤٠-

1H-NMR (300MHz, CDCl3): 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]

Ethyl 2-({[(tert-butoxy)carbonyl])({[2- 5

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino}methyl)pyridine-4-(t)carboxylate

General Procedure G (Protection with Boc Amines Group)

amine (ethyl 2-{[({[2-dissolved

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-10

(1) (#65) carboxylate equiv and 1,2 equiv Boc2O in H2O/THF. The solid (4 equiv. NaHCO3 equiv.) was added. The reaction mixture was stirred at room temperature overnight. After removing the solvent, The residue was purified by column chromatography by using a graduated amount of 0-10 MeOH% in DCM to provide the product mentioned in the title as yellow 15 oil.

1H-NMR (300MHz, CDCl3): δ 8.52 (m, 1H), 7.84 (m, 1H), 7.74 (m, 1H),

4.65 (m, 2H), 4.23 (m, 2H), 3.45 (m, 4H), 2.50 (m, 2H), 2.25 (m, 6H), .1.43 (m, 9H), 1.19 (m, 3H)

tert-butyl N-({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)-N-({4-)y) [(pyridin-4-yl)carbamoyl]pyridin-2-yl}methyl) carbamate 20

General Procedure H (formation of esters, amides, and sulfonamides)

Anhydride of 2,0 (equivalent Et3N) and propane phosphonic acid (acid anhydride equivalent) was added to a solution of amine

٥٦٠١

-١٤١-

(pyridin-4-amine) or alcohol or 1,5 sulfonamide (sulfonamide equivalent) and

acid (2-({[(tert-butoxy)carbonyl])({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino}methyl)pyridine-4-

carboxylic acid (x) (1.0 equiv) in DMF. The reaction mixture was stirred for 12 hours at

5 At room temperature, the DMF was removed at reduced pressure, diluted with DCM and washed with water to obtain the compound mentioned in the title as brown oil. The purification is done by column chromatotogenesis or used without further purification.

1H-NMR (300MHz, D2O): δ 8.59 (d, 2H ), 8.21 (d, 2H), 7.88 (d, 2H),

6.75 (d, 1H), 4.35-4.32 (m, 2H), 3.71-3.66 (m, 2H), 3.38-3.24 (m, 2H), .3.13-3.06 (m, 4H), 2.90 (s, 6H) , 1.20-1.15 (m, 12H) 10

Ethyl 2-{[2,2,2-trifluoro-N-(3-hydroxypropyl)acetamido]methyl}pyridine-

(4) H-carboxylate

It was prepared by general procedure A from -3}-ethyl 2-[(2,2,2-trifluoro-N).

(g) [(trifluoroacetyl)oxy]propyl}acetamido)methyl]pyridine-4-carboxylate.

15th Purification by flash chromatophoresis yields the compound mentioned in the title.

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-4-20(x) carboxylic acid

It was prepared by general procedure A from -2]})[ethyl 2-({[(tert-butoxy)carbonyl]

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino}methyl)pyridine-4-

carboxylate to obtain the compound mentioned in the title as a yellow solid.

٥٦٠١

-١٤٢-

1H NMR (300 MHz, CD3OD) 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)

Intermediate amine compounds

Benzyl N-[(1R)-2-hydroxy-1-{methyl[3-(1-methyl-1H-imidazol-2- 5 yl)propyl]carbamoyl}ethyl]carbamate

A reaction mixture comprising -2-methyl[3-(1-methyl-1H-imidazol .) was stirred

1,1(yl)propyl]amine equivalent), -3-{2R)-2-{[(benzyloxy)carbonyl]amino)

(1.0) hydroxypropanoic acid (equivalent), (1.2 HATU equivalent), and (1.4) DIPEA equivalent),

10 in DMF at room temperature until TLC demonstrates the complete reaction. The reaction mixture is then divided between saturated NaHCO3/EtOAc. The EtOAc extraction product was concentrated to provide the compound mentioned in the title.

(2R)-2-amino-3-hydroxy-N-methyl-N-[3-(1-methyl-1H-imidazol-2-yl)propyl]propanamide

Benzyl N-[(1R)-2-hydroxy-1-{methyl]3-(1-methyl-1H-15) A mixture of 5% wt.(Pd/C 10% and imidazol-2-yl)propyl]carbamoyl was stirred. } ethyl]carbamate

in MeOH in hydrogen atmosphere (40 psi) so that TLC could not be detected. The mixture was filtered through a sialite pad and shaken to obtain the compound mentioned in the title.

Hh 2-amino-N-[2-(dimethylamino)ethyl]-N-ethylacetamide 20

Prepared by general procedure E from -2] Boc-Glycine and

MeOH in HCl perform the following treatment with (dimethylamino)ethyl](ethyl)amine.

To provide the product mentioned in the title as hydrochloride.

٥٦٠١

-١٤٣-

1H NMR (300 MHz, CDCl3) δ 3.41 (m, 4H), 3.23 (m, 2H), 2.39 (m, 2H),

2.22 (s, 6H), 1.52 (s(br), 2H), 1.11 (m, 3H)

Intermediate alcohol compounds

Hh2,2,2-trifluoro-N-(3-hydroxybutyl)acetamide

5 General Procedure i (formation of trifluoroacetamides)

Ethyl 2,2,2-trifluoroacetate was added at 0°C to a solution of 4-aminobutan-2-ol in MTBE. The mixture was cooled to room temperature and stirred in nitrogen overnight. The solvent was evaporated at reduced pressure to provide the compound mentioned in the title as a colorless oil.

1H NMR (300 MHz, CDCl3), δ 8.0 (brs, 1H), 3.95 (m, 1H), 3.6 (m, 1H), 10

3.3 (m, 2h), 1.75 (m, 1h), 1.6 (m, 1h), 1.2 (d, 6h).

Tert-butyl N-(3-hydroxybutyl)carbamate

It has been prepared by a general procedure g of 4-aminobutane-2-ol to provide the product mentioned in the title in the form of a colorless gum.

1H NMR (300 MHz, CDCl3), δ ppm: 5.0 (brs, 1H), 3.7 (m, 1H), 3.4 brs, 15 1H), 3.2 (m, 2H), 1.6 (m, 2H), 1.4 (s , 9h), 1.2 (d, 3h).

ES-MS: 224 [M+1].

4-(methylamino)butan-2-ol

LAH was added at 0 °C to a solution of t-butyl 3-hydroxybutyl

20 Carbamatet-butyl 3-hydroxybutylcarbamate in THF. The mixture was agitated to room temperature and heated at 70 °C with stirring in nitrogen for 3 h. It was completed

٥٦٠١

-١٤٤-

Quench the reaction with 10% NaOH solution. Hydrotherapy provides the product mentioned in the title in the form of a colorless oil.

1H NMR (300 MHz, CDCl3), δ ppm: 3.9 (m, 1H), 3.6 (brs, 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 5

It has been prepared by General Procedure I from 4-(methylamino)butan-2-ol to provide the product mentioned in the title in the form of a colorless oil.

1H NMR (300 MHz, CDCl3), 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]. 10

2,2,2-trifluoro-N-(3-hydroxypent-4-en-1-yl)acetamide

It was prepared by general procedure i from 5-Aminopent-1-en-3-ol to provide the compound

mentioned in the title in the form of a brown foam.

1H-NMR (300MHz, CDCl3): δ 7.50 (br s, 1H), 5.90 (m, 1H), 5.28 (d,

1H), 5.20 (d, 1H), 4.40 (m, 1H), 3.75 (m, 1H), 3.40 (m, 1H), 2.00-1.60 15

(m, 2h).

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

It was prepared by general procedure i-ethyl trifluroacetate 3,3-diethoxypropan 1-amine to obtain N-(3,3-diethoxypropyl)-2,2,2-trifluoroacetamide,

20 which was treated with 2 moles of HCl to obtain the compound mentioned in the title.

1H-NMR (300MHz, CDCl3): δ 9.81 (s, 1H), 7.15 (br s, 1H), 3.64 (q,

.2H), 2.83 (t, 2H)

٥٦٠١

-١٤٥-

trimethyl({[1-(propan-2-yloxy)ethenyl]oxy})silane

To a solution of propan-2-yl acetate (1 equivalent) propan-2-yl acetate in THF (1.1 LDA equivalent) was added at -78 °C. The reaction mixture was stirred for 30 minutes and allowed to warm (1TMSCl equivalent) ., at room temperature, stirred for an hour

5 Using hexane, washing with water, brine and its concentration to obtain the compound mentioned in the title.

propan-2-yl 3-hydroxy-5-(trifluoroacetamido)pentanoate

DCM 2,2,2(1 equivalent) in-trifluoro-N-(3-oxopropyl)acetamide to a solution of

TiCl4 (1equivalent) and (trimethyl({[1-(propan-2-yloxy)ethenyl]oxy})silane was added

10 1 equiv. at -78 °C. The reaction mixture was allowed to warm at room temperature

And stir for an hour. Extraction with DCM, washing with water, brine and concentration to obtain the compound mentioned in the title.

1H-NMR (300MHz, CDCl3): δ 7.65 (br s, 1H), 5.05 (m, 1H), 4.19 (m, 1H), 3.35 (m, 1H), 2.46 (d, 2H), 1.85 – 1.61 ( m, 2h), 1.25 (d, 6h).

Propan-2-yl 3-hydroxy-4-(trifluoroacetamido)butanoate 15

It was prepared by general procedure i from propan-2-yl 4-amino-3-hydroxybutanoate

1H-NMR (300MHz, CDCl3): 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).

20 Example 2: Tests for the enzymes Histone lysine demethylase AlphaLISA to determine the value of

.IC50

٥٦٠١

-١٤٦-

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

Roy et al. The results are illustrated by PerkinElmer. The tests were performed similarly to the protocol mentioned. (PerkinElmer Technical Note: AlphaLISA #12, Apr. 2011)

5 in table 03

general method

Enzymes were dissolved in enzyme-buffering solution and incubated for 1 0 min before adding e μl to e μl 3% DMSO solutions of the compounds in enzyme-buffering solution. and incubation for another 1 0 min, before adding 1 µl of substrate solution and the reaction mixture was incubated at 1 0 ºC for a specified period of time. 0 μl acceptor beads were added, suspended at

Specific dilutions in epigenetic buffer (Perkin Elmer Α1008) from crude, and the suspension was incubated 0 6 min in the dark at room temperature, before adding 1 0 μl of suspension (at indicated dilutions of epigenetic buffer) to streptavidin-donor beads (6760002 Perkin Elmer) in epigenetic sequence buffer solution. After 1 5 incubation at room temperature in the dark the plates are read. The reaction conditions are noted in Table 2b.

<tr><td colspan="4"><p dir="rtl">22 AH</p></td></tr><tr><td><p dir="rtl">organism for genetic expression</p></td><td><p dir="rtl">progression</p></td><td><p dir="rtl">source seller</p></td><td><p dir="rtl">protein name</p></td></tr><tr><td><p>Back</p></td><td><p dir="rtl">١ - ٦٥٠</p></td><td><p>BPS, Bioscience,</p><p dir="rtl">unless</p></td><td><p>KDM2A (FBXUO)</p></td></tr>

٥٦٠١

-١٤٧-

<tr><td><p>Back</p></td><td><p>1761-842</p></td><td><p>BRIC</p></td><td><p>KDM3B (JMJD1B)</p></td></tr><tr><td><p>E.coli</p></td><td><p>350-1</p></td><td><p>BPS, Bioscience, US</p></td><td><p>KDM4A (JMJD2A)</p></td></tr><tr><td><p>Back</p></td><td><p>500-2</p></td><td><p>BPS</p></td><td><p>KDM4B (JMJD2B)</p></td></tr><tr><td><p>E.coli</p></td><td><p>349-1</p></td><td><p>BRIC, Denmark</p></td><td><p>KDM4C</p><p>(JMJD2C)</p></td></tr><tr><td><p>Back</p></td><td><p>1560-2</p></td><td><p>BPS</p></td><td><p>KDM5 (JARID1C)</p></td></tr><tr><td><p>E.coli</p></td><td><p>809-1</p></td><td><p>BRIC</p></td><td><p>KDM5B (PLU-1)</p></td></tr><tr><td><p>E.coli</p></td><td><p>1401-919</p></td><td><p>BRIC</p></td><td><p>KDM6A (UTX)</p></td></tr><tr><td><p>Back</p></td><td><p dir="rtl">party 1043</p></td><td><p>BPS</p></td><td><p>KDM6B (JMJD3)</p></td></tr><tr><td><p>Back</p></td><td><p>1322-1</p></td><td><p>BRIC</p></td><td><p>KDM7</p><p>(PHF8)</p></td></tr><tr><td><p>Back</p></td><td><p dir="rtl">tip -2</p></td><td><p>BPS, Bioscience, US</p></td><td><p>KDM3A</p><p>(JMJD1A)</p></td></tr>

substrates:

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

: BK9M2

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

BK9M1: 5

٥٦٠١

-١٤٨-

Biotin-ARTKQTAR(KMel)STGGKAPRKQ-NH2 (AnaSpec 64358)

:Η3Κ4Μ3Β

H-ART(Kme3)QTARKSTGGKAPRKQLA-NH-Biotin (Casio, Denmark)

:ΒΚ27Μ3 5

Biotin-ATKAAR(Kme3)SAPATGGVKKPHRY-NH2? (Casio,

Denmark)

:ΒΗ3Κ36Μ2

RKAAPATGGVK(Me2)KPHRYRPGIVK-(BIOTIN)? (Anaspec)

0 1 enzyme buffer solution

: 0 5 mM Hepes (pH see Table 2b), 0.00% Tween-20, 0.1 858; 5 μmol2(504)5]2(14A)

buffer solution A:

50 mM Hepes (pH see Table 2b), 0.003% Tween-20,

١٥ ٠,١%85٨

reaction conditions

Table 2b

<tr><td><p dir="rtl">time</p><p dir="rtl">sheep</p></td><td><p dir="rtl">beads</p><p dir="rtl">donor</p></td><td><p dir="rtl">Receiver beads</p></td><td><p dir="rtl">substrate solution</p></td><td><p dir="rtl">enzyme</p></td><td><p dir="rtl">[Enzyme</p></td></tr><tr><td><p dir="rtl">٦٠</p></td><td><p dir="rtl">dilute</p></td><td><p>Η3Κ36Μ1</p></td><td><p dir="rtl">buffer solution A,</p></td><td><p dir="rtl">solution</p></td><td><p dir="rtl">7 A0&gt;A2B</p></td></tr>

٥٦٠١

-١٤٩-

<tr><td><p dir="rtl">Accurate</p></td><td><p dir="rtl">200:1</p><p dir="rtl">of raw</p></td><td><p>PerkinElmer</p><p>Custom, 10120327R</p><p>S</p><p dir="rtl">Dilute 200:1 of raw</p></td><td><p dir="rtl">pH 8.0 + 25 μl-L 10 μl Asc. α-KG</p><p dir="rtl">final pillar</p><p>(BH3K36M2)</p><p dir="rtl">Concentration: 50 nanomolar</p></td><td><p dir="rtl">Regulator A, pH 8.0</p><p dir="rtl">Final enzyme concentration: 2 nM</p></td><td></td></tr><tr><td><p dir="rtl">60</p><p dir="rtl">Accurate</p></td><td><p dir="rtl">dilute</p><p dir="rtl">200:1 of raw</p></td><td><p>H3K9Me1</p><p dir="rtl">(not self-attached)</p><p dir="rtl">Dilute 200:1 of raw</p></td><td><p dir="rtl">Buffer Solution A, No.</p><p dir="rtl">pH7,4 + 25 μl-L 10 μl Asc, α-KG</p><p dir="rtl">final pillar</p><p>(BK9M2)</p><p dir="rtl">Concentration: 100 nanomolar</p></td><td><p dir="rtl">Buffer A, pH 7.4</p><p dir="rtl">Final enzyme concentration: 1.6 nM</p></td><td><p>KDM2B</p></td></tr><tr><td><p dir="rtl">60</p><p dir="rtl">Accurate</p></td><td><p dir="rtl">dilute</p><p dir="rtl">200:1 of raw</p></td><td><p>( H3K9Me1</p><p dir="rtl">not self-attach(</p><p dir="rtl">Diluted 200:1</p><p dir="rtl">of raw</p></td><td><p dir="rtl">Buffer Solution A, No.</p><p dir="rtl">pH7,4 + 25 µl-L 10, Asc µl</p></td><td><p dir="rtl">Buffer A, pH 7.4</p></td><td><p>KDM3A</p></td></tr>

٥٦٠١

-١٥٠-

<tr><td></td><td></td><td></td><td><p dir="rtl">l α-KG.</p><p dir="rtl">final pillar</p><p>(BK9M2)</p><p dir="rtl">Concentration: 100 nanomolar</p></td><td><p dir="rtl">Final enzyme concentration: 0.1 nM</p></td><td></td></tr><tr><td><p dir="rtl">60</p><p dir="rtl">Accurate</p></td><td><p dir="rtl">Dilute 400:1 of raw</p></td><td><p>(H3K9Me2</p><p dir="rtl">catalog number</p><p>AL117,Perki</p><p>n Elmer</p><p dir="rtl">Dilute 400:1 of raw</p></td><td><p dir="rtl">Buffer Solution A, No.</p><p dir="rtl">pH7,4 + 25 μl-L 10 μl Asc, α-KG</p><p dir="rtl">final pillar</p><p>(3M9BK)</p><p dir="rtl">Concentration: 100 nanomolar</p></td><td><p dir="rtl">Buffer A, pH 7.4</p><p dir="rtl">Final enzyme concentration: 0.2 nM</p></td><td><p>KDM3B</p></td></tr><tr><td><p dir="rtl">60</p><p dir="rtl">Accurate</p></td><td><p dir="rtl">dilute</p><p dir="rtl">400:1 of raw</p></td><td><p>(H3K9Me2</p><p dir="rtl">number</p><p dir="rtl">AL117 catalog,</p><p>Perkin</p><p>(Elmer .)</p><p dir="rtl">Dilute 400:1 of raw</p></td><td><p dir="rtl">Buffer Solution A, No.</p><p dir="rtl">pH7,4 + 25 μl-L 10 μl Asc, α-KG</p><p dir="rtl">final pillar</p><p>(3M9BK)</p></td><td><p dir="rtl">Buffer A, pH 7.4</p><p dir="rtl">Final enzyme concentration: 1 nanomolar</p></td><td><p>KDM4A</p></td></tr>

٥٦٠١

-١٥١-

<tr><td></td><td></td><td></td><td><p dir="rtl">Concentration: 100 nano</p></td><td></td><td></td></tr><tr><td><p dir="rtl">60</p><p dir="rtl">Accurate</p></td><td><p dir="rtl">dilute</p><p dir="rtl">400:1 of raw</p></td><td><p>(H3K9Me2</p><p dir="rtl">number</p><p dir="rtl">AL117 catalog,</p><p>Perkin</p><p>(Elmer .)</p><p dir="rtl">Dilute 400:1 of raw</p></td><td><p dir="rtl">Buffer Solution A, No.</p><p dir="rtl">pH7,4 + 25 μl-L 10 μl Asc, α-KG</p><p dir="rtl">final pillar</p><p>(3M9BK)</p><p dir="rtl">Concentration: 200 nm</p></td><td><p dir="rtl">Buffer Solution A, No. 7.4</p><p dir="rtl">Final enzyme: 1 nanomolar</p></td><td><p>KDM4B</p></td></tr><tr><td><p dir="rtl">20</p><p dir="rtl">Accurate</p></td><td><p dir="rtl">dilute</p><p dir="rtl">200:1 of raw</p></td><td><p>H3K4Me2-1</p><p>Perkin (Elmer</p><p>(AL116 .)</p><p dir="rtl">Dilute 200:1 of raw</p></td><td><p dir="rtl">Buffer Solution A, No.</p><p dir="rtl">pH7,4 + 25 μl-L 10 μl Asc, α-KG</p><p dir="rtl">final pillar</p><p>(H3K4M3B)</p><p dir="rtl">Concentration: 200 nm</p></td><td><p dir="rtl">Buffer A, pH 7.4</p><p dir="rtl">Final enzyme concentration: 2 nM</p></td><td><p>KDM4C</p></td></tr>

٥٦٠١

-١٥٢-

<tr><td><p dir="rtl">30 Accurate</p></td><td><p dir="rtl">dilute</p><p dir="rtl">200:1 of raw</p></td><td><p>H3K4Me2-1</p><p>Perkin (Elmer</p><p>(AL116 .)</p><p dir="rtl">Dilute 200:1 of raw</p></td><td><p dir="rtl">Buffer Solution A, No.</p><p dir="rtl">pH7,4 + 25 μl-L 10 μl Asc, α-KG</p><p dir="rtl">final pillar</p><p>(H3K4M3B)</p><p dir="rtl">100 nano molar</p></td><td><p dir="rtl">Buffer A, pH 7.4</p><p dir="rtl">Final enzyme concentration: 1 nanomolar</p></td><td><p>KDM5B</p></td></tr><tr><td><p dir="rtl">60</p><p dir="rtl">Accurate</p></td><td><p dir="rtl">dilute</p><p dir="rtl">200:1 of raw</p></td><td><p>H3K27me2-</p><p>Perkin ( 1 Elmer</p><p>(AL121 .)</p><p dir="rtl">Dilute 200:1 of raw</p></td><td><p dir="rtl">Buffer Solution A, No.</p><p dir="rtl">pH7,4 + 25 μl-L 10 μl Asc, α-KG</p><p dir="rtl">final pillar</p><p>(BK27M3)</p><p dir="rtl">Concentration: 100 nanomolar</p></td><td><p dir="rtl">Buffer A, pH 7.4</p><p dir="rtl">Final enzyme concentration: 2 nM</p></td><td><p>KDM5C</p></td></tr><tr><td><p dir="rtl">60</p><p dir="rtl">Accurate</p></td><td><p dir="rtl">dilute</p><p dir="rtl">200:1 of raw</p></td><td><p>H3K27me2</p><p>Perkin (Elmer</p><p>(AL121 .)</p></td><td><p dir="rtl">Buffer Solution A, No.</p><p dir="rtl">pH7,4 + 25 µl-L 10, Asc µl</p></td><td><p dir="rtl">buffer solution A, pH</p></td><td><p>KDM6A</p></td></tr>

٥٦٠١

-١٥٣-

<tr><td></td><td></td><td><p dir="rtl">Diluted 200:1</p><p dir="rtl">of raw</p></td><td><p dir="rtl">l α-KG.</p><p dir="rtl">final pillar</p><p>(BK27M3)</p><p dir="rtl">Concentration: 50 nanomolar</p></td><td><p dir="rtl">7,4</p><p dir="rtl">enzyme concentration</p><p dir="rtl">Final: 1 nanomolar</p></td><td></td></tr><tr><td><p dir="rtl">60</p><p dir="rtl">Accurate</p></td><td><p dir="rtl">dilute</p><p dir="rtl">200:1 of raw</p></td><td><p>(H3K9Me1</p><p dir="rtl">not self-attach(</p><p dir="rtl">Diluted 200:1</p><p dir="rtl">of raw</p></td><td><p dir="rtl">Buffer Solution A, No.</p><p dir="rtl">pH7,4 + 25 μl-L 10 μl Asc, α-KG</p><p dir="rtl">final pillar</p><p>(BK9M2)</p><p dir="rtl">Concentration: 100 nanomolar</p></td><td><p dir="rtl">Buffer A, pH 7.4</p><p dir="rtl">Final enzyme concentration:</p><p>nM2,5</p></td><td><p>KDM6B</p></td></tr>

HDME inhibition

Table 3

<tr><td><p>FB</p><p>XL</p><p>10</p></td><td><p>GAS</p><p>C1</p></td><td><p dir="rtl">name</p></td><td><p dir="rtl">structural formula</p></td></tr><tr><td><p>+</p></td><td><p>++</p></td><td><p>2-({[3-(1H-imidazol-amino}propyl] 1-yl)methyl)pyridine-4-</p></td><td></td></tr>

٥٦٠١

-١٥٤-

<tr><td></td><td></td><td><p>carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-({[2-(dimethylamino)ethyl]amino}methyl)pyri dine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>++</p></td><td><p>2-({[(2R)-2,3-dihydroxypropyl]amino}</p><p>pyridine-4-methyl)</p><p>carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>++</p></td><td><p>-2-{[(cyclopropy lmethyl)amino]methyl}p yridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2[(cyclopropylmethyl)a mino]methyl}pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td></td><td><p>2-({[2-(dimethylamino) ethyl](methyl)amino}me thyl)pyridine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-١٥٥-

<tr><td></td><td><p>tt</p></td><td><p>2-{[methyl(prop-2-yn-</p><p>1-</p><p>yl)amino]methyl}pyridin e-4-ca2boxy,ic acid</p></td><td><p>HO o</p><p>. * "</p></td></tr><tr><td></td><td><p>tt</p></td><td><p>2-{[(2-fluoroethyl)amino]methyl}pyridine-4-carboxylicacid</p></td><td><p>HO m</p><p>Clip</p></td></tr><tr><td></td><td><p>tttt</p></td><td><p>2-{[(furan-2-yl methyl)amino]methyl}pyridine-4-carboxylicacid</p></td><td><p>HO o</p><p dir="rtl">gold</p></td></tr><tr><td></td><td><p>t</p></td><td><p>2-({[(5-phenylfuran-2-amino} methyl] but)methyl)pyridine-4-carboxylic acid</p></td><td><p>ri actually</p><p dir="rtl">NS</p></td></tr><tr><td></td><td><p>t</p></td><td><p dir="rtl">-2,4)a))-2</p><p>dimethoxyphenyl(methy l]amino}methyl)pyridine</p><p>-4-carboxylic acid</p></td><td><p dir="rtl">for 'yours'</p><p dir="rtl">Umm h: b</p></td></tr>

٥٦٠١

-١٥٦-

<tr><td></td><td><p>+++</p></td><td><p>2-({[2-(methylsulfanyl)ethyl]amino}methyl)pyri dine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p><p>+</p></td><td><p>+++</p></td><td><p>2-({[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino}methyl)p yridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p><p>+</p></td><td><p>+++</p></td><td><p>2-[({[butyl(methyl) carbamoyl]methyl}amin o)methyl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>++</p></td><td><p>2-({[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]amino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-[({2-[4-(2-methoxyethyl)piperazin-1-yl]-2-oxoethyl}amino)methyl]pyridine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-١٥٧-

<tr><td></td><td><p>+++</p></td><td><p>2-[({[bis(prop-2-en-</p><p>1-yl)carbamoyl]methyl}amino)methyl]py ridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-[({2-oxo-2-[(2R)]-</p><p>2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}amino)methyl]p yridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+</p></td><td><p>2-({[(3R)-1-[(tert-butoxy)carbonyl]pyrrolid in-3-yl]amino}methyl)pyridin e-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+</p></td><td><p>2-({[(3R)-1-[(tert-butoxy)carbonyl]pyrrolid in-3-yl]amino}methyl)pyridin e-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-{[(3-{[3-(pyrrolidin-</p><p>1-yl)propyl]amino}propyl)</p></td><td></td></tr>

٥٦٠١

-١٥٨-

<tr><td></td><td></td><td><p>amino]methyl}pyridine-</p><p>carboxylic acid4-</p></td><td></td></tr><tr><td></td><td><p>++</p></td><td><p>2-{[(3-methylbutyl)amino]meth yl}pyridine-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-[({[(2-carbamoylethyl)(methyl)carbamoyl]met hyl}amino)methyl]pyridi ne-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-[({2-[2-(hydroxyl-methyl)piperidin-1-yl]-</p><p>2-oxoethyl}amino)methyl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-{[({methyl[3-(1-methyl-1H-imidazol-]</p><p>2-yl)propyl]carbamoylmethyl)amino [methyl}pyridine-4-</p><p>carboxylic acid</p></td><td></td></tr>

٥٦٠١

-١٥٩-

<tr><td></td><td><p>+++</p></td><td><p>2-{[({[(1-thylpyrrolidin-2-yl)methyl] carbamoyl}methyl)amin o]methyl}pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-{[({methyl[(1-methyl-1H-pyrazol-5-yl)methyl]carbamoyl}me thyl)amino]methyl}pyridi ne-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td><p>+</p></td><td><p>2-({[(3R)-1-(3-phenylpropyl)pyrrolidin-3-yl]amino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p><p>+</p></td><td><p>+++</p></td><td><p>2-({[({1-[(2-methoxyphenyl)methyl]]piridin-4-yl}carbamoyl)methyl]am ino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-١٦٠-

<tr><td></td><td><p>+++</p></td><td><p>2-{[({[1-(3-phenylpropyl)piperidin-4-yl]carbamoyl} methyl)amino]methyl}py ridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-{[({[1-(furan-2-ylmethyl)piperidin-4-yl]carbamoyl}methyl)am ino]methyl}pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-({[({1-[(5-phenylfuran-2-])</p><p>yl)methyl]piperidin-4-yl}carbamoyl)methyl]am ino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-[({[(2-cyanoethyl) (ethyl)carbamoyl]methyl }amino)methyl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-({[2-(1-butylpyrrolidin-2-yl)ethyl]amino}methyl)p</p></td><td></td></tr>

٥٦٠١

-١٦١-

<tr><td></td><td></td><td><p>yridine-4-carboxylic</p><p>acid</p></td><td></td></tr><tr><td><p>++</p></td><td><p>+++</p></td><td><p>2-{[({[1-(3,7-dimethyloct-6-en-1-)</p><p>yl)pyrrolidin-3-yl]carbamoyl}methyl)am ino]methyl}pyridine-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-{[(3-{[(2-fluorophenyl)methyl](m ethyl)amino}propyl)ami no]methyl}pyridine-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td><p>+++</p></td><td><p>2-({[(1R)-2-hydroxy-1-{methyl[3-(1-methyl-1H-imidazol-2-]</p><p>yl)propyl]carbamoyl}ethyl]amino}methyl)pyridin e-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-[({2-[3-(1H-1,3-</p><p>benzodiazol-2-ylmethyl)piperidin-1-</p></td><td></td></tr>

٥٦٠١

-١٦٢-

<tr><td></td><td></td><td><p>yl]-2-oxoethyl}amino)methyl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-{[({[1-(2-phenylethyl)pyrrolidin]-</p><p>3-yl]carbamoyl} methyl)amino]methyl}py ridine-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-({[3-(4-benzylpiperidin-1-yl)propyl]amino}methyl) pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-[({3-[(2-phenoxyethyl)amino]pr opyl}amino)methyl]pyrid ine-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-[({[methyl({4-[(4-methylpiperazin-1-yl)methyl]phenyl}methyl)carbamoyl]methyl}ami)</p></td><td></td></tr>

٥٦٠١

-١٦٣-

<tr><td></td><td></td><td><p>no)methyl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-({[2-(2-benzylpyrrolidin-1-yl)-)</p><p>2-oxoethyl]amino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p><p>+</p></td><td><p>+++</p></td><td><p>2-({[({4-[benzyl (cyclopropyl)amino]buty l}(methyl)carbamoyl)me thyl]amino}methyl)pyridi ne-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-[({2-[(2S)-1-benzylpyrrolidin-2-yl]ethyl}amino)methyl]p yridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>++</p></td><td><p>2-({[3-(pyrrolidin-1-yl)propyl]amino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-١٦٤-

<tr><td></td><td><p>+</p></td><td><p>methyl 2-({[3-(pyrrolidin-1-)</p><p>yl)propyl]amino}methyl)pyridine-4-carboxylate</p></td><td colspan="2"></td></tr><tr><td></td><td><p>+++</p></td><td><p>2-({[4-(diethylamino)butyl]ami no}methyl)pyridine-4-</p><p>carboxylic acid</p></td><td colspan="2"></td></tr><tr><td><p>++</p></td><td><p>+++</p></td><td><p>2-{[({[2-</p><p>(dimethylamino)ethyl](e thyl)carbamoyl}methyl)amino]methyl}pyridine-</p><p>4-carboxylic acid</p></td><td colspan="2"></td></tr><tr><td></td><td><p>++</p></td><td colspan="2"><p>4-methoxyphenyl 2-({[4-</p><p>(diethylamino)butyl]amino}methyl)pyridine-4-carboxylate</p></td><td><p dir="rtl">less</p></td></tr>

Continue Table 3

<tr><td><p>PLU1</p></td><td><p>UTX</p></td><td><p>PHF8</p></td><td><p>JMJD</p><p>3</p></td><td><p>JMJD</p><p>2B</p></td><td><p>JMJD</p><p>2</p></td><td><p>JMJD</p><p>1B</p></td><td><p>JARID</p><p>1C</p></td></tr><tr><td></td><td><p>+</p></td><td></td><td><p>+</p></td><td></td><td><p>+++</p></td><td></td><td><p>+++</p></td></tr>

٥٦٠١

-١٦٥-

<tr><td></td><td><p>+</p></td><td></td><td><p>+</p></td><td><p>+++</p></td><td><p>+++</p></td><td><p>+</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td><p>+++</p></td><td><p>+++</p></td><td></td><td><p>+++</p></td></tr><tr><td><p>++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td><p>+</p></td><td><p>+</p></td><td><p>+</p></td><td><p>+</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td><p>++</p></td><td><p>+</p></td><td><p>+++</p></td><td><p>+++</p></td><td><p>+</p></td><td><p>+++</p></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td><p>++</p></td><td><p>+</p></td><td><p>+++</p></td><td></td><td><p>+</p></td><td><p>+++</p></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td><p>+</p></td><td><p>+++</p></td><td><p>+++</p></td><td></td><td><p>+++</p></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr>

٥٦٠١

-١٦٦-

<tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td><p>+</p></td><td><p>+</p></td><td><p>+</p></td><td><p>++</p></td><td><p>++</p></td><td><p>+</p></td><td></td></tr><tr><td><p>+++</p></td><td></td><td><p>+++</p></td><td></td><td><p>+++</p></td><td><p>+++</p></td><td><p>++</p></td><td><p>+++</p></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>++</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td><p>+</p></td><td><p>+</p></td><td><p>+++</p></td><td><p>+++</p></td><td><p>+</p></td><td><p>+++</p></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td><p>++</p></td><td><p>++</p></td><td><p>+++</p></td><td><p>+++</p></td><td><p>+</p></td><td><p>+++</p></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td><p>+</p></td><td><p>+</p></td><td><p>+</p></td><td><p>+++</p></td><td><p>+++</p></td><td><p>+</p></td><td><p>++</p></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>++</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td><p>++</p></td><td></td><td><p>+++</p></td><td><p>+++</p></td><td><p>+</p></td><td><p>+++</p></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td><p>+</p></td><td><p>+</p></td><td><p>+++</p></td><td><p>++</p></td><td></td><td><p>+++</p></td></tr><tr><td><p>++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td><p>+</p></td><td><p>+</p></td><td><p>+++</p></td><td><p>+</p></td><td></td><td><p>+++</p></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td><p>++</p></td><td><p>+</p></td><td><p>+++</p></td><td><p>+++</p></td><td><p>+</p></td><td><p>+++</p></td></tr>

٥٦٠١

-١٦٧-

<img file="SA5601B1_D0039.tif" />

<tr><td><p>* *</p></td><td><p>t</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>tt</p></td><td><p>ethoxycarbonyl)p henyl 2-(4a-</p><p>(diethylamino)but yl]amino}methyl)p yridine-4-carboxylate</p></td><td><p dir="rtl">Less</p></td></tr>

<img file="SA5601B1_D0040.tif" />

٥٦٠١

-١٦٨-

<tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>carboxylate</p></td><td colspan="2"></td></tr><tr><td><p>* *</p></td><td><p>t</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+*</p></td><td><p>3-(dim ethylamino)</p><p>propyl 2-</p><p dir="rtl">-4A))</p><p>(diethylamine o)butyl]amin o}methyl)pyr</p><p>idine-4-carboxylate</p></td><td colspan="2"><p>CH3</p><p dir="rtl">٦٧١/١١</p></td></tr><tr><td><p>* *</p></td><td><p>t</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+*</p></td><td colspan="2"><p>{4-[(ethoxyc-arbonyl)amino]p henyljmethyl 2-({[4-(diethy!am ino)butyl]amino} methyl)pyridine-4-carboxylate</p></td><td><p dir="rtl">less</p></td></tr>

<img file="SA5601B1_D0041.tif" />

_p19 thurs

٥٦٠١

-١٦٩-

<tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td><p>2,6-dimethoxyphen yl 2-({[4-(diethylamino)b utyl]amino}meth yl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>2,6-dimethylphenyl</p><p>2-({[4-(diethylamino)b utyl]amino}meth yl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td><p>4-methoxyphenyl</p><p>2-{[({[2-(dimethylamino) ethyl](ethyl)carb amoyl}methyl)a mino]methyl}pyr</p><p>idine-4-carboxylate</p></td><td><p dir="rtl">less</p></td></tr>

٥٦٠١

-١٧٠-

<img file="SA5601B1_D0042.tif" />

<tr><td><p>* *</p></td><td><p>tt</p><p>t</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>tttt</p></td><td><p>2-</p><p>ethoxycarbonyl)phenyl)</p><p dir="rtl">-2]0)a-2</p><p>(dimethylamino) ethyl](ethyl)carbamoyl} methyl)amino]methyl}p yridine-4-carboxylate</p></td><td><p dir="rtl">less</p></td></tr>

<img file="SA5601B1_D0043.tif" />

<tr><td><p>* *</p></td><td><p>+++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>t</p></td><td><p>ethoxyc-)]-{4 arbonyl)(methyl)a mino]phenyl}methy</p><p dir="rtl">-4a) -2 1</p><p>(diethylamino)butyl [amino}methyl)pyri dine-4-</p><p>carboxylate</p></td><td><p dir="rtl">less</p></td></tr>

٥٦٠١

-١٧١-

<img file="SA5601B1_D0044.tif" />

<img file="SA5601B1_D0045.tif" />

<img file="SA5601B1_D0046.tif" />

<tr><td><p>+++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+++</p></td><td><p>4-tert—</p><p>butylphenyl 2-{[({[?-(dimethyl-amino)ethyl](ethyl)carbamoyljmeth yl)amino]methyl}p yridine-4-carboxylate</p></td><td><p dir="rtl">less</p></td></tr>

<img file="SA5601B1_D0047.tif" />

<tr><td><p>* *</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>tttt</p></td><td><p>4-oxopentan-</p><p dir="rtl">-2]0)a-2l-2</p><p>(dimethylamin o)ethylj(ethyl) carbamoyljme thyl)amino]me thyljpyridine-4-carboxylate</p></td><td colspan="2"><p dir="rtl">paint</p><p>^CHg</p></td></tr><tr><td><p>++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td colspan="2"><p>4-</p><p>(trifluoroacetamido)buta</p></td><td></td></tr>

٥٦٠١

-١٧٢-

<tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>n-2-yl 2-2]0)a-(dimethylamino)ethyl](et hyl)carbamoyl}methyl)a mino]methyl}pyrid ine-</p><p>4-carboxylate</p></td><td><p dir="rtl">less</p></td></tr>

<img file="SA5601B1_D0048.tif" />

<tr><td><p>+*</p></td><td><p>*</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>* *</p></td><td><p>4-(2,2,2-trifluoro-N-methylacetamido)butan-</p><p dir="rtl">-2a)) a-2l-2</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amin o]methyl}pyridine-4-carboxylate</p></td><td><p dir="rtl">less</p></td></tr>

<img file="SA5601B1_D0049.tif" />

٥٦٠١

-١٧٣-

<tr><td><p>++</p></td><td><p>+++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td><p>ethyl 2-</p><p>{[({[2-(dimethylami no)ethyl](ethyl)carbamoyl }methyl)amin o]methyl}pyri</p><p>dine-4-carboxylate</p></td><td colspan="2"></td></tr><tr><td><p>++</p></td><td><p>+++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td colspan="2"><p>5-(trifluoroacet-amido)pent-1-en-3-yl</p><p>2-{[({[2-(dimethylamino)ethyl]]</p><p>(ethyl)carbamoyl}meth yl)amino]methyl}pyridine-</p><p>4-carboxylate</p></td><td><p dir="rtl">less</p></td></tr>

<img file="SA5601B1_D0050.tif" />

<tr><td><p>++</p></td><td><p>+++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td><p>5-(2,2,2-trifluoro-</p><p>N-methylacet-amido)pent-1-en-</p></td><td><p dir="rtl">less</p></td></tr>

٥٦٠١

-١٧٤-

<tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>3-yl 2-{[({[2-(dimethylamino)ethyl] (ethyl)carbamoyl}met hyl)amino]methyl}pyri</p><p>dine-4-carboxylate</p></td><td></td></tr>

<img file="SA5601B1_D0051.tif" />

<tr><td><p>++</p></td><td><p>++</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>++</p></td><td><p>2-(2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine</p><p>-4-carbonyloxy)-3-(hexadecanoyloxy)pro pyl hexadecanoate</p></td><td><p dir="rtl">less</p></td></tr>

<img file="SA5601B1_D0052.tif" />

<img file="SA5601B1_D0053.tif" />

<tr><td><p>++</p></td><td><p>+++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td><p>jdhsjfhsd1-(2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino])</p></td><td><p dir="rtl">less</p></td></tr>

٥٦٠١

-١٧٥-

<tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>methyl}pyridine-4-carbonyloxy)-3-(hexadecanoyloxy)propan</p><p>-2-yl hexadecanoate</p></td><td></td></tr>

<img file="SA5601B1_D0054.tif" />

methyl 2-{[({[2-

(dimethylamino)ethyl](ethyl)carba moyl}methyl)amino]methyl}pyridin

e-4-carboxylate

propan-2-yl 3-(2-{[({[2-

(dimethylamino)ethyl](ethyl)carbamoyl}methyl)a

mino]methyl}pyridine-4-carbonyloxy)-4-

(trifluoroacetamido)butanoate

<img file="SA5601B1_D0055.tif" />

less

٥٦٠١

-١٧٦-

<img file="SA5601B1_D0056.tif" />

<img file="SA5601B1_D0057.tif" />

<tr><td><p>+*</p><p>t</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>t</p><p>t</p></td><td><p>propan-2-y0</p><p dir="rtl">-02)A-2)-3</p><p>(dimethylamin o)ethyl](ethyl) carbamoyljme thyl)amino]me thyljpyridine-</p><p>4-</p><p>carbonyloxy)-5-</p><p>(trifluoroaceta mido)pentano</p><p>ate</p></td><td><p dir="rtl">WL</p><p dir="rtl">, g</p></td></tr><tr><td><p>t</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>t</p></td><td><p>2-(pipe2idin-</p><p>1-</p><p>ylmethyl)pyridi</p><p>ne-4-</p></td><td><p dir="rtl">NS</p><p>ο7ο</p></td></tr>

٥٦٠١

-١٧٧-

<tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>carboxylic</p><p>acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>+</p></td><td><p>2-(azetidin-</p><p>1-ylmethyl)pyridi ne-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>++</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>+</p><p>+</p><p>+</p></td><td><p>2,2,2-trifluoroethyl</p><p>2-{[({ [2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p></td><td><p>+</p><p>+</p></td><td><p>2-({ethyl[2-oxo-2-</p><p>(piperidin-1-yl)ethyl]amino}methyl)pyridi ne-4-</p><p>carboxylic</p></td><td></td></tr>

٥٦٠١

-١٧٨-

<tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p></td><td><p>+</p></td><td><p>2-({butyl[2-oxo-2-</p><p>(piperidin-1-yl)ethyl]amino}methyl)pyridi ne-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p></td><td><p>+</p></td><td><p>2-({benzyl[2-oxo-2-</p><p>(piperidin-1-yl)ethyl]amino}methyl)pyridi ne-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p></td><td><p>2,6-bis(propan-2-</p><p>yloxy)phenyl 2-{[({[2-(dimethylamin .])</p></td><td><p dir="rtl">less</p></td></tr>

٥٦٠١

-١٧٩-

<tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td></td></tr>

<img file="SA5601B1_D0058.tif" />

<tr><td><p>++</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p></td><td><p>propan-2-yl 3-(2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-</p><p>carbonyloxy)-5-</p><p>(trifluoroaceta mido)pentano ate</p></td><td></td></tr>

٥٦٠١

-١٨٠-

<tr><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>2-(piperidin-</p><p>1-ylmethyl)pyridi ne-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>+</p></td><td><p>2-(azetidin-</p><p>1-ylmethyl)pyridi ne-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>++</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>+</p><p>+</p><p>+</p></td><td><p>2,2,2-trifluoroethyl</p><p>2-{[({[2-(dimethylamin o)ethyl](ethyl) carbamoyl}me thyl)amino]me thyl}pyridine-4-carboxylate</p></td><td></td></tr>

٥٦٠١

-١٨١-

<tr><td><p>++</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p></td><td><p>+</p><p>+</p></td><td><p>2-({ethyl[2-oxo-2-</p><p>(piperidin-1-yl)ethyl]amino}methyl)pyridi ne-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p></td><td><p>+</p></td><td><p>2-({butyl[2-oxo-2-</p><p>(piperidin-1-yl)ethyl]amino}methyl)pyridi ne-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p></td><td><p>+</p></td><td><p>2-({benzyl[2-oxo-2-</p><p>(piperidin-1-yl)ethyl]amino}methyl)pyridi ne-4-</p><p>carboxylic acid</p></td><td></td></tr>

٥٦٠١

-١٨٢-

<tr><td><p>+*</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>t</p><p>t</p></td><td><p>2,6-bis(propan-</p><p>2-</p><p>yloxy)phenyl</p><p dir="rtl">-02)A-2</p><p>(dimethylamin o)ethyl](ethyl) carbamoyljme thyl)amino]me thyljpyridine-4-carboxylate</p></td><td><p dir="rtl">less</p></td></tr>

<img file="SA5601B1_D0059.tif" />

<img file="SA5601B1_D0060.tif" />

٥٦٠١

-١٨٣-

<tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>carboxylic acid</p></td><td></td></tr><tr><td><p>+</p><p>+</p></td><td><p>+</p><p>+</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td><p>+</p></td><td><p>2-({[2-oxo-2-(piperidin-</p><p>1-yl)ethyl](propyl)amino}methyl</p><p>pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td><p>+</p><p>+</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td><p>+</p></td><td><p>2-({[2-oxo-2-(piperidin-</p><p>1-yl)ethyl](propa</p><p>n-2-yl)amino}meth yl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p><p>+</p><p>+</p></td><td><p>+</p><p>+</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>+</p><p>+</p></td><td><p>2-fluoroethyl</p><p>2-{[({[2-(dimethylamin o)ethyl](ethyl)c arbamoyl}met hyl)amino]met hyl}pyridine-</p><p>4-carboxylate</p></td><td></td></tr>

٥٦٠١

-١٨٤-

<tr><td><p>+</p><p>+</p><p>+</p></td><td><p>+</p><p>+</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>+</p><p>+</p><p>+</p></td><td><p>2,2-difluoroethyl</p><p>2-{[({[2-(dimethylamin o)ethyl](ethyl)c arbamoyl}met hyl)amino]met hyl}pyridine-</p><p>4-carboxylate</p></td><td></td></tr><tr><td><p>+</p></td><td><p>+</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td><p>+</p></td><td><p>2-({[(1S)-1-(tert-butylcarbamoy l)-3-methylbutyl]a mino}methyl)p yridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>2-</p><p>({methyl[(2S)-4-methyl-1-</p><p>oxo-1-</p><p>(piperidin-1-yl)pentan-2-yl]amino}methyl)pyridine-4-</p></td><td></td></tr>

٥٦٠١

-١٨٥-

<tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>carboxylic acid</p></td><td></td></tr><tr><td><p>+</p><p>+</p><p>+</p></td><td><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>++</p></td><td><p>+</p><p>+</p><p>+</p></td><td><p>2-{[({[2-(dimethylamin o)ethyl](ethyl)c arbamoyl}met hyl)amino]met hyl}-N-methanesulfon</p><p>yl-N-methylpyridine-4-carboxamide</p></td><td></td></tr><tr><td><p>+</p><p>+</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p></td><td><p>+</p><p>+</p><p>+</p></td><td><p>N-[2-(dimethylamin o)ethyl]-N-ethyl-2-({[4-(2-oxo-1,3-oxazolidine-3-carbonyl)pyridi n-2-yl]methyl}amin o) acetamide</p></td><td></td></tr>

٥٦٠١

-١٨٦-

<tr><td><p>+</p><p>+</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p></td><td><p>2-{[({[2-(dimethylamin o)ethyl](ethyl)c arbamoyl}met hyl)amino]met hyl}-N-</p><p>(pyridin-4-yl)pyridine-4-carboxamide</p></td><td></td></tr><tr><td><p>+</p><p>+</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p><p>+</p></td><td><p>2-{[({[2-(dimethylamin o)ethyl](ethyl)c arbamoyl}met hyl)amino]met</p><p>hyl}-N-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-4-carboxamide</p></td><td></td></tr><tr><td><p>+</p><p>+</p><p>+</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>+</p><p>+</p><p>+</p></td><td><p>2-{[({[2-(dimethylamin o)ethyl](ethyl)c arbamoyl}met hyl)amino]met</p><p>hyl}-N-(1-</p></td><td></td></tr>

٥٦٠١

-١٨٧-

<tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>methyl-ΙΗ-pyrazo0-5-yl)pyridine-4-carboxamide</p></td><td colspan="2"></td></tr><tr><td><p>t</p><p>t</p><p>t</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>t</p><p>t</p><p>t</p></td><td colspan="2"><p dir="rtl">-2]0)a-2</p><p>(dimethylamino)ethyl ](ethyl)carbamoyl}me</p><p>thyl)amino]methyl}-</p><p dir="rtl">-2-A0520-1,3)-no</p><p>yl)pyridine-4-carboxamide</p></td><td><p dir="rtl">less</p></td></tr>

<img file="SA5601B1_D0061.tif" />

<tr><td><p>+++</p></td><td><p>* *</p></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td><p>t</p><p>t</p></td><td><p>hfjkh2-{[[({[2-(dimethylamino)ethyl](et hyl)carbamoyl}methyl)a mino]methy,}-N-(l-methyl-lH-imidazol-2-yl)pyridine-4-carboxamide</p></td><td><p dir="rtl">less</p></td></tr>

٥٦٠١

<img file="SA5601B1_D0062.tif" />

a)-a-a-a-: IC50 &lt; 1 μM; ++: 1 μM IC50 h 0 5 μM; +:

IC50 &gt; 0 5 μM

In this specification, unless otherwise specified, the expression “or” is used in this sense to refer the operator to the actual value when any or both of the said conditions are satisfied, as opposed to an “operator exclusively”) which requires that at least one condition be satisfied. The expression 'include' is used in the sense of 'include' rather than 'consist of'. All foregoing instructions set forth herein shall be used by identifying the reference number of any prior published document herein which is approved or represents instructions in common knowledge in Australia or elsewhere to date.

0 1 Example 3: Histone lysine demethylase immunofluorescence assays to determine a value of 1050 in . cells

Histone lysine demethylase immunofluorescence tests to determine the value of 1050, cells that have not been transfected

This example indicates the ability of the compounds of the invention to inhibit Η3Κ4 demethylation in the human osteosarcoma carcinoma cell lineage.

E 1 the general method

U20S cells were harvested and cultured in multi-eye dishes within a media containing compound. be

After 0 2 hours. Pen/strep and FBS % e DMEM includes the media used

From the incubation of cells with the compounds, cells were washed once at 085, harvested by fixation with 4% formaldehyde aqueous solution, and washed twice in PBS. Respectively, 20 cells were permeated in PBS with 0.2% 100-&gt;/Triton for 10 10 min at room temperature.

Immobilization was carried out in PBS with 0.2% Triton 100Χ and %FBS for 45 minutes.

٥٦٠١

-١٨٩-

at room temperature. Cells were incubated with 4003&gt;A13M0 primary antibody (Cell Signal Transmission, #59751) diluted 1:1000 in blocking buffer overnight at 4 °C. After incubation with primary antibody, cells were washed 3 times with PBS, and incubated with secondary antibody diluted 1:0 0 0 (IgG from Alexa fluor 594 goat anti-rabbit,

5 Hoechst (lnvitrogen,A11012, 20 μg/mL Sigma,33342) in blocking solution, and washed again 3 times with 85. Finally, PBS was added and high-output imaging and analysis were performed by 1000 cell analysis unit (GE Healthcare) The 1050 values ​​observed in Table 4 are based on the measurement of the mean spotting of the H3K4me3 tag in cells.

10 Inhibition of histone lysine demethylase

Table 4

<tr><td><p>1050</p></td><td><p dir="rtl">The name</p></td><td><p dir="rtl">[Structural formula</p></td></tr><tr><td><p>t</p></td><td><p dir="rtl">-3)-1a0)aa-2</p><p>phenylpropyl)piperidin</p><p>-4-</p><p>yl]carbamoyl}methyl)a mino]methyl}pyridine-4-carboxylicacid</p></td><td><p dir="rtl">* Msila</p></td></tr><tr><td><p>++</p></td><td><p>methyl 2-(0[3-(pyrrolidin-l-yl)propyl]amino}methyl</p><p>pyridine-4-</p></td><td><p>CH</p><p dir="rtl">fill</p></td></tr>

٥٦٠١

-١٩٠-

<tr><td></td><td><p>carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-({[4-(diethylamino)butyl]am ino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin</p><p>e-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>4-methoxyphenyl 2-({[4-</p><p>(diethylamino)butyl]am ino}methyl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2-</p><p>(ethoxycarbonyl)pheny l 2-({[4-</p><p>(diethylamino)butyl]am ino}methyl)pyridine-4-carboxylate</p></td><td></td></tr>

٥٦٠١

-١٩١-

<tr><td><p>++</p></td><td><p>2-</p><p>(dimethylamino)ethyl 2-({[4-</p><p>(diethylamino)butyl]am ino}methyl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td><p>3-(dimethylamino)propyl</p><p>2-({[4-(diethylamino)butyl]am ino}methyl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>{4-</p><p>[(ethoxycarbonyl)amin o]phenyl}methyl 2-({[4-</p><p>(diethylamino)butyl]am ino}methyl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2,6-dimethoxyphenyl 2-({[4-(diethylamino)butyl]am ino}methyl)pyridine-4-carboxylate</p></td><td></td></tr>

٥٦٠١

-١٩٢-

<tr><td><p>+++</p></td><td><p>2,6-dimethylphenyl 2-({[4-</p><p>(diethylamino)butyl]am ino}methyl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>4-methoxyphenyl 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin e-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2-</p><p>(ethoxycarbonyl)pheny l 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin e-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>{4-[(ethoxycarbonyl)(met hyl)amino]phenyl}meth yl 2-({[4-(diethylamino)butyl]am ino}methyl)pyridine-4-</p></td><td></td></tr>

٥٦٠١

-١٩٣-

<tr><td></td><td><p>carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>4-tert-butylphenyl 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin e-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>4-oxopentan-2-yl 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin e-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>4-</p><p>(trifluoroacetamido)but an-2-yl 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin e-4-carboxylate</p></td><td></td></tr>

٥٦٠١

-١٩٤-

<tr><td><p>+++</p></td><td><p>4-(2,2,2-trifluoro-N-methylacetamido)buta n-2-yl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin e- 4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>ethyl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin</p><p>e-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>5-</p><p>(trifluoroacetamido)pe nt-1-en-3-yl 2-</p><p>{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin</p><p>e-4-carboxylate</p></td><td></td></tr>

٥٦٠١

-١٩٥-

<tr><td><p>+++</p></td><td><p>5-(2,2,2-trifluoro-N-methylacetamido)pent -1-en-3-yl 2-{[(({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl} pyridin e-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2-(2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin e-4-carbonyloxy)-3-(hexadecanoyloxy)pro pyl hexadecanoate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>1-(2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin e-4-carbonyloxy)-3-(hexadecanoyloxy)pro pan-2-yl</p><p>hexadecanoate</p></td><td></td></tr>

٥٦٠١

-١٩٦-

<tr><td><p>+++</p></td><td><p>methyl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin</p><p>e-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy)</p><p>l)amino]methyl}-N-methanesulfonyl-N-</p><p>methylpyridine-4-carboxamide</p></td><td></td></tr><tr><td><p>++</p></td><td><p>N-[2-(dimethylamino)ethyl]-</p><p>N-ethyl-2-({[4-(2-oxo-1,3-oxazolidine-3-carbonyl)pyridin-2-yl]methyl}amino)aceta mide</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>propan-2-yl 3-(2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}p yridine-4-</p><p>carbonyloxy) -4-</p></td><td></td></tr>

٥٦٠١

-١٩٧-

<tr><td></td><td><p>(trifluoroacetamido)but anoate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>propan-2-yl 3-(2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}p yridine-4-</p><p>carbonyloxy)-5-(trifluoroacetamido)pe ntanoate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2,2,2-trifluoroethyl 2-{[({[2-(dimethylamino)ethyl]]</p><p>(ethyl)carbamoyl}methyl)amino]</p><p>methyl}pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}meth yl)amino]methyl}-N-(1,3-oxazol-2-yl)pyridine-4-carboxamide</p></td><td></td></tr>

٥٦٠١

-١٩٨-

<tr><td><p>++</p></td><td><p>2,6-bis(propan-2-yloxy)phenyl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}pyridin</p><p>e-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methy l)amino]methyl}-N-</p><p>(1-methyl-1H-imidazol-2-yl)pyridine-4-carboxamide</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2-fluoroethyl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridi ne-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2,2-difluoroethyl 2-{[({[2-(dimethylethyl]])</p><p>(ethyl)carbamoyl}methyl)amino]methyl}p yridine-4-carboxylate</p></td><td></td></tr>

٥٦٠١

-١٩٩-

(a) +++6 IC50 &lt; 1 μM; ++: 1 μM IC50 h. e micromolar; IC50 &gt; 0 5 mM

Example 4: Cell proliferation tests to determine the value of EC50

The example indicates the ability of the compounds of the invention to inhibit the proliferation of the human cancer cell lineage.

e General method: MCF7 cells were cultured at 1250 cells/eye in 0 μl medium/eye in black 96-well plates. Cells were incubated for 24 hours. before adding a compound. Complete medium (0.05 μl/eye) was diluted and added to plates in double quantity. The total media in the eyes is 0 0 μl, and the final concentration of DMSO is 0.5%. The complete medium used is DMEM with GlutaMAX containing 0 1%.

0 1 FBS and pen/strep.

After 1 0 2 hours of addition of the compounds, the plates were harvested and analyzed by Step 1 ATPIite (Perkin Elmer, catalog no. 6016739) according to manufacturer's suggestions. Briefly, 1 0 µl ATP light solution was added to each eye, plates were swirled at 0 0 7 rpm for 2 min, followed by 2 0 min of incubation in the dark, then analyzed for flash

15 on the Perkin Elmer (EnSpire 2300 Mulitilabel) reading device. EC50 values ​​were calculated using 6 GraphPad Prism. The results are shown in Table 5.

<tr><td><p>EC50</p></td><td><p dir="rtl">The name</p></td><td><p dir="rtl">lyric summer</p></td></tr><tr><td><p>++</p></td><td><p dir="rtl">-2 l) to 3)</p><p>{[(cyclopropylmethyl)a mino]methyl}pyridine-</p><p>4-carboxylicacid</p></td><td><p dir="rtl">millimeter</p><p dir="rtl">NS</p></td></tr>

٥٦٠١

٢٠٠-

<tr><td><p>++</p></td><td></td><td></td></tr><tr><td><p>++</p></td><td><p>2-({[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]amino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-[({[bis(prop-2-en-1-</p><p>yl)carbamoyl]methyl}a mino)methyl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-{[({methyl[3-(1-methyl-1H-imidazol-]</p><p>2-</p><p>yl)propyl]carbamoyl}m ethyl)amino]methyl}pyri dine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-٢٠١-

<tr><td><p>++</p></td><td><p>2-({[({1-[(2-methoxyphenyl)methyl]]piridin-4-yl}carbamoyl)methyl]a mino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-[({[(2-cyanoethyl)(ethyl)carb amoyl]methyl}amino)m</p><p>ethyl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-{[(3-{[(2-fluorophenyl)methyl](m ethyl)amino}propyl)ami no]methyl}pyridine-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-({[3-(4-benzylpiperidin-1-</p><p>yl)propyl]amino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-٢٠٢-

++

2-[({3-[(2-phenoxyethyl)amino]pr opyl}amino)methyl]pyri dine-4-carboxylic acid

<img file="SA5601B1_D0063.tif" />

<tr><td><p>+</p></td><td><p>2-({[({4-[benzyl(cyclopropyl)am ino]butyl}(methyl)carba moyl)methyl]amino}me)</p><p>thyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine</p><p>-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>4-methoxyphenyl 2-({[4-</p><p>(diethylamino)butyl]ami no}methyl)pyridine-4-carboxylate</p></td><td></td></tr>

٥٦٠١

-٢٠٣-

2-

(ethoxycarbonyl)phenyl

+++

2-({[4-(diethylamino)butyl]ami

no}methyl)pyridine-4-carboxylate

<img file="SA5601B1_D0064.tif" />

3-

(dimethylamino)propyl

++

2-({[4-(diethylamino)butyl]ami

no}methyl)pyridine-4-

carboxylate

{4-

[(ethoxycarbonyl)amine o]phenyl}methyl 2-

++

({[4-

(diethylamino)butyl]ami no}methyl)pyridine-4-carboxylate

<img file="SA5601B1_D0065.tif" />

<img file="SA5601B1_D0066.tif" />

٥٦٠١

-٢٠٤-

<tr><td><p>+++</p></td><td><p>2,6-dimethoxyphenyl 2-({[4-</p><p>(diethylamino)butyl]ami no}methyl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2,6-dimethylphenyl 2-({[4-</p><p>(diethylamino)butyl]ami no}methyl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td><p>4-methoxyphenyl 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methyl (amino]methyl}pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-</p><p>(ethoxycarbonyl)phenyl 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methyl (amino]methyl}pyridine-4-carboxylate</p></td><td></td></tr>

٥٦٠١

-٢٠٥-

<tr><td><p>+++</p></td><td><p>{4-[(ethoxycarbonyl)(meth yl)amino]phenyl}methyl</p><p>2-({[4-(diethylamino)butyl]ami no}methyl)pyridine-4-</p><p>carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>4-tert-butylphenyl 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methyl (amino]methyl}pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>4-oxopentan-2-yl 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methyl (amino]methyl}pyridine-4-carboxylate</p></td><td></td></tr>

٥٦٠١

-٢٠٦-

<tr><td><p>+++</p></td><td><p>4-</p><p>(trifluoroacetamido)but an-2-yl 2-{[({[2-(dimethylamino)ethyl]( ethyl)carbamoyl}methyl (amino]methyl}pyridine-4-carboxylate)</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>4-(2,2,2-trifluoro-N-methylacetamido)buta n-2-yl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4- carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>ethyl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine</p><p>-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>5-</p><p>(trifluoroacetamido)pen t-1-en-3-yl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl])</p></td><td></td></tr>

٥٦٠١

-٢٠٧-

<tr><td></td><td><p>)amino]methyl}pyridine</p><p>-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>5-(2,2,2-trifluoro-N-methylacetamido)pent -1-en-3-yl 2-{[(({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine -4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2-(2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine</p><p>-4-carbonyloxy)-3-(hexadecanoyloxy)pro pyl hexadecanoate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>1-(2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine</p><p>-4-carbonyloxy)-3-(hexadecanoyloxy)pro pan-2-yl</p><p>hexadecanoate</p></td><td></td></tr>

٥٦٠١

-٢٠٨-

<tr><td><p>+++</p></td><td><p>methyl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine</p><p>-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}-N-methanesulfonyl-N-methylpyridine-4-carboxamide</p></td><td></td></tr><tr><td><p>++</p></td><td><p>N-[2-(dimethylamino)ethyl]-</p><p>N-ethyl-2-({[4-(2-oxo-1,3-oxazolidine-3-carbonyl)pyridin-2-yl]methyl}amino)aceta mide</p></td><td></td></tr><tr><td><p>++</p></td><td><p>propan-2-yl 3-(2-{[({[2-(dimethylamino)ethyl]) ethyl)carbamoyl}methyl]</p></td><td></td></tr>

٥٦٠١

-٢٠٩-

<tr><td></td><td><p>)amino]methyl}pyridine</p><p>-4-carbonyloxy)-4-(trifluoroacetamido)but anoate</p></td><td></td></tr><tr><td><p>++</p></td><td><p>propan-2-yl 3-(2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methyl (amino]methyl}pyridine-4-carbonyloxy)-5-(trifluoroacetamido)pen tanoate</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2,2,2-trifluoroethyl 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methyl (amino]methyl}pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}-N-(1,3-oxazol-2-yl)pyridine-4-</p></td><td></td></tr>

٥٦٠١

-٢١٠-

<tr><td></td><td><p>carboxamide</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2-fluoroethyl 2-{[({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)amino]methyl}pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>+++</p></td><td><p>2,2-difluoroethyl 2-{[({[2-</p><p>(dimethylamino)ethyl](ethyl)carbamoyl}methyl (amino]methyl}pyridine-4-carboxylate</p></td><td></td></tr>

(a) +++: &lt;1 EC50 mM; +: 1 mM ≥ 50 ≤ EC50 mM; +:

50 &gt;EC50 Micro Maller

Example 5:

I tested histone Lysine Demethylase Immunostaining

5 Immunofluorescence fluorescence to determine the IC50 value in cells

This example indicates the ability of the invention compounds to inhibit H3 lysine demethylation in a human osteosarcoma cell line that was transfected to express histone lysine demethylases.

٥٦٠١

-٢١١-

general method

U2OS cells were cultured 24 hours before transfection. The infection was transferred using Fugene HD t as the factory suggested.

6 hours after transfection, cells were harvested and cultured in multi-ocular dishes in

5 Compound media. The media used is DMEM comprising 5% FBS and

.pen/strep

After 20 incubation of cells with compounds, cells were washed once in PBS, harvested by fixation with 4% formaldehyde aqueous solution, and washed twice in PBS.

Respectively, the cells were permeated in PBS with 0.2% 100-Triton X for 10 minutes

10 at room temperature.

Inhibition was carried out in PBS with 0.2% 100-Triton X and 5% FBS for 45 minutes at room temperature. Cells were incubated with the primary antibody diluted 1 μg/ml in blocking solution overnight at 4 °C. be primary antibodies

. The antibody detects HA.11 (Covance, MMS-101P).

15th About the mark specified in the next 6. After incubation with primary antibodies, cells were washed

3 Mart with PBS, and incubated with secondary antibodies diluted 1:1000 (IgG from goat anti-rabbit 594 Invitrogen, A11012, Alexa fluor; IgG was taken from anti-mouse donkey 488 Invitrogen, Alexa flour A21202 and Hoechst, 20 μg/ml (Sigma, 33342) in blocking solution, and 3 MAR washing with PBS.

20 Finally, PBS is added and high-output imaging is performed with a 1000 cell analysis unit (GE Healthcare). The robot analyzes individual cells and divides them into HA+ (infected cells) and -HA (non-infected cells) The IC50 values ​​in the following Table are based on the mean spotting measurement of the marker specified in the following Table 6. in transfected cells.

٥٦٠١

-٢١٢-

Table 6

<tr><td><p dir="rtl">ID A03/</p><p dir="rtl">plasmid</p></td><td><p dir="rtl">A first antibody used for the detection of Ulah</p></td><td><p dir="rtl">Done sign</p><p dir="rtl">detected</p></td><td><p dir="rtl">progression</p></td><td><p dir="rtl">source seller</p></td><td><p dir="rtl">[Poison part origin</p></td></tr><tr><td><p>ΝΜ-014663</p></td><td><p>Abeam</p><p>Ab8898</p></td><td><p>H3K9me3</p></td><td><p dir="rtl">complete</p><p dir="rtl">height</p></td><td><p>BRIC</p></td><td><p>pCMVHA</p><p>JMJD2C</p></td></tr><tr><td><p>ΝΜ-015061</p></td><td><p>Abeam</p><p>Ab8898</p></td><td><p>H3K9me3</p></td><td><p dir="rtl">complete</p><p dir="rtl">height</p></td><td><p>BRIC</p></td><td><p>pCMVHA</p><p>JMJD2A</p></td></tr><tr><td><p>ΝΜ-006618</p></td><td><p>Millipore</p><p>07-030</p></td><td><p>H3K4me2</p></td><td><p dir="rtl">Fragment (1 752)</p></td><td><p>BRIC</p></td><td><p>pCMVHA</p><p>PI 111</p></td></tr>

HDME inhibition

Table 7

<tr><td><p>PI 111</p><p>(KDM</p><p>5Β)</p></td><td><p>ΙΜ.Ι</p><p>D2A</p><p>(KD</p><p>Μ4Α)</p></td><td><p>GASC</p><p>1</p><p>(KDM</p><p>4C)</p></td><td><p dir="rtl">The name</p></td><td><p dir="rtl">remote summer</p></td></tr><tr><td><p>+*</p></td><td></td><td><p>t</p></td><td><p>2-({[3-(lH-imidazol-l-yl)propyl]amino}methyl)p yridine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-٢١٣-

<tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>++</p></td><td><p>2-({[2-(dimethylamino)ethyl]am</p><p>ino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td><p>+</p></td><td><p>2-({[(2R)-2,3-dihydroxypropyl]amino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>+</p></td><td><p>2-</p><p>{[(cyclopropylmethyl)ami no]methyl}pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>+</p></td><td><p>2-({[4-</p><p>(dimethylamino)butyl]am ino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-٢١٤-

<tr><td><p>+</p></td><td></td><td><p>+</p></td><td><p>2-({[2-</p><p>(dimethylamino)ethyl](m ethyl)amino}methyl)pyrid ine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td><p>+</p></td><td><p>2-{[methyl(prop-2-yn-</p><p>1-</p><p>yl)amino]methyl}pyridine</p><p>-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td><p>++</p></td><td><p>++</p></td><td><p>2-{[(furan-2-ylmethyl)amino]methyl}p yridine-4-carboxylic acid</p></td><td></td></tr><tr><td></td><td><p>++</p></td><td></td><td><p>2-({[2-</p><p>(methylsulfanyl)ethyl]am ino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td><p>++</p></td><td><p>2-({[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino}methyl)py ridine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-٢١٥-

<tr><td><p>+</p></td><td></td><td><p>++</p></td><td><p>2-</p><p>[({[butyl(methyl)carbamo yl]methyl}amino)methyl] pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>+</p></td><td><p>2-({[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]amino}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td><p>+</p></td><td><p>2-[({2-[4-(2-methoxyethyl)piperazin-1-yl]-2-oxoethyl}amino)methyl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>++</p></td><td><p>2-[({[bis(prop-2-en-1-yl)carbamoyl]methyl}ami no)methyl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td><p>+</p></td><td><p>2-{[(3-{[3-(pyrrolidin-yl)propyl]amino}propyl)a mino]methyl}pyridine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-٢١٦-

<tr><td></td><td></td><td><p>+</p></td><td><p>2-[({[(2-carbamoylethyl)(methyl) carbamoyl]methyl}amino</p><p>(methyl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>++</p></td><td><p>2-{[({methyl[3-(1-methyl-1H-imidazol-2-yl)propyl]carbamoyl}met hyl)amino]methyl}pyridin e-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>+</p></td><td><p>2-{[({[(1-ethylpyrrolidin-2-</p><p>yl)methyl]carbamoyl}met hyl)amino]methyl}pyridin</p><p>e-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td><p>+</p></td><td><p>2-{[({methyl[(1-methyl-1H-pyrazol-5-yl)methyl]carbamoyl}met hyl)amino]methyl}pyridin e-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>+</p></td><td><p>2-({[(3R)-1-(3-phenylpropyl)pyrrolidin-3-yl]amino}methyl)pyridine-4-carboxylic</p></td><td></td></tr>

٥٦٠١

-٢١٧-

<tr><td><p>++</p></td><td></td><td></td><td><p>2-({[({1-[(2-methoxyphenyl)methyl]]p iperidin-4-</p><p>yl}carbamoyl)methyl]ami no}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td><p>+</p></td><td><p>2-{[({[1-(3-phenylpropyl)piperidin-4-)]</p><p>yl]carbamoyl}methyl)ami no]methyl}pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td><p>+</p></td><td><p>2-{[({[1-(furan-2-ylmethyl)piperidin-4-yl]carbamoyl}methyl)ami no]methyl}pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td><p>+</p></td><td><p>2-({[({1-[(5-phenylfuran-2-])</p><p>yl)methyl]piperidin-4-yl}carbamoyl)methyl]ami</p><p>no}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr>

٥٦٠١

-٢١٨-

<tr><td><p>++</p></td><td></td><td></td><td><p>2-[({[(2-cyanoethyl)(ethyl)carba moyl]methyl}amino)meth yl]pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td></td><td><p>2-({[2-(1-butylpyrrolidin-2-</p><p>yl)ethyl]amino}methyl)py ridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>+</p></td><td><p>2-{[(3-{[(2-fluorophenyl)methyl])(me thyl)amino}propyl)amino</p><p>]methyl}pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>+</p></td><td></td><td></td><td><p>2-({[({4-[benzyl(cyclopropyl)ami no]butyl}(methyl)carbam oyl)methyl]amino}methyl</p><p>pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>+</p></td><td><p>2-[({2-[(2S)-1-]</p><p>benzylpyrrolidin-2-yl]ethyl}amino)methyl]py ridine-4-carboxylic acid</p></td><td></td></tr>

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<tr><td><p>++</p></td><td></td><td><p>++</p></td><td><p>2-({[3-(pyrrolidin-1-yl)propyl]amino}methyl)p yridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>++</p></td><td><p>methyl 2-({[3-(pyrrolidin-1-)</p><p>yl)propyl]amino}methyl)p yridine-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>++</p></td><td><p>2-({[4-</p><p>(diethylamino)butyl]amin o}methyl)pyridine-4-carboxylic acid</p></td><td></td></tr><tr><td><p>++</p></td><td><p>++</p></td><td><p>+</p></td><td><p>2-{[({[2-(dimethylamino)ethyl](et hyl)carbamoyl}methyl)a mino]methyl}pyridine-4-</p><p>carboxylic acid</p></td><td></td></tr><tr><td><p>+++</p></td><td></td><td><p>++</p></td><td><p>4-methoxyphenyl 2-({[4-(diethylamino)butyl]amin</p><p>o}methyl)pyridine-4-carboxylate</p></td><td></td></tr>

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<tr><td><p>+++</p></td><td></td><td><p>++</p></td><td><p>2-</p><p>(ethoxycarbonyl)phenyl 2-({[4-</p><p>(diethylamino)butyl]amin o}methyl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>++</p></td><td><p>2-(dimethylamino)ethyl 2-({[4-</p><p>(diethylamino)butyl]amin o}methyl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td><p>++</p></td><td></td><td><p>++</p></td><td><p>3-</p><p>(dimethylamino)propyl 2-({[4-</p><p>(diethylamino)butyl]amin o}methyl)pyridine-4-carboxylate</p></td><td></td></tr><tr><td></td><td><p>+++</p></td><td></td><td><p>{4-</p><p>[(ethoxycarbonyl)(methy l)amino]phenyl}methyl</p><p>2-({[4-</p><p>(diethylamino)butyl]amin o}methyl)pyridine-4-carboxylate</p></td><td></td></tr>

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<tr><td></td><td><p>+*</p></td><td></td><td><p dir="rtl">-2a0)a-2)-2</p><p>(dimethylamino)ethyl^etL hyl)carbamoyl}methylja</p><p>mino]methyl}pyridine-4^carbonyloxy)-3-(hexadecanoyloxy)propy</p><p>1 hexadecanoate</p></td><td><p dir="rtl">1 piece</p></td></tr>

In this specification

, unless otherwise specified, the expression "or" is used in this sense to refer the operator to the actual value when any or both of the said conditions are satisfied, in contrast to the fact that the operator exclusively requires that at least one condition be satisfied. The expression 'includes' is used in the sense of 'contain' instead of e meaning 'consists of'. All foregoing instructions set forth herein shall be used by identifying the reference number of any prior published document herein which is approved or the instruction therein is common knowledge in Australia or elsewhere in its history.

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Hayami 5. et al. (2010) Cancer 9 He L et al.. Blood 117 (14), 3869-80, 2011 He L et al. Nat struct Mol Biol 15(11), 2008 Kelly, Τ.Κ. , Nat. Biotechnol. 28; 1069-"Epigenetic modifications as apoptotic targets" et al. (2010),

1078 Klose, Rd et al.. Nature 442, 312-16, 2006 liu, G. Et al., 5 1

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Oncogene 28, 4491-500, 2009 Margueron, R., et al., Curr. Opinion

Genet. Dev. 15, 163-76, 2005 Morton and Houghton,

From a human tumor in an immunocompromised rat, Nature Protocols 2, 247-247, 250.

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, Biochem. Pharmacol. 72; 1563-1569 (2006) “Chromatin Structure and Epigenetics),

Roy et al. PerkinElmer Technical Note: AlphaLISA #12, Apr. 2011

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. Cell 25, 801-12, 2007 Xiang Y. et al. (2007) PNAS 104 10

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