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WO2016102493A1 - Inhibiteurs d'ezh2 de type imidazopyridine - Google Patents

Inhibiteurs d'ezh2 de type imidazopyridine Download PDF

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Publication number
WO2016102493A1
WO2016102493A1 PCT/EP2015/080835 EP2015080835W WO2016102493A1 WO 2016102493 A1 WO2016102493 A1 WO 2016102493A1 EP 2015080835 W EP2015080835 W EP 2015080835W WO 2016102493 A1 WO2016102493 A1 WO 2016102493A1
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Prior art keywords
alkyl
group
phenyl
membered monocyclic
cycloalkyl
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PCT/EP2015/080835
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English (en)
Inventor
Amaury FERNANDEZ-MONTALVAN
Carlo STRESEMANN
Clara CHRIST
Detlef STÖCKIGT
Duy Nguyen
Ingo Hartung
Stefan Prechtl
Thomas Brumby
Timo Stellfeld
Richard Alexander BOUGLAS
Raymond Fisher
Hassan Youssef HARB
Andrew J. Phillips
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Bayer Pharma AG
Broad Institute Inc
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Bayer Pharma AG
Broad Institute Inc
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Publication of WO2016102493A1 publication Critical patent/WO2016102493A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom

Definitions

  • the present invention relates to imidazopyridines, to a method for their preparation, to intermediates for their preparation, to pharmaceutical compositions, and to the use thereof.
  • Epigenetic changes refer to modifications in gene expression without alterations of the DNA sequence.
  • the DNA within eukaryotic cell nuclei is packaged together with histones and other proteins to form the complex known as chromatin.
  • Gene transcription is regulated by selective, enzyme-catalyzed post-translational modifications of the histone proteins (Jenuwein and Allis, Science, 2001, 10;293(5532): 1074-80).
  • the transcription of each gene can change from high-level expression to complete silencing, depending on the influence of the histone modification pattern which regulates the accessibility of promoters and the activity of the transcription machinery (Li et al, Cell, 2007, 23;128(4):707-19).
  • the Polycomb Repressive Complex 2 (PRC2) has emerged as a key histone modifying complex frequently de-regulated in cancer (Deb et al, Mol Cancer Res., 2014, 12(5):639-53).
  • PRC2 has a histone methyltransferase function responsible for the mono-, di- and tri-methylation of lysine-27 of histone H3 (H3K27).
  • Methylation of H3K27 is a repressive chromatin mark correlated with silencing of gene expression.
  • PRC2 is composed of the catalytic SET domain-containing histone methyltransferase EZH2 (enhancer of zeste homolog 2) or its functional homologue EZH1 (enhancer of zeste homolog 1) and core accessory proteins EED, SUZ12, and RbAp48.
  • EZH2 histone methyltransferase
  • EZH1 enhancer of zeste homolog 1
  • core accessory proteins EED, SUZ12, and RbAp48 core accessory proteins
  • the PRC2 complex is a master regulator that controls differentiation by repression of lineage control genes (Bracken and Helin, Nat Rev Cancer., 2009, 9(l l):773-84).
  • Overexpression of core proteins of PRC2 has been found in a wide variety of cancers (Simon and Lange, Mutat Res., 2008, l ;647(l-2):21-9).
  • EZH2 expression increases with tumor stage in colorectal (Wang et al, World J Gastroenterol., 2010, 21 ;16(19):2421-7) and lung adenocarcinomas (Lv et al, Oncol Rep., - -
  • Activating mutations are found especially in germinal center B-cells and induce a sustained silencing of PRC2 target genes, inhibit normal differentiation and promote proliferation and transformation (Beguelin et al., Cancer Cell, 2013, 13;23(5):677-92.18; Harms et al, Human Pathology: Case Reports, 2014, 1,21-28). Beside overexpression or mutations of PRC2 core proteins, many additional mutations in proteins influencing H3K27 methylation and PRC2 activity have been found.
  • H3K27 methylation caused silencing of key tumor suppressor genes such as pl5/16, DAB2IP and CDH1 (Gil and Peters, Nat Rev Mol Cell Biol., 2006,7(9) :667-77; Min et al.
  • PRC2 was validated as an important oncogenic driver, in experiments where overexpression of EZH2 induced neoplastic transformation of benign epithelial cells and this activity was dependent on the catalytic SET domain (Kleer et al, Proc Natl Acad Sci U S A., 2003, 30;100(20): 11606-11). Knockdown of EZH2 has been demonstrated to cause re-expression of tumor suppressor genes, as well as inhibition of proliferation, invasion and migration (Crea et al. Cancer Metastasis Rev., 2012, 31(3- 4):753-61).
  • WO 2012/118812 discloses substituted 6,5-fused bicyclic heteroaryl compounds as inhibitors of EZH2.
  • US 2013/0040906 discloses, inter alia, compounds and pharmaceutical compositions as inhibitors of EZH2.
  • WO 2014/100665 discloses 1,4-pyridone bicyclic heteroaryl compounds as inhibitors of EZH2.
  • WO 2014/144747 discloses 6,5-fused bicyclic heteroaryl compounds as inhibitors of the histone methyltransf erase activity of EZH2. - -
  • WO 2011/140324 discloses a method of treating cancer, inter alia comprising the administration of an EZH2 inhibitor.
  • WO 2013/067296, WO 2013/067300 and WO 2013/076302 disclose methods of treating T cell mediated immune diseases or T cell mediated hypersensitivity diseases which comprise administering to a human in need thereof an effective amount of a compound which inhibits EZH2 and/or EZH1.
  • WO 2014/097041 discloses aryl and heteroaryl fused lactams as inhibitors of EZH2.
  • the present invention relates to compounds of general formula (I)
  • R represents a group selected from Ci-C6-alkyl-, C2-C6-alkenyl, C3-C7-cycloalkyl-, (C3-C7- cycloalkyl)-(L 1 )-, 4- to 7-membered monocyclic heterocycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-(L 1 )-, Ci-C6-haloalkyl-, C2-C6-haloalkenyl-, Ci-C6-alkoxy-,
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH 2 -CH 2 -CH 2 -, - CH2-CH2-O-, -O-CH2-O-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-O- and
  • L 1 represents a group selected from -CH2-, -CH2-O- and -0-;
  • L 3 represents, independently for each occurrence, a group selected from -CH2- and -CH2CH2-; and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N- oxides, tautomers, or stereoisomers.
  • the present invention relates to compounds of general formula (I) in which R 1 represents a group selected from Ci-C t-aikyl-, C3-C6-cycloalkyl-, (C3-C6- cycloalkyl)-(L 1 )-, 4- to 6-membered monocyclic heterocycloalkyl-, 4- to 6-membered monocyclic heterocycloalkyl-(L 1 )-, Ci-C t-fluoroalkyl-, C 2 -C4-fluoroalkenyl-, C 1 -C4- alkoxy-, Ci-C4-fluoroalkoxy-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl-) and phenyl-(Ci-C 2 -alkyl)- , wherein any C3-C6-cycloalkyl- or 4- to 6-membered monocyclic heterocycloalkyl- group is optionally substitute
  • R represents a hydrogen atom or a methyl- group
  • R' represents a hydrogen atom or a group selected from Ci-C6-alkyl-, (Ci-C2-alkoxy)-(Ci-C2- alkyl)-, C3-C7-cycloalkyl- and 4- to 7-membered monocyclic heterocycloalkyl-, wherein any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted once with a Ci-C3-alkyl-, and
  • R represents a group selected from phenyl-, naphthyl-, heteroaryl-, -NR 6 R 10 , phenyl-(L 2 )- and heteroaryl-(L 2 )-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R 11 ;
  • R ⁇ represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group; R represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C 4 -alkyl-, Ci-C 4 -fluoroalkyl-, hydroxy-(Ci-C 4 -alkyl)-, (Ci-C2-alkoxy)-(Ci-C 2 -alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C 2 -alkyl)-, phenyl- and 5- to 6-membered monocyclic heteroaryl-, wherein any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, hydroxy-, oxo
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group-; represents, independently for each occurrence, a group selected from Ci-C4-alkyl-, C3-C6- cycloalkyl- and benzyl- , wherein the phenyl group present in said benzyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C 2 -alkyl-, trifluoromethyl- and C 1 -C 2 - alkoxy-; - -
  • R 9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C t-alkyl-, C3-C6-cycloalkyl- and benzyl-, wherein the phenyl group present in said benzyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C 2 -alkyl-, trifluoromethyl- and C 1 -C 2 - alkoxy-;
  • R 10 represents, independently for each occurrence, a phenyl group which is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-;
  • R 11 represents, independently for each occurrence, a halogen atom or a group selected from hydroxy-, cyano-, Ci-C/t-alkyl-, Ci-C/t-fluoroaikyl-, Ci-C4-fluoroalkoxy-, hydroxy-(Ci-C 4 -alkyl)-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phen
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH 2 -CH 2 -O-, -O- CH2-O- and -O-CH2-CH2-O-;
  • L 1 represents a group selected from -CH 2 -O- and -0-;
  • the present invention relates to compounds of general formula (I) in which
  • R 1 represents a group selected from Ci-C3-alkyl-, C3-C6-cycloalkyl-, (C3-C6-cycloalkyl)-(L 1 )-, Ci-C3-fluoroalkyl-, C 2 -C3-fluoroalkenyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (C 1 -C 2 - alkoxy)-(Ci-C 2 -alkyl-) and benzyl-;
  • R 2 represents a Ci-C3-alkyl- group
  • R 3 represents a hydrogen atom or a methyl- group
  • R 4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, C3-C6-cycloalkyl- and 4- to 6-membered monocyclic heterocycloalkyl-;
  • R 5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, phenyl-(L 2 )- and heteroaryl-(L 2 )-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R 11 ;
  • R 6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group
  • R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C 4 -alkyl-, Ci-C 4 -fluoroalkyl-, hydroxy-(Ci-C 4 -alkyl)-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C 2 -alkyl)-, phenyl- and 5- to 6-membered monocyclic heteroaryl-, wherein any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, oxo, Ci-C3-alkyl-, acetyl- and tert- butoxycarbonyl-, and where
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group; - -
  • R represents, independently for each occurrence, a group selected from Ci-C t-alkyl- and benzyl-;
  • R 9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C/t-alkyl- and benzyl-;
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH 2 -CH 2 -O-, -O-CH2-O- and -O-CH2-CH2-O-.
  • L 1 represents a group selected from -CH2-O- and -0-;
  • the present invention relates to compounds of general formula (I) - -
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group;
  • R 8 represents, independently for each occurrence, a group selected from Ci-C t-aikyl- and benzyl-;
  • R 9 represents a Ci-C2-alkyl- group
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH2-CH2-O-, -O-CH2-O- and -O-CH2-CH2-O-;
  • L 1 represents a -CH2-O- group; and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N- oxides, tautomers, or stereoisomers.
  • the present invention relates to compounds of general formula (I) in which
  • R 1 represents a group selected from « -propyl-, cyclobutylmethoxy-, 1,1-difluoro-n-propyl-, - - methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy-, 2,2,2-trifluoroethoxy- and benzyl-;
  • R 2 represents a methyl- group;
  • R 3 represents a hydrogen atom or a methyl- group;
  • R 4 represents a group selected from Cs-C t-alkyl-, cyclopentyl- and tetrahydropyran-4-yl-;
  • R 5 represents a group selected from phenyl-, pyridyl-, pyrimidyl- or pyrazolyl-, said group being optionally substituted with one or two substituents, each substituent independently selected from R 11 ;
  • R 6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group
  • R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C3-alkyl-, hydroxy-(Ci-C4-alkyl)-, 4- to 7-membered monocyclic heterocycloalkyl-, wherein any 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from oxo and Ci-C3-alkyl, or R 6 and R 7 , together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group;
  • R 8 represents, independently for each occurrence, a Ci-C3-alkyl- group
  • the present invention relates to compounds of general formula (I) in which - - represents a group selected from Ci-C6-alkyl-, C2-C6-alkenyl, C3-C7-cycloalkyl-, 4- to 7- membered monocyclic heterocycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl- (L 1 )-, Ci-C6-haloalkyl-, C2-C6-haloalkenyl-, Ci-C6-alkoxy-, Ci-C6-haloalkoxy-, (C1-C3- alkoxy)-(Ci-C 3 -alkyl)-, -NR 6 R 7 , and phenyl-(Ci-C 3 -alkyl)-, wherein any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two, or three substituents
  • R 8 represents, independently for each occurrence, a group selected from Ci-C6-alkyl-, C1-C6- haloalkyl-, C3-C7-cycloalkyl- and phenyl-(Ci-C3-alkyl)-, wherein the phenyl group present in said phenyl-(Ci-C3-alkyl)- group is optionally substituted with one, two or three substituents, each substituent independently selected from halogen-, cyano-, hydroxy-, Ci-C 2 -alkyl-, trifluoromethyl-, C 1 -C 2 - alkoxy-, and Ci-C 2 -haloalkoxy-;
  • R 9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C6-alkyl-, Ci-C6-haloalkyl-, C3-C7-cycloalkyl- and phenyl-(Ci-C3-alkyl)-, wherein the phenyl group present in said phenyl-(Ci-C3-alkyl)- group is optionally substituted with one, two or three substituents, each substituent independently selected from halogen-, cyano-, hydroxy-, Ci-C 2 -alkyl-, trifluoromethyl-, C 1 -C 2 - alkoxy-, and Ci-C2-haloalkoxy-;
  • R 10 represents a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, wherein said group is optionally substituted with one, two or three substituents, each substituent independently selected from halogen-, cyano-, hydroxy-, Ci-C3-alkyl-, Ci-C3-haloalkyl-, Ci-C3-alkoxy-, and Ci-C3-haloalkoxy-; independently for each occurrence, represents a halogen atom or a group selected from hydroxy-, cyano-, nitro-, Ci-C6-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, Ci-C6-haloalkyl-, Ci-Ce-haloalkoxy-, hydroxy-(Ci-C 6 -alkyl)-, (Ci-C3-alkoxy)-(Ci-C 3 -alkyl)-,
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH 2 -CH 2 -CH 2 -, - CH2-CH2-O-, -O-CH2-O-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-O- and
  • L 1 represents a group selected from -CH2-, -CH2-O- and -0-;
  • L 3 represents, independently for each occurrence, a group selected from -CH 2 - and -CH 2 CH 2 -; and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N- oxides, tautomers, or stereoisomers.
  • the present invention relates to compounds of general formula (I) - -
  • R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group-; represents, independently for each occurrence, a group selected from Ci-C t-alkyl-, C3-C6- cycloalkyl- and benzyl- , wherein the phenyl group present in said benzyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and C1-C2- alkoxy-; represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C/t-alkyl-, C3-C6-cycloalkyl- and benzyl-, wherein the phenyl group present in said benzyl- group is optionally substituted with one, two or three substituent
  • two R groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH 2 -CH 2 -O-, -O- CH2-O- and -O-CH2-CH2-O-;
  • L 1 represents a group selected from -CH 2 -O- and -0-;
  • the present invention relates to compounds of general formula (I) in which
  • R 1 represents a group selected from Ci-C3-alkyl-, C3-C6-cycloalkyl-, Ci-C3-fluoroalkyl-, C 2 - C3-fluoroalkenyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl-) and benzyl-;
  • R 2 represents a Ci-C3-alkyl- group
  • R 3 represents a hydrogen atom or a methyl- group
  • R 4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, C3-C6-cycloalkyl-;
  • R 5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, phenyl-(L 2 )- and heteroaryl-(L 2 )-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R 11 ;
  • R 6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group
  • R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C 4 -alkyl-, Ci-C 4 -fluoroalkyl-, hydroxy-(Ci-C 4 -alkyl)-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C 2 -alkyl)-, phenyl- and 5- to 6-membered monocyclic heteroaryl-, - - wherein any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, oxo, Ci-C3-alkyl-, acetyl- and tert- butoxycarbonyl
  • R 8 represents, independently for each occurrence, a group selected from Ci-C t-alkyl- and benzyl-;
  • R 9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C/t-alkyl- and benzyl-;
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered - - monocyclic heteroaryl- group, represent a group selected from -CH2-CH2-O-, -O-CH2-O- and -O-CH2-CH2-O-.
  • L 1 represents a group selected from -CH 2 -O- and -0-;
  • the present invention relates to compounds of general formula (I) in which
  • R 1 represents a group selected from Ci-C3-alkyl-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, C 1 -C3- fluoroalkoxy-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl-) and benzyl-;
  • R 2 represents a methyl- group
  • R 3 represents a hydrogen atom or a methyl- group
  • R 4 represents a group selected from C 2 -Cs-alkyl-, C3-C6-cycloalkyl-;
  • R 5 represents a group selected from phenyl- and 5- to 6-membered monocyclic heteroaryl-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R 11 ;
  • R 6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group
  • R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C 4 -alkyl-, Ci-C 4 -fluoroalkyl-, hydroxy-(Ci-C 4 -alkyl)-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C 2 -alkyl)-, phenyl- and 5- to 6-membered monocyclic heteroaryl-, wherein any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, oxo, Ci-C3-alkyl-, acetyl- and tert- butoxycarbonyl-, and where
  • R 8 represents, independently for each occurrence, a group selected from Ci-C t-aikyl- and benzyl-;
  • R 9 represents a Ci-C 2 -alkyl- group;
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH 2 -CH 2 -O-, -O-CH2-O- and -O-CH2-CH2-O-;
  • L 1 represents a -CH 2 -O- group; and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N- oxides, tautomers, or stereoisomers.
  • the present invention relates to compounds of general formula (I) in which - -
  • R represents a group selected from « -propyl-, 1,1-difluoro-n-propyl-, methoxy-, ethoxy-, iso- propoxy-, difluoromethoxy-, 2,2,2-trifluoroethoxy- and benzyl-;
  • R 2 represents a methyl- group
  • R 3 represents a hydrogen atom or a methyl- group
  • R 4 represents a group selected from C3-C4-alkyl- and cyclopentyl-;
  • R 5 represents a group selected from phenyl-, pyridyl-, pyrimidyl- or pyrazolyl-, said group being optionally substituted with one or two substituents, each substituent independently selected from R 11 ;
  • R 6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group
  • R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C3-alkyl-, hydroxy-(Ci-C4-alkyl)-, 4- to 7-membered monocyclic heterocycloalkyl-, wherein any 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from oxo and Ci-C3-alkyl, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group;
  • R 8 represents, independently for each occurrence, a Ci-C3-alkyl- group
  • the present invention relates to compounds of general formula (I), - - which R represents a group selected from Ci-C6-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L 1 )-, 4- to 7-membered monocyclic heterocycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-(L 1 )-, Ci-C6-haloalkyl-, C 2 -C6-haloalkenyl-, Ci-C6-alkoxy-, C 1 -C6- haloalkoxy-, (Ci-C 3 -alkoxy)-(Ci-C 3 -alkyl-), -NR 6 R 7 and phenyl-(Ci-C 3 -alkyl)-,
  • phenyl group present in said phenyl-(Ci-C3-alkyl)- group is optionally substituted with one, two or three substituents, each substituent independently selected from halogen, cyano-, hydroxy-, Ci-C3-alkyl-, Ci-C3-haloalkyl- and Ci-C3-alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 1 represents a group selected from Ci-C t-alkyl-, C3-C6-cycloalkyl-, (C3-C6-cycloalkyl)-(L 1 )-, 4- to 6-membered monocyclic heterocycloalkyl-, 4- to 6-membered monocyclic heterocycloalkyl-(L 1 )-, Ci-C4-fluoroalkyl-, C 2 -C4-fluoroalkenyl-, Ci-C t-alkoxy-, C 1 -C4- fluoroalkoxy-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl-) and phenyl-(Ci-C 2 -alkyl)-,
  • any C3-C6-cycloalkyl- or 4- to 6-membered monocyclic heterocycloalkyl- group is optionally substituted once with a Ci-C3-alkyl-, and
  • phenyl group present in said phenyl-(Ci-C 2 -alkyl)- group is optionally substituted with one, two or three substituents, each substituent independently, selected from fluorine, chlorine, bromine, cyano-, Ci-C 2 -alkyl-, trifluoromethyl- and Ci-C 2 -alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 1 represents a group selected from Ci-C3-alkyl-, C3-C6-cycloalkyl-, (C3-C6-cycloalkyl)-(L 1 )-, Ci-C3-fluoroalkyl-, C 2 -C3-fluoroalkenyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl-) and benzyl-.
  • R 1 represents a group selected from Ci-C3-alkyl-, C3-C6-cycloalkyl-, (C3-C6-cycloalkyl)-(L 1 )-, Ci-C3-fluoroalkyl-, C 2 -C3-fluoroalkenyl-, Ci-C3-alkoxy-, Ci-C3-fluoroal
  • the present invention relates to compounds of general formula (I), in which R 1 represents a group selected from Ci-C3-alkyl-, (C3-C6-cycloalkyl)-(L 1 )-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-.
  • R 1 represents a group selected from Ci-C3-alkyl-, (C3-C6-cycloalkyl)-(L 1 )-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-.
  • the present invention relates to compounds of general formula (I), in which R 1 represents a group selected from Ci-C3-alkyl-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl-) and benzyl-.
  • R 1 represents a group selected from Ci-C3-alkyl-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl-) and benzyl-.
  • the present invention relates to compounds of general formula (I), in which R 1 represents a group selected from « -propyl-, cyclobutylmethoxy-, 1,1- difluoro-n-propyl-, methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy-, 2,2,2-trifluoroethoxy- and benzyl-. - -
  • the present invention relates to compounds of general formula (I), in which R 1 represents a group selected from « -propyl-, 1,1-difluoro-n-propyl-, methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy-, 2,2,2-trifluoroethoxy- and benzyl-.
  • the present invention relates to compounds of general formula (I), in which R 1 represents a group selected from n-propyl-, 1,1-difluoro-n-propyl- and benzyl-.
  • the present invention relates to compounds of general formula (I), in which R 1 represents a group selected from cyclobutylmethoxy-, methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy- and 2,2,2-trifluoroethoxy-.
  • R 1 represents a group selected from methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy- and 2,2,2-trifluoroethoxy-.
  • the present invention relates to compounds of general formula (I), in which R 2 represents a Ci-C3-alkyl- group. In certain such embodiments, the present invention relates to compounds of general formula (I), in which R 2 represents an n-propyl- group.
  • the present invention relates to compounds of general formula (I), in which R 2 represents a Ci-C 2 -alkyl- group, especially a methyl group.
  • the present invention relates to compounds of general formula (I), in which R 3 represents represents a hydrogen atom or a Ci-C3-alkyl- group.
  • the present invention relates to compounds of general formula (I), in which R 3 represents a Ci-C3-alkyl- group.
  • the present invention relates to compounds of general formula (I), in which R 3 represents a hydrogen atom or a Ci-C2-alkyl- group, especially a methyl group. In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R 3 represents a hydrogen atom or a methyl- group.
  • the present invention relates to compounds of general formula (I), in which R 3 represents a hydrogen atom.
  • phenyl group present in said phenyl-(Ci-C3-alkyl)- group is optionally substituted with one, two or three substituents, each substituent independently selected from halogen, cyano-, hydroxy-, Ci-C3-alkyl-, Ci-C3-haloalkyl- and Ci-C3-alkoxy-.
  • phenyl group present in said phenyl-(Ci-C3-alkyl)- group is optionally substituted with one, two or three substituents, each substituent independently selected from halogen, cyano-, hydroxy-, Ci-C3-alkyl-, Ci-C3-haloalkyl- and Ci-C3-alkoxy-, with the proviso that said 4- to 10-membered heterocycloalkyl- group is attached to the rest of the molecule via a carbon ring atom.
  • the present invention relates to compounds of general formula (I), in which R 4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, (Ci-C 2 -alkoxy)-(Ci- C2-alkyl)-, C3-C7-cycloalkyl- and 4- to 7-membered monocyclic heterocycloalkyl-,
  • the present invention relates to compounds of general formula (I), in which R 4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, (Ci-C 2 -alkoxy)-(Ci- C 2 -alkyl)-, C3-C7-cycloalkyl- and 4- to 7-membered monocyclic heterocycloalkyl-,
  • any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted once with a Ci-C3-alkyl-,
  • the present invention relates to compounds of general formula (I), in which R 4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, C3-C6-cycloalkyl- and 4- to 6-membered monocyclic heterocycloalkyl-.
  • the present invention relates to compounds of general formula (I), - - which R 4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, C3-C6-cycloalkyl- and 4- to 6-membered monocyclic heterocycloalkyl-,
  • the present invention relates to compounds of general formula (I), in which R 4 represents a group selected from C 2 -C5-alkyl-, C3-C6-cycloalkyl- and 5- to 6- membered monocyclic heterocycloalkyl-.
  • the present invention relates to compounds of general formula (I), in which R 4 represents a group selected from C2-Cs-alkyl- and C3-C6-cycloalkyl-. In certain such preferred embodiments, the present invention relates to compounds of general formula (I), in which R 4 represents a group selected from C 2 -Cs-alkyl-, C3-C6-cycloalkyl- and 5- to
  • the present invention relates to compounds of general formula (I), in which R 4 represents a group selected from Cs-C t-alkyl-, cyclopentyl- and tetrahydropyran-4-yl-.
  • the present invention relates to compounds of general formula (I), in which R 4 represents a group selected from C3-C t-alkyl- and cyclopentyl-.
  • the present invention relates to compounds of general formula (I), in which R 4 represents a group selected from wo-propyl-, wo-butyl, sec-butyl, cyclopentyl- and tetrahydropyran-4-yl-.
  • the present invention relates to compounds of general formula (I), in which R 4 represents a group selected from wo-propyl-, wo-butyl-, sec-butyl- and cyclopentyl-.
  • the present invention relates to compounds of general formula (I), in which R 5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, C3-Cio-cycloalkyl-, 4- to 10- membered heterocycloalkyl-, -NR 6 R 10 , phenyl-(L 2 )- and heteroaryl-(L 2 )-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R 11 .
  • R 5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, C3-Cio-cycloalkyl-, 4- to 10- membered heterocycloalkyl-, -NR 6 R 10 , phenyl-(L 2 )- and heteroaryl-(L 2 )-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R 11 .
  • the present invention relates to compounds of general formula (I), in which R 5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, C3-C7-cycloalkyl-, 4- to
  • the present invention relates to compounds of general formula (I), in which R 5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, -NR 6 R 10 , phenyl-(L 2 )- and heteroaryl-(L 2 )-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from group R 11 .
  • the present invention relates to compounds of general formula (I), in which R 5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, phenyl-(L 2 )- and heteroaryl-(L 2 )-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R 11 .
  • the present invention relates to compounds of general formula (I), in which R 5 represents a group selected from phenyl- and 5- to 6-membered monocyclic heteroaryl-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R 11 .
  • the present invention relates to compounds of general formula (I), in which R 5 represents a group selected from phenyl-, pyridyl-, pyrimidyl- or pyrazolyl-, said group being optionally substituted with one or two substituents, each substituent independently selected from R 11 .
  • the present invention relates to compounds of general formula (I), in which R 5 represents a phenyl- group which is optionally substituted with one or two substituents, each substituent independently selected from R 11 .
  • the present invention relates to compounds of general formula (I), in which R 5 represents a group selected from
  • R and R the pyridyl- or pyrimidyl- ring of which being optionally additionally substituted with one fluoro atom,
  • R 13 represents a hydrogen atom or a methyl- group
  • R 14 represents a group selected from Ci-C3-alkyl- and hydroxy-(Ci-C4-alkyl)-, or
  • R 13 and R 14 together with the nitrogen atom they are attached to, represent a 4- to 7- - - membered monocyclic heterocycloalkyl- group which is optionally substituted with one or two substituents, each substituent independently selected from oxo and Ci-C 2 -alkyl-.
  • the present invention relates to compounds of general formula (I), in which R 5 represents a pyrazolyl- group which is optionally substituted with one or two substituents, each substituent independently selected from Ci-C3-alkyl- group.
  • the present invention relates to compounds of general formula (I), in which R 6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group.
  • the present invention relates to compounds of general formula (I), in which R 6 represents, independently for each occurrence, a hydrogen atom or a Ci-C2-alkyl- group. In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R 6 , independently for each occurrence, represents a hydrogen atom or a methyl- group.
  • the present invention relates to compounds of general formula (I), in which R 6 represents a hydrogen atom. In certain other preferred embodiments, the present invention relates to compounds of general formula (I), in which R 6 represents a methyl- group.
  • the present invention relates to compounds of general formula (I), in which R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-Ce-alkyl-, G-Ce-haloalkyl-, hydroxy-(Ci-C 6 -alkyl)-, (Ci-C3-alkoxy)-(Ci-C 3 -alkyl)-, C 3 -C 7 - cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C3-alkyl)-, phenyl- and 5- to 6-membered monocyclic heteroaryl-,
  • any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C3-alkyl)- group is optionally substituted with one, two or three substituents, each substituent independently selected from halogen, cyano-, hydroxy-, Ci-C 2 -alkyl-, trifluoromethyl- and Ci-C 2 -alkoxy-,
  • the present invention relates to compounds of general formula (I), in - - which R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C 4 -alkyl-, Ci-C 4 -fluoroalkyl-, hydroxy-(Ci-C 4 -alkyl)-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl)-, C3-C7- cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C 2 -alkyl)-, phenyl- and 5- to 6-membered monocyclic heteroaryl-,
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group.
  • the present invention relates to compounds of general formula (I), in which R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C 4 -alkyl-, Ci-C -fluoroalkyl-, hydroxy-(Ci-C -alkyl)-, (Ci-C2-alkoxy)-(Ci-C 2 -alkyl)-, C3-C7- cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C 2 -alkyl)-, phenyl- and 5- to 6-membered monocyclic heteroaryl-,
  • the present invention relates to compounds of general formula (I), in which R 6 and R 7 , together with the nitrogen atom they are attached to, represent a 4- to 7- membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group.
  • the present invention relates to compounds of general formula (I), in which R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C 4 -alkyl-, Ci-C 4 -fluoroalkyl-, hydroxy-(Ci-C 4 -alkyl)-, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl)-, C 3 - C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-alkyl)-, phenyl- and 5- to 6-membered monocyclic heteroaryl-,
  • any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is - - optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, oxo, Ci-C3-alkyl-, acetyl- and ieri-butoxycarbonyl-, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C 2 -alkyl)- group is optionally substituted with one or two substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C 2 -alkyl-, trifluoromethyl- and Ci-C 2 -alkoxy-,
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group.
  • the present invention relates to compounds of general formula (I), in which R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C 4 -alkyl-, Ci-C 4 -fluoroalkyl-, hydroxy-(Ci-C 4 -alkyl)-, (Ci-C2-alkoxy)-(Ci-C 2 -alkyl)-, C 3 - C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C 2 -alkyl)-, phenyl- and 5- to 6-membered monocyclic heteroaryl-,
  • any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, oxo, Ci-C 3 -alkyl-, acetyl- and ieri-butoxycarbonyl-, and wherein said phenyl- and 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C 2 -alkyl)- group is optionally substituted with one or two substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C 2 -alkyl-, trifluoromethyl- and Ci-C 2 -alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C3-alkyl-, hydroxy-(Ci-C4-alkyl)-, 4- to 7-membered monocyclic heterocycloalkyl-,
  • any 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from oxo and Ci-C3-alkyl-,
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group.
  • the present invention relates to compounds of general formula (I), in which R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C3-alkyl-, hydroxy-(Ci-C4-alkyl)-, 4- to 7-membered monocyclic heterocycloalkyl-, - - wherein any 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independentlyselected from oxo and Ci-C3-alkyl-.
  • R 7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C3-alkyl-, hydroxy-(Ci-C4-alkyl)-, 4- to 7-membered monocyclic heterocycloalkyl-, - - wherein any 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independentlys
  • the present invention relates to compounds of general formula (I), in which R 8 represents, independently for each occurrence, a group selected from Ci-C6-alkyl-, C3-C7- cycloalkyl- and phenyl-(Ci-C3-alkyl)-,
  • the present invention relates to compounds of general formula (I), in which R 8 represents, independently for each occurrence, a group selected from Ci-C t-aikyl-, C3-C6- cycloalkyl- and benzyl-,
  • phenyl group present in said benzyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C 2 -alkyl-, trifluoromethyl- and Ci-C 2 -alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 8 represents, independently for each occurrence, a group selected from Ci-C t-alkyl- and benzyl-,
  • phenyl group present in said benzyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, chlorine, bromine,cyano-, Ci-C 2 -alkyl-, trifluoromethyl- and Ci-C 2 -alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 8 represents, independently for each occurrence, a group selected from Ci-C t-alkyl- and benzyl-. In certain embodiments, the present invention relates to compounds of general formula (I), in which R 8 represents, independently for each occurrence, a Ci-C3-alkyl- group.
  • the present invention relates to compounds of general formula (I), in which R 9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C6-alkyl-, C3-C7-cycloalkyl- and phenyl-(Ci-C3-alkyl)-,
  • phenyl group present in said phenyl-(Ci-C3-alkyl)- group is optionally substituted with one, two or three substituents, each substituent independently selected from halogen, cyano-, hydroxy-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 9 represents, independently for each occurrence, a hydrogen atom or a group selected from - -
  • the present invention relates to compounds of general formula (I), in which R 9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C t-alkyl- and benzyl-.
  • the present invention relates to compounds of general formula (I), in which R 9 represents, independently for each occurrence, a Ci-C t-alkyl- group. In other such embodiments, the present invention relates to compounds of general formula (I), in which R 9 represents a benzyl- group.
  • the present invention relates to compounds of general formula (I), in which R 9 represents, independently for each occurrence, a Ci-C 2 -alkyl- group.
  • the present invention relates to compounds of general formula (I), in which R 10 represents, independently for each occurrence, a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, wherein said groups are optionally substituted with one, two or three substituents, each substituent indepdently selected from halogen, cyano-, hydroxy-, Ci-C3-alkyl-, Ci-C3-haloalkyl- and Ci-C3-alkoxy-.
  • R 10 represents, independently for each occurrence, a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, wherein said groups are optionally substituted with one, two or three substituents, each substituent indepdently selected from halogen, cyano-, hydroxy-, Ci-C3-alkyl-, Ci-C3-haloalkyl- and Ci-C3-alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 10 represents, independently for each occurrence, a phenyl group which is optionally substituted with one, two or three substituents, each substituent independently selected from halogen, cyano-, hydroxy-, Ci-C3-alkyl-, Ci-C3-haloalkyl- and Ci-C3-alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 10 represents, independently for each occurrence, a 5- to 6-membered monocyclic heteroaryl- group which is optionally substituted with one, two or three substituents, each substituent independently selected from halogen, cyano-, hydroxy-, Ci-C3-alkyl-, Ci-C3-haloalkyl- and Ci-C3-alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 10 represents, independently for each occurrence, a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, wherein said groups are optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci- C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-.
  • R 10 represents, independently for each occurrence, a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, wherein said groups are optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci- C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-.
  • the present invention relates to compounds of general formula (I), in - - which R represents, independently for each occurrence, a phenyl group which is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 10 represents, independently for each occurrence, a 5- to 6-membered monocyclic heteroaryl- group which is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-.
  • the present invention relates to compounds of general formula (I), in which R 11 represents, independently for each occurrence, a halogen atom or a group selected from hydroxy-, cyano-, nitro-, Ci-C6-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, Ci-C6-haloalkyl-, Ci-Ce-haloalkoxy-, hydroxy-(Ci-C 6 -alkyl)-, (Ci-C3-alkoxy)-(Ci-C 3 -alkyl)-,
  • any phenyl- or 5- to 6-membered monocyclic heteroaryl- group is optionally substituted with one, two or three substituents, each substituent independently selected from halogen, cyano-, hydroxy-, Ci-C3-alkyl-, Ci-C3-haloalkyl- and Ci-C3-alkoxy-, or
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH2-CH2-CH2-, -CH2-CH2-O-, -O-CH2-O-, -CH2-CH2-CH2-, -CH2-CH2-CH2-O- and -O-CH2-CH2-O-.
  • any phenyl- or 5- to 6-membered monocyclic heteroaryl- group is optionally substituted with one, two or three substituents, each substituent independently, selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-, or
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH2-CH2-O-, -O-CH2-O- and -O-
  • R 11 represents, independently for each occurrence, a fluoro atom, a chloro atom, a bromo atom, or a group selected from cyano-, Ci-C t-alkyl-, Ci-C t-fluoroaikyl-, C1-C 4 -fluoro alkoxy-, hydroxy-(Ci-C 4 -alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C 7 -cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, -OR 7 , -N
  • any C3-C 7 -cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one or two substituents, each substituent independently selected - - from fluorine, hydroxy-, oxo, Ci-C2-alkyl-, acetyl- and feri-butoxycarbonyl-,
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH 2 -CH 2 -O-, -O-CH2-O- and -0-CH 2 -CH 2 -0-;
  • said 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one or two substituents, each substituent independently selected from oxo and Ci-C 2 -alkyl-.
  • the present invention relates to compounds of general formula (I), in which R 12 represents, independently for each occurrence, a hydrogen atom or a cyano- group.
  • the present invention relates to compounds of general formula (I), in which R 12 represents a cyano- group.
  • the present invention relates to compounds of general - - formula (I), in which R represents a hydrogen atom.
  • the present invention relates to compounds of general formula (I), in which L 1 represents a group selected from -CH2-, -CH2-O- and -0-.
  • the present invention relates to compounds of general formula (I), in which L 1 represents a group selected from -CH 2 -O- and -0-.
  • the present invention relates to compounds of general formula (I), in which L 1 represents a group selected from -CH 2 - and -0-.
  • the present invention relates to compounds of general formula (I), in which L 1 represents a group selected from -CH2- and -CH2-O-. In certain embodiments, the present invention relates to compounds of general formula (I), in which L 1 represents a group -CH2-.
  • the present invention relates to compounds of general formula (I), in which L 1 represents a group -0-.
  • the present invention relates to compounds of general formula (I), in which L 1 represents a group -CH2-O-.
  • the present invention relates to compounds of general formula (I), in which L 2 represents a group selected from -C ⁇ C- and -CH2-.
  • the present invention relates to compounds of general formula (I), in which L 3 represents, independently for each occurrence, a group selected from -CH2- and - In certain such embodiments, the present invention relates to compounds of general formula (I), in which L 3 represents a group -CH2-.
  • the present invention relates to compounds of general formula (I), in which R 1 represents a group selected from Ci-C3-alkyl-, (C3-C6-cycloalkyl)-(L 1 )-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-, R 2 represents a methyl- group, R 3 represents a hydrogen atom, and R 4 represents a group selected from C 2 -C5-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-.
  • R 1 represents a group selected from Ci-C3-alkyl-, (C3-C6-cycloalkyl)-(L 1 )-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, Ci
  • the present invention relates to compounds of general formula (I), in which R 2 represents a methyl- group, R 3 represents a hydrogen atom, R 4 represents a group selected from C 2 -Cs-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-, and R 5 represents a group selected from phenyl- and 5- to 6-membered monocyclic heteroaryl-, said phenyl- and 5- to 6-membered monocyclic heteroaryl- group being optionally substituted with one, two or three substituents, each substituent independently selected from R 11 .
  • R 2 represents a methyl- group
  • R 3 represents a hydrogen atom
  • R 4 represents a group selected from C 2 -Cs-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-
  • R 5 represents a group selected from phenyl- and 5- to 6-membered mono
  • the present invention relates to compounds of general formula (I), in which R 2 represents a methyl- group, R 3 represents a hydrogen atom, and R 4 represents a group selected from C 2 -Cs-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-.
  • the present invention relates to compounds of general formula (I), in which R 2 represents a methyl- group, R 3 represents a hydrogen atom, and R 4 represents a group selected from C 2 -Cs-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-, with the proviso that said 5- to 6-membered monocyclic heterocycloalkyl- group is attached to the rest of the molecule via a carbon ring atom.
  • R 2 represents a methyl- group
  • R 3 represents a hydrogen atom
  • R 4 represents a group selected from C 2 -Cs-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-, with the proviso that said 5- to 6-membered monocyclic heterocycloalkyl- group is attached to the rest of the molecule via a carbon ring atom.
  • the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom.
  • Oxo may be attached to atoms of suitable valency, for example to a saturated carbon atom or to a sulfur atom.
  • Ci-Cs-alkyl- means a linear or branched, saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g., a methyl-, ethyl-, propyl-, wo-propyl-, n-butyl-, wo-butyl-, sec-butyl-, ieri-butyl-, n-pentyl-, wo-pentyl-, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-, neo-pentyl-, 1,1-dimethylpropyl-, n-hexyl-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-, 1-ethylbutyl-, 3,3-dimethylbutyl-,
  • said group has 1, 2, 3, 4, 5 or 6 carbon atoms ("Ci-C6-alkyl-"), e.g., a methyl-, ethyl-, n-propyl-, wo-propyl-, n-butyl-, wo-butyl-, sec- butyl-, ieri-butyl-, n-pentyl-, wo-pentyl-, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-, neo-pentyl-, 1,1-dimethylpropyl-, n-hexyl-, 4-methylpentyl-, 3-methylpentyl-,
  • said group has 1, 2, 3 or 4 carbon atoms ("Ci-C t-alkyl-”), e.g., a methyl-, ethyl-, n-propyl-, wo-propyl-, n-butyl-, wo-butyl-, sec-butyl- or ieri-butyl- group, 1, 2 or 3 carbon atoms ("Ci-C3-alkyl-”), e.g., a methyl-, ethyl-, n-propyl- or wo-propyl- group, or 1 or 2 carbon atoms ("Ci-C2-alkyl-”), e.g., a methyl-, ethyl- group.
  • C2-C6-alkenyl- means a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, preferably 2, 3 or 4 carbon atoms ("C 2 -C4-alkenyl-”) or 2 or 3 carbon atoms (“C 2 -C3-alkenyl-”), it being understood that in the case in which said alkenyl- group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
  • alkenyl- groups include, for example, an ethenyl-, prop-2-enyl-, (£)-prop-l-enyl-, (Z)-prop-l-enyl-, wo-propenyl-, but-3-enyl-, (£)-but-2-enyl-, (Z)-but-2-enyl-, (£)-but-l-enyl-, (Z)-but-l-enyl-, 2-methylprop-2-enyl-, l-methylprop-2-enyl-, 2-methylprop-l-enyl-, (£)-l-methylprop-l-enyl-, (Z)-l-methylprop-l-enyl-, buta-l,3-dienyl-, pent-4-enyl-, (£)-pent-3-enyl-, (Z)-pent-3-enyl-, (£)-pent-2-enyl-, (Z)-pent-2-
  • C2-C6-alkynyl- means a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, preferably 2, 3 or 4 carbon atoms ("C2-C4-alkynyl-") or 2 or 3 carbon atoms ("C2-C3-alkynyl-")-
  • Representative C 2 -C6-alkynyl- groups include, for example, ethynyl-, prop-l-ynyl-, prop-2-ynyl-, but-l-ynyl-, but-2-ynyl-, but-3-ynyl-, pent-l-ynyl-, pent-2-ynyl-, pent-3-ynyl-, pent-4-ynyl-, hex-l-ynyl-, hex-2-ynyl-, hex-3-ynyl-, hex-4-ynyl
  • Ci-C6-haloalkyl- means a linear or branched, saturated hydrocarbon group in which one or more of the hydrogen atoms of a "Ci-C6-alkyl-" as defined supra are each replaced, identically or differently, by a halogen atom.
  • each said halogen atom is fluorine, resulting in a group referred herein as "Ci-C6-fluoroalkyl-”.
  • Ci-C6-fluoroalkyl- groups include, for example, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 and - CH(CH 2 F) 2 .
  • C 2 -C6-haloalkenyl- means a linear or branched hydrocarbon group in which one or more of the hydrogen atoms of a "C 2 -C6-alkenyl-" as defined supra are each replaced, identically or differently, by a halogen atom.
  • said halogen atom is fluorine, resulting in a group referred herein as "C 2 -C6-fluoroalkenyl-”.
  • hydroxy-(Ci-C6-alkyl)- means a linear or branched, saturated, hydrocarbon group in which one or more hydrogen atoms of a "Ci-C6-alkyl-" as defined supra are each replaced by a hydroxy group, e.g., a hydroxy methyl-, 1 -hydroxy ethyl-, 2-hydroxyethyl-, 1,2-dihydroxyethyl-, 3- hydroxypropyl-, 2-hydroxypropyl-, 2,3-dihydroxypropyl-, l,3-dihydroxypropan-2-yl-, 3-hydroxy- 2-methyl-propyl-, 2-hydroxy-2-methyl-propyl-, or l-hydroxy-2-methyl -propyl- group.
  • Ci-C6-alkoxy- means a linear or branched, saturated, monovalent group of formula (Ci- C6-alkyl)-0-, in which the term "Ci-C6-alkyl” is as defined supra, e.g., a methoxy-, ethoxy-, n- propoxy-, wo-propoxy-, n-butoxy-, wo-butoxy-, ieri-butoxy-, seobutoxy-, pentyloxy-, wo-pentyloxy- or n-hexyloxy- group, or an isomer thereof.
  • Ci-C6-haloalkoxy- means a linear or branched, saturated, monovalent Ci-C6-alkoxy- group, as defined supra, in which one or more of the hydrogen atoms are each replaced, identically or differently, by a halogen atom.
  • said halogen atom in "Ci-C6-haloalkoxy-” is fluorine, resulting in a group referred herein as "Ci-C6-fluoroalkoxy-”.
  • Representative Ci-C6-fluoroalkoxy- groups include, for example, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCF 2 CF 3 and -OCH 2 CF 3 .
  • C 3 -Cio-cycloalkyl- means a saturated mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C 3 -Cio-cycloalkyl-")-
  • Said C 3 -Cio-cycloalkyl- group may be, for example, a monocyclic hydrocarbon ring, e.g., a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- group, or a bicyclic hydrocarbon ring, such as decalinyl-.
  • said hydrocarbon ring is monocyclic and contains 3, 4, 5, 6 or 7 carbon atoms ("C3-C7- cycloalkyl-”), e.g., a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- group, or 3, 4, 5 or 6 carbon atoms ("C 3 -C6-cycloalkyl-”), e.g., a cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexyl- group.
  • a cycloalkyl group may be optionally substituted as defined at the respective part wherein such term is used.
  • heterocycloalkyl- means a saturated mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and which contains 1, 2, 3 or 4 heteroatoms which may be identical or different, said heteroatoms preferably selected from oxygen, nitrogen or sulfur, and wherein carbon atoms and heteroatoms add up to 4, 5, 6, 7, 8, 9 or 10 ring atoms in total, it being possible for said heterocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Heterospirocycloalkyl- "heterobicycloalkyl-” and “bridged heterocycloalkyl-", as defined infra, are also included within the scope of this definition.
  • said "4- to 10-membered heterocycloalkyl-" is monocyclic and contains 3, 4, 5 or 6 carbon atoms, and one or two of the above-mentioned heteroatoms, adding up to 4, 5, 6 or 7 ring atoms in total (a "4- to 7-membered monocyclic heterocycloalkyl-"), or contains 3, 4 or 5 carbon atoms, and one or two of the above-mentioned heteroatoms, adding up to 4, 5 or 6 ring atoms in total (a "4- to 6-membered monocyclic heterocycloalkyl-"), or contains 3, 4 or 5 carbon atoms, and one or two of the above-mentioned heteroatoms, adding up to 5 or 6 ring atoms in total (a "5- to 6-membered monocyclic heterocycloalkyl-"); it being possible for said heterocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or the nitrogen atoms,
  • said "4- to 7-membered monocyclic heterocycloalkyl-" can be a 4-membered ring, a "4-membered heterocycloalkyl-", such as azetidinyl- or oxetanyl-; or a 5-membered ring, a "5-membered heterocycloalkyl-", such as tetrahydrofuranyl-, dioxolinyl-, pyrrolidinyl-, imidazolidinyl-, pyrazolidinyl- or pyrrolinyl-; or a 6- membered ring, a "6-membered heterocycloalkyl-", such as tetrahydropyranyl-, piperidinyl-, morpholinyl-, dithianyl-, thiomorpholinyl- or piperazinyl-; or a 7-membered ring, a "7-membered heterocycloalkyl-", such
  • heterocycloalkyl- is to be understood as meaning a saturated, monovalent bicyclic hydrocarbon radical in which the two rings share two immediately adjacent ring atoms, and wherein said bicyclic hydrocarbon radical contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and which contains 1, 2, 3 or 4 heteroatoms which may be identical or different, said heteroatoms preferably selectedfrom oxygen, nitrogen or sulfur; it being possible for said heterobicycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • heterobicycoalkyl- groups include, for example, azabicyclo[3.3.0]octyl-, azabicyclo[4.3.0]nonyl-, diazabicyclo[4.3.0]nonyl-, oxazabicyclo[4.3.0]nonyl-, thiazabicyclo[4.3.0]nonyl-, and azabicyclo[4.4.0]decyl-.
  • bridged heterocycloalkyl- is to be understood as meaning a saturated, monovalent - - bicyclic hydrocarbon radical in which the two rings share two common ring atoms which are not immediately adjacent, and wherein said bicyclic hydrocarbon radical contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and which contains 1, 2, 3 or 4 heteroatoms which may be identical or different, said heteroatoms preferably selected from oxygen, nitrogen and sulfur; it being possible for said bridged heterocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Exemplary bridged heterocycloalkyl- groups include, for example, azabicyclo[2.2.1]heptyl-, oxazabicyclo[2.2.1]heptyl-, thiazabicyclo[2.2.1]heptyl-, diazabicyclo [2.2.1 ]heptyl-, azabicyclo [2.2.2] octyl-, diazabicyclo [2.2.2] octyl-, oxazabicyclo[2.2.2]octyl-, thiazabicyclo[2.2.2]octyl-, azabicyclo[3.2.1]octyl-, diazabicyclo[3.2.1]octyl-, oxazabicyclo[3.2.1]octyl-, thiazabicyclo[3.2.1]octyl-, azabicyclo [3.3.1] nonyl-, diazabicyclo [3.3.1] nonyl-, oxazabicyclo [3.
  • heterospirocycloalkyl- is to be understood as meaning a saturated, bicyclic hydrocarbon radical in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon radical contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and which contains 1, 2, 3 or 4 heteroatoms which may be identical or different, said heteroatoms preferably selected from oxygen, nitrogen or sulfur; it being possible for said heterospirocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • heterospirocycloalkyl- groups include, for example, azaspiro[2.3]hexyl-, azaspiro[3.3]heptyl-, oxaazaspiro[3.3]heptyl-, thiaazaspiro[3.3]heptyl-, oxaspiro[3.3]heptyl-, oxazaspiro[5.3]nonyl-, oxazaspiro[4.3]octyl-, oxazaspiro[5.5]undecyl-, diazaspiro[3.3]heptyl-, thiazaspiro[3.3]heptyl-, thiazaspiro[4.3]octyl-, and azaspiro[5.5]decyl-.
  • heteroaryl- means a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl-" group), preferably 5, 6, 9 or 10 ring atoms, and which contains 1, 2, 3 or 4 heteroatoms which may be identical or different, said heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • Said heteroaryl- group can be a 5-membered heteroaryl- group, such as, for example, thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl- or tetrazolyl-; or a 6-membered heteroaryl- group, such as, for example, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl- or triazinyl-; or a benzo-fused 5-membered heteroaryl- group, such as, for example, benzofuranyl-, benzothienyl-, benzoxazolyl-, benzisoxazolyl-, benzimidazolyl-, benzothiazoly
  • heteroaryl- is a monocyclic aromatic ring system having 5 or 6 ring atoms and which contains at least one heteroatom, if more than one, they may be identical or different, said heteroatom being selected from the group consisting of oxygen, nitrogen and sulfur ("5- to 6- membered monocyclic heteroaryl-”), such as, for example, thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl- or triazinyl-.
  • oxygen nitrogen and sulfur
  • heteroaryl- groups include all the possible isomeric forms thereof, e.g., the positional isomers thereof.
  • pyridyl- includes pyridin-2-yl-, pyridin-3-yl- and pyridin-4-yl-
  • thienyl- includes thien-2-yl- and thien-3-yl-.
  • heteroaryl- groups can be attached to the rest of the molecule via any one of the carbon atoms, or, if applicable, a nitrogen atom, e.g., pyrrol- l-yl-, pyrazol-l-yl- or imidazol-l-yl-.
  • the term "leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons, e.g., typically forming an anion.
  • a leaving group is selected from the group comprising: halo, in particular chloro, bromo or iodo, (methylsulfonyl)oxy-, [(4-methylphenyl)sulfonyl]oxy-,
  • Ci-Ce as used throughout this text, e.g., in the context of the definition of "Ci-C6-alkyl-", “Ci-C6-haloalkyl-", “Ci-C6-alkoxy-” or “Ci-C6-haloalkoxy-” is to be understood as meaning an alkyl group having a whole number of carbon atoms from 1 to 6, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “Ci-Ce” is to be interpreted as disclosing any sub-range comprised therein, e.g.
  • Ci-Ce Ci-Ce , C2-C5 , C3-C4 , C1-C2 , C1-C3 , C1-C4 , C1-C5 , C1-C6 ; preferably C1-C2 , C1-C3 , C1-C4 , C1-C5 , C1-C6 ; more preferably C1-C4 ; in the case of "C1-C6- haloalkyl-" or "Ci-C6-haloalkoxy-" even more preferably C 1 -C 2 .
  • C 2 -C6 as used throughout this text, e.g., in the context of the definitions of "C 2 -C6-alkenyl-” and “C 2 -C6-alkynyl-”, is to be understood as meaning an alkenyl- group or an alkynyl group having a whole number of carbon atoms from 2 to 6, i.e., 2, 3, 4, 5 or 6 carbon atoms.
  • C 2 -C6 is to be interpreted as disclosing any sub-range comprised therein, e.g., d- e , C3-C5 , C3-C4 , C2-C3 , C2-C4 , C2-C5 ; preferably C2-C3.
  • C3-C7 as used throughout this text, e.g., in the context of the - - definition of "C3-C7-cycloalkyl-”, is to be understood as meaning a cycloalkyl- group having a whole number of carbon atoms of 3 to 7, i.e., 3, 4, 5, 6 or 7 carbon atoms.
  • C3-C7 is to be interpreted as disclosing any sub-range comprised therein, e.g., C 3 -C 6 , C4-C5 , C3-C5 , C3-C4 , C 4 -C 6 , C5-C7 ; preferably C 3 -C 6 .
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio.
  • Isolation of a single stereoisomer, e.g., a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable method, such as chromatography, especially chiral chromatography, for example.
  • the compounds of this invention may contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds (atropisomerism).
  • Substituents on sp 3 carbons in a ring may also be disposed in either cis or trans dispositions relative to each other. It is intended that all such configurations are included within the scope of the present invention.
  • Optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, - - optimally chosen to maximise the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials, enantioselective catalytic reactions, and other suitable methods.
  • the compounds of the present invention may exist as tautomers.
  • any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers, viz. -
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), U C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br, 123 I, 124 I, 129 I and 131 I, respectively. Accordingly, recitation of "hydrogen” or “H” should be understood to encompass 3 ⁇ 4 (protium), 2 H (deuterium), and 3 H (tritium) unless otherwise specified.
  • isotopic variations of a compound of the invention are useful in drug and/or substrate tissue distribution studies.
  • Tritiated and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a - - person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also concerns other forms related to the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention form a crystal that contains molecules of polar solvents, in particular water, methanol or ethanol, for example, as structural element of the crystal lattice of the compounds.
  • the molecules of polar solvents, in particular water may be present in a stoichiometric or non-stoichiometric ratio with the molecules of the compound.
  • stoichiometric solvates e.g., a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • derivatives of the compounds of formula (I) and the salts thereof which are converted into a compound of formula (I) or a salt thereof in a biological system are covered by the invention.
  • Said biological system may be, for example, a mammalian organism, particularly a human subject.
  • the bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes.
  • the compounds of the present invention can exist in free form, e.g., as a free base or a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19. It includes any physiologically acceptable salt as referred to below.
  • Salts which are preferred for the purposes of administration are physiologically acceptable salts of the compounds according to the invention.
  • salts which are not suitable for pharmaceutical applications per se, but which, for example, can be used for the isolation or purification of the compounds according to the invention are also part of the present invention.
  • Physiologically acceptable salts of the compounds according to the invention encompass acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, hydroiodic, sulfuric acid, bisulfuric acid, phosphoric acid, nitric acid or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3- phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic
  • Physiologically acceptable salts of the compounds according to the invention also comprise salts of conventional bases, such as, by way of example and by preference, alkali metal salts (for example lithium, sodium and potassium salts), alkaline earth metal salts (for example calcium, strontium and magnesium salts), other salts (such as, e.g., aluminium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 C atoms, such as, by way of example and by preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, -mefhylmorpholine, arginine, lysine, ethylenediamine, /V-methylpiperidine, N- methylglucamine, dimethylglucamine, ethylgluc
  • the compounds according to the invention may form salts with a quaternary ammonium ion obtainable, e.g., by quaternisation of a basic nitrogen-containing group with agents such as lower alkylhalides such as methyl-, ethyl-, propyl-, and butylchlorides, -bromides and -iodides ; dialkylsulfates such as dimethyl-, diethyl-, dibutyl- and diamylsulfates, long chain halides such as decyl-, lauryl-, myristyl- and stearylchlorides, -bromides and -iodides, aralkylhalides such as benzyl- and phenethylbromides and others.
  • agents such as lower alkylhalides such as methyl-, ethyl-, propyl-, and butylchlorides, -bromides and -iodides ; dial
  • quaternary ammonium ions are tetramethylammonium, tetraethylammonium, tetra( «-propyl)ammonium, tetra (n-butyl)ammonium, or -benzyl-AW -trimethylammonium.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio. - -
  • the Suzuki coupling reaction is catalyzed by palladium catalysts, such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] , tris(dibenzylideneacetone)di-palladium(0) [Pd2(dba)3] , dichlorobis(triphenylphosphine)-palladium(II) [Pd(PPli3)2Cl2], palladium(II) acetate and triphenylphosphine,by [l,l'-bis(diphenylphosphino)ferrocene]palladium dichloride, or by palladacycle precatalysts known to the person skilled in the art, for example (2'-aminobiphenyl-2- yl)(chloro)dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)palladium (CAS 1375325-
  • Preferred is the use of tetrakis(triphenylphosphine)palladium(0) [Pd(PPli3)4] , or (2'-aminobiphenyl-2-yl)(chloro)dicyclohexyl(2',6'-diisopropoxybiphenyl-2- yl)palladium.
  • the reaction is carried out in solvents selected from water, toluene, 1,2-dimethoxyethane, 1,4- dioxane, -dimethylformamide, /V-dimefhylacetamide, /V-methylpyrrolidin-2-one, tetrahydrofuran, and an aliphatic alcohol of the formula Ci-C3-alkyl-OH, or a mixture containing two or more of said solvents, preferably a mixture of two solvents selected from ethanol, toluene and 1,2-dimethoxyethane, optionally containing up to 20 v/v % of water, more preferred a mixture of toluene and ethanol, optionally containing up to 10 v/v % of water, or a mixture of toluene and 1,2-dimethoxyethane, optionally containing up to 10 v/v % of water.
  • solvents selected from water, toluene, 1,2-dimethoxyethane, 1,
  • the reaction is carried out in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, in solid form or in aqueous solution in a concentration ranging from 0.5 N to 3 N, preferably sodium carbonate or potassium carbonate, in solid form or in aqueous solution in a concentration ranging from 1.0 N to 2.5 N, more preferably sodium carbonate in aqueous solution in a concentration ranging from 1.5 N to 2.5 N.
  • a base such as sodium carbonate, potassium carbonate or potassium phosphate
  • the reaction is carried out in a temperature range between 60°C and 180°C, preferably 80°C and 150°C, more preferably 100°C and 140 °C, over a time between 15 minutes and 24 hours, - - preferably between 30 minutes and 4 hours, preferably under an atmosphere of argon, in a microwave oven or in an oil bath.
  • Said chloroimidazopyridine derivates of formula (IV) can, in turn, be assembled from 3- aminomethyl pyridone derivatives of formula (II), in which R 1 and R 2 are as defined for the compounds of general formula (I), and chloroimidazopyridine carboxylic acid derivatives of formula (III), in which R 3 and R 4 are as defined for the compounds of general formula (I), by means of carboxamide (or peptide) coupling reaction well known to the person skilled in the art, according to Scheme la.
  • Said coupling reaction can be performed by reaction of compounds of the formulae (II) and (III) in the presence of a suitable coupling reagent, such as HATU (0-(7- azabenzotriazol-l-y ⁇ -AWA ⁇ '-tetramethyluronium hexafluorophosphate), TBTU (O- (benzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyluronium tetrafluoroborate), PyBOP (benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate), T3P (2,4,6-tripropyl-l, 3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide), or EDC (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with HOBt (1 -hydroxy- lH
  • compounds of general formula (I) can also be assembled from 3-aminomethyl pyridone derivatives of formula (II), in which R 1 and R 2 are as defined for the compounds of general formula (I), and imidazopyridine carboxylic acid derivatives of formula (VI), in which R 3 , R 4 and R 5 are as defined for the compounds of general formula (I), by means of carboxamide (or peptide) coupling reaction well known to the person skilled in the art, according to Scheme lb.
  • Said coupling reaction can be performed by reaction of compounds of the formulae (II) and (VI) in the presence of a suitable coupling reagent, such as HATU (0-(7-azabenzotriazol-l-yl)-A',/V,/V',/V'- tetramethyluronium hexafluorophosphate), TBTU (0-(benzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyl- uronium tetrafluoroborate), PyBOP (benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluoro- phosphate), T3P (2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide), or EDC (l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with
  • Preferred herein is the performance of said carboxamide coupling reaction using 0-(7-azabenzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate (HATU) as a coupling agent, in the presence of /V,/V-diisopropylethylamine as a base, and in -dimethylformamide as a solvent, within a temperature range from 0°C to 50°C.
  • HATU 0-(7-azabenzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate
  • 3-Aminomethyl pyridone derivatives and imidazopyridine carboxylic acids of formulae (II), (III) and (VI) can be prepared using synthetic methods described in more detail as according to Schemes 2a, 2b, 2c, 3a, 3b, 3c, 3d, 3e, 4a and 4b, shown below.
  • Scheme 2a Preparation of chloroimidazopyridine carboxylic acids of formula (Ilia) from 2- methyl-4-nitropyridine 1 -oxide (VII).
  • Scheme 2a displays a synthesis route which can be used for the preparation of chloroimidazopyridine carboxylic acids of formula (Ilia), in which R 3 represents a hydrogen atom and in which R 4 is as defined for the compounds of general formula (I) and which constitutes a sub-compartment of formula (III), from 2-methyl-4-nitropyridine 1 -oxide (VII), which can be converted into 4-chloro-2-methylpyridine 1 -oxide (VIII) by reaction with sodium chloride in the presence of concentrated aqueous hydrochloric acid and a quarternary ammonium halide, such as benzyltrimethyl ammonium chloride, followed by rearrangement of thus formed (VIII) in the presence of trimethylsilyl cyanide and a base such as a tertiary aliphatic
  • Said intermediate (IX) can be subsequently reacted with Grignard reagents of formula R 4 MgZ, in which Z represents chloro, bromo or iodo, and in which R 4 is as defined for the compounds of general formula (I), in an ether such as tetrahydrofuran as a solvent, followed by reduction with a suitable agent such as sodium borohydride, in order to convert the intermediate imines to amines of formula (X).
  • Amines of formula (X) can be further elaborated into formamides of formula (XI) by means of reaction with formic acid or a Ci-C3-alkyl ester thereof, such as ethyl formate.
  • Heating of formamides (XI) in the presence of phosophorus oxychloride (POCb) in a suitable solvent such as toluene can be used to obtain chloroimidazopyridine derivatives of formula (XII) featuring a methyl group at C-7, which can be subsequently converted into enamines of formula (XIII) by reacting with N,N- dimethylformamide dimethylacetal (CH30-C(H)-N(C13 ⁇ 4)2) in the presence of a secondary amine R A R A NH, preferably pyrrolidine (in which R A and R A ' together represent a group -(CE ).
  • Oxidative cleavage of said enamines of formula (XIII) using an oxidant such as sodium periodate can be used to obtain aldehydes of formula (XIV), which can be further elaborated into carboxylic esters of formula (XV), in which R E represents a Ci-C3-alkyl- group, preferably a methyl- group, by reacting with sodium cyanide in the presence of manganese dioxide in a mixture of tetrahydrofuran and methanol as a solvent, followed by saponification of carboxylic esters of formula (XV) using an alkali hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, in an aqueous aliphatic alcohol of the formula (Ci-C3-alkyl)-OH, optionally additionally containing a cyclic ether such as tetrahydrofuran, as a solvent, as well known to the person skilled in the art, to give rise to the desired chloroimidazopyridine carboxy
  • Scheme 2b illustrates the preparation of chloroimidazopyridine carboxylic acids of formula (Illb), in which R 3 represents a Ci-C3-alkyl- group, and in which R 4 is as defined for the compounds of general formula (I) and which constitutes a further sub-set of formula ( ⁇ ), from carboxylic esters of formula (XV), in which R E represents a Ci-C3-alkyl- group, preferably a methyl- group, and in which R 4 is as defined for the compounds of general formula (I).
  • Said carboxylic esters of formula (XV) can also be prepared from carboxylic acids of formula (Ilia; see Scheme 2a) by an esterification reaction well known to the person skilled in the art, e.g.
  • an alkylating agent of the formula (Ci-C3-alkyl)-LG in which LG represents a leaving group as defined herein, preferably - - bromo, iodo or (methylsulfonyl)oxy-, in the presence of a base, such as sodium carbonate, potassium carbonate or cesium carbonate, in a solvent such as A ⁇ -dimefhylformamide.
  • Said carboxylic esters of formula (XV) can be brominated using a suitable brominating agent, preferably -bromo succinimide, in A ⁇ -dimefhylformamide as a solvent, to give 2-bromo imidazopyridine derivatives of formula (XVI), which can be subsequently reacted in a palladium catalysed coupling reaction with a boroxine reagent (see e.g.
  • R 3 represents a Ci-C3-alkyl- group, preferably in the presence of tetrakis (triphenylphosphinato)palladium(O) as a catalyst, sodium carbonate as a base, and aqueous 1,4- dioxane as a solvent, to give chloroimidazopyridine carboxylic esters of formula (XVa), in which R 3 a Ci-C3-alkyl- group, followed by saponification using an alkali hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, in an aqueous aliphatic alcohol of the formula (Ci-C3-alkyl)-OH, optionally additionally containing a cyclic ether such as tetrahydrofuran, as a solvent, as well known to the person skilled in the art, to give rise to the desired chloroimidazopyridine carboxylic acids of formula (Illb), in which R 3 represents a Ci-C3-alkyl- group,
  • Scheme 2c Preparation of imidazopyridine carboxylic acids of formula (VI) from chloroimidazopyridine carboxylic acids and their esters of formulae (III), (XV) and (XVa).
  • Imidazopyridine carboxylic acid derivatives of formula (VI) are available from chloroimidazopyridine carboxylic acids of formula (III), or the corresponding carboxylic esters, - -
  • carboxylic esters of formulae (XV) or (XVa) are employed, carboxylic esters of formula (XVIII) are formed initially which can be cleaved by methods known to the person skilled in the art, in a similar fashion as discussed supra for the conversion of chloroimidazopyridine carboxylic esters (XV) into chloroimidazopyridine carboxylic acids (Scheme 2a).
  • Schemes 3a, 3b, 3c, 3d and 3e display synthesis routes suitable for the preparation of 3 aminomethyl pyridone intermediates of formulae (Ila), (lib), (lie), all of them constituting sub compartments of the formula (II) shown supra.
  • Scheme 3a Preparation of 3-aminomethyl pyridone intermediates of formula (Ila) from ⁇ , ⁇ - unsaturated ketones of formula (XIX).
  • Scheme 3a illustrates the synthesis of 3-aminomethyl pyridone intermediates of formula (Ila), in which R l represents a group selected from the groups representing R 1 as defined for the compounds of general formula (I) which is linked to the pyridone ring via a carbon atom, e.g. Ci- C3-alkyl-, Ci-C3-haloalkyl- or benzyl- group, and in which R 2 represents a Ci-C3-alkyl- group, and their salts, e.g.
  • hydrochloride, hydrobromide or trifluoroacetate salts preferably hydrochloride salts, from ⁇ , ⁇ -unsaturated ketones of formula (XIX), which can be reacted with 2-cyanoacetamide (XX; see also e.g.
  • WO 2011/140325 in the presence of a suitable base, such as an aliphatic amine, preferably piperidine, in an aliphatic alcohol of the formula (Ci-C3-alkyl)-OH, preferably ethanol, - - or, alternatively, in the presence of an alkoxide of an alkali metal, preferably potassium tert- butoxide, as a base, and in dimethyl sulfoxide as a solvent, to give 2-oxo-l,2-dihydropyridine-3- carbonitriles of formula (XXI).
  • a suitable base such as an aliphatic amine, preferably piperidine
  • an aliphatic alcohol of the formula (Ci-C3-alkyl)-OH preferably ethanol, - -
  • an alkoxide of an alkali metal preferably potassium tert- butoxide
  • Said 2-oxo-l,2-dihydropyridine-3-carbonitriles of formula (XXI) can subsequently be reduced to 3-aminomethyl pyridone derivatives of formula (Ila) by methods known to the person skilled in the art, such as by reaction with hydrogen gas in the presence of palladium(II)hydroxide (Pd(OH) 2 ) in methanol containing aqueous hydrochloric acid, or by reaction with hydrogen gas in the presence of Raney Nickel in -dimefhylformamide as a solvent.
  • Pd(OH) 2 palladium(II)hydroxide
  • Raney Nickel Raney Nickel in -dimefhylformamide
  • Said regioisomers can be separated either immediately after their formation, or at a later stage, by methods well known to the person skilled in the art, exemplified by but not limited to the introduction of a ieri-butoxycarbonyl group onto the aminomethyl group present in compounds of the formula (Ila) and their regioisomers, followed by isomer separation by means of column chromatography or preparative HPLC, and removal of the ieri-butoxycarbonyl group as illustrated in the experimental section (see e.g. protocols of intermediates 145 A and 147A).
  • the resulting 3-aminomethyl pyridone intermediates of formula (Ila) can be isolated as free bases, or, depending on the reaction conditions in the final step, and/or the work-up procedure, as salts, e.g. hydrochloride, hydrobromide or trifluoroacetate salts.
  • the intermediates of formula (Ila) are isolated as hydrochloride salts.
  • Scheme 3b illustrates the synthesis of 3-aminomethyl pyridone intermediates of formula (lib), in which R lb represents a group selected from the groups representing R 1 as defined for the compounds of general formula (I) which is linked to the pyridone ring via a carbon atom, e.g. a (Ci-C3-alkoxy)-(Ci-C3-alkyl)- or Ci-C3-haloalkyl- group, and in which R 2 represents a Ci-C3-alkyl- group, and their salts, e.g.
  • a suitable base such as an aliphatic amine, preferably piperidine
  • an aliphatic alcohol of the formula (Ci-C3-alkyl)-OH preferably ethanol
  • the resulting 3-aminomethyl pyridone intermediates of formula (lib) can be isolated as free bases, or, depending on the reaction conditions in the final step, and/or the work-up procedure, as salts, e.g. hydrochloride, hydrobromide or trifluoroacetate salts.
  • the intermediates of formula (lib) are isolated as hydrochloride salts.
  • R lc represents a group selected from the groups representing R 1 as defined for the compounds of general formula (I) which is linked to the pyridone ring via an oxygen atom, e.g. a Ci-C3-alkoxy- or Ci-C3-haloalkoxy- group, or a (C3-C7-cycloalkyl)-(L 1 )- group in which L 1 represents -CH 2 O- or -0-, and in which R 2 represents a methyl- group, as outlined in Schemes 3c, 3d and 3e.
  • Scheme 3c illustrates the preparation of said 3-aminopyridone intermediates of formula (He) starting from ethyl 2,4-dihydroxynicotinate (CAS-No. 10350-10-4; XXIV) which can be selectively benzylated at 2-OH using benzyl bromide and silver carbonate in tetrahydrofuran to give monobenzyl ether (XXV), which, in turn, can be reacted with a compound of formula (XXVI), in which R lc represents e.g.
  • LG represents a leaving group as defined herein, preferably bromo, iodo or [(trifluoromethyl)sulfonyl]oxy-
  • Reduction of the azide group with concomitant cleavage of the benzyl ether present in azides of formula (IXXX) can be achieved using methods well known to the person skilled in the art, such as reaction with hydrogen gas in the presence of palladium on carbon in an aliphatic alcohol of the formula (Ci-C3-alkyl)-OH, preferably methanol, or in the presence of palladium(II) hydroxide, in a mixture comprising an aliphatic alcohol of the formula (Ci-C3-alkyl)-OH, preferably ethanol, and an aliphatic carboxylic acid of the formula (Ci-C 2 -alkyl)-OH, preferably acetic acid, under elevated hydrogen pressure if needed, and optionally followed by treatment with an acid, to yield 3-aminomethyl pyridone intermediates of formula (He) either as free base or as salt, preferably as hydrochloride salt.
  • Scheme 3d Preparation of 3-aminomethyl pyridone intermediates of formula (He) from 4-methyleneoxetan-2-one (XXX).
  • Scheme 3d illustrates an alternative preparation of said 3-aminomethylpyridone intermediates of formula (He) starting from commercially available 4-methyleneoxetan-2-one (XXX), which can be reacted with malonodinitrile in the presence of sodium hydride to give 2-amino-6-mefhyl-4-oxo- 4H-pyran-3-carbonitrile (XXXI) which can be further converted into 2,4-dihydroxy-6- methylnicotinonitrile (XXXII) by heating in aqueous hydrochloric acid.
  • XXXII can be chlorinated using e.g. phosphorus oxychloride (POCI 3 ) in -dimefhylformamide to give 2,4- dichloro-6-methylnicotinonitrile (XXXIII), which can be reacted with a suitable alkoxide, e.g. with sodium methoxide in methanol, to yield intermediates of formula (XXXIV), followed by reduction of the cyano group by methods known to the person skilled in the art, e.g.
  • carbamate intermediates of formula (XXXV) Reacting of carbamate intermediates (XXXV) with aqueous hydrochloric acid can be used to obtain 3-aminomethyl pyridone intermediates of formula (He), preferably as hydrochloride salt.
  • Scheme 4a describes a synthetic approach to starting materials of formula (XIX) which are not commercially available, by methods which however are well known to the person skilled in the art.
  • Carboxylic esters of formula (XXXIX) in which R l represents e.g. a Ci-C 3 -alkyl-, C 1 -C3- haloalkyl- or benzyl- group, and in which R E represents a Ci-C3-alkyl- group, can be readily converted into the corresponding aldehydes (XL) using well-known standard reduction and oxidation protocols (e.g.
  • aldehydes can be subjected to a Wittig olefination using phosphoranes of formula (XLI), in which R 2 represents a Ci-C 3 -alkyl- group, to give ⁇ , ⁇ - unsaturated ketones of formula (XIX).
  • XLI phosphoranes of formula (XLI), in which R 2 represents a Ci-C 3 -alkyl- group, to give ⁇ , ⁇ - unsaturated ketones of formula (XIX).
  • carboxylic esters of formula (XXXIX) can be directly converted into ⁇ , ⁇ -unsaturated ketones of formula (XIX) by reaction with methyl ketones of formula (XLII), in which R 2 represents a Ci-C3-alkyl- group, in the presence of an alkali amide, e.g. sodium amide.
  • an alkali amide e.g. sodium amide.
  • Scheme 4b Preparation of ⁇ -diketones of formula (XXII) from carboxylic esters of formula (XXXIXa).
  • Scheme 4b describes the synthesis of starting materials of formula (XXII) which are not - - commercially available. They can be readily prepared by reacting commercially available carboxylic esters of formula (XXXIXa) in which R lb represents e.g. a (Ci-C3-alkoxy)-(Ci-C3- alkyl)- or Ci-C3-haloalkyl- group, and in which R E represents a Ci-C3-alkyl- group, with sodium metal in toluene, followed by a methyl ketone of formula (XLII).
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate compound of formula (IV)
  • the present invention relates to a method of preparing compounds of general formula (I), supra; in which method an intermediate compound of formula (VI):
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined for the compounds of general formula (I), supra.
  • the present invention relates to intermediate compounds which are useful for the preparation of compounds of the present invention of general formula (I), particularly in the method described herein.
  • the present invention relates to intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), particularly in the method described herein.
  • the present invention further covers compounds of formula (VI): - -
  • the present invention covers the use and a method of using of the intermediate compounds of formula (IV):
  • the compounds according to general formula (I) have valuable pharmaceutical properties which make them commercially utilizable.
  • the compounds of the formula (I) inhibit PRC2, especially EZH2, its mechanism being explained in the Background section, and exhibit cellular activity. They are expected to be commercially applicable in the treatment of diseases (e.g., characterized in activation of PRC2).
  • one aspect of the present invention is the use of the compounds of formula (I) for the treatment of diseases.
  • Another aspect of the present invention is a compound of formula (I) for use in the treatment of a disease/diseases.
  • the compounds of general formula (I) are suitable for prophylaxis and/or treatment of hyperproliferative disorders, for example psoriasis, keloids and other hyperplasias which affect the skin, benign prostate hyperplasias (BPH), solid tumors and haematological tumors.
  • hyperproliferative disorders for example psoriasis, keloids and other hyperplasias which affect the skin, benign prostate hyperplasias (BPH), solid tumors and haematological tumors.
  • BPH benign prostate hyperplasias
  • solid tumors solid tumors
  • haematological tumors haematological tumors.
  • prophylaxis includes a use of the compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample, when administered to prior to the onset of the disorder or condition.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of hyperproliferative diseases.
  • a further aspect is the method of prophylaxis and/or treatment of hyperproliferative diseaes comprising administering an effective amount of one or more compound(s) of formula (I), especially a method of treatment of a hyperproliferative disease.
  • the compounds of formula (I) are also suitable for prophylaxis and/or treatment of benign hyperproliferative diseases, for example endometriosis, leiomyoma and benign prostate hyperplasia.
  • the hyperproliferative disease is a benign hyperproliferative disease.
  • Another aspect of the present invention is a compound of formula (I) for use in the treatment of cancer . They are particular useful in treating metastatic or malignant tumors.
  • Another aspect of the invention is a method of treatment of cancer comprising administering an effective amount of at least one compound of formula (I) .
  • a further aspect of the invention is a method of treatment of metastatic or malignant tumors comprising administering an effective amount of a compound of formula (I).
  • Another aspect of the invention is the use of a compound of formula (I) for the treament of solid tumors.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of solid tumors.
  • a further aspect of the invention is a method of treatment of solid tumors comprising administering an effective amount of a compound of formula (I).
  • solid tumors that can be treated as, for example, tumors of the breast, the respiratory tract, the brain, the bones, the central and peripheral nervous system, the colon, the rectum, the anus, the reproductive organs (e.g., cervix, ovary, prostate), the gastrointestinal tract, the urogenital tract, the endocrine glands (e.g., thyroid and adrenal cortex), the thyroid gland, the parathyroid gland, the esophagus, the endometrium, the eye, the germ cells, the head and the neck, the kidney, the liver, the larynx and hypopharynx, the lung, the mesothelioma, the pancreas, the prostate, the rectum, the kidney, the small intestine, the skin, the soft tissue, the stomach, the testis, ureter, vagina and vulva and the connective tissue and metastases of these tumors.
  • Malignant neoplasias include inherited cancers exemplified by Re
  • Still another aspect of the invention is a method of treatment of the tumors mentioned above comprising administering an effective amount of a compound of formula (I).
  • Another aspect of the invention is the use of a compound of formula (I) for the treament of hematological tumors.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of hematological tumors. - -
  • a further aspect of the invention is a method of treatment of hematological tumors comprising administering an effective amount of a compound of formula (I).
  • Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplasia syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS related malignancies.
  • Still another aspect of the invention is a method of treatment of the hematological tumors mentioned above comprising administering an effective amount of a compound of formula (I).
  • a further aspect of the invention is a method of administering to a subject having a cancer expressing a mutant EZH2 (e.g., tyrosine 641, alanine 677 and/or alanine 687 mutant EZH2) a therapeutically effective amount of the compound of formula (I), wherein the compound inhibits histone methyltransferase activity of PRC2, thereby treating the cancer.
  • a mutant EZH2 e.g., tyrosine 641, alanine 677 and/or alanine 687 mutant EZH2
  • this invention relates to a method of administering to a subject having a cancer expressing a loss of function mutation in the H3K27 demethylase KDM6A/UTX (e.g., medulloblastoma, bladder cancer, T-cell acute lymphoblastic leukemia) a therapeutically effective amount of the compound of formula (I), wherein the compound inhibits histone methyltransferase activity of PRC2, thereby treating the cancer.
  • a cancer expressing a loss of function mutation in the H3K27 demethylase KDM6A/UTX e.g., medulloblastoma, bladder cancer, T-cell acute lymphoblastic leukemia
  • Another aspect of the invention is the use of a compound of formula (I) for the treatment of a subject having a cancer with aberrant H3K27 methylation.
  • aberrant H3K27 methylation may include a genome-wide increase and/or a gene-specific altered distribution of H3K27 mono-, di- or trimethylation within the cancer cell chromatin.
  • Another aspect of the invention is the use of a compound of formula (I) for the treament of a subject having a cancer with a mutation in a gene of the SWI/SNF chromatin remodeling complex proteins.
  • SWI/SNF complex has been described to antagonizing PRC2 complex activities.
  • SWI/SNF chromatin remodeling complex genes examples include SMARCB 1/INI mutations (e.g., found in malignant rhabdoid tumors or atypical teratoid/rhabdoid tumors), ARID1A mutations (e.g., found in endometrial, ovarian, or uterine cancers), SS18-SSX fusion protein caused by the t(X;18)(pl l.2;ql l.2) translocation in synovial sarcoma, and SMARCA4 mutations (e.g., found in lung, bladder, or colorectal cancer).
  • SMARCB 1/INI mutations e.g., found in malignant rhabdoid tumors or atypical teratoid/rhabdoid tumors
  • ARID1A mutations e.g., found in endometrial, ovarian, or uterine cancers
  • SS18-SSX fusion protein caused by the t(X
  • breast tumors that can be treated include, for example, mammary carcinoma with positive hormone receptor status, mammary carcinoma with negative hormone receptor status, Her-2-positive mammary carcinoma, hormone receptor- and Her-2-negative mammary carcinoma, BRCA- associated mammary carcinoma and inflammatory mammary carcinoma. - -
  • Tumors of the respiratory tract that can be treated include, for example, non-small-cell bronchial carcinoma and small-cell bronchial carcinoma, non-small cell lung cancer, and small cell lung cancer.
  • Brain tumors that can be treated include, for example, glioma, glioblastoma, astrocytoma, meningioma and medulloblastoma.
  • Tumors of the male reproductive organs that can be treated include, for example, prostate carcinoma, malignant epididymal tumors, malignant testicular tumors and penile carcinoma.
  • Tumors of the female reproductive organs that can be treated include, for example, endometrial carcinoma, cervical carcinoma, ovarian carcinoma, vaginal carcinoma and vulvar carcinoma.
  • Tumors of the gastrointestinal tract that can be treated include, for example, colorectal carcinoma, anal carcinoma, gastric carcinoma, pancreatic carcinoma, oesophageal carcinoma, gallbladder carcinoma, small-intestinal carcinoma, salivary gland carcinoma, neuroendocrine tumors and gastrointestinal stromal tumors.
  • Tumors of the urogenital tract that can be treated include, for example, urinary bladder carcinoma, renal cell carcinoma, and carcinoma of the renal pelvis and of the urinary tract.
  • Tumors of the eye that can be treated include, for example, retinoblastoma and intraocular melanoma.
  • Tumors of the liver that can be treated include, for example, hepatocellular carcinoma and cholangiocellular carcinoma.
  • Tumors of the skin that can be treated include, for example, malignant melanoma, basalioma, spinalioma, Kaposi's sarcoma and Merkel cell carcinoma.
  • Tumors of the head and neck that can be treated include, for example, laryngeal carcinoma and carcinoma of the pharynx and of the oral cavity.
  • Sarcomas that can be treated include, for example, soft tissue sarcoma, synovial sarcoma, rhabdoid sarcoma and osteosarcoma.
  • Lymphomas that can be treated include, for example, non-Hodgkin's lymphoma, Hodgkin's lymphoma, cutaneous lymphoma, lymphoma of the central nervous system and AIDS-associated lymphoma.
  • Leukaemias that can be treated include, for example, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia, chronic lymphatic leukaemia and hair cell leukaemia.
  • the compounds of formula (I) can be used for prophylaxis and/or treatment of - -
  • Bladder cancer Brain cancer, Breast cancer, Colorectal cancer, Chronic myelomonocytic leukemia, MLL-rearranged leukemia, Lung adenocarcinomas, Lymphoma, Medulloblastoma, Melanoma, Multiple myeloma, Prostate cancer, Malignant rhabdoid tumors, Synovial sarcoma, Teratoid/rhabdoid tumors, or T-cell acute lymphoblastic leukemia.
  • Another aspect of the invention is the use of a compound of formula (I) for the treament of Bladder cancer, Brain cancer, Breast cancer, Colorectal cancer, Chronic myelomonocytic leukemia, MLL-rearranged leukemia, Lung adenocarcinomas, Lymphoma, Medulloblastoma, Melanoma, Multiple myeloma, Prostate cancer, Malignant rhabdoid tumors, Synovial sarcoma, Teratoid/rhabdoid tumors, or T-cell acute lymphoblastic leukemia.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of Bladder cancer, Brain cancer, Breast cancer, Colorectal cancer, Chronic myelomonocytic leukemia, MLL- rearranged leukemia, Lung adenocarcinomas, Lymphoma, Medulloblastoma, Melanoma, Multiple myeloma, Prostate cancer, Malignant rhabdoid tumors, Synovial sarcoma, Teratoid/rhabdoid tumors, or T-cell acute lymphoblastic leukemia tumors.
  • a further aspect of the invention is a method of treatment of Bladder cancer, Brain cancer, Breast cancer, Colorectal cancer, Chronic myelomonocytic leukemia, MLL-rearranged leukemia, Lung adenocarcinomas, Lymphoma, Medulloblastoma, Melanoma, Multiple myeloma, Prostate cancer, Malignant rhabdoid tumors, Synovial sarcoma, Teratoid/rhabdoid tumors, T-cell acute lymphoblastic leukemia tumors comprising administering an effective amount of a compound of formula (I).
  • the compounds of formula (I) can be used for prophylaxis and/or treatment of Breast cancer.
  • Another aspect of the invention is the use of a compound of formula (I) for the treament of Breast cancer.
  • Another aspect of the invention is the use of the compounds of formula (I) for the production of a medicament for the treatment or prophylaxis of breast cancer.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of Breast cancer.
  • a further aspect of the invention is a method of treatment of Breast cancer comprising administering an effective amount of a compound of formula (I).
  • the compounds of formula (I) can be used for prophylaxis and/or treatment of mammary carcinoma, particularly for the treatment.
  • Another aspect of the invention is the use of a compound of formula (I) for the treatment of - - mammary carcinoma.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of mammary carcinoma.
  • a further aspect of the invention is a method of treatment of mammary carcinoma comprising administering an effective amount of a compound of formula (I).
  • the present application further provides the compounds of formula (I) for use as medicaments, especially for prophylaxis and/or treatment of neoplastic disorders.
  • the invention further provides for the use of the compounds of formula (I) for production of a medicament.
  • a further aspect of the invention is a method of using the compound of formula (I) for the production of a pharmaceutical composition.
  • the present invention further provides for the use of the inventive compounds for production of a medicament for prophylaxis and/or treatment of neoplastic disorders.
  • the present application further provides for the use of the inventive compounds for prophylaxis and/or treatment of neoplastic disorders.
  • the invention further provides for the use of the inventive compounds for treatment of benign hyperplasias, inflammation disorders, autoimmune disorders, sepsis, viral infections, vascular disorders and neurodegenerative disorders.
  • compositions comprising at least a compound of general formula (I) together with one or more excipientspharmaceutically acceptable exipients, especially for the treatment and/or prophylaxis of the diseases mentioned above.
  • the invention relates to a method of treatment according to any one of a method disclosed herein comprising administering a pharmaceutical composition comprising a compound of general formula (I) according to claim 1 together with one or more pharmaceutically acceptable excipients.
  • the compounds of general formula (I) may be utilized, as such or in compositions, in research and diagnostics, or as analytical reference standards, and the like, which are well known in the art.
  • the compounds according to the invention can act systemically and/or locally.
  • the administration of the compounds, pharmaceutical compositions or combinations according to - - the invention may be performed in any of the generally accepted modes of administration available in the art.
  • suitable modes of administration include intravenous, oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, topical, transdermal, conjunctival or otic route, or as an implant or stent.
  • Suitable for oral administration are administration forms which work as described in the prior art and deliver the compounds according to the invention rapidly and/or in modified form, which comprise the compounds according to the invention in crystalline and/or amorphous and/or dissolved form, such as, for example, tablets (coated or uncoated, for example tablets provided with enteric coatings or coatings whose dissolution is delayed or which are insoluble and which control the release of the compound according to the invention), tablets which rapidly decompose in the oral cavity, or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets coated or uncoated, for example tablets provided with enteric coatings or coatings whose dissolution is delayed or which are insoluble and which control the release of the compound according to the invention
  • tablets which rapidly decompose in the oral cavity or films/wafers, films/lyophilizates, capsule
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with inclusion of absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • Examples suitable for the other administration routes are pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops/solutions/sprays; tablets to be administered lingually, sublingually or buccally, films/wafers or capsules, suppositories, preparations for the eyes or ears, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, microemulsions, ointments, creams, transdermal therapeutic systems (such as plasters, for example), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops/solutions/sprays tablets to be administered lingually, sublingually or buccally, films/wafers or capsules, suppositories, preparations for the eyes or ears, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions
  • the compounds according to the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, nontoxic, pharmaceutically suitable excipients.
  • excipients include, inter alia,
  • fillers and carriers for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )),
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), - -
  • bases for suppositories for example polyethylene glycols, cacao butter, hard fat
  • solvents for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins
  • surfactants for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette ® ), sorbitan fatty acid esters (such as, for example, Span ® ), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween ® ), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor ® ), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic ® ),
  • ⁇ buffers for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • acids and bases for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • isotonicity agents for example glucose, sodium chloride
  • adsorbents for example highly-disperse silicas
  • viscosity-increasing agents for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol ® ); alginates, gelatine),
  • binders for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol ® ); alginates, gelatine),
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab ® ), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol ® )
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab ® ), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol ® )
  • lubricants for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil ® )
  • mould release agents for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil ® )
  • coating materials for example sugar, shellac
  • film formers for films or diffusion membranes which dissolve rapidly or in a modified manner for example polyvinylpyrrolidones (such as, for example, Kollidon ® ), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit ® )),
  • ⁇ capsule materials for example gelatine, hydroxypropylmethylcellulose
  • polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit ® ), polyvinylpyrrolidones (such as, for - - example, Kollidon ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
  • synthetic polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit ® ), polyvinylpyrrolidones (such as, for - - example, Kollidon ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
  • plasticizers for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate
  • stabilisers for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • antioxidants for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • preservatives for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate
  • ⁇ colourants for example inorganic pigments such as, for example, iron oxides, titanium dioxide
  • flavourings • flavourings, sweeteners, flavour- and/or odour-masking agents.
  • the present invention furthermore provides medicaments or pharmaceutical composition comprising at least one compound according to the invention, usually together with one or more inert, nontoxic, pharmaceutically suitable excipient, and their use for the purposes mentioned above.
  • the compounds of the present invention are administered as pharmaceuticals, to humans or animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of active ingredient in combination with one or more inert, nontoxic, pharmaceutically suitable excipient.
  • the compounds of the invention of general formula (I) and/or the pharmaceutical composition of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient without being toxic to the patient, depending on his/her actual weight.
  • the pharmaceutical composition can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day.
  • a single dose unit of the pharmaceutical composition can contain, e.g., from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1500 mg, most preferably 1 to 500 mg, of the active compound.
  • the compounds of the present invention can be used alone or, if required, in combination with one or more further pharmacologically active substances, provided that this combination does not lead to undesirable and unacceptable side effects.
  • the present invention therefore further provides medicaments and compositions comprising an inventive compound and one or more further active ingredients, especially for prophylaxis and/or treatment of the aforementioned disorders.
  • the compounds of formula (I) can be combined with known antihyperproliferative, cytostatic or cytotoxic chemical and biological substances for treatment of cancer.
  • a "fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • (chemotherapeutic) anti-cancer agents includes but is not limited to
  • alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®), Ifosfamid (Holoxan®), Thiotepa (Thiotepa Lederle®), Melphalan (Alkeran®), or chloroethylnitrosourea (BCNU);
  • platinum derivatives like cisplatin platinum derivatives like cisplatin (Platinex® BMS), oxaliplatin (Eloxatin®), satraplatin or carboplatin (Cabroplat® BMS);
  • antimitotic agents / tubulin inhibitors such as vinca alkaloids (vincristine, vinblastine,
  • Taxanes such as Paclitaxel (Taxol®), Docetaxel (Taxotere®) and analogs as - - well as new formulations and conjugates thereof (like the nanoparticle formulation Abraxane® with paclitaxel bound to albumin), epothilones such as Epothilone B
  • topoisomerase inhibitors such as anthracyclines (exemplified by Doxorubicin / Adriblastin®), epipodophyllotoxins (examplified by Etoposide / Etopophos®) and camptothecin and camptothecin analogs (exemplified by Irinotecan / Camptosar® or Topotecan /
  • pyrimidine antagonists such as 5-fluorouracil (5-FU), Capecitabine (Xeloda®),
  • purine antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanine or fludarabine (Fludara®) and
  • folic acid antagonists such as methotrexate (Farmitrexat®) or premetrexed (Alimta®).
  • target specific anti-cancer agent includes but is not limited to
  • kinase inhibitors such as e.g. Imatinib (Glivec®), ZD- 1839 / Gefitinib (Iressa®), Bay43-9006 (Sorafenib, Nexavar®), SU11248 / Sunitinib (Sutent®), OSI-774 / Erlotinib (Tarceva®),
  • proteasome inhibitors such as PS-341 / Bortezomib (Velcade®);
  • histone deacetylase inhibitors like SAHA (Zolinza®), PXDIOI, MS275, MGCD0103, Depsipeptide / FK228, NVP-LBH589, Valproic acid (VPA), CRA / PCI 24781, ITF2357,
  • heat shock protein 90 inhibitors like 17-allylaminogeldanamycin (17-AAG) or 17- dimethylaminogeldanamycin ( 17-DMAG) ;
  • VTAs vascular targeting agents
  • combretastin A4 phosphate or AVE8062 / AC7700 anti-angiogenic drugs like the VEGF antibodies, such as Bevacizumab (Avastin®), or
  • KDR tyrosine kinase inhibitors such as PTK787 (Vatalanib®) or Vandetanib (Zactima®) or Pazopanib;
  • Rituxan® Alemtuzumab (Campath®), Tositumomab (Bexxar®), C225/ Cetuximab (Erbitux®), Avastin (see above) or Panitumumab (Vectibix®) as well as mutants and conjugates of monoclonal antibodies, e.g., Gemtuzumab ozogamicin (Mylotarg®) or Ibritumomab tiuxetan (Zevalin®), and antibody fragments;
  • oligonucleotide based therapeutics like G-3139 / Oblimersen (Genasense®) or the DNMTl inhibitor MG98;
  • TLR 7/8 agonists like Resiquimod as - - well as immunostimulatory RNA as TLR 7/8 agonists;
  • protease inhibitors include, (ix) protease inhibitors; (x) hormonal therapeutics such as anti-estrogens (e.g. Tamoxifen or
  • Raloxifen e.g. Flutamide or Casodex
  • LHRH analogs e.g. Leuprolide, Goserelin or Triptorelin
  • aromatase inhibitors e.g. Femara, Arimedex or Aromasin
  • target specific anti-cancer agents include bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as 5-Aza-2'-deoxycytidine (Decitabine, Dacogen®) and 5-azacytidine (Vidaza®), alanosine, cytokines such as interleukin-2, interferons such as interferon a2 or interferon- ⁇ , bcl2 antagonists (e.g. ABT-737 or analogs), death receptor agonists, such as TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists (e.g. TRAIL receptor agonists like mapatumumab or lexatumumab).
  • ATRA all-trans retinoic acid
  • DNA methyltransferase inhibitors such as 5-Aza-2'-deoxycytidine (Decitabine, Dacogen®) and 5-azacytidine (Vid
  • anti-cancer agents include, but are not limited to 1311-chTNT, abarelix, abiraterone, aclarubicin, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bort
  • the compounds of formula (I) can be combined with antibodies, for example aflibercept, alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab, denosumab, edrecolomab, gemtuzumab, ibritumomab, ipilimumab, ofatumumab, panitumumab, pertuzumab, rituximab, tositumumab or trastuzumab, and also with recombinant proteins.
  • antibodies for example aflibercept, alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab, denosumab, edrecolomab, gemtuzumab, ibritumomab, ipilimumab, ofatumumab, panitumuma
  • the compounds of formula (I) can be used in combination with treatments directed against angiogenesis, for example axitinib, bevacizumab, cediranib, copanlisib, lenalidomide, pomalidomide, regorafenib, sorafenib, sunitinib, or thalidomide.
  • treatments directed against angiogenesis for example axitinib, bevacizumab, cediranib, copanlisib, lenalidomide, pomalidomide, regorafenib, sorafenib, sunitinib, or thalidomide.
  • Combinations with antihormones and steroidal metabolic enzyme inhibitors may also be suitable.
  • the compounds of the invention can also be used in conjunction with radiotherapy and/or surgical intervention.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallisation. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash chromatography, using for example pre-packed silica gel cartridges, e.g.
  • Biotage®SNAP cartridges containing stationary phases such as silica gel (KP-Sil cartridges), NH-functionalised media (KP-NH cartridges) or reversed phase CI 8 spherical silica (KP-C18-HS cartridges), in combination with a suitable chromatographic system such as an Isolera system (Biotage) and eluents such as, for example, gradients of hexane/ethyl acetate or DCM/methanol.
  • a suitable chromatographic system such as an Isolera system (Biotage) and eluents such as, for example, gradients of hexane/ethyl acetate or DCM/methanol.
  • the compounds may be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluants such as, for example, gradients of water and acetonitrile which may contain additives such - - as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluants such as, for example, gradients of water and acetonitrile which may contain additives such - - as trifluoroacetic acid, formic acid or aqueous ammonia.
  • Optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • intermediate 4A To a solution of intermediate 4A (87.0 g, 383 mmol) in toluene (800 ml) was added phosphorus oxy chloride (POCI 3 ; 43 ml, 460 mmol) portion wise at 100 °C, over a period of 10 min. Once the addition was complete, the mixture was stirred at 100 °C for 1 h and then concentrated. The resultant oil was added carefully to a solution of 10% aqueous sodium carbonate (1 1) and dichloromethane (1 1). The layers were then separated and the aqueous layer was extracted with - - dichloromethane (2 x 750 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated to give intermediate 5A (76.0 g, 95%) as a dark solid.
  • phosphorus oxy chloride POCI 3 ; 43 ml, 460 mmol
  • intermediate 8A a solution of intermediate 8A (1.1 g, 4.61 mmol) in dimethylformamide 23 ml and potassium carbonate (1.9 g, 13.83 mmol) was added iodomethane (0.57 ml, 9.22 mmol) and stirred for 18 h.
  • the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic fractions were washed with brine (40 ml) and the organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo (azeotrope with toluene) to yield intermediate 9A as a black crystalline solid, 1.15 g (79% yield, 80% purity).
  • N-[l-(4-chloro-6-methylpyridin-2-yl)-2-methylbutyl]formamide (intermediate 14A) (31.5 g, 131 mmol) was dissolved in toluene (400 ml). Phosphorus oxychloride (14.6 ml, 157 mmol) was added and the solution was stirred 2 hours at reflux temperature. A TLC analysis (silica gel, heptane/ethyl acetate 1/1) indicated that the reaction was finished. The mixture was allowed to cool to room temperature and concentrated to dryness. A mixture of dichloromethane (400 ml) and an aqueous saturated sodium bicarbonate solution (400 ml) were added.
  • the suspension was filtered and the filter cake was washed thoroughly with ethyl acetate.
  • the organic layer was separated, washed three times with a saturated aqueous sodium bicarbonate solution and once with brine.
  • the organic phase was dried over magnesium sulfate, filtered and concentrated to give a black oil (12.9 g).
  • the product was applied on a silica gel column and the product was eluted with ethyl acetate to give the expected product (9.8 g, 80%).
  • Methyl l-sec-butyl-7-chloroimidazo[l,5-a]pyridine-5-carboxylate (intermediate 18A) (6.71 g, 25.1 - - mmol) was dissolved in diisopropyl ether. The organic layer was extracted three times with an aqueous hydrochloric acid solution (IN). The combined aqueous phases were basified until pH ⁇ 10 using a sodium hydroxide solution (6 N). The mixture was cooled using and ice/water batch and the precipitated solid was filtered. The solid was re-dissolved into dichloromethane and the product was extracted with water. The aqueous phase was acidified to pH5 and the precipitated solid was filtered giving the expected product (4.75 g, 75%).
  • N-[(4-Chloro-6-methylpyridin-2-yl)(cyclopentyl)methyl]formamide (intermediate 21A) (44 g, 174 mmol) was dissolved in toluene (708 ml). About 200 mL of solvent was evaporated to remove residual water. Phosphorus oxychloride (27.7 ml, 264 mmol) was added and the solution was stirred 1 h at reflux temperature. A TLC analysis (silica gel, heptane/ethyl acetate 1/1) indicated that the reaction was finished. The mixture was allowed to cool to room temperature and concentrated to dryness.
  • Methyl 7-chloro-l-cyclopentylimidazo[l,5-a]pyridine-5-carboxylate (intermediate 25A) (3.98 g, 14.3 mmol) was dissolved in a mixture of water (12.2 ml) and dioxane (122 ml). Potassium hydroxide (4 g, 71 mmol) was added and the mixture was heated at 50 °C for 30 min. The mixture was concentrated to dryness and the residue was re-dissolved in water (60 ml). The aqueous layer was washed with diisopropyl ether and residual organic solvent was removed by evaporation.
  • the aqueous phase was acidified to pH ⁇ 5.4 using an aqueous solution of hydrochloric acid (IN).
  • the solid was filtered and dried in vacuo over phosphorus pentoxide giving the expected product (3.72 - - g, 98%).
  • the aqueous phase was further extracted with dichloromethane/2-isopropanol (7:3 mixture) three times, the organic phases were combined dried over magnesium sulphate, filtered and evaporated to - - dryness. The residue was combined with the residue from the filtrate along with the initial 1.15 g of 7-chloro-l-(tetrahydro-2ii-pyran-4-yl)imidazo[l,5-a]pyridine-5-carboxylic acid.
  • the crude solid was triturated with dichloromethane and the resulting grey solid was dissolved into sodium hydroxide solution (50 ml, 2M) and extracted into an isopropyl alcohol chloroform mixture (3:7; 5 x 100 ml) to yield after concentration intermediate 108A as an off-white solid, 2.15 g (54% yield).
  • intermediate 115A 55 g, 164 mmol
  • dioxane 500 ml
  • hydrochloric acid 6M, aq, 140 ml
  • the mixture was stirred at room temperature for 18 h and was then concentrated.
  • the residue was subjected to repeated azeotropic distillation with toluene and was then triturated with diethyl ether to give intermediate 116A (51.6 g, 99%) as a white solid.
  • reaction was neutralized by 4N aqueous hydrochloric acid and concentrated in vacuo to give 2-amino-6-mefhyl-4-oxo-4H-pyran-3- carbonitrile, intermediate 127A (combined yield from 4 batches: 240 g, 88% yield) as orange oil, which was used in the next step without purification.

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Abstract

Cette invention concerne des imidazopyridines de formule générale (I), leur procédé de préparation, des intermédiaires pour les préparer, des compositions pharmaceutiques comprenant au moins un desdits composés, et leur utilisation.
PCT/EP2015/080835 2014-12-22 2015-12-21 Inhibiteurs d'ezh2 de type imidazopyridine Ceased WO2016102493A1 (fr)

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