WO2016102493A1 - Imidazopyridine ezh2 inhibitors - Google Patents

Imidazopyridine ezh2 inhibitors 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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French (fr)
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 Aktiengesellschaft
The Broad Institute Inc.
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Publication of WO2016102493A1 publication Critical patent/WO2016102493A1/en

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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

The present invention relates to imidazopyridines of general formula (I), to a method for their preparation, to intermediates for their preparation, to pharmaceutical compositions comprising at least one of those compounds, and to the use thereof.

Description

Imidazopyridine EZH2 Inhibitors
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.
Background
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). Epigenetic mechanisms are crucial to establish cellular identities during differentiation, and alterations in histone modification marks can result in inappropriate gene expression patterns and subsequent de-regulation of various cellular signaling pathways leading to cancer (Suva et al, Science, 2013, 29;339(6127): 1567-70). In contrast to genetic mutations these alterations in histone modifications are maintained by enzymes that can be targeted with specific inhibitors (Mair et al, Trends Pharmacol Sci., 2014, 35(3): 136-45).
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. In non- transformed cells 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). In solid tumors high levels of EZH2 expression have been reported to be especially associated with the development of de-differentiated and highly aggressive tumors with a poor prognosis (Bachmann et al., J Clin Oncol., 2006, 10;24(2):268-73; Kleer et al, Proc Natl Acad Sci U S A, 2003, 100: 11606-11.; Crea et al, Crit Rev Oncol Hematol., 2012, 83(2): 184-93). 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., - -
2012, 28(1): 147-54) and with tumor grade in brain cancer (Crea et al, Mol Cancer., 2010, 30;9:265). EZH2 expression has also been correlated with hormone-independence in both breast (Reijm et al., Breast Cancer Res Treat., 2011, 125(2):387-94) and prostate cancers (Varambally et al., Nature, 2002, 10;419(6907):624-9). In synovial sarcoma high EZH2 expression is associated with low differentiation and was associated with unfavorable clinical outcome (Changchien et al. J Transl Med., 2012, 30; 10:216). Moreover, activating mutations within the SET domain of EZH2 at tyrosine 641, alanine 677/ 687 have been found in lymphoma and melanoma (Morin et al., Nat Genet., 2010, 42(2): 181-5; McCabe et al., Proc Natl Acad Sci U S A., 2012, 21;109(8):2989-94). These mutations change the catalytic preferences of EZH2 and generate a genome-wide increase in tri-methylation of lysine-27 of histone H3 (H3K27me3) (McCabe et al, Proc Natl Acad Sci U S A, 2012, 21 ;109(8):2989-94). 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. It has been suggested that these mutations often lead to an increase of H3K27me3 and PRC2 mediated gene silencing and sensitizes those cancers to a therapeutic approach with PRC2 inhibitors (Ezponda and Licht, Clin Cancer Res., 2014, pii: clincanres.2499.2014; Sneeringer et al., Proc Natl Acad Sci U S A., 2010, 107(49):20980-5). For instance mutations in the H3K27me3 demethylase UTX/KDM6A have been found in several cancer cell lines (Van Haaften et al, Nat Genet., 2009, 41(5):521-3) as well as in bladder cancer, multiple myeloma, medulloblastoma, T-cell acute lymphoblastic leukemia, and chronic myelomonocytic leukemia patients (Jankowska et al., Blood, 2011, 6;118(14):3932-41, Jones et al., Nature, 2012, 2;488(7409); Dubuc et al, Acta Neuropathol., 2013, 125(3):373-84; Fuchs, Cardiovasc Hematol Disord Drug Targets., 2013, 1 ;13(1): 16-34; Gui et al, Nat Genet., 2011, 7;43(9): 875-8; Van der Meulen et al, Blood., 2014, pii: blood-2014-05-577270). . In subgroup 3 and 4 of meduloblastoma patients PRC2 was proposed as a therapeutic target, since it was demonstrated that different alterations (e.g. somatic copy number aberrations in KDM6A, mutations of the methyltransferase MLL2, increased EZH2 expression, and increased H3K27me3) converged to transcriptional profiles leading to silencing of PRC2-target genes (Dubuc et al, Acta Neuropathol., 2013, 125(3):373-84; Robinson et al, Nature, 2012, 2;488(7409):43-8; Alimova et al, hit J Cancer, 2012, 15;131(8): 1800-9). Additionally mutations in the SWI/SNF remodeling complex result in an altered H3K27 methylation regulated expression profile and a tumor dependency on PRC2 for survival (Wilson et al, Cancer Cell. 2010 Oct 19;18(4):316-28.). For example, in malignant rhabdoid or teratoid/rhabdoid tumors (which have frequently an inactivation of the SWI/SNF gene SMARCB1/INI by mutations or deletions) a dependency on PRC2 function has been demonstrated in pre-clinical models (Knutson et al, Proc Natl Acad Sci U S A, 2013, 110(19):7922-7; Alimova et al, Neuro Oncol., 2013,15(2): 149-60). On the functional level, increased PRC2 activity and up-regulation of H3K27 methylation has directly been connected in genome-wide analysis with an altered gene expression program leading to de-differentiation, induction of cell migration and invasion (Yu et al., Cancer Res, 2007, 67: 10657-10663 and Ben- Porath et al, Nat Genet., 2008, 40(5):499-507). Gene specific analyses revealed that 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. 2010, Nat Med., 2010, 16(3):286-94; Cao et al., Oncogene., 2008, l l ;27(58):7274-84.) In addition to histone methylation activity, other non-histone substrates have been described as relevant for the oncogenic function of PRC2, such as the transcription factor STAT3 whose altered methylation leads to de-regulation of the STAT3 signaling pathway (Kim et al., Cancer Cell., 2013, 10;23(6):839-52). 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). Furthermore first molecules that directly target EZH2 and compete with the cofactor S- adenosylmethionin (SAM) binding have been described (McCabe et al., Nature 2012, 492: 108-12; Knutson et al., Mol Cancer Ther., 2014, 13(4):842-54). These inhibitors show de-repressed expression of PRC2 target genes and decreased tumor cell growth in malignant rhabdoid tumor, synovial sarcoma, MLL-rearranged leukemia, and diffuse large B-cell lymphoma pre-clinical cancer models (Keilhack et al., CTOS 2014 Annual Meeting; Knutson et al., Proc Natl Acad Sci U S A, 2013, 110(19):7922-7; Beguelin et al, Cancer Cell, 2013, 13;23(5):677-92.18; McCabe et al, Nature 2012, 492: 108- 12). Taken together, de-regulated H3K27 methylation at tumor-suppressive genes is a widespread and important alteration in cancer. In contrast to protein mutations, these changes are reversible and depend on the catalytic activity of PRC2. Therefore PRC2 has emerged as an important therapeutic target with a high need for the development of novel inhibitors.
Several published patent applications disclose various compounds as modulators / inhibitors of EZH2. WO 2013/120104 and WO 2014/151142 (Constellation Pharmaceuticals) disclose carboxamide derivatives as inhibitors of EZH2.
WO 2012/118812 (Epizyme, Inc.) discloses substituted 6,5-fused bicyclic heteroaryl compounds as inhibitors of EZH2. US 2013/0040906 (K. W. Kuntz et. al.) discloses, inter alia, compounds and pharmaceutical compositions as inhibitors of EZH2. WO 2014/100665 (Epizyme, Inc.) discloses 1,4-pyridone bicyclic heteroaryl compounds as inhibitors of EZH2. WO 2014/144747 (Epizyme Inc.) discloses 6,5-fused bicyclic heteroaryl compounds as inhibitors of the histone methyltransf erase activity of EZH2. - -
In WO 2011/140324, WO 2011/140325, WO 2012/005805, WO 2012/075080 WO 2013/039988 Indole, Indazole or Azaindole derivatives as inhibitors of EZH2 are disclosed. WO 2013/049770 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.
Description
In a first aspect, the present invention relates to compounds of general formula (I)
Figure imgf000006_0001
( I )
in which
R represents a group selected from Ci-C6-alkyl-, C2-C6-alkenyl, C3-C7-cycloalkyl-, (C3-C7- cycloalkyl)-(L1)-, 4- to 7-membered monocyclic heterocycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-(L1)-, Ci-C6-haloalkyl-, C2-C6-haloalkenyl-, Ci-C6-alkoxy-,
Ci-Ce-haloalkoxy-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, -NR6R7, and phenyl-(Ci-C3-alkyl)-, 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, Ci-C3-alkyl-, C1-C3- haloalkyl-, Ci-C3-alkoxy-, Ci-C3-haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and - S(=0)2-R8, and 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-C3-alkyl-, Ci-C3-haloalkyl-, C1-C3- alkoxy-, and Ci-C3-haloalkoxy-; represents a Ci-C3-alkyl- group; represents a hydrogen atom or a Ci-C3-alkyl- group; represents a hydrogen atom or a group selected from Ci-Cs-aikyl-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3-Cio-cycloalkyl-, 4- to 10-membered heterocycloalkyl- and phenyl-(Ci-C3-alkyl)-, wherein any C3-Cio-cycloalkyl- or 4- to 10-membered heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, hydroxy-, oxo, Ci-C3-alkyl-, C1-C3- haloalkyl-, Ci-C3-alkoxy-, Ci-C3-haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and - S(=0)2-R8, and 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-C3-alkyl-, Ci-C3-haloalkyl-, C1-C3- alkoxy-, and Ci-C3-haloalkoxy-; represents a group selected from phenyl-, naphthyl-, heteroaryl-, C3-Cio-cycloalkyl-, 4- to 10- membered heterocycloalkyl-, -NR6R10, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R11; represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group; represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-Ce-alkyl-, Ci-Ce-haloalkyl-, hydroxy-(Ci-C6-alkyl)-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3- C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C3-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, Ci-C3-alkyl-, C1-C3- haloalkyl-, Ci-Cs-alkoxy-, Ci-Cs-haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and - S(=0)2R8, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, including 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-C2-alkyl-, trifluoromethyl-, C1-C2- - - alkoxy-, and Ci-C2-haloalkoxy-, or
R7, 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 group selected from Ci-C3-alkyl-, Ci-C3-haloalkyl-, -C(=0)-R8 and -C(=0)-OR9; 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-C2-alkyl-, trifluoromethyl-, C1-C2- alkoxy-, and Ci-C2-haloalkoxy-; 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-C2-alkyl-, trifluoromethyl-, C1-C2- alkoxy-, and Ci-C2-haloalkoxy-; 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-C6-alkyl)-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-,
(Ci-C3-haloalkoxy)-(Ci-C3-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, C3-C7-cycloalkyl-(L3)-, 4- to 7-membered monocyclic heterocycloalkyl-(L3)-, phenyl-(L3)-, 5- to 6-membered monocyclic heteroaryl-(L3)-, -OR7, -C(=0)-R8, -C(=0)-OR9, -O- C(=0)-R8, -N(R6)-C(=0)-R7, -N(R6)-C(=0)-NR6R7, -NR6R7, -C(=0)-NR6R7, -SR8, - S(=0)-R8, -S(=0)2-R8, -N(R6)-S(=0)-R8, -S(=0)-NR6R7, -N(R6)-S(=0)2- R8, -S(=0)2-NR6R7, -S(=0)(=NR12)-R8 and -N=S(=0)(R6)-R8; 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, Ci-C3-alkyl-, C1-C3- haloalkyl-, C3-C6-cycloalkyl, cyclopropylmethyl-, Ci-C3-alkoxy-, C1-C3- haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and -S(=0)2-R8, and wherein 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-, C1-C3- haloalkyl-, Ci-C3-alkoxy-, and Ci-C3-haloalkoxy-, or
two R11 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-CH2-O- and
Figure imgf000009_0001
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, G-Ce-alkyl-, C3-C7-cycloalkyl-, phenyl-(Ci-C3-alkyl)- and -C(=0)-OR9;
L1 represents a group selected from -CH2-, -CH2-O- and -0-;
L2 represents a group selected from -CH=CH-, -C≡C-, -CH2- and -CH2CH2-;
L3 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.
In a second embodiment, the present invention relates to compounds of general formula (I) in which R1 represents a group selected from Ci-C t-aikyl-, C3-C6-cycloalkyl-, (C3-C6- cycloalkyl)-(L1)-, 4- to 6-membered monocyclic heterocycloalkyl-, 4- to 6-membered monocyclic heterocycloalkyl-(L1)-, Ci-C t-fluoroalkyl-, C2-C4-fluoroalkenyl-, C1-C4- alkoxy-, Ci-C4-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and phenyl-(Ci-C2-alkyl)- , wherein any C3-C6-cycloalkyl- or 4- to 6-membered monocyclic heterocycloalkyl- group is optionally substituted once with a Ci-C3-alkyl-, and wherein the phenyl group present in said phenyl-(Ci-C2-alkyl)- 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-; represents a Ci-C3-alkyl- group; - -
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-, -NR6R10, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R11;
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-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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, Ci-C3-alkyl-, -C(=0)-R8 and - C(=0)-OR9, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C2-alkyl)- 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-,
R6 and R7, 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-C2-alkyl-, trifluoromethyl- and C1-C2- alkoxy-; - -
R9 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-C2-alkyl-, trifluoromethyl- and C1-C2- alkoxy-;
R10 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-; R11 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-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, -OR7, -C(=0)- R8, -C(=0)-OR9, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, -S(=0)-R8, -
S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8, 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, Ci-C3-alkyl-, Ci-C3-alkoxy-, - C(=0)-R8, -C(=0)-OR9 and -S(=0)2-R8, and wherein 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 R11 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-;
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, Ci-C4-alkyl- and -C(=0)-OR9;
L1 represents a group selected from -CH2-O- and -0-;
L2 represents a group selected from -CH=CH-, -C≡C- and -CH2-; and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N- - - oxides, tautomers, or stereoisomers.
In another embodiment, the present invention relates to compounds of general formula (I) in which
R1 represents a group selected from Ci-C3-alkyl-, C3-C6-cycloalkyl-, (C3-C6-cycloalkyl)-(L1)-, Ci-C3-fluoroalkyl-, C2-C3-fluoroalkenyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (C1-C2- alkoxy)-(Ci-C2-alkyl-) and benzyl-;
R2 represents a Ci-C3-alkyl- group;
R3 represents a hydrogen atom or a methyl- group;
R4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, C3-C6-cycloalkyl- and 4- to 6-membered monocyclic heterocycloalkyl-;
R5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R11;
R6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group;
R7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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 wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C2-alkyl)- group is optionally substituted with one or two substituents, each substituent selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-, or
R6 and R7, 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-;
R9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C/t-alkyl- and benzyl-;
R11 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-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, -OR7, -C(=0)- R8, -C(=0)-OR9, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7,
-S(=0)-R8, -S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8, 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, Ci-C2-alkyl-, -C(=0)-R8 and - C(=0)-OR9, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group is optionally substituted with one, two or three subsituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-, or
two R11 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-.
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, Ci-C4-alkyl- and -C(=0)-OR9;
L1 represents a group selected from -CH2-O- and -0-;
L2 represents a group selected from -CH=CH-, -C≡C- and -CH2-; and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N- oxides, tautomers, or stereoisomers.
In preferred embodiments, the present invention relates to compounds of general formula (I) - -
Figure imgf000014_0001
represents a group selected from Ci-C3-alkyl-, (C3-C6-cycloalkyl)-(L )-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-; represents a methylgroup; represents a hydrogen atom or a methyl group; represents a group selected from C2-Cs-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-; 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 R11; represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group; represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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 wherein any phenyl- and 5- to 6-membered monocyclic heteroaryl- group, including the phenyl group present in said phenyl-(Ci-C2-alkyl)- group, is optionally substituted with one or two substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- - - and Ci-C2-alkoxy-, or
R6 and R7, 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;
R8 represents, independently for each occurrence, a group selected from Ci-C t-aikyl- and benzyl-;
R9 represents a Ci-C2-alkyl- group;
R11 represents, independently for each occurrence, a fluoro atom, a chloro atom, a bromo atom, or a group selected from cyano-, Ci-C t-aikyl-, Ci-C t-fluoroalkyl-, Ci-C/t-fluoroaikoxy-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, Cs-Cv-cycloalkyl-, 4- to 7- membered monocyclic heterocycloalkyl-, -OR7, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, -S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8, wherein any C3-C7-cycloalkyl- and 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one or two substituents, each substituent independently selected from hydroxy-, fluorine, oxo, Ci-C2-alkyl-, acetyl- and ieri-butoxycarbonyl-, or
two R11 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-;
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano- and -C(=0)-OR9;
L1 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.
In particularly preferred embodiments, the present invention relates to compounds of general formula (I) in which
R1 represents a group selected from « -propyl-, cyclobutylmethoxy-, 1,1-difluoro-n-propyl-, - - methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy-, 2,2,2-trifluoroethoxy- and benzyl-; R2 represents a methyl- group; R3 represents a hydrogen atom or a methyl- group;
R4 represents a group selected from Cs-C t-alkyl-, cyclopentyl- and tetrahydropyran-4-yl-; R5 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 R11;
R6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group;
R7 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 R6 and R7, 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;
R8 represents, independently for each occurrence, a Ci-C3-alkyl- group;
R11 represents, independently for each occurrence, a fluoro atom, a chloro atom, or a group selected from cyano-, Ci-C3-alkyl-, hydroxy-(Ci-C4-alkyl)-, 4- to 7-membered monocyclic heterocycloalkyl-, -OR7, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, -S(=0)2-R8, -N(R6)- S(=0)2-R8, -S(=0)2-NR6R7 and-S(=0)(=NH)-R8, wherein any 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one or two substituents, each substituent independently selected from oxo and Ci-C2-alkyl-; and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N- oxides, tautomers, or stereoisomers.
In a further embodiment 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- (L1)-, Ci-C6-haloalkyl-, C2-C6-haloalkenyl-, Ci-C6-alkoxy-, Ci-C6-haloalkoxy-, (C1-C3- alkoxy)-(Ci-C3-alkyl)-, -NR6R7, and phenyl-(Ci-C3-alkyl)-, 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, Ci-C3-alkyl-, C1-C3- haloalkyl-, Ci-C3-alkoxy-, Ci-C3-haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and - S(=0)2-R8, and 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-C3-alkyl-, Ci-C3-haloalkyl-, C1-C3- alkoxy-, and Ci-C3-haloalkoxy-; represents a Ci-C3-alkyl- group; represents a hydrogen atom or a Ci-C3-alkyl- group; represents a hydrogen atom or a group selected from Ci-Cs-alkyl-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, Cs-Go-cycloalkyl-, and phenyl-(Ci-C3-alkyl)-, wherein any C3-Cio-cycloalkyl- or 4- to 10-membered heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, hydroxy-, oxo, Ci-C3-alkyl-, C1-C3- haloalkyl-, Ci-C3-alkoxy-, Ci-C3-haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and - S(=0)2-R8, and 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-C3-alkyl-, Ci-C3-haloalkyl-, C1-C3- alkoxy-, and Ci-C3-haloalkoxy-; represents a group selected from phenyl-, naphthyl-, heteroaryl-, C3-Cio-cycloalkyl-, 4- to 10- membered heterocycloalkyl-, -NR6R10, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R11; represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group; represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-Ce-alkyl-, G-Ce-haloalkyl-, hydroxy-(Ci-C6-alkyl)-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3- - -
C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C3-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, Ci-C3-alkyl-, C1-C3- haloalkyl-, Ci-C3-alkoxy-, Ci-C3-haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and - S(=0)2R8, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, including 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-C2-alkyl-, trifluoromethyl-, C1-C2- alkoxy-, and Ci-C2-haloalkoxy-, or
R6 and R7, 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 group selected from Ci-C3-alkyl-, Ci-C3-haloalkyl-, -C(=0)-R8 and -C(=0)-OR9;
R8 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-C2-alkyl-, trifluoromethyl-, C1-C2- alkoxy-, and Ci-C2-haloalkoxy-;
R9 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-C2-alkyl-, trifluoromethyl-, C1-C2- alkoxy-, and Ci-C2-haloalkoxy-;
R10 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-C6-alkyl)-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-,
(Ci-C3-haloalkoxy)-(Ci-C3-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, C3-C7-cycloalkyl-(L3)-, 4- to 7-membered monocyclic heterocycloalkyl-(L3)-, phenyl-(L3)-,
5- to 6-membered monocyclic heteroaryl-(L3)-, -OR7, -C(=0)-R8, -C(=0)-OR9, -O- C(=0)-R8, -N(R6)-C(=0)-R7, -N(R6)-C(=0)-NR6R7, -NR6R7, -C(=0)-NR6R7, -SR8, - S(=0)-R8, -S(=0)2-R8, -N(R6)-S(=0)-R8, -S(=0)-NR6R7, -N(R6)-S(=0)2- R8, -S(=0)2-NR6R7, -S(=0)(=NR12)-R8 and -N=S(=0)(R6)-R8; 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, Ci-C3-alkyl-, C1-C3- haloalkyl-, C3-C6-cycloalkyl, cyclopropylmethyl-, Ci-C3-alkoxy-, C1-C3- haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and -S(=0)2-R8, and wherein 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-, C1-C3- haloalkyl-, Ci-C3-alkoxy-, and Ci-C3-haloalkoxy-, or
two R11 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-CH2-O- and
Figure imgf000019_0001
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, G-Ce-alkyl-, C3-C7-cycloalkyl-, phenyl-(Ci-C3-alkyl)- and -C(=0)-OR9;
L1 represents a group selected from -CH2-, -CH2-O- and -0-;
L2 represents a group selected from -CH=CH-, -C≡C-, -CH2- and -CH2CH2-;
L3 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.
In another embodiment, the present invention relates to compounds of general formula (I) - -
represents a group selected from Ci-C t-alkyl-, C3-C6-cycloalkyl-, 4- to 6-membered monocyclic heterocycloalkyl-, 4- to 6-membered monocyclic heterocycloalkyl-(L1)-, Ci- C4-fluoroalkyl-, C2-C4-fluoroalkenyl-, Ci-C4-alkoxy-, Ci-C4-fluoroalkoxy-, (Ci-C2-alkoxy)- (Ci-C2-alkyl-) and phenyl-(Ci-C2-alkyl)-, wherein any C3-C6-cycloalkyl- or 4- to 6-membered monocyclic heterocycloalkyl- group is optionally substituted once with a Ci-C3-alkyl-, and wherein the phenyl group present in said phenyl-(Ci-C2-alkyl)- 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-; represents a Ci-C3-alkyl- group; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a group selected from Ci-C6-alkyl-, (Ci-C2-alkoxy)-(Ci-C2- alkyl)-, C3-C7-cycloalkyl-, wherein any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted once with a Ci-C3-alkyl-, and represents a group selected from phenyl-, naphthyl-, heteroaryl-, -NR6R10, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R11; represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group; represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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, Ci-C3-alkyl-, -C(=0)-R8 and - C(=0)-OR9, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C2-alkyl)- 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-, or
R7, 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 substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and C1-C2- alkoxy-; 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-; 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-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, -OR7, -C(=0)- R8, -C(=0)-OR9, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, -S(=0)-R8, - S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8, 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, Ci-C3-alkyl-, Ci-C3-alkoxy-, - C(=0)-R8, -C(=0)-OR9 and -S(=0)2-R8, and wherein 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 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-;
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, Ci-C4-alkyl- and -C(=0)-OR9; L1 represents a group selected from -CH2-O- and -0-;
L2 represents a group selected from -CH=CH-, -C≡C- and -CE -and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N-oxides, tautomers, or stereoisomers.
In another embodiment, the present invention relates to compounds of general formula (I) in which
R1 represents a group selected from Ci-C3-alkyl-, C3-C6-cycloalkyl-, Ci-C3-fluoroalkyl-, C2- C3-fluoroalkenyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-;
R2 represents a Ci-C3-alkyl- group;
R3 represents a hydrogen atom or a methyl- group;
R4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, C3-C6-cycloalkyl-;
R5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R11;
R6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group;
R7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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 wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C2-alkyl)- group is optionally substituted with one or two substituents, each substituent selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-, or R6 and R7, 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;
R8 represents, independently for each occurrence, a group selected from Ci-C t-alkyl- and benzyl-; R9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C/t-alkyl- and benzyl-;
R11 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-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, -OR7, -C(=0)- R8, -C(=0)-OR9, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7,
-S(=0)-R8, -S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8, 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, Ci-C2-alkyl-, -C(=0)-R8 and - C(=0)-OR9, and wherein 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 R11 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-.
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, Ci-C4-alkyl- and -C(=0)-OR9; L1 represents a group selected from -CH2-O- and -0-;
L2 represents a group selected from -CH=CH-, -C≡C- and -CH2-; and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N- oxides, tautomers, or stereoisomers.
In preferred embodiments, the present invention relates to compounds of general formula (I) in which
R1 represents a group selected from Ci-C3-alkyl-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, C1-C3- fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-;
R2 represents a methyl- group;
R3 represents a hydrogen atom or a methyl- group;
R4 represents a group selected from C2-Cs-alkyl-, C3-C6-cycloalkyl-;
R5 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 R11;
R6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group;
R7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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 wherein any phenyl- and 5- to 6-membered monocyclic heteroaryl- group, including the phenyl group present in said phenyl-(Ci-C2-alkyl)- group, is - - optionally substituted with one or two substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-, or R6 and R7, 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;
R8 represents, independently for each occurrence, a group selected from Ci-C t-aikyl- and benzyl-; R9 represents a Ci-C2-alkyl- group;
R11 represents, independently for each occurrence, a fluoro atom, a chloro atom, a bromo atom, or a group selected from cyano-, Ci-C t-aikyl-, Ci-C t-fluoroalkyl-, Ci-C/t-fluoroaikoxy-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7- membered monocyclic heterocycloalkyl-, -OR7, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, -S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8, wherein any C3-C7-cycloalkyl- and 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one or two substituents, each substituent independently selected from hydroxy-, fluorine, oxo, Ci-C2-alkyl-, acetyl- and ieri-butoxycarbonyl-, or
two R11 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-;
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano- and -C(=0)-OR9;
L1 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.
In other preferred embodiments, 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-;
R2 represents a methyl- group;
R3 represents a hydrogen atom or a methyl- group;
R4 represents a group selected from C3-C4-alkyl- and cyclopentyl-;
R5 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 R11;
R6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group;
R7 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
R6 and R7, 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;
R8 represents, independently for each occurrence, a Ci-C3-alkyl- group;
R11 represents, independently for each occurrence, a fluoro atom, a chloro atom, or a group selected from cyano-, Ci-C3-alkyl-, hydroxy-(Ci-C4-alkyl)-, 4- to 7-membered monocyclic heterocycloalkyl-, -OR7, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, -S(=0)2-R8, -N(R6)- S(=0)2-R8, -S(=0)2-NR6R7 and-S(=0)(=NH)-R8, wherein any 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one or two substituents, each substituent independently selected from oxo and Ci-C2-alkyl-; and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N- oxides, tautomers, or stereoisomers.
In certain embodiments, 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)-(L1)-, 4- to 7-membered monocyclic heterocycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-(L1)-, Ci-C6-haloalkyl-, C2-C6-haloalkenyl-, Ci-C6-alkoxy-, C1-C6- haloalkoxy-, (Ci-C3-alkoxy)-(Ci-C3-alkyl-), -NR6R7 and phenyl-(Ci-C3-alkyl)-,
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, Ci-C3-alkyl-, Ci-C3-alkoxy-, -C(=0)-R8, -C(=0)-OR9 and -S(=0)2-R8, and
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-C3-alkyl-, Ci-C3-haloalkyl- and Ci-C3-alkoxy-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R1 represents a group selected from Ci-C t-alkyl-, C3-C6-cycloalkyl-, (C3-C6-cycloalkyl)-(L1)-, 4- to 6-membered monocyclic heterocycloalkyl-, 4- to 6-membered monocyclic heterocycloalkyl-(L1)-, Ci-C4-fluoroalkyl-, C2-C4-fluoroalkenyl-, Ci-C t-alkoxy-, C1-C4- fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and phenyl-(Ci-C2-alkyl)-,
wherein any C3-C6-cycloalkyl- or 4- to 6-membered monocyclic heterocycloalkyl- group is optionally substituted once with a Ci-C3-alkyl-, and
wherein the phenyl group present in said phenyl-(Ci-C2-alkyl)- 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-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R1 represents a group selected from Ci-C3-alkyl-, C3-C6-cycloalkyl-, (C3-C6-cycloalkyl)-(L1)-, Ci-C3-fluoroalkyl-, C2-C3-fluoroalkenyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R1 represents a group selected from Ci-C3-alkyl-, (C3-C6-cycloalkyl)-(L1)-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R1 represents a group selected from Ci-C3-alkyl-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-.
In particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R1 represents a group selected from « -propyl-, cyclobutylmethoxy-, 1,1- difluoro-n-propyl-, methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy-, 2,2,2-trifluoroethoxy- and benzyl-. - -
In particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R1 represents a group selected from « -propyl-, 1,1-difluoro-n-propyl-, methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy-, 2,2,2-trifluoroethoxy- and benzyl-.
In other particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R1 represents a group selected from n-propyl-, 1,1-difluoro-n-propyl- and benzyl-.
In other particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R1 represents a group selected from cyclobutylmethoxy-, methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy- and 2,2,2-trifluoroethoxy-. In other particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R1 represents a group selected from methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy- and 2,2,2-trifluoroethoxy-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R2 represents a Ci-C3-alkyl- group. In certain such embodiments, the present invention relates to compounds of general formula (I), in which R2 represents an n-propyl- group.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R2 represents a Ci-C2-alkyl- group, especially a methyl group.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R3 represents represents a hydrogen atom or a Ci-C3-alkyl- group.
In certain such embodiments, the present invention relates to compounds of general formula (I), in which R3 represents a Ci-C3-alkyl- group.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R3 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 R3 represents a hydrogen atom or a methyl- group.
In particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R3 represents a hydrogen atom.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R4 represents a hydrogen atom or a group selected from Ci-Cs-alkyl-, (Ci-C3-alkoxy)-(Ci- C3-alkyl)-, C3-Cio-cycloalkyl-, 4- to 10-membered heterocycloalkyl- and phenyl-(Ci-C3-alkyl)-, - - wherein any C3-Cio-cycloalkyl- or 4- to 10-membered heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, hydroxy-, oxo, Ci-C3-alkyl-, Ci-C3-alkoxy-, -C(=0)-R8, -C(=0)-OR9 and - S(=0)2-R8, and
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-C3-alkyl-, Ci-C3-haloalkyl- and Ci-C3-alkoxy-.
In certain such embodiments, the present invention relates to compounds of general formula (I), in which R4 represents a hydrogen atom or a group selected from Ci-Cs-alkyl-, (Ci-C3-alkoxy)-(Ci- C3-alkyl)-, C3-Cio-cycloalkyl-, 4- to 10-membered heterocycloalkyl- and phenyl-(Ci-C3-alkyl)-, wherein any C3-Cio-cycloalkyl- or 4- to 10-membered heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, hydroxy-, oxo, Ci-Cs-alkyl-, Ci-C3-alkoxy-, -C(=0)-R8, -C(=0)-OR9 and - S(=0)2-R8, and
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-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. In certain embodiments, the present invention relates to compounds of general formula (I), in which R4 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-. In certain such embodiments, the present invention relates to compounds of general formula (I), in which R4 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-,
with the proviso that said 4- to 7-membered monocyclic heterocycloalkyl- group is attached to the rest of the molecule via a carbon ring atom.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, C3-C6-cycloalkyl- and 4- to 6-membered monocyclic heterocycloalkyl-.
In certain embodiments, the present invention relates to compounds of general formula (I), - - which R4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, C3-C6-cycloalkyl- and 4- to 6-membered monocyclic heterocycloalkyl-,
with the proviso that said 4- to 6-membered monocyclic heterocycloalkyl- group is attached to the rest of the molecule via a carbon ring atom. In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R4 represents a group selected from C2-C5-alkyl-, C3-C6-cycloalkyl- and 5- to 6- membered monocyclic heterocycloalkyl-.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R4 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 R4 represents a group selected from C2-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. In particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R4 represents a group selected from Cs-C t-alkyl-, cyclopentyl- and tetrahydropyran-4-yl-.
In particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R4 represents a group selected from C3-C t-alkyl- and cyclopentyl-. In certain other particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R4 represents a group selected from wo-propyl-, wo-butyl, sec-butyl, cyclopentyl- and tetrahydropyran-4-yl-.
In certain other particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R4 represents a group selected from wo-propyl-, wo-butyl-, sec-butyl- and cyclopentyl-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, C3-Cio-cycloalkyl-, 4- to 10- membered heterocycloalkyl-, -NR6R10, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R11.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, C3-C7-cycloalkyl-, 4- to
7- membered monocyclic heterocycloalkyl-, -NR6R10, phenyl-(L2)- and heteroaryl-(L2)-, said group - - being optionally substituted with one, two or three substituents, each substituent independently selected from R11.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, -NR6R10, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from group R11.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R11.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R5 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 R11. In certain particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R5 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 R11.
In certain other particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R5 represents a phenyl- group which is optionally substituted with one or two substituents, each substituent independently selected from R11.
In certain other particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R5 represents a group selected from
Figure imgf000031_0001
R and R the pyridyl- or pyrimidyl- ring of which being optionally additionally substituted with one fluoro atom,
in which "*" represents the point of attachment to the rest of the molecule,
and in which R13 represents a hydrogen atom or a methyl- group, and R14 represents a group selected from Ci-C3-alkyl- and hydroxy-(Ci-C4-alkyl)-, or
in which R13 and R14, 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-C2-alkyl-.
In certain other particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R5 represents a pyrazolyl- group which is optionally substituted with one or two substituents, each substituent independently selected from Ci-C3-alkyl- group.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group.
In certain such embodiments, the present invention relates to compounds of general formula (I), in which R6 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 R6, independently for each occurrence, represents a hydrogen atom or a methyl- group.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R6 represents a hydrogen atom. In certain other preferred embodiments, the present invention relates to compounds of general formula (I), in which R6 represents a methyl- group.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-Ce-alkyl-, G-Ce-haloalkyl-, hydroxy-(Ci-C6-alkyl)-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3-C7- cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C3-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, Ci-C3-alkyl-, Ci-C3-alkoxy-, -C(=0)-R8, -C(=0)- OR9 and -S(=0)2R8, and
wherein 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-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-,
or
R6 and R7, 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 group selected from Ci-Cs-alkyl-, -C(=0)-R8 and -C(=0)-OR9.
In certain other embodiments, the present invention relates to compounds of general formula (I), in - - which R7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7- cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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, Ci-C3-alkyl-,-C(=0)-R8 and -C(=0)-OR9, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C2-alkyl)- 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
R6 and R7, 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. In certain other embodiments, the present invention relates to compounds of general formula (I), in which R7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C -fluoroalkyl-, hydroxy-(Ci-C -alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7- cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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, Ci-C3-alkyl-,-C(=0)-R8 and -C(=0)-OR9, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C2-alkyl)- 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-.
In certain other embodiments, the present invention relates to compounds of general formula (I), in which R6 and R7, 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.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3- C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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 ieri-butoxycarbonyl-, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C2-alkyl)- group is optionally substituted with one or two substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-,
or
R6 and R7, 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.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3- C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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 ieri-butoxycarbonyl-, and wherein said phenyl- and 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C2-alkyl)- group is optionally substituted with one or two substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-.
In certain particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R7 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
R6 and R7, 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.
In certain particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R7 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-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R8 represents, independently for each occurrence, a group selected from Ci-C6-alkyl-, 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-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-. In certain embodiments, the present invention relates to compounds of general formula (I), in which R8 represents, independently for each occurrence, a group selected from Ci-C t-aikyl-, 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 Ci-C2-alkoxy-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R8 represents, independently for each occurrence, a group selected from Ci-C t-alkyl- 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 Ci-C2-alkoxy-.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R8 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 R8 represents, independently for each occurrence, a Ci-C3-alkyl- group.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C6-alkyl-, 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-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R9 represents, independently for each occurrence, a hydrogen atom or 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 indepdently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-. In certain embodiments, the present invention relates to compounds of general formula (I), in which R9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C t-alkyl- and benzyl-.
In certain such embodiments, the present invention relates to compounds of general formula (I), in which R9 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 R9 represents a benzyl- group.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R9 represents, independently for each occurrence, a Ci-C2-alkyl- group.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R10 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-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R10 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-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R10 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-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R10 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-.
In certain embodiments, 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-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R10 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-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R11 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-C6-alkyl)-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-,
(Ci-C3-haloalkoxy)-(Ci-C3-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, C3-C7-cycloalkyl-(L3)-, 4- to 7-membered monocyclic heterocycloalkyl-(L3)-, phenyl-(L3)-, 5- to 6-membered monocyclic heteroaryl-(L3)-, -OR7, -C(=0)-R8, -C(=0)-OR9, -0-C(=0)-R8, -N(R6)-C(=0)-R7, -N(R6)-C(=0)- NR6R7, -NR6R7, -C(=0)-NR6R7, -SR8, -S(=0)-R8, -S(=0)2-R8, -N(R6)-S(=0)-R8, -S(=0)- NR6R7, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7, -S(=0)(=NR12)-R8 and -N=S(=0)(R6)-R8;
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, Ci-C3-alkyl-, C3-C6-cycloalkyl, cyclopropylmethyl-, d-Cs-alkoxy-, -C(=0)-R8, -C(=0)-OR9 and -S(=0)2-R8, and
wherein 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 R11 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-CH2-O- and -O-CH2-CH2-O-. In certain embodiments, the present invention relates to compounds of general formula (I), in which R11 represents, independently for each occurrence, a halogen atom or a group selected from hydroxy-, cyano-, Ci-C t-alkyl-, Ci-C t-fluoroalkyl-, Ci-C t-fluoroalkoxy-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci-C2-alkyl)-, Cs-Cv-cycloalkyl-, 4- to 7- membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, - OR7, -C(=0)-R8, -C(=0)-OR9, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, -S(=0)-R8, -S(=0)2-R8, -N(R6)-S(=0)2- - -
R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8;
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, Ci-C3-alkyl-, Ci-C3-alkoxy-, -C(=0)-R8, -C(=0)-OR9 and -S(=0)2-R8, and
wherein 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 R11 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-
In certain embodiments, the present invention relates to compounds of general formula (I), in which R11 represents, independently for each occurrence, a halogen atom or a group selected from hydroxy-, cyano-, Ci-C t-aikyl-, Ci-C t-fluoroaikyl-, Ci-C t-fluoroalkoxy-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci-C2-alkyl)-, Cs-Cv-cycloalkyl-, 4- to 7- membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, - OR7, -C(=0)-R8, -C(=0)-OR9, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, -S(=0)-R8, - S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8,
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, Ci-C2-alkyl-, -C(=0)-R8 and -C(=0)-OR9, and wherein 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 R11 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- In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R11 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-C4 -fluoro alkoxy-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, -OR7, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, -S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8,
wherein any C3-C7-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-,
or
two R11 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 -0-CH2-CH2-0-;
In particularly preferred embodiments, the present invention relates to compounds of general formula (I), in which R11 represents, independently for each occurrence, a fluoro atom, a chloro atom, or a group selected from cyano-, Ci-C3-alkyl-, hydroxy-(Ci-C4-alkyl)-, 4- to 7-membered monocyclic heterocycloalkyl-, -OR7, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, - S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NH)-R8,
wherein said 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one or two substituents, each substituent independently selected from oxo and Ci-C2-alkyl-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, G-Ce-alkyl-, C3-C7-cycloalkyl-, phenyl-(Ci-C3-alkyl)- and -C(=0)-OR9.
In certain embodiments, the present invention relates to compounds of general formula (I), in which R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, Ci-C4-alkyl- and -C(=0)-OR9. In preferred embodiments, the present invention relates to compounds of general formula (I), in which R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano- and -C(=0)-OR9.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R12 represents, independently for each occurrence, a hydrogen atom or a cyano- group.
In other preferred embodiments, the present invention relates to compounds of general formula (I), in which R12 represents, independently for each occurrence, a hydrogen atom or a group -C(=0)- OR9.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R12 represents a cyano- group.
In other preferred embodiments, the present invention relates to compounds of general formula (I), in which R12 represents a group -C(=0)-OR9.
In particularly preferred embodiments, the present invention relates to compounds of general - - formula (I), in which R represents a hydrogen atom.
In certain embodiments, the present invention relates to compounds of general formula (I), in which L1 represents a group selected from -CH2-, -CH2-O- and -0-.
In certain such embodiments, the present invention relates to compounds of general formula (I), in which L1 represents a group selected from -CH2-O- and -0-.
In other such embodiments, the present invention relates to compounds of general formula (I), in which L1 represents a group selected from -CH2- and -0-.
In yet other such embodiments, the present invention relates to compounds of general formula (I), in which L1 represents a group selected from -CH2- and -CH2-O-. In certain embodiments, the present invention relates to compounds of general formula (I), in which L1 represents a group -CH2-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which L1 represents a group -0-.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which L1 represents a group -CH2-O-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which L2 represents a group selected from -CH=CH-, -C≡C-, -CH2- and- CH2CH2-.
In certain such embodiments, the present invention relates to compounds of general formula (I), in which L2 represents a group selected from -CH=CH-, -C≡C- and -CH2-. In certain such embodiments, the present invention relates to compounds of general formula (I), in which L2 represents a group selected from -CH=CH- and -C≡C-.
In other embodiments, the present invention relates to compounds of general formula (I), in which L2 represents a group selected from -C≡C- and -CH2-.
In yet other embodiments, the present invention relates to compounds of general formula (I), in which L2 represents a group selected from -CH=CH- and -CH2-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which L2 represents a group -CH=CH-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which L2 represents a group -CH2- In certain embodiments, the present invention relates to compounds of general formula (I), in - - which L2 represents a group -C=C-.
In certain embodiments, the present invention relates to compounds of general formula (I), in which L3 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 L3 represents a group -CH2-.
In certain preferred embodiments, the present invention relates to compounds of general formula (I), in which R1 represents a group selected from Ci-C3-alkyl-, (C3-C6-cycloalkyl)-(L1)-, Ci-C3-fluoroalkyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-, R2 represents a methyl- group, R3 represents a hydrogen atom, and R4 represents a group selected from C2-C5-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-.
In other preferred embodiments, the present invention relates to compounds of general formula (I), in which R2 represents a methyl- group, R3 represents a hydrogen atom, R4 represents a group selected from C2-Cs-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-, and R5 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 R11.
In other preferred embodiments, the present invention relates to compounds of general formula (I), in which R2 represents a methyl- group, R3 represents a hydrogen atom, and R4 represents a group selected from C2-Cs-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-.
In other preferred embodiments, the present invention relates to compounds of general formula (I), in which R2 represents a methyl- group, R3 represents a hydrogen atom, and R4 represents a group selected from C2-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.
It is to be understood that the present invention relates to any further sub-combination of the various embodiments of the present invention of compounds of general formula (I), supra.
In particularly preferred embodiments, the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.
Definitions
The terms "halogen atom", "halogen", "halo" or "Hal" mean a fluorine, chlorine, bromine or iodine atom. - -
Oxo, an oxo group or an oxo substituent means a doubly attached oxygen atom =0. Oxo may be attached to atoms of suitable valency, for example to a saturated carbon atom or to a sulfur atom. For example, but without limitation, one oxo group can be attached to a carbon atom, resulting in the formation of a carbonyl group -C(=0)-, or two oxo groups can be attached to one sulfur atom, resulting in the formation of a sulfonyl group -S(=0)2-.
The term "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-,
2.2- dimethylbutyl-, 1,1-dimethylbutyl-, 2,3-dimethylbutyl-, 1,3-dimethylbutyl-, 1,2-dimethylbutyl-, n-heptyl-, 5-methylhexyl-, 4-methylhexyl-, 2-methylhexyl-, 1-methylhexyl-, 2-ethylpentyl-,
1- ethylpentyl-, 3,3-dimethylpentyl-, 2,2-dimethylpentyl-, 1,1-dimethylpentyl-, 2,3-dimethylpentyl-,
1.3- dimethylpentyl-, 1,2-dimethylpentyl-, n-octyl-, 6-methylheptyl-, 4-methylheptyl-, 2-methylheptyl-, 1-methylheptyl-, 2-ethylhexyl-, 1-ethylhexyl-, 3,3-dimethylhexyl-,
2,2-dimethylhexyl-, 1,1-dimethylhexyl-, 2,3-dimethylhexyl-, 1,3-dimethylhexyl-, 1,2-dimethylhexyl- group, or an isomer thereof. Preferably, 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-,
2- methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-, 1-ethylbutyl-, 3,3-dimethylbutyl-, 2,2-dimethylbutyl-, 1,1-dimethylbutyl-, 2,3-dimethylbutyl-, 1,3-dimethylbutyl- or 1,2-dimethylbutyl- group, or an isomer thereof. More preferably, 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.
The term "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 ("C2-C4-alkenyl-") or 2 or 3 carbon atoms ("C2-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. Representative 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-enyl-, (£)-pent-l-enyl-, (Z)-pent-l-enyl-, 3-methylbut-3-enyl-, - -
2-methylbut-3-enyl-, l-mefhylbut-3-enyl-, 3-methylbut-2-enyl-, (£')-2-methylbut-2-enyl-, (Z)-2-mefhylbut-2-enyl-, (£)- 1 -methylbut-2-enyl-, (Z)- 1 -methylbut-2-enyl-,
(£)-3-methyibut-l-enyl-, (Z)-3-methylbut-l-enyl-, (£')-2-methylbut-l-enyl-,
(Z)-2-methylbut- 1 -enyl-, (£)- 1 -methylbut- 1 -enyl-, (Z)- 1 -methylbut- 1 -enyl-, l,l-dimethylprop-2-enyl-, 1-ethylprop-l-enyl-, 1-propylvinyl-, 1-isopropylvinyl-, (£)-3,3-dimethylprop-l-enyl-, (Z)-3,3-dimethylprop-l-enyl-, penta-l,4-dienyl-, hex-5-enyl-, (£)-hex-4-enyl-, (Z)-hex-4-enyl-, (£)-hex-3-enyl-, (Z)-hex-3-enyl-, (£)-hex-2-enyl-, (Z)-hex-2-enyl-, (£)-hex-l-enyl-, (Z)-hex-l-enyl-, 4-methylpent-4-enyl-, 3-methylpent-4-enyl-, 2-methylpent-4-enyl-, l-methylpent-4-enyl-, 4-methylpent-3-enyl-, (£')-3-methylpent-3-enyl-, (Z)-3-methylpent-3-enyl-, (£)-2-methylpent-3-eriyl-, (Z)-2-methylpent-3-enyl-,
(£')-l-methylpent-3-enyl-, (Z)-l-methylpent-3-enyl-, (£')-4-methylpent-2-enyl-,
(Z)-4-mefhylpent-2-enyl-, (£')-3-methylpent-2-enyl-, (Z)-3-methylpent-2-enyl-,
(£')-2-methylpent-2-enyl-, (Z)-2-methylpent-2-enyl-, (£)-l-methylpent-2-eriyl-,
(Z)- 1 -methylpent-2-enyl-, (£')-4-methylpent- 1 -enyl-, (Z)-4-methylpent- 1 -enyl-, (£')-3-methylpent-l-enyl-, (Z)-3-methylpent-l-enyl-, (£')-2-methylpent-l-enyl-,
(Z)-2-methylpent- 1 -enyl-, (£)- 1 -methylpent- 1 -enyl-, (Z)- 1 -methylpent- 1 -enyl-, 3 -ethylbut-3-enyl-,
2- ethylbut-3-enyl-, l-ethylbut-3-enyl-, (£)-3-ethylbut-2-enyl-, (Z)-3-ethylbut-2-enyl-, (£)-2-ethylbut-2-enyl-, (Z)-2-ethylbut-2-enyl-, (£)-l-ethylbut-2-enyl-, (Z)-l-ethylbut-2-enyl-, (£)-3-ethylbut-l-enyl-, (Z)-3-ethylbut-l-enyl-, 2-ethylbut-l-enyl-, (£)-l-ethylbut-l-enyl-, (Z)-l-ethylbut-l-enyl-, 2-propylprop-2-enyl-, l-propylprop-2-enyl-, 2-isopropylprop-2-enyl-, 1 -isopropylprop-2-enyl-, (£')-2-propylprop- 1 -enyl-, (Z)-2-propylprop- 1 -enyl-,
(£)- 1 -propylprop- 1 -enyl-, (Z)- 1 -propylprop- 1 -enyl-, (£')-2-isopropylprop- 1 -enyl-,
(Z)-2-isopropylprop- 1 -enyl-, (£)- 1 -isopropylprop- 1 -enyl-, (Z)- 1 -isopropylprop- 1 -enyl-, hexa-l,5-dienyl- and l-(l,l-dimethylethyl-)ethenyl- group. Particularly, said group is ethenyl- or prop-2-enyl-.
The term "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 C2-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-, hex-5-ynyl-, l-methylprop-2-ynyl-, 2-methylbut-3-ynyl-, l-methylbut-3-ynyl-, l-methylbut-2-ynyl-, 3-methylbut-l-ynyl-, l-ethylprop-2-ynyl-,
3- methylpent-4-ynyl-, 2-methylpent-4-ynyl-, l-methylpent-4-ynyl-, 2-methylpent-3-ynyl-, l-methylpent-3-ynyl-, 4-methylpent-2-ynyl-, l-methylpent-2-ynyl-, 4-methylpent-l-ynyl-, 3-methylpent-l-ynyl-, 2-ethylbut-3-ynyl-, l-ethylbut-3-ynyl-, l-ethylbut-2-ynyl-, 1 -propylprop-2-ynyl-, 1 -isopropylprop-2-ynyl-, 2,2-dimethylbut-3-ynyl-, 1 ,1 -dimethylbut-3-ynyl-, l,l-dimethylbut-2-ynyl- and 3,3-dimethylbut-l-ynyl- group. Particularly, said alkynyl- group is - - ethynyl-, prop-l-ynyl- or prop-2-ynyl-.
The term "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. Preferably, each said halogen atom is fluorine, resulting in a group referred herein as "Ci-C6-fluoroalkyl-". Exemplary Ci-C6-fluoroalkyl- groups include, for example, -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CHF2, -CF2CF3, -CH2CF3, -CH2CH2CF3 and - CH(CH2F)2.
The term "C2-C6-haloalkenyl-" means a linear or branched hydrocarbon group in which one or more of the hydrogen atoms of a "C2-C6-alkenyl-" as defined supra are each replaced, identically or differently, by a halogen atom. Preferably, said halogen atom is fluorine, resulting in a group referred herein as "C2-C6-fluoroalkenyl-". Representative C2-C6-fluoroalkenyl- groups include, for example, -CH=CF2, -CF=CH2, -CF=CF2, -C(CH3)=CF2,
-CH=C(F)-CH3, -CH2-CF=CF2 and -CF2-CH=CH2.
The term "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.
The term "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.
The term "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. Preferably, 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, -OCF3, -OCHF2, -OCH2F, -OCF2CF3 and -OCH2CF3.
The term "C3-Cio-cycloalkyl-" means a saturated mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C3-Cio-cycloalkyl-")- Said C3-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-. Preferably, 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 ("C3-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. - -
The term "4- to 10-membered 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.
Preferably, 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, if present.
Exemplarily, without being limited thereto, 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 as azepanyl-, diazepanyl- or oxazepanyl-, for example. Preferred are the heterocycloalkyl moieties as disclosed in the example section, N-morpholinyl, N-piperazinyl and N-Methyl-piperazinyl.
The term "heterobicycloalkyl-" 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. Exemplary 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-.
The term "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 [3.3.1] nonyl-, thiazabicyclo[3.3.1]nonyl-, azabicyclo[4.2.1]nonyl-, diazabicyclo[4.2.1]nonyl-, oxazabicyclo [4.2.1] nonyl, thiazabicy clo [4.2.1] nonyl-, azabicyclo [3.3.2] decyl-, diazabicyclo[3.3.2]decyl-, oxazabicyclo[3.3.2]decyl-, thiazabicyclo[3.3.2]decyl-, or azabicyclo[4.2.2]decyl-.
The term "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. Exemplary 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-.
The term "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-, benzothiazolyl-, benzotriazolyl-, indazolyl-, indolyl- or isoindolyl-; or a benzo-fused 6-membered heteroaryl- group, such as, for example, quinolinyl-, quinazolinyl-, isoquinolinyl-, cinnolinyl-, phthalazinyl- or quinoxalinyl-; or another bicyclic group, - - such as, for example, indolizinyl-, purinyl- or pteridinyl-; or a tricyclic heteroaryl- group, such as, for example, carbazolyl-, acridinyl- or phenazinyl-.
Preferably, "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-.
In general, and unless otherwise mentioned, said heteroaryl- groups include all the possible isomeric forms thereof, e.g., the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridyl- includes pyridin-2-yl-, pyridin-3-yl- and pyridin-4-yl-; the term thienyl- includes thien-2-yl- and thien-3-yl-. Furthermore, said 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-. As used herein, 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. Preferably, a leaving group is selected from the group comprising: halo, in particular chloro, bromo or iodo, (methylsulfonyl)oxy-, [(4-methylphenyl)sulfonyl]oxy-,
[(trifluoromethyl)sulfonyl]oxy-, [(nonafluorobutyl)sulfonyl]oxy-, [(4-bromophenyl)sulfonyl]oxy-, [(4-nitrophenyl)sulfonyl]oxy-, [(2-nitrophenyl)sulfonyl]oxy-, [(4-isopropylphenyl)sulfonyl]oxy-, [(2,4,6-triisopropylphenyl)sulfonyl]oxy-, [(2,4,6-trimethylphenyl)sulfonyl]oxy-, [(4-ieri-butylphenyl)sulfonyl]oxy-, (phenylsulfonyl)oxy- and [(4-methoxyphenyl)sulfonyl]oxy-.
The term "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 , 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 C1-C2.
Similarly, as used herein, the term "C2-C6", as used throughout this text, e.g., in the context of the definitions of "C2-C6-alkenyl-" and "C2-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. It is to be understood further that said term "C2-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. Further, as used herein, the term "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. It is to be understood further that said term "C3-C7" is to be interpreted as disclosing any sub-range comprised therein, e.g., C3-C6 , C4-C5 , C3-C5 , C3-C4 , C4-C6, C5-C7 ; preferably C3-C6.
Should a residue be composed of several parts which were defined only separately in the section above it is to be understood that the respective parts of said residue are defined as shown above and connected by the bond as shown at any carbon atom of each respective part of the residue , e.g. (Ci- C3-alkoxy)-(Ci-C3-alkyl)- is not defined itself but both of its parts, "(Ci-C3-alkoxy)" and "(C1-C3- alkyl)" shall have the definition as shown above, with the understanding that the alkoxy group replaces a hydrogen atom of the alkyl group..
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
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 sp3 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. Examples of 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.
In order to delimit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
Further, the compounds of the present invention may exist as tautomers. For example, 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. -
Figure imgf000049_0001
1 H-tautomer 2H-tautomer 4H-tautomer
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. Examples of 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 2H (deuterium), 3H (tritium), UC, 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36C1, 82Br, 123I, 124I, 129I and 131I, respectively. Accordingly, recitation of "hydrogen" or "H" should be understood to encompass ¾ (protium), 2H (deuterium), and 3H (tritium) unless otherwise specified. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon- 14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, 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.
Further, 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. In the case of 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.
Furthermore, 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 (bioprecursors or pro-drugs) 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.
Further, 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.
The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see 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. However, 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, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2-naphthalenesulfonic, naphthalenedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.
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, ethylglucamine, 1,6-hexadiamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropanediol, Sovak base, and l-amino-2,3,4- butanetriol.
Additionally, 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. Examples of suitable 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.
Furthermore, 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. - -
General synthesis of compounds of general formula (I)
The following paragraphs outline a variety of synthetic approaches suitable to prepare compounds of the general formula (I), and intermediates useful for their synthesis.
In addition to the routes described below, also other routes may be used to synthesise the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis. The order of transformations exemplified in the following schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences. In addition, interconversion of any of the substituents, such as R1, R2, R3, R4 or R5, can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal catalysed coupling reactions, exemplified by but not limited to Suzuki, Sonogashira and Ullmann coupling, ester saponifications, amide coupling reactions, and/or substitution or other reactions known to a person skilled in the art. These transformations include those which introduce a functionality allowing for further interconversion of substituents. Appropriate protective groups and their introduction and cleavage are well-known to a person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 4th edition, Wiley 2006).
Specific examples of said interconversions are described in the subsequent paragraphs and in the experimental section, infra, e.g. for the elaboration of a sulfoximino group from a sulfoxide (see the protocols for Intermediates 149A and 151 A).
Figure imgf000052_0001
Scheme la: Preparation of compounds of general formula (I) from 3-aminomethyl pyridone derivatives of formula (II) and chloroimidazopyridine carboxylic acids of formula (III).
Compounds of general formula (I) can be readily prepared from chloroimidazopyridine derivatives of formula (IV), in which R1, R2, R3 and R4 are as defined for the compounds of general formula - -
(I), and boronic acid derivatives R5-B(OR)2 of formula (V), in which R5 is as defined for the compound of general formula (I), by means of a palladium catalysed Suzuki coupling reaction well known to the person skilled in the art, according to Scheme la. Said boronic acid derivatives of formula (V) may preferably be boronic acids (R = -H), or, also preferably, a cyclic ester, in which R-R together represent a -C2-C6-alkylene- group, more preferably a cyclic ester derived from pinacol in which the -B(OR)2 forms a -4,4,5,5-tetramethyl-l,3,2-dioxaborolane (R-R = -C(C¾)2- C(CH3)2-), or, alternatively, acyclic esters of said boronic acids, in which R represents a C1-C3- alkyl- group, e.g. an isopropyl ester (R = -CH(C]¾)2). Boronic acids and their esters are commercially available and well-known to the person skilled in the art; see e.g. D.G. Hall, Boronic Acids, 2005 WILEY- VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein; see also the protocols of Intermediates 150A and 152A for boronic acid esters featuring a sulfoximino group and which are not commercially available.
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 1375325-68-0, 2nd generation RuPhos precatalyst). 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. 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. 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 R1 and R2 are as defined for the compounds of general formula (I), and chloroimidazopyridine carboxylic acid derivatives of formula (III), in which R3 and R4 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-benzotriazole hydrate), in the presence of a base such as an aliphatic or aromatic tertiary amine, preferably a tertiary aliphatic amine of the formula N(Ci-C4-alkyl)3, in an appropriate solvent, e.g. -dimefhylformamide.
The preparation of amides from 3-aminomethyl pyridone derivatives of formula (II), in which R1 and R2 are as defined for the compounds of general formula (I), and chloroimidazopyridine carboxylic acid derivatives of formula (III), in which R3 and R4 are as defined for the compounds of general formula (I), can furthermore be accomplished, as well known to the person skilled in the art, by converting carboxylic acids of the formula (III) into the corresponding acyl halides, e.g. by reacting with a halogenating agent such as thionyl chloride, oxalyl chloride, or phosphoroxy chloride, and subsequent aminolysis using said 3-aminomethyl pyridone derivatives of formula (II).
Figure imgf000054_0001
Scheme lb: Preparation of compounds of general formula (I) from 3-aminomethyl pyridone derivatives of formula (II) and imidazopyridine carboxylic acids of formula (VI). - -
Vice versa, compounds of general formula (I) can also be assembled from 3-aminomethyl pyridone derivatives of formula (II), in which R1 and R2 are as defined for the compounds of general formula (I), and imidazopyridine carboxylic acid derivatives of formula (VI), in which R3, R4 and R5 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 HOBt (1-hydroxy- lH-benzotriazole hydrate), in the presence of a base such as an aliphatic or aromatic tertiary amine, preferably a tertiary aliphatic amine of the formula N(Ci-C4-alkyl)3, in an appropriate solvent.
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.
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.
Figure imgf000055_0001
- -
Figure imgf000056_0001
( Ilia )
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 R3 represents a hydrogen atom and in which R4 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 amine N(Ci-C3-alkyl)3, preferably triethylamine, in an aliphatic nitrile of the formula (Ci-C3-alkyl)-CN, preferably propionitrile, to give 4-chloro-6-methylpyridine-2-carbonitrile (IX). Said intermediate (IX) can be subsequently reacted with Grignard reagents of formula R4MgZ, in which Z represents chloro, bromo or iodo, and in which R4 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(C1¾)2) in the presence of a secondary amine RARANH, preferably pyrrolidine (in which RA and RA' 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 RE 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 carboxylic acids of formula (Ilia). Alternatively, the conversion of aldehydes of formula (XIV) into to the desired chloroimidazopyridine carboxylic acids of formula (Ilia) can be accomplished in one step by reaction with aqueous hydrogen peroxide in formic acid.
Figure imgf000057_0001
( XV ) ( XVI ) ( XVa )
Figure imgf000057_0002
( 1Mb )
Scheme 2b: Preparation of chloroimidazopyridine carboxylic acids of formula (Illb) from carboxylic esters of formula (XV).
Scheme 2b illustrates the preparation of chloroimidazopyridine carboxylic acids of formula (Illb), in which R3 represents a Ci-C3-alkyl- group, and in which R4 is as defined for the compounds of general formula (I) and which constitutes a further sub-set of formula (ΠΙ), from carboxylic esters of formula (XV), in which RE represents a Ci-C3-alkyl- group, preferably a methyl- group, and in which R4 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. using 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. EP 1792904) of formula (XVII), in which R3 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 R3 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 R3 represents a C1-C3- alkyl- group, or, depending on the work-up, their salts, e.g. lithium, sodium or potassium salts. Boroxine reagents of the formula (XVII) are well known to the person skilled in the art and commercially available in certain cases.
Figure imgf000058_0001
( Ill; Y = H )
( XV; Y = RE, R3 = H )
( XVa; Y = RE, R3 = Ci-Cs-alkyl )
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, - -
(XV) or (XVa), in which RE represents a Ci-C3-alkyl- group, and boronic acid derivatives R5- B(OR)2 of formula (V), in which R5 is as defined for the compound of general formula (I), and in which R represents a hydrogen atom or a Ci-C3-alkyl- group, or R-R together represent a -C2-C6- alkylene- group, by means of a palladium catalysed Suzuki coupling reaction well known to the person skilled in the art, according to Scheme 2c, in an analogous fashion as described for the conversion of chloroimidazopyridine derivates of formula (IV) into compounds of general formula (I) in context of Scheme la, supra. If 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.
Figure imgf000059_0001
Scheme 3a: Preparation of 3-aminomethyl pyridone intermediates of formula (Ila) from α,β- unsaturated ketones of formula (XIX). Scheme 3a illustrates the synthesis of 3-aminomethyl pyridone intermediates of formula (Ila), in which Rl represents a group selected from the groups representing R1 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 R2 represents a Ci-C3-alkyl- group, and their salts, e.g. hydrochloride, hydrobromide or trifluoroacetate salts, preferably hydrochloride salts, from α,β-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). 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. Depending on the substituents Rl and R2, concomitant formation of regioisomers of formula (XXIa) may occur. 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. Preferably, the intermediates of formula (Ila) are isolated as hydrochloride salts.
The α,β-unsaturated ketones of formula (XIX) used as starting material are well known to the person skilled in the art and commercially available in certain cases, see also Scheme 4a for less common starting materials of formula (XIX).
Figure imgf000060_0001
( XXIII )
Figure imgf000060_0002
Scheme 3b: Preparation of 3-aminomethyl pyridone intermediates of formula (lib) from β- diketones of formula (XXII). - -
Scheme 3b illustrates the synthesis of 3-aminomethyl pyridone intermediates of formula (lib), in which Rlb represents a group selected from the groups representing R1 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 R2 represents a Ci-C3-alkyl- group, and their salts, e.g. hydrochloride, hydrobromide or trifluoroacetate salts, preferably hydrochloride salts, from β-diketones of formula (XXII), which can be reacted with 2- cyanoacetamide (XX), 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, to give 2- oxo-l,2-dihydropyridine-3-carbonitriles of formula (XXIII), which can be further converted into 3- aminomethyl pyridone intermediates of formula (Kb) in a similar fashion as described in Scheme 3a, supra.
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. Preferably, the intermediates of formula (lib) are isolated as hydrochloride salts.
The β-diketones of formula (XXII) used as starting material are well known to the person skilled in the art and commercially available in certain cases, see also Scheme 4b for less common starting material of formula (XXII).
Figure imgf000061_0001
( XXVII ) ( xviii ) ( IXXX )
Figure imgf000061_0002
Scheme 3c: Preparation of 3-aminomethyl pyridone intermediates of formula (lie) from ethyl 2,4- - - dihydroxynicotinate (XXIV).
Various routes are suitable for the preparation of 3-aminopyridone intermediates of formula (lie), in which Rlc represents a group selected from the groups representing R1 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)-(L1)- group in which L1 represents -CH2O- or -0-, and in which R2 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 Rlc represents e.g. a Ci-C3-alkyl-, C3-C7-cycloalkyl-, C3-C7-cycloalkylmethyl- or Ci-C3-haloalkyl- group, and in which LG represents a leaving group as defined herein, preferably bromo, iodo or [(trifluoromethyl)sulfonyl]oxy-, to give intermediates of formula (XXVII). Reduction of the carboxylic ester present in compounds of formula (XXVII) by methods known to the person skilled in the art, e.g. using lithium aluminium hydride in tetrahydrofuran or sodium bis(2-methoxyethoxy)aluminium dihydride in toluene, can be used to obtain the corresponding hydroxymethyl pyridine derivatives of formula (XXVIII), which can be readily converted into the corresponding azides of formula (IXXX) via intermediate mesylates by reacting compounds of formula (XXVIII) with methanesulfonyl chloride in the presence of a base such as triethylamine or -diisopropylethylamine, in dichloromethane as a solvent, followed by work-up and subsequent reaction with sodium azide in -dimefhylformamide. 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-C2-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. - -
Figure imgf000063_0001
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 (POCI3) 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. with hydrogen gas in the presence of Raney Nickel, triethylamine as a base and di-ieri-butyl dicarbonate (B0C2O) in a mixture of tetrahydrofuran and methanol as a solvent, to give 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. - -
Figure imgf000064_0001
Figure imgf000064_0002
Scheme 3e: Preparation of 3-aminomethyl pyridone intermediates of formula (lie) from 2,4-dichloro-6-methylnicotinonitrile (XXXIII) .
As a further alternative, Scheme 3e outlines the synthesis of 3-aminomethylpyridone intermediates of formula (He) starting from 2,4-dichloro-6-methylnicotinonitrile (XXXIII). Selective hydrolysis of 4-Cl can be achieved under suitable conditions, e.g. using potassium acetate in N,N- dimethylformamide at a temperature of 80°C to give hydroxypyridine (XXXVI), which can be converted into monomethyl ether (XXXVII), allowing for the elaboration of Rlc, either by standard alkylation reactions analogous to the conversion of (XXV) into (XXVII) in Scheme 3c, or, if mandated by the nature or the respective Rlc, by specific methodology such as the use of ethyl 2- chloro-2,2-difluoroacetate and sodium hydride in -dimethylformamide for the elaboration of Rlc = F2HC-O- (see also protocol of Intermediate 135A). The further conversion into 3- aminomethylpyridone intermediates of formula (He) can be accomplished via carbamate (XXXVIII) using the methods outlined in Scheme 3d for the conversion of intermediates of formula (XXXIV) into 3-aminomethyl pyridone intermediates of formula (He), which are preferably isolated as hydrochloride salt.
- -
Figure imgf000065_0001
( XL )
( XIX )
Figure imgf000065_0002
(XXXIX)
Scheme 4a: Preparation of α,β-unsaturated ketones of formula (XIX) from carboxylic esters of formula (XXXIX).
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 Rl represents e.g. a Ci-C3-alkyl-, C1-C3- haloalkyl- or benzyl- group, and in which RE 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. reduction with sodium borohydride, lithium borohydride or lithium aluminium hydride, followed by oxidation with Dess-Martin's reagent or tetrapropyl perruthenate / /V-methylmorpholine -oxide). Said aldehydes can be subjected to a Wittig olefination using phosphoranes of formula (XLI), in which R2 represents a Ci-C3-alkyl- group, to give α,β- unsaturated ketones of formula (XIX). Alternatively, carboxylic esters of formula (XXXIX) can be directly converted into α,β-unsaturated ketones of formula (XIX) by reaction with methyl ketones of formula (XLII), in which R2 represents a Ci-C3-alkyl- group, in the presence of an alkali amide, e.g. sodium amide.
Figure imgf000065_0003
( XLII )
Scheme 4b: Preparation of β-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 Rlb represents e.g. a (Ci-C3-alkoxy)-(Ci-C3- alkyl)- or Ci-C3-haloalkyl- group, and in which RE represents a Ci-C3-alkyl- group, with sodium metal in toluene, followed by a methyl ketone of formula (XLII). In accordance with another aspect, the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
In a preferred embodiment, the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate compound of formula (IV)
Figure imgf000066_0001
( IV )
in which R1, R2, R3, and R4 are as defined for the compounds of general formula (I), supra; is allowed to react with a compound of formula (V) :
R-0
B-R
R-0
( V ) in which R5 is as defined for the compounds of general formula (I), supra, and in which R represents a hydrogen atom or a Ci-C3-alkyl- group, or R-R together represent a -C2-C6-alkylene- group, thus providing a compound of general formula (I) : - -
Figure imgf000067_0001
( I )
in which R1, R2, R3, R4, and R5 are as defined for the compounds of general formula (I),
In another preferred embodiment, the present invention relates to a method of preparing compounds of general formula (I), supra; in which method an intermediate compound of formula (VI):
Figure imgf000067_0002
( VI ) in which R3, R4, and R5 are as defined for the compounds of general formula (I), supra; is allowed to react with a compound of formula (II):
Figure imgf000067_0003
in which R1 and R2 are as defined for the compounds of general formula (I), supra; thus providing a compound of general formula (I): - -
Figure imgf000068_0001
( I )
in which R1, R2, R3, R4, and R5 are as defined for the compounds of general formula (I), supra.
In accordance with a further aspect, 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.
In particular, the present invention relates to intermediate compounds of formula (IV):
Figure imgf000068_0002
( IV ) in which R1, R2, R3, and R4 are as defined for the compounds of general formula (I), supra; as well as to the use and a method of using intermediate compound (IV) for the preparation of compounds of general formula (I).
In another preferred embodiment, 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.
In particular, the present invention further covers compounds of formula (VI): - -
Figure imgf000069_0001
( VI ) in which R3, R4, and R5 are as defined for the compounds of general formula (I), supra; as well as to the use and the method of using intermediate compound (VI) for the preparation of compounds of general formula (I). In accordance with yet another aspect, the present invention relates to the use and a method of using of the intermediate compounds of formula (IV):
Figure imgf000069_0002
( IV ) in which R1, R2, R3, and R4 are as defined for the compounds of general formula (I), supra; for the preparation of a compound of general formula (I) as defined supra.
In another preferred embodiment, the present invention covers the use and a method of using of the intermediate compounds of formula (IV):
Figure imgf000069_0003
( VI ) in which R3, R4, and R5 are as defined for the compounds of general formula (I), supra; for the preparation of a compound of general formula (I) as defined supra. - -
Utility
As discussed in the introduction it has been shown for various tumor types that tumor progression and survival seems to be dependent on PRC2 activation. And thus there is strong evidence that inhibition of EZH2 methylation activity activity as being a part of the PRC2 complex modulates gene expression and inhibits cell proliferation. PRC2 is widely considered a valuable target for tumor therapy. Consequently compounds inhibiting EZH2 would be useful for the treatment of hyperproliferative disorders, especially in the case of neoplastic disorders, more especially cancer.
The compounds according to general formula (I) have valuable pharmaceutical properties which make them commercially utilizable. In particular 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).
Thus 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. Thus another aspect of the invention is the use of the compounds of formula (I) for prophylaxis and/or treatment of hyperproliferative diseases, especially for treatment of hyperproliferative diseases.
As used herein, "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.
Thus a further aspect is that 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.
Thus 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).
In accordance with the invention 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 Retinoblastoma and Wilms tumor.
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.
In still another aspect, 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.
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. Examples of 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. Examples of mutations of SWI/SNF chromatin remodeling complex genes are 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).
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.
Advantageously, 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. Thus 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).
Particularly advantageously, the compounds of formula (I) can be used for prophylaxis and/or treatment of Breast cancer.
Thus 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).
Particularly advantageously, 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.
Pharmaceutical Compositions A further aspect of the invention are pharmaceutical 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.
Thus in another aspect 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.
Furthermore, 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. Illustrative examples of 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. For these administration routes, it is possible to administer the compounds according to the invention in suitable application forms.
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.
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.
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. These 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, emulsifiers, dispersants or wetters (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, 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, gel formers, thickeners and/or 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®)),
• flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),
• coating materials (for example sugar, shellac) and 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),
• 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),
· penetration enhancers,
• stabilisers (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, 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.
When 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.
Regardless of the route of administration selected, 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.
For example, the compounds of formula (I) can be combined with known antihyperproliferative, cytostatic or cytotoxic chemical and biological substances for treatment of cancer. The combination of the compounds of formula (I) with other substances commonly used for cancer treatment, or else with radiotherapy, is particularly appropriate.
The term "combination" in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of-parts.
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. One example of 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. One example of 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.
The term "(chemotherapeutic) anti-cancer agents", includes but is not limited to
(i) alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®), Ifosfamid (Holoxan®), Thiotepa (Thiotepa Lederle®), Melphalan (Alkeran®), or chloroethylnitrosourea (BCNU);
(ii) platinum derivatives like cisplatin (Platinex® BMS), oxaliplatin (Eloxatin®), satraplatin or carboplatin (Cabroplat® BMS);
(iii) antimitotic agents / tubulin inhibitors such as vinca alkaloids (vincristine, vinblastine,
vinorelbine), 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
(Patupilone®), Azaepothilone (Ixabepilone®) or Sagopilone;
(iv) 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 /
Hycamtin®);
(v) pyrimidine antagonists such as 5-fluorouracil (5-FU), Capecitabine (Xeloda®),
Arabinosylcytosine / Cytarabin (Alexan®) or Gemcitabine (Gemzar®);
(vi) purine antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanine or fludarabine (Fludara®) and
(vii) folic acid antagonists such as methotrexate (Farmitrexat®) or premetrexed (Alimta®).
The term "target specific anti-cancer agent", includes but is not limited to
(i) kinase inhibitors such as e.g. Imatinib (Glivec®), ZD- 1839 / Gefitinib (Iressa®), Bay43-9006 (Sorafenib, Nexavar®), SU11248 / Sunitinib (Sutent®), OSI-774 / Erlotinib (Tarceva®),
Dasatinib (Sprycel®), Lapatinib (Tykerb®), or, see also below, Vatalanib, Vandetanib (Zactima®) or Pazopanib;
(ii) proteasome inhibitors such as PS-341 / Bortezomib (Velcade®);
(iii) histone deacetylase inhibitors like SAHA (Zolinza®), PXDIOI, MS275, MGCD0103, Depsipeptide / FK228, NVP-LBH589, Valproic acid (VPA), CRA / PCI 24781, ITF2357,
SB939 and butyrates
(iv) heat shock protein 90 inhibitors like 17-allylaminogeldanamycin (17-AAG) or 17- dimethylaminogeldanamycin ( 17-DMAG) ;
(v) vascular targeting agents (VTAs) like combretastin A4 phosphate or AVE8062 / AC7700 and 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;
(vi) monoclonal antibodies such as Trastuzumab (Herceptin®), Rituximab (MabThera /
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;
(vii) oligonucleotide based therapeutics like G-3139 / Oblimersen (Genasense®) or the DNMTl inhibitor MG98;
(viii) Toll-like receptor / TLR 9 agonists like Promune®, TLR 7 agonists like Imiquimod
(Aldara®) or Isatoribine and analogues thereof, or TLR 7/8 agonists like Resiquimod as - - well as immunostimulatory RNA as TLR 7/8 agonists;
(ix) protease inhibitors; (x) hormonal therapeutics such as anti-estrogens (e.g. Tamoxifen or
Raloxifen), anti-androgens (e.g. Flutamide or Casodex), LHRH analogs (e.g. Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors (e.g. Femara, Arimedex or Aromasin). Other "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-γ, 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).
Specific examples of 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, bortezomib, buserelin, bosutinib, Brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib , crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, Iasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, - - lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methyl aminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, p53 gene therapy, paclitaxel, palifermin, palladium- 103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium- 186 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]- octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin..
In another aspect, 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. More particularly, 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. - -
Combinations with antihormones and steroidal metabolic enzyme inhibitors may also be suitable.
Generally, the following aims can be pursued with the combination of the inventive compounds with other cytostatically or cytotoxically active agents:
• improved efficacy in slowing the growth of a tumour, in reducing its size or even in completely eliminating it, compared with treatment with an individual active ingredient;
• the possibility of using the chemotherapeutics used in a lower dosage than in the case of monotherapy;
• the possibility of a more tolerable therapy with fewer side effects compared with individual administration; · the possibility of treatment of a broader spectrum of neoplastic disorders;
• the attainment of a higher rate of response to the therapy;
• a longer survival time of the patient compared with present standard therapy.
In addition, the compounds of the invention can also be used in conjunction with radiotherapy and/or surgical intervention.
Experimental Section
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. If not stated otherwise, silica gel has been used herein as stationary phase in flash chromatography. In some cases, 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.
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. Examples of 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.
In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HC1", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form.
This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition.
The IUPAC names of the examples and intermediates were generated using the program 'ACD/Name batch version 12.01 ' from ACD LABS, and were adapted if needed. - -
General Methods - UPLC and HPLC conditions
UPLC Conditions 1.1 - "short-basic" Column: XBridge BEH CI 8 2.5 μιη, 2.1 mm x 50 mm
Eluent: A: 10 mM aqueous ammonium hydrogen carbonate (pHIO); B: acetonitrile
Gradient: 0 - 1.0 min 2-98% B, 1.0 - 1.2 min 98% B
UPLC Conditions 1.2 - "short-basic"
Column: XBridge CI 8 2.5 μιη, 2.1 mm x 20 mm IS
Eluent: A: 10 mM aqueous ammonium hydrogen carbonate (pHIO); B: acetonitrile
Gradient: 0 - 2.0 min 0-95% B, 2.0 - 2.6 min 95% B LCMS Conditions 2.1:
Instrument: Waters Acquity LCT
Column: Phenomenex Kinetex C18 2.6 μιη, 50 mm x 2.1 mm
Eluents: A: 0.05% aqueous formic acid; B: acetonitrile + 0.05% formic acid
Gradient: 0 - 0.2 min 98% A, 0.2 - 1.7 min: 98-10% A, 1.7 - 1.9 min 10% A, 1.9 - 2.0 min: 10- 98% A, 2.0 - 2.5 min 98% A; flow: 1,3 ml/min; temperature: 60°C; UV detection: 200-400 nm.
LCMS Conditions 2.2: Instrument: Waters Acquity Platform Agilent
Column: Waters BEHC 18 1,7 μιη, 50 mm x 2,1 mm
Eluents: A: 0.05% aqueous formic acid; B: acetonitrile + 0.05% formic acid
Gradient: 0 - 0.2 min 98% A, 0.2 - 1.7 min: 98-10% A, 1.7 - 1.9 min 10% A, 1.9 - 2.0 min: 10-
98% A, 2.0 - 2.5 min 98% A; flow: 1,3 ml/min; temperature: 60°C; UV detection: 200-400 nm.
LCMS Conditions 2.3:
Instrument: Waters Acquity Platform SQD
Column: Waters BEHC 18 1,7μιη, 50 mm x 2,1 mm
Eluents: A: 0.05% aqueous formic acid; B: acetonitrile + 0.05% formic acid
Gradient:
0 - 0.2 min 98% A, 0.2 - 1.7 min: 98-10% A, 1.7 - 1.9 min 10% A, 1.9 - 2.0 min: 10- 98% A, 2.0 - 2.5 min 98% A; flow: 1,3 ml/min; temperature: 60 °C; UV detection: 200-400 nm. - -
LCMS Conditions 2.4:
Instrument: UPLC Acquity (Waters) with PDA Detector und Waters ZQ mass spectrometer Column: Acquity BEH CI 8 1.7 μηι 2.1 mm x 50 mm
Eluents: A: 0.1 % aqueous formic acid; B: acetonitrile
Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow: 0.8 ml/min;
Temperature: 60°C; UV detection: 210-400 nm LCMS Conditions 2.5
Instrument: Waters Acquity UPLC-MS SQD
Column: Acquity UPLC BEH C18 1.7 μηι 50 mm x 2.1 mm
Eluents: A: 0.1 % aqueous formic acid; B: acetonitrile
Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min
Temperature: 60 °C; UV detection: 210-400 nm
LCMS Conditions 2.6
Instrument: Waters Acquity UPLC-MS SQD
Column: Acquity UPLC BEH CI 8 1.7 μιη 50 mm x 2.1 mm
Eluents: A: water + 0.2% aquous ammonia (32%); B: acetonitrile
Gradient: 0 - 1.6 min 1-99% B, 1.6 - 2.0 min 99% B; flow: 0.8 ml/min
Temperatur: 60 °C; UV detection: 210-400 nm.
Preparative HPLC conditions 1 (acidic)
Instrument: Waters Autopurificationsystem SQD
Column: Waters XBrigde CI 8 5μιη 100x30mm
Eluents: A: 0.1% aqueous formic acid; B: acetonitrile
Gradient: 0,00 - 0.50 min 5% B (25ml/min), 0.51 - 5.50 min 10-100% B (70 ml/min), 5.51 - 6.50 min 100% B (70 ml/min); temperature: Rt; UV detection: 210-400 nm
Preparative HPLC conditions 2 (basic)
Instrument: Waters Autopurificationsystem SQD
Column: Waters XBrigde CI 8 5μιη 100x30mm
Eluents: A: water + 0.2% aqueous ammonia (32%); B: acetonitrile
Gradient: 0.00 - 0.50 min 5% B (25mL/min), 0.51 - 5.50 min 10-100% B (70 mL/min), 5.51 - 6.50 min 100% B (70 mL/min); temperature: Rt; UV detection: 210-400 nm
The following table provides a list of abbreviations used in the experimental part.
Figure imgf000087_0001
Synthesis of Intermediates - Part 1 - Imidazopyridine cores Synthesis of 7-Chloro-l-(propan-2-yl)imidazo[l,5-a]pyridine-5-carboxylic acid 8A (Scheme A) - -
Figure imgf000088_0001
Intermediate 1A - 4-Chloro-2-methylpyridine 1-oxide
Figure imgf000088_0002
A mixture of 2-methyl-4-nitropyridine 1-oxide (CAS 696-08-2, 168.0 g, 1.09 mol), sodium chloride (191 g, 3.27 mol), cone, aqueous hydrochloric acid (400 ml) and benzyltributylammonium chloride (3.4 g, 11.0 mmol) in acetonitrile (1.7 1) was stirred at reflux for 72 h. The reaction mixture was cooled to -10 °C and basified by the addition of aqueous sodium hydroxide (220 g in 300 ml) whilst maintaining a temperature of < 10 °C. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 750 ml). The dichloromethane layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was crystallized from 2-propanol, the crystals were filtered off to give unreacted starting material. The mother liquors were concentrated and the residue was purified by flash chromatography (silicagel, 0-15% methanol in ethyl acetate) to give intermediate 1A (128.6 g). - -
H NMR (400 MHz, CDC13) δ [ppm] = 8.16 (d, 1H), 7.25 (d, 1H), 7.12 (dd, 1H), 2.48 (s, Intermediate 2A - 4-Chloro-6-methylpyridine-2-carbonitrile
Figure imgf000089_0001
To a solution of intermediate 1A (128.0 g, 889 mmol) and triethylamine (260 ml) in propionitrile (1.5 1) was added trimethylsilyl cyanide (334 ml, 2.67 mol). The mixture was stirred at reflux for 26 h then left to stand at room temperature for 18 h. The reaction was quenched by the addition of 30% aqueous potassium carbonate solution and the layers were separated. The organic layer was washed with 10% aqueous potassium carbonate solution, brine, dried over magnesium sulfate, filtered and concentrated. The resulting dark solid was recrystallized from hot isopropanol (150 ml) and water (300 ml) to give intermediate 2A (114.3 g, 84%).
¾ NMR (400 MHz, CDC13) δ [ppm] = 7.51 (d, 1H), 7.39 (d, 1H), 2.59 (s, 3H). Intermediate 3A - rac-l-(4-Chloro-6-methylpyridin-2-yl)-2-methylpropan-l-amine
Figure imgf000089_0002
To a solution of intermediate 2A (114 g, 745 mmol) in tetrahydrofuran (1.5 1) was added isopropyl magnesium chloride (2M, 0.48 1, 968 mmol) dropwise, at -78 °C. After the addition was complete the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then cooled to 0 °C and methanol (0.5 1) was added over a period of 10 min. The mixture was then warmed to room temperature and sodium borohydride (16.9 g, 447 mmol) was added portion wise over a period of 30 min. The mixture was then stirred at room temperature for 18 h and the reaction was then stopped by the addition of ice. The mixture was concentrated; then, dichloromethane was - - added followed by celite. The mixture was filtered, washed with dichloromethane and the layers separated. The organic layer was dried and concentrated. The residue was purified by flash chromatography (0-15% methanol in ethyl acetate) to give intermediate 3A (78.5 g, 53%) as a black oil.
¾ NMR (400 MHz, CDC13) δ [ppm] = 7.07 (d, 1H), 7.00 (d, 1H), 3.64 (d, 1H), 2.47 (s, 3H), 2.02 (sept, 1H), 1.68 (bs, 2H), 0.91 (d, 3H), 0.82 (d, 3H).
Intermediate 4A - rac-N-[l-(4-Chloro-6-methylpyridin-2-yl)-2-methylpropyl]formamide
Figure imgf000090_0001
A mixture of intermediate 3A (78.5 g, 394 mmol) and ethyl formate (200 ml) was heated at reflux for 2 h then cooled to room temperature. The mixture was concentrated and subjected to repeated azeotropic distillation with toluene to give intermediate 4A (87.0 g, 97%) as a dark oil.
¾ NMR (300 MHz, CDC13) δ [ppm] = 8.27 (s, 1H), 7.05 (s, 1H), 7.00 (s, 1H), 4.88 (m, 1H), 2.50 (s, 3H), 2.11 (sept., 1H), 0.92 (d, 3H), 0.84 (d, 3H). Intermediate 5A - 7-Chloro-5-methyl-l-(propan-2-yl)imidazo[l,5-a]pyridine
Figure imgf000090_0002
To a solution of intermediate 4A (87.0 g, 383 mmol) in toluene (800 ml) was added phosphorus oxy chloride (POCI3; 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.
¾ NMR (300 MHz, CDC13) δ [ppm] = 7.91 (s, 1H), 7.34 (s, 1H), 6.31 (s, 1H), 3.26 (sept., 1H), 2.51 (s, 3H), 1.37 (d, 6H).
Intermediate 6A - 7-Chloro-l-(propan-2-yl)-5-[(E)-2-(pyrrolidin-l-yl)ethenyl]imidazo[l,5- alpyridine
Figure imgf000091_0001
A mixture of intermediate 5A (76.0 g, 364 mmol), pyrrolidine (91 ml, 1.09 mol) and N,N- dimethylformamide dimethyl acetal (96 ml, 727 mmol) was stirred at reflux for 18 h. The mixture was cooled and added to ice-cold water (1.5 kg). The mixture was stirred for 1 h. The resulting solid was filtered, triturated with diethyl ether and dried to give intermediate 6A (102.8 g, 97%).
H NMR (400 MHz, CDC13) δ [ppm] = 8.00 (s, 1H), 7.32 (d, 1H), 7.06 (d, 1H), 6.24 (d, 1H), 4.91 (s, 1H), 4.87 (m, 4H), 3.33 (m, 4H), 3.20 (sept., 1H), 1.34 (d, 6H).
Intermediate 7A - 7-Chloro-l-(propan-2-yl)imidazo[l,5-a]pyridine-5-carbaldehyde
Figure imgf000091_0002
To a solution of intermediate 6A (83.8 g, 289 mmol) in tetrahydrofuran (1.5 1) and water (300 ml) was added sodium periodate (123.7 g, 578 mmol) portionwise, at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 3 h. The mixture was then filtered through a pad of celite, and the filter cake was then washed thoroughly with ethyl acetate. The - - filtrate was concentrated and the residue was poured into saturated aqueous sodium bicarbonate solution (1.0 1), which was subsequently extracted with ethyl acetate (3 x 500 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (20% ethyl acetate in heptane) to give intermediate 7A (34.7 g, 54%).
¾ NMR (400 MHz, CDC13) δ [ppm] = 9.79 (s, 1H), 9.35 (s, 1H), 7.79 (s, 1H), 7.23 (s, 1H), 3.32 (sept, 1H), 1.39 (d, 6H). Intermediate 8A - 7-Chloro-l-(propan-2-yl)imidazo[l,5-a]pyridine-5-carboxylic acid
Figure imgf000092_0001
To a solution of intermediate 7A (14.0 g, 62.9 mmol) in formic acid (280 ml) was added 50% aqueous hydrogen peroxide (4.5 ml, 66.0 mmol) dropwise at 5 °C over a period of 15 min. The mixture was then allowed to warm to room temperature and stirred for 18 h - during the day the reaction mixture was cooled occasionally to keep temperature below 22 °C as the reaction was slightly exothermic. The mixture was then cooled to 5 °C and carefully quenched by the addition of brine (300 ml) (an exothermia was observed on small scale when the brine was added in one portion at room temperature which subsequently reduced the yield). The mixture was then extracted with chloroform/2-isopropanol (7:3 mixture, 1 x 500 ml and 2 x 250 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give a brown solid which was triturated with diethyl ether, filtered, washed and dried to give intermediate 8A as a brown/green solid (14.5 g, 97%).
¾ NMR (400 MHz, DMSO-d6) δ [ppm] = 9.60 (s, 1H), 8.35 (s, 1H), 7.61 (s, 1H), 3.51 (sept, 1H), 1.29 (d, 6H).
Synthesis of lithium 7-chloro-3-methyl-l-(propan-2-yl)imidazo[l,5-a]pyridine-5-carboxylate 12A
(Scheme B) - -
Figure imgf000093_0001
1 1 A 12A
Scheme B Intermediate 9A - Methyl 7-chloro-l-(propan-2-yl)imidazo[l,5-a]pyridine-5-carboxylate
Figure imgf000093_0002
To 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). ¾ NMR (400 MHz, CDC13) δ [ppm] = 1.39 (d, 6H), 3.29 (sept, 1H), 4.00 (s, 3H), 7.49 (d, 1H), 7.68 (d, 1H), 9.20 (s, 1H).
UPLC-MS (conditions 1.1): Rt = 0.84 min, 94%. MS (ESIpos): m/z = 253 (M+H)+. - -
Methyl 3-bromo-7-chloro-l-(propan-2-yl)imidazo[l,5-a]pyridine-5-
Figure imgf000094_0001
To intermediate 9A (1.15 g, 4.55 mmol) in DMF (11.5 ml) was added /V-bromosuccinimide (0.81 g, 4.55 mmol) and the reaction mixture was stirred for 2 h. Brine (10 ml) was added and the product extracted into ethyl acetate (3 x 20 ml). The organic layer was washed with saturated sodium hydrogen carbonate solution (20 ml) and dried over sodium sulfate, filtered and the solvent removed to yield a black oil. Purification by dry flash chromatography was performed (eluent: 1 :4 ethyl acetate/heptanes) to yield intermediate 10A as a yellow oil, 1.15 g (76%).
H NMR (400 MHz, CDC13) δ [ppm] = 1.34 (d, 6H), 3.20 (sept, 1H), 4.00 (s, 3H), 6.89 (d, 1H), 7.50 (d, 1H).
UPLC-MS (conditions 1.1): Rt = 0.91 min, 91.16%. MS (ESIpos): m/z = 333 (M+H)+.
Intermediate 11A - Methyl 7-chloro-3-methyl-l-(propan-2-yl)imidazo[l,5-a]pyridine-5- carboxylate
Figure imgf000094_0002
To intermediate 10A (1.15 g, 3.47 mmol) in degassed dioxane (20 ml) was added water (125 μΐ, 6.94 mmol), sodium carbonate (368 mg, 6.94 mmol), tetrakis(triphenylphosphine)palladium(0) (400 mg, 0.347 mmol) and trimethylboroxine (970 μΐ, 6.94 mmol). The reaction mixture was heated at 110 °C (oil bath temperature) under argon for 18 h. The reaction mixture was cooled to room temperature then brine solution (20 ml) was added and the crude product was extracted with ethyl acetate (3 x 50 ml). The organic layers were combined, dried over sodium sulfate, filtered and the solvent evaporated in vacuo to yield a crude orange oil which was purified by flash - - chromatography (eluent: 1 :9, 1 :4, 1 :3 ethyl acetate/heptanes) to yield intermediate 11A as a yellow oil, 538 mg (58%).
¾ NMR (400 MHz, CDC13) δ [ppm] = 1.35 (d, 6H), 2.52 (s, 3H), 3.22 (sept, 1H), 3.98 (s, 3H), 7.02 (d, 1H), 7.52 (d, 1H).
UPLC-MS (conditions 1.2): Rt = 1.96 min, 95%. MS (ESIpos): m/z = 267 (M+H)+.
Intermediate 12A - Lithium 7-chloro-3-methyl-l-(propan-2-yl)imidazo[l,5-a]pyridine-5- carboxylate
Figure imgf000095_0001
To Iintermediate 11A (538 mg, 2.02 mmol) in tetrahydrofuran (5 ml) was added lithium hydroxide (93 mg, 2.22 mmol) in water (5 ml). The reaction mixture was stirred for 1 hour, then the solvent was evaporated in vacuo to give intermediate 12A as a straw coloured solid, 530 mg (96 %).
H NMR (400 MHz, DMSO) δ [ppm] = 1.19 (d, 6H), 2.49 (s, 3H), 3.18 (sept, 1H), 6.10 (d, 1H), 7.36 (d, 1H).
UPLC-MS (conditions 1.2): Rt = 1.41 min, >90%. MS (ESIpos): m/z = 253 (M+H)+. Synthesis of rac-l-sec-butyl-7-chloroimidazo[l,5-a]pyridine-5-carboxylic acid - intermediate
19A
(Scheme C)
- -
Figure imgf000096_0001
Scheme C
Intermediate 13A - l-(4-chloro-6-methylpyridin-2-yl)-2-methylbutan-l-amine
Figure imgf000096_0002
4-chloro-6-methylpyridine-2-carbonitrile (CAS 104711-65-1, 45 g, 295 mmol) was dissolved in tetrahydrofuran (700 ml). The mixture was cooled to -60°C and isobutyl magnesium chloride solution (25% w/w in THF, 180 g, 384 mmol) was added dropwise. The mixture was stirred for two hours at room temperature. The mixture was adjusted to 0 °C and methanol (230 ml) was added dropwise. Sodium borohydride (7 g, 177 mmol) was added to the mixture portionwise. The solution was stirred one hour at 0 °C. The solution was poured into an ice/water mixture (1.3 1) and the mixture was stirred overnight at room temperature. Dichloromethane (1.5 1) was added and the resulting emulsion was filtered over Celite. The aqueous layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a black oil (62.2 g). The crude product was purified by column chromatography to give several batches of the - - expected product as in a combined yield of 50% as a mixture of diastereomers.
H NMR (300 MHz, CDC13) δ [ppm] = 7.28 (s, 1H), 7.03 (s, 1H), 3.85 (isomer 1) and 3.73 (isomer 2) (d, 1H), 2.51 (s., 3H), 1.70 - 1.90 (isomer 1) and 1.11 - 1.29 (isomer 2) (m, 2H), 1.52 - 1.67 (isomer 2) and 1.33 - 1.49 (isomer 1) (m, 1 H), 0.80 - 1.01 (m, 3H), 0.74 - 0.88 (m, 3H).
Intermediate 14A - rac-N-[l-(4-chloro-6-methylpyridin-2-yl)-2-methylbutyl]formamide
Figure imgf000097_0001
l-(4-chloro-6-methylpyridin-2-yl)-2-methylbutan-l -amine (intermediate 13A) (31.5 g, 148 mmol) was mixed with formic acid (83.7 ml, 2.2 mol) and the solution was heated at 100°C for 1 h. The mixture was allowed to cool to room temperature and concentrated to dryness. The resulting product was co-evaporated twice with toluene. A mixture of dichloromethane (400 ml) and an aqueous saturated sodium bicarbonate solution (400 ml) were added. The mixture was stirred until gas evolution had ceased. The organic layer was collected and the aqueous phase was further extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the expected product (31.5 g, 88%), which was used in the subsequent step without further purification. Intermediate 15A - rac-l-sec-butyl-7-chloro-5-methylimidazo[l,5-a]pyridine
Figure imgf000097_0002
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 mixture was stirred until gas evolution had ceased. The organic layer was collected and the aqueous phase was further extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give a brown oil (29.5 g). The product was purified by column chromatography - -
(silica gel, gradient heptane/ethyl acetate) to give the expected product (22.8 g, 78%).
H NMR (300 MHz, CDC13) δ [ppm] = 7.95 (s, 1H), 7.34 (s, 1H), 6.32 (s, 1H), 2.91 - 3.03 (m., 1H), 2.57 (s, 3H), 1.66 - 1.90 (m, 2 H), 1.37 (d, 3H), 0.82 (t, 3 H).
Intermediate 16A - rac-l-sec-butyl-7-chloro-5-[(E)-2-(pyrrolidin-l-yl)vinyl]imidazo[l,5- a] pyridine
Figure imgf000098_0001
l-sec-butyl-7-chloro-5-methylimidazo[l,5-a]pyridine (intermediate 15A) (10.33 g, 47 mmol) was dissolved in a mixture of dimethylformamide dimethylacetal (12.6 ml, 94 mmol) and pyrrolidine (11.5 ml). The solution was stirred at reflux temperature for 20 hours. The solution was poured into an ice/water mixture and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give a crude product. The product was triturated in diisopropyl ether at room temperature. The filtrate was concentrated and the resulting solid was triturated in diisopropyl ether at 0 °C. The solid was dried to give the expected product (10.56 g, 74%).
¾ NMR (300 MHz, CDC13) δ [ppm] = 8.05 (s, 1H), 7.32 (d, 1H), 7.06 (d, 1H), 6.25 (d, 1H), 4.93 (d, 1H), 3.36 (m, 4H), 2.96 (m, 1H), 2.00 (m, 4 H), 1.70 - 1.90 (m, 2 H), 1.36 (d, 3H), 0.82 (t, 3 H).
Intermediate 17A - rac-l-sec-butyl-7-chloroimidazo[l,5-a]pyridine-5-carbaldehyde
Figure imgf000098_0002
1 -sec-butyl-7-chloro-5-[(E)-2-(pyrrolidin- l-yl)vinyl]imidazo[ 1 ,5-a]pyridine (intermediate 16A) (15.8 g, 52 mmol) was dissolved in a mixture of tetrahydrofuran (166 ml) and water (20.2 ml). Sodium periodate (22 g, 102 mmol) was added at 0 °C and the mixture was stirred at this temperature for 75 minutes. A TLC analysis (silica gel, heptane/ethyl acetate 7/3) indicated that the - - reaction was finished. 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%).
H NMR (300 MHz, CDC13) δ [ppm] = 9.80 (s, 1 H), 9.37 (s, 1H), 7.77 (d, 1H), 7.23 (d, 1 H), 3.01 (m, 1H), 1.74 - 1.81 (m, 2 H), 1.38 (d, 3H), 0.82 (t, 3 H). Intermediate 18A - rac-methyl l-sec-butyl-7-chloroimidazo[l,5-a]pyridine-5-carboxylate
Figure imgf000099_0001
l-sec-Butyl-7-chloroimidazo[l,5-a]pyridine-5-carbaldehyde (9.8 g, 41.4 mmol) (intermediate 17A) was dissolved in tetrahydrofuran (410 ml). Sodium cyanide (2.5 g, 51 mmol), manganese dioxide (28.8 g, 331 mmol) and methanol (8.4 ml) were added. The suspension was heated at reflux temperature for 6 hours. A TLC analysis (silica gel, heptane/ethyl acetate 7/3) indicated that the reaction was finished. The suspension was filtered over Celite and the filter cake was rinsed with hot dichloromethane. The organic phase was 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 crude product (12.2 g). The product was purified by column chromatography (silica gel, heptane/ethyl acetate 85/15) to give the expected product (4.97 g,
45%).
H NMR (300 MHz, CDC13) δ [ppm] = 9.19 (s, 1H), 7.64 (s, 1H), 7.48 (s, 1 H), 4.00 (s, 3 H), 2.97 (m, 1H), 1.72 - 1.82 (m, 2 H), 1.36 (d, 3H), 0.80 (t, 3 H).
Intermediate 19A - rac-l-sec-butyl-7-chloroimidazo[l,5-a]pyridine-5-carboxylic acid
Figure imgf000099_0002
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%).
¾ NMR (300 MHz, DMSO) δ [ppm] = 9.07 (s, 1H), 8.09 (s, 1H), 7.38 (s, 1 H), 3.10 (m, 1H), 1.60 - 1.70 (m, 2 H), 1.25 (d, 3H), 0.72 (t, 3 H).
13C NMR (75 MHz, DMSO): 12.42, 21.18, 30.08, 32.84, 120.32, 120.86, 121.50, 125.09, 127.20, 129.06, 138.61, 162.82.
MS (ESIpos): m/z = 253 (M+H)+.
Synthesis of 7-chloro-l-cyclopentylimidazo[l,5-a]pyridine-5-carbonyl chloride - intermediate 27A
(Scheme D)
Figure imgf000100_0001
- -
Scheme D
Intermediate 20A - rac-l-(4-chloro-6-methylpyridin-2-yl)-l-cyclopentylmethanamine
Figure imgf000101_0001
4-Chloro-6-methylpyridine-2-carbonitrile (CAS 104711-65-1, 43.6 g, 286 mmol) was dissolved in tetrahydrofuran (840 ml). The mixture was cooled to -60°C and cyclopentyl magnesium chloride solution (2M in diethyl ether, 185 mL, 370 mmol) was added dropwise. The mixture was stirred for two hours at room temperature. The mixture was adjusted to 0°C and methanol (284 ml) was added dropwise. Sodium borohydride (6.5 g, 171 mmol) was added to the mixture portionwise. The solution was stirred two hours at 0°C. The solution was poured into an ice/water mixture (1.3 1) and the mixture was stirred overnight at room temperature. Dichloromethane (1.5 1) was added and the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a crude product. The product was mixed with hydrochloric acid solution (400 ml, 2M in ether). The resulting precipitate was filtered and rinsed with tetrahydrofuran. The combined filtrates were concentrated and treated a second time with a hydrochloric acid solution (400 ml, 2M in ether). Diisopropyl ether was added to the resulting suspension and the solid was filtered. The combined solids where re-dissolved into water and the aqueous layer was made basic using a saturated aqueous sodium hydrogen carbonate solution. The product was extracted three times using dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give an impure product that was purified using column chromatography on silica gel eluting with ethyl acetate, giving the expected product (41.8 g, 65%). Intermediate 21A - rac-N-[(4-chloro-6-methylpyridin-2-yl)(cyclopentyl)methyl]formamide
Figure imgf000101_0002
l-(4-Chloro-6-methylpyridin-2-yl)-l-cyclopentylmethanamine (intermediate 20A) (41.7 g, 185 mmol) was mixed with formic acid (122 ml, 3.23 mol) and the solution was heated at 100°C for 1 h. A TLC analysis (silica gel, dichloromethane/methanol/ammonia 98/2/1%) indicated that the - - reaction was finished. The mixture was allowed to cool to room temperature and concentrated to dryness. The resulting product was co-evaporated twice with toluene. A mixture of dichloromethane (400 ml) and an aqueous saturated sodium bicarbonate solution (400 ml) were added. The mixture was stirred until gas evolution had ceased. The organic layer was collected and the aqueous phase was further extracted with dichloromethane. The combined organics were dried over magnesium sulfate, filtered and concentrated to give the expected product (44 g, 94%), which was used in the subsequent step without further purification.
Intermediate 22A - 7-chloro-l-cyclopentyl-5-methylimidazo[l,5-a]pyridine
Figure imgf000102_0001
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. A mixture of dichloromethane (500 ml) and an aqueous saturated aqueous sodium bicarbonate solution (500 ml) were added. The mixture was stirred until gas evolution had ceased. The organic layer was collected and the aqueous phase was further extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give a brown oil (29.5 g). The product was purified by column chromatography (silica gel, gradient heptane/ethyl acetate) to give the expected product (21.03 g, 51%).
¾ NMR (300 MHz, CDC13) δ [ppm] = 7.91 (s, 1H), 7.34 (s, 1H), 6.29 (s, 1H), 3.31 (m., 1H), 2.50 (s, 3H), 2.00 - 2.12 (m, 2 H), 1.80 - 1.95 (m, 4 H), 1.70 - 1.82 (m, 2 H).
Intermediate 23A - 7-chloro-l-cyclopentyl-5-[(E)-2-(pyrrolidin-l-yl)vinyl]imidazo[l,5- alpyridine
Figure imgf000103_0001
7-Chloro-l-cyclopentyl-5-methylimidazo[l,5-a]pyridine (intermediate 22A) (20.94 g, 89 mmol) was dissolved in a mixture of dimethylformamide dimethylacetal (23.6 ml, 178.5 mmol) and pyrrolidine (18.3 ml). The solution was stirred at reflux temperature for 20 h. The solution was poured into an ice/water mixture and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give a crude product. The crude product was purified on a column of silica gel eluting with ethyl acetate resulting in a solid product. The product was triturated in diisopropyl ether at 0 °C giving the expected product (17.2 g, 61%).
¾ NMR (300 MHz, CDC13) δ [ppm] = 8.02 (s, 1H), 7.31 (d, 1H), 7.07 (s, 1H), 6.24 (s, 1H), 4.91 (d, 1H), 3.34 (m, 4H), 3.30 (m, 1H), 1.80 - 2.10 (m, 10 H), 1.60 - 1.80 (m, 2 H). Intermediate 24A - 7-chloro-l-cyclopentylimidazo[l,5-a]pyridine-5-carbaldehyde
Figure imgf000103_0002
7-Chloro-l-cyclopentyl-5-[(E)-2-(pyrrolidin-l-yl)vinyl]imidazo[l,5-a]pyridine (intermediate 23 A) (17.11 g, 54.2 mmol) was dissolved in a mixture of tetrahydrofuran (172 ml) and water (20 ml). Sodium periodate (23.2 g, 108.5 mmol) was added at 0 °C and the mixture was stirred at this temperature for 1 h. A The suspension was filtered over Celite 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 (18.2 g). The product was applied on a silica gel column and the product was eluted with ethyl acetate to give the expected product (10.6 g, 79%).
¾ NMR (300 MHz, CDC13) δ [ppm] = 9.79 (s, 1 H), 9.35 (s, 1H), 7.80 (d, 1H), 7.23 (d, 1 H), 3.37 - -
(m, 1H), 2.00 - 2.15 (m, 2 H), 1.80 - 1.95 (m, 4 H), 1.70 - 1.80 (m, 2 H).
Intermediate 25A - Methyl 7-chloro-l-cyclopentylimidazo[l,5-a]pyridine-5-carboxylate
Figure imgf000104_0001
7-Chloro- l-cyclopentylimidazo[l,5-a]pyridine-5-carbaldehyde (intermediate 24A) (10.6 g, 42.6 mmol) was dissolved in tetrahydrofuran (43 ml). Sodium cyanide (2.5 g, 51 mmol), manganese dioxide (22.4 g, 257 mmol) and methanol (8.6 ml) were added. The suspension was heated at reflux temperature for 7 hours. A TLC analysis (silica gel, heptane/ethyl acetate 7/3) indicated that the reaction was finished. The suspension was filtered over Celite and the filter cake was rinsed with hot dichloromethane. The organic phase was washed two 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 crude product (11.4 g). The product was purified by column chromatography (silica gel, heptane/ethyl acetate 85/15) to give the expected product (4.97 g, 42%).
¾ NMR (300 MHz, CDC13) δ [ppm] = 9.18 (s, 1H), 7.69 (s, 1H), 7.48 (s, 1 H), 4.01 (s, 3 H), 2.34 (m, 1H), 2.00 - 2.15 (m, 2 H), 1.85 - 2.00 (m, 4 H), 1.65 - 1.85 (m, 2 H). Intermediate 26A - 7-chloro-l-cyclopentylimidazo[l,5-a]pyridine-5-carboxylic acid
Figure imgf000104_0002
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%).
H NMR (300 MHz, DMSO) δ [ppm] = 9.09 (s, 1H), 8.04 (s, 1H), 7.34 (s, 1 H), 3.44 (pent., 1H), 1.90 - 2.10 (m, 2 H), 1.70 - 1.90 (m, 4 H), 1.60 - 1.70 (m, 2 H).
13C NMR (75 MHz, DMSO): 25.70, 33.39, 36.97, 119.75, 120.89, 121.00, 126.17, 126.90, 129.00, 137.72, 162.85.
MS (ESIpos): m/z = 265 (M+H)+.
Intermediate 27A - 7-chloro-l-cyclopentylimidazo[l,5-a]pyridine-5-carbonyl chloride
Figure imgf000105_0001
To a solution of 1.5 g 7-chloro-l-cyclopentylimidazo[l,5-a]pyridine-5-carboxylic acid (intermediate 26A) (5.66 mmol) in dichloromethane (100 ml) were added 2 drops of DMF. At 5°C were added 2.16g ethanedioyl dichloride (16.99 mmol, 3eq.). The reaction mixture stirred 1 h at 50 °C. The mixture was concentrated and dried in high vacuum to provide 1.6 g (100%) of the crude product which was used for the next reactions. Synthesis of 7-chloro-l-(tetrahydro-2H-pyran-4-yl)imidazo[l,5-a]pyridine-5-carboxylic acid- intermediate 33A
(Scheme Q)
- -
Figure imgf000106_0001
Scheme Q
Intermediate 28A - rac-(4-Chloro-6-methylpyridin-2-yl)(tetrahydro-2//-pyran-4- yl)methanamine
Figure imgf000106_0002
Preparation of the Grignard (carried out in flame dried glassware under argon) - Magnesium turnings 3.00 g (125 mmol) were stirred in tetrahydrofuran 75 mL, one flake of iodine was added. The mixture was stirred for 2 hours until the colour had dissipated. 4-Chlorotetrahydropyran (2.00 g) was added and the mixture was heated to 60 °C, and one drop of methyl iodide was added. The mixture turned cloudy and an exothermia was observed. A further portion of 4- chlorotetrahydropyran 8.00 g was added and the mixture was stirred at 60 °C for 2 hours. - -
To a solution of 4-chloro-6-methylpicolinonitrile (intermediate 2A, 8.50 g, 56.0 mmol) in tetrahydrofuran 400 mL was added the Grignard solution drop-wise, at -78 °C, under argon. After the addition was complete the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was then cooled to 5 °C and methanol 150 mL was added drop- wise followed by sodium borohydride 1.50 g (0.40 mmol) which was added portion- wise. After the addition was complete the mixture was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of water and ethyl acetate. The phases were separated and the aqueous phase was extracted again with ethyl acetate. The organic phases were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by dry flash chromatography (silica gel, eluent: ethyl acetate/methanol 9: 1 to 4: 1) to yield 5.90 g (44%) of (4-chloro-6-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanamine.
¾-NMR (400 MHz, CDC13): δ [ppm] = 1.14-1.45 (m, 4H), 1.83-1.93 (m, 1H), 2.51 (s, 3H), 3.33 (m, 2H), 3.61 (d, 1H), 3.90 (dd, 1H), 4.01 (dd, 1H), 7.02 (s, 1H), 7.04 (s, 1H).
Intermediate 29A - rac-N-((4-Chloro-6-methylpyridin-2-yl)(tetrahydro-2//-pyran-4- yl)methyl)formamide
Figure imgf000107_0001
A mixture of (4-chloro-6-methylpyridin-2-yl)(tetrahydro-2ii-pyran-4-yl)methanamine (intermediate 28A, 5.90 g, 24.5 mmol) and ethyl formate 18.0 mL was stirred at reflux for 3 hours. The reaction mixture was then evaporated to dryness, followed by co-evaporation with toluene (five times) to yield /V-((4-chloro-6-methylpyridin-2-yl)(tetrahydro-2ii-pyran-4- yl)methyl)formamide which was used without further purification in the next step. ¾-NMR (400 MHz, CDC13): δ [ppm] = 1.80 (m, 2H), 2.10 (m, 2H), 2.52 (s, 3H), 3.13 (m, 1H), 3.56 (td, 2H), 4.10 (dd, 2H), 6.45 (s, 1H), 7.37 (s, 1H), 7.97 (s, 1H).
Intermediate 30A - 7-Chloro-5-methyl-l-(tetrahydro-2//-pyran-4-yl)imidazo[l,5-a]pyridine
Figure imgf000107_0002
- -
A solution of Ar-((4-chloro-6-methylpyridin-2-yl)(tetrahydro-2 i-pyran-4-yl)methyl)formamide (intermediate 29 A, 24.5 mmol) in toluene 100 mL was stirred at reflux and phosphoryl chloride (POCI3; 2.75 mL; 29.4 mmol) was added drop-wise. The reaction mixture was stirred at reflux for 1 hour and 10 minutes then evaporated to dryness. The residue was dissolved in dichloromethane and was then added carefully to a mixture of dichloromethane and aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness to yield 7-chloro-5-methyl-l-(tetrahydro-2ii-pyran-4-yl)imidazo[l,5-a]pyridine which was used without further purification in the next step.
Intermediate 31A - (E)-7-Chloro-5-(2-(pyrrolidin-l-yl)vinyl)-l-(tetrahydro-2//-pyran-4- yl)imidazo[l,5-a] pyridine
Figure imgf000108_0001
A mixture of 7-chloro-5-methyl-l-(tetrahydro-2ii-pyran-4-yl)imidazo[l,5-a]pyridine (intermediate 30A, 24.5 mmol) and pyrrolidine 6.14 mL (73.5 mmol) in /V,/V-dimefhylformamide dimethyl acetal 6.50 mL (49.0 mmol) was stirred at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature then was carefully poured onto a mixture of ice and dichloromethane. Brine was added and the phases were separated. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness to yield 7.70 g of (E)-7-chloro-5-(2-(pyrrolidin-l-yl)vinyl)-l- (tetrahydro-2ii-pyran-4-yl)imidazo[l,5-a]pyridine which was used without further purification in the next step.
1H-NMR (400 MHz, CDC13): δ [ppm] = 1.68-2.15 (m, 8H), 3.27-3.60 (m, 7H), 4.10 (m, 2H), 4.90 (d, 1H), 6.25 (s, 1H), 7.09 (s, 1H), 7.33 (d, 1H), 8.01 (s, 1H).
Intermediate 32A - 7-Chloro-l-(tetrahydro-2H-pyran-4-yl)imidazo[l,5-a]pyridine-5- carbaldehyde - -
Figure imgf000109_0001
A solution of (E)-7-chloro-5-(2-(pyrrolidin-l-yl)vinyl)-l-(tetrahydro-2 i-pyran-4-yl)imidazo[l,5- a]pyridine (intermediate 31 A, 24.5 mmol) in tetrahydrofuran 125 mL and water 25 mL was cooled to 0 °C, and sodium periodate 10.5 g (49.0 mmol) was added portion-wise over a period of 20 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with ethyl acetate, followed by filtration through celite. The filtrate was poured onto a saturated aqueous solution of sodium bicarbonate and the phases were separated. The organic phase was washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness to yield 7-chloro-l-(tetrahydro-2ii-pyran-4-yl)imidazo[l,5-a]pyridine-5-carbaldehyde which was used without further purification in the next step.
1H-NMR (400 MHz, CDC13): δ [ppm] = 9.80 (s, 1H), 9.37 (s, 1H), 7.82 (s, 1H), 7.24 (s, 1H), 4.10 (m, 2H), 3.58 (m, 2H), 3.20-3.58 (m, 1H), 1.60-2.20 (m, 4H)
Intermediate 33A - 7-Chloro-l-(tetrahydro-2//-pyran-4-yl)imidazo[l,5-a]pyridine-5- carboxylic acid
Figure imgf000109_0002
A mixture of 7-chloro-l-(tetrahydro-2ii-pyran-4-yl)imidazo[l,5-a]pyridine-5-carbaldehyde (intermediate 32A, 24.5 mmol) and formic acid 100 mL was cooled to 0 °C and hydrogen peroxide 1.76 mL (25.7 mmol) was added drop-wise. The mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then cooled to 0 °C and quenched with brine 100 mL which was added slowly. The mixture was extracted with chloroform/2-isopropanol (7:1 mixture) three times. The organic phases were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was triturated in diethyl ether and the resulting solid was slurried in cold 2-isopropanol for 30 minutes then filtered, washed with diethyl ether and dried to yield 1.15 g of 7-chloro-l-(tetrahydro-2ii-pyran-4-yl)imidazo[l,5- a]pyridine-5-carboxylic acid. The filtrates were combined and evaporated under vacuum. 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 combined residues were then slurried in cold diethyl ether and dried to yield 1.64 g (24 % yield over 5 steps) of 7-chloro-l-(tetrahydro-2ii-pyran-4-yl)imidazo[l,5-a]pyridine-5-carboxylic acid.
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.87 (m, 2H), 1.99 (m, 2H), 3.29 (m, 3H), 4.06 (m,
2H), 7.94 (s, 1H), 8.36 (s, 1H), 10.06 (s, 1H).
Synthesis of Intermediates - Part 2 - Pyridone building blocks 3-(Aminomethyl)-4,6-dimethylpyridin-2(lH)-one hydrochloride is commercially available from various vendors. The other pyridones were prepared as described in the subsequent paragraphs.
Synthesis of 3-(aminomethyl)-6-methyl-4-propylpyridin-2(lH)-one hydrochlorid acid salt - 102A
(Scheme E)
Figure imgf000110_0001
102A
Scheme E
Intermediate 101A - 6-methyl-2-oxo-4-propyl-l,2-dihydropyridine-3-carbonitrile
Figure imgf000110_0002
To a stirred solution of potassium tert-butoxide (20 g, 0.178 mol) and cyano acetamide (16.49 g, 0.196 mol) in DMSO (300 ml) was added 3-hepten-2-one (20 g, 23.26 ml, 0.178 mol) under argon atmosphere at room temperature. Reaction was exothermic, and the temperature was maintained between 25-30 °C using an ice-bath. The reaction mixture was stirred at room temperature for 30 min and then additional potassium tert-butoxide was added to the reaction mixture (exothermic - - reaction; the temperature was maintained below 35 °C using a cold water bath). The argon was then displaced with air and the reaction mixture was stirred for 16 h. UPLC (conditions 1) showed essentially complete turnover. The reaction mixture was cooled to 0 °C under argon and the reaction was stopped by addition of water (50 ml), followed by 2N aqueous hydrochloric acid (350 ml) until the reaction mixture was acidic. The mixture was stirred for 30 min and then the solid was collected by filtration. The solid was washed with water (700 ml) and dried to afford the product 15 g (47.7%) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ [ppm] = 0.87 (t, 3H), 1.53-1.59 (m, 2H), 2.19 (s, 3H), 2.51 (m, 2H), 6.15 (s,lH), 2.31 (br s, 1H).
UPLC-MS (conditions 1.1): Rt = 0.55 min, 98.77%. MS (ESIpos): m/z =177 (M+H)+
Intermediate 102A - 3-(aminomethyl)-6-methyl-4-propylpyridin-2(lH)-one hydrochloride
Figure imgf000111_0001
HCI
To a stirred solution of 6-methyl-2-oxo-4-propyl-l,2-dihydropyridine-3-carbonitrile (intermediate 101A) (1 g, 5.67 mmol) in methanol (40 ml) and concentrated hydrogen chloride solution (1 ml) was added palladium hydroxide (0.95 g, 6.8 mmol). The mixture was stirred for 72 h under hydrogen pressure (34 bar). The reaction mixture was filtered and the filtrate concentrated under vacuum to give the crude product 1.2 g (97%).
H NMR (400 MHz, DMSO-d6) δ [ppm] = 0.85 (t, 3H), 1.48 (m, 2H), 2.12 (s, 3H), 2.41 (m, 2H), 3.72 (m, 2H), 5.95 (s, 1H), 8.05 (br s, 3H), 11.83 (br, s, 1H).
LC-MS (conditions 1.1): Rt = 1.31 min, 96.6%. MS (ESIpos): m/z = 181 (M+H)+.
Synthesis of 3-(Aminomethyl)-4-ethoxy-6-methylpyridin-2(lH)-one - 108A
(Scheme F) - -
Figure imgf000112_0001
1 08A
Scheme F
Intermediate 103A - Ethyl 2-(benzyloxy)-4-hydroxy-6-methylpyridine-3-carboxylate
Figure imgf000112_0002
A mixture of ethyl 2,4-dihydroxy-6-methylnicotinate (CAS 10350- 10-4) (175 g; 0.887 mol), benzyl bromide 110.8 ml (0.932 mol) and silver carbonate 129.7 g (0.470 mol) in toluene (2.6 1) was stirred at 60 °C (oil bath temperature) under an argon atmosphere for 24 h. The reaction mixture was filtered over celite then allowed to cool to room temperature and heptane (2 1) was added. A white precipitate formed which was collected by filtration, washed with heptane to recover unreacted 2,4-dihydroxy-6-methylnicotinate. The filtrate was evaporated in vacuo to yield an orange oil which crystallized upon standing at room temperature. The crude product was recrystallized from a minimum of heptane under cooling to -18 °C over night to yield off-white crystals which were filtered, washed with a minimum of cold heptane and dried in vacuo to yield intermediate 103A, 124.6 g (49 %).
H NMR (400 MHz, CDC13) δ [ppm] = 1.34 (t, 3H), 2.38 (s, 3H), 4.38 (q, 2H), 5.43 (s, 2H), 6.40 (s, 1H), 7.28-7.39 (m, 3H), 7.51 (d, 2H), 12.30 (s, 1H).
Intermediate 104A - Ethyl 2-(benzyloxy)-4-ethoxy-6-methylpyridine-3-carboxylate
Figure imgf000113_0001
A mixture of intermediate 103A (15.6 g, 54.3 mmol), potassium carbonate (22.5 g, 162.9 mmol) and iodoethane (4.34 ml, 54.3 mmol) in DMF (150 mL) was stirred at room temperature under an argon atmosphere for 18 h. The mixture was filtered over celite and the celite cake was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was mixed with dichloromethane (0.60 1). The solids were filtered and washed with dichloromethane. The filtrate was concentrated in vacuo to give intermediate 104A, 13.4 g (78 %) as yellow oil.
¾ NMR (400 MHz, CDC13) δ [ppm] = 1.24 (t, 3H), 1.30 (t, 3H), 2.33 (s, 3H), 3.99 (q, 2H), 4.28 (q, 2H), 5.35 (s, 2H), 6.30 (s, 1H), 7.16-7.36 (m, 5H).
UPLC-MS (conditions 1.1): Rt = 0.79 min, 91.97%. MS (ESIpos): m/z = 315 (M+H)+.
Intermediate 105A - [2-(Benzyloxy)-4-ethoxy-6-methylpyridin-3-yl]methanol
Figure imgf000113_0002
To sodium bis(2-methoxyethoxy)aluminum dihydride (109 ml; 3.5 M in toluene, 377 mmol) in toluene (1 1) was slowly added intermediate 104A (119 g, 377 mmol) in toluene (1 1) at room temperature. The temperature rose to 30 °C and the mixture was stirred at 80 °C (oil bath temperature) for 2 h under an argon atmosphere; LC analysis indicated approximately 30% product formation. A further portion of sodium bis(2-methoxyethoxy)aluminum dihydride (218 ml, 754 mmol) was added slowly to the reaction mixture at room temperature, then the reaction mixture - - was heated at 80 °C (oil bath temperature) for 1.5 h after which time LC analysis indicated total consumption of the starting material. The reaction mixture was cooled to 5 °C in an ice bath and aqueous sodium hydroxide (2 M) was added dropwise until no further effervescence was observed. The organic partition was collected and washed with brine (2 x 250 mL), dried over sodium sulfate, filtered and concentrated to give a crude yellow solid. The crude product was recrystallized from heptane to yield intermediate 105A, 79.4 g (77 %) as an off-white solid.
¾ NMR (400 MHz, CDC13) δ [ppm] = 1.42 (t, 3H), 2.41 (s, 3H), 4.07 (q, 2H), 4.72 (d, 2H), 5.41 (s, 2H), 6.36 (s, 1H), 7.28-7.45 (m, 5H).
UPLC-MS (conditions 1.1): Rt = 0.40 min, 98.54%. MS (ESIpos): m/z = 273 (M+H)+.
Intermediate 106A - [2-(Benzyloxy)-4-ethoxy-6-methylpyridin-3-yl]methyl methanesulfonate
Figure imgf000114_0001
To ice-cooled intermediate 105A (5 g, 18.29 mmol) in dichloromethane (200 ml) was added N,N- diisopropylethylamine (4.14 ml, 23.78 mmol) followed by methanesulfonyl chloride (1.56 ml, 20.12 mmol) in dichloromethane (50 ml) dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The solvent was removed in vacuo (water bath 20 °C) to yield intermediate 106A as a pale yellow solid, 6.43 g (99 %), which was used in the next step without purification.
¾ NMR (400 MHz, CDCI3) δ [ppm] = 1.49 (t, 3H), 2.42 (s, 3H), 2.77 (s, 3H), 4.11 (q, 2H), 4.69 (s, 2H), 5.44 (s, 2H), 6.36 (s, 1H), 7.28-7.49 (m, 5H).
UPLC-MS (conditions 1.1): Rt = 1.16 min, 97.53%. MS (ESIpos): m/z = 288 (mesylate reacts rapidly with methanol in MS solution).
Intermediate 107A - 3-(Azidomethyl)-2-(benzyloxy)-4-ethoxy-6-methylpyridine - -
Figure imgf000115_0001
To intermediate 106A (6.43 g, 18.29 mmol) in DMF (240 ml) was added diisopropylethylamine (4.14 ml, 23.78 mmol), followed by sodium azide (1.31 g, 20.12 mmol), and the reaction mixture was stirred under argon at room temperature for 1 h. The reaction mixture was quenched with dilute sodium hydroxide solution (200 ml, 2 M) and extracted with ethyl acetate (3 x 200 ml). The organic layer was collected and washed with brine solution, dried over sodium sulfate, filtered and the solution was concentrated in vacuo (water bath 20 °C) to one tenth of its original volume. This solution of intermediate 107A was used in the next step.
¾ NMR (400 MHz, CDC13) δ [ppm] = 1.40 (t, 3H), 2.40 (s, 3H), 4.12 (q, 2H), 4.31 (s, 2H), 5.35 (s, 2H), 6.59 (s, 1H), 7.24-7.42 (m, 5H).
UPLC-MS (conditions 1.1): Rt = 0.92 min, 80.46%. MS (ESIpos): m/z = 299 (M+H)+. Intermediate 108A - 3-(Aminomethyl)-4-ethoxy-6-methylpyridin-2(lH)-one
Figure imgf000115_0002
To intermediate 107A in an autoclave was added industrial methylated spirits (denaturated ethanol) (190 ml) and acetic acid (2 ml; 36.59 mmol) followed by palladium hydroxide 0.55 g (3.9 mmol). The autoclave was pressurized with hydrogen (41 bar) and the reaction mixture was stirred for 18 h at room temperature. A further portion of palladium hydroxide was added (0.5 g, 3.56 mmol) and the reaction mixture was pressurized with hydrogen (41 bar) and stirred for 16 h. The reaction mixture was filtered through celite, washed with methanol and the solvent removed in vacuo to yield a dark brown solid. 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).
H NMR (400 MHz, methanol-d4) δ [ppm] = 1.39 (t, 3H), 2.26 (s, 3H), 3.64 (s, 2H), 4.14 (q, 2H), - -
6.19 (s, 1H). UPLC-MS (conditions 1.1): Rt = 0.44 min, 84.27%. MS (ESIpos): m/z = 183 (M+H)+.
Synthesis of 3-(aniinoniethyl)-4-(methoxymethyl)-6-methylpyridin-2(lH)-one hydrochloride salt- 109A
(Scheme G) o o o o
H,C'°^^O^CH3 + H,C^CH, " H,C'°^^^CH,
Figure imgf000116_0001
1 09A
Scheme G The synthesis of Intermediate 109A is described in WO2011/140324 and was used with slight modifications.
Intermediate 109A - 3-(aminomethyl)-4-(methoxymethyl)-6-methylpyridin-2(lH)-one hydrochloride salt
Figure imgf000116_0002
Step 1)
To a suspension of sodium (17.52 g, 761.87 mmol) in anhydrous toluene (250 ml) was added ethyl 2-methoxyacetate (72.00 g, 609.49 mmol) at -5 °C. After stirring for 3 h, acetone (42.13 g, 725.30 mmol) was added slowly and the mixture became brown and viscous. Then ieri-butyl methyl ether (252.0 ml) was added. The reaction mixture was stirred at 15 °C for 12 h. The formed sodium salt precipitate was collected, washed with ieri-butyl methyl ether (200 ml), and dissolved in 20% - - quueous sulfuric acid (250 ml). The aqueous solution was extracted with ieri-butyl methyl ether (150 ml x 3). The combined organic layers were concentrated to afford l-mefhoxypentane-2,4- dione (45.0 g, 57%) as a red oil. ¾ NMR (400 MHz, CDC13) δ [ppm] = 5.76 (s, 1H), 3.95 (s, 2H), 3.39 (s, 3H), 2.06 (s, 3H). Step 2)
To a solution of l-methoxypentane-2,4-dione (45.0 g, 345.78 mmol) and cyanoacetamide (29.07 g, 345.78 mmol) in ethanol (450 ml) was added slowly piperidine (29.44 g, 345.78 mmol) at 70 °C. The mixture was stirred for 2 h at 80 °C, and then cooled to 20 °C. The contents were filtered to give a solid, which was triturated with ethanol (100 ml) to give 4-(methoxymethyl)-6-methyl-2- oxo-lH-pyridine-3-carbonitrile (45.0 g, 73%) as a gray solid.
¾ NMR (400 MHz, DMSO-d6) δ [ppm] = 6.29 (s, 1H), 4.43 (s, 2H), 3.35 (s, 3H), 2.28 (s, 3H).
Step 3)
To a solution of 4-(methoxymethyl)-6-methyl-2-oxo-lH-pyridine-3-carbonitrile (45.0 g, 252.54 mmol) in methanol (500 ml) was added Raney-Nickel (147.9 g) and aqueous ammonia (70 mL) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for three times. The mixture was stirred under hydrogen (1.8 bar) atmosphere at 15 °C for 6 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by precipitation upon addition of hydrogen chloride in methanol (500.0 ml, 4.0 M), and the solid was filtered and dried to give 3-(aminomethyl)-4-(methoxymethyl)-6- methylpyridin-2(lH)-one hydrochloride (intermediate 109A, 20.0 g, 36%) as white solid.
¾ NMR (400 MHz, DMSO-d6): δ = 12.03 (br, 1H), 8.03 (br, 3H), 6.15 (s, 1H), 4.45 (s, 2H), 3.78- 3.74 (m, 2H), 3.33 (s, 3H), 2.21 (s, 3H).
- -
Synthesis of 3-(Aminomethyl)-6-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ol hydrochloride -
116A
(Scheme H)
Figure imgf000118_0001
Scheme H Ethyl 2-(benzyloxy)-4-hydroxy-6-methylnicotinate
Figure imgf000118_0002
To a mixture of ethyl-2,4-dihydroxy-6-methylnicotinate (CAS 70254-52-3, 250 g, 1.27 mol) and silver carbonate (182 g, 0.66 mol) in tetrahydrofuran (3.0 1) was added benzyl bromide (260 g, 1.54 mol). The mixture was stirred at 60 °C for 12 h then cooled to room temperature and filtered. The filtrate was concentrated and the resulting residue was re-dissolved in heptane. The resulting solid - - was filtered off and the filtrate cooled to -10 °C. The solid that formed was then filtered off and washed with cold heptane and dried to give intermediate 111A (235 g, 64%).
¾ NMR (400MHz, CDC13) δ [ppm] = 12.29 (s, 1H), 7.26-7.53 (m, 5H), 6.40 (s, 1H), 5.43 (s, 2H), 4.38 (q, 2H), 2.38 (s, 3H), 1.35 (t, 1H). Ethyl 2-(benzyloxy)-6-methyl-4-(2,2,2-trifluoroethoxy)nicotinate
Figure imgf000119_0001
Step 1)
A mixture of trifluoroethanol (142 g, 1.42 mol) and triflic anhydride (350 g, 1.24 mol) was stirred at room temperature for 30 min then heated at reflux for 3 h. The mixture was then distilled at atmospheric pressure to give the corresponding triflate of trifluoroethanol (280 g, 100%, bp. 118 °C).
¾ NMR (400MHz, CDC13) δ [ppm] = 4.70 (q, 2H). Step 2)
A mixture of intermediate 111A (224 g, 0.78 mol), the crude product of step 1 (234 g, 1.02 mol) and potassium carbonate (430 g, 3.11 mol) in acetone (2.2 1) was stirred at reflux, under argon, for 4 h. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated and the residue was triturated with heptane. The resulting solid was filtered then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulphate and concentrated to give intermediate 112A (192 g). A second batch was isolated from the initial filtrate to give a total of 251 g (88%) of intermediate 112A.
H NMR (300MHz, CDC13) δ [ppm] = 7.28-7.45 (m, 5H), 6.32 (s, 1H), 5.43 (s, 2H), 4.36 (m, 4H), 2.43 (s, 3H), 1.31 (t, 3H).
Intermediate 113A - (2-(Benzyloxy)-6-methyl-4-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol - -
Figure imgf000120_0001
To a solution of intermediate 112A (120 g, 0.32 mol) in tetrahydrofuran (1.0 1) at 0 °C was added lithium aluminium hydride (1M solution in tetrahydrofuran, 320 ml, 0.32 mol), under argon, whilst maintaining a temperature below -10 °C. Once the addition was complete the mixture was allowed to warm to room temperature and stirred under argon for 2 h. The mixture was then cooled to 10 °C and water was added (6 ml) dropwise followed by sodium hydroxide (15%, aq, 6 ml) then water (18 ml). The resulting mixture was stirred for 20 min then filtered. The filtrate was concentrated to give an oil which crystallized upon cooling to give intermediate 113A.
¾ NMR (400MHz, CDC13) δ [ppm] = 7.30-7.46 (m, 5H), 6.32 (s, 1H), 5.40 (s, 2H), 4.72 (d, 2H), 4.37 (q, 2H), 2.43 (s, 3H), 2.29 (t, 1H).
Intermediate 114A - 3-(Azidomethyl)-2-(benzyloxy)-6-methyl-4-(2,2,2- trifluoroethoxy)pyridine
Figure imgf000120_0002
A solution of intermediate 113A (165 g, 505 mmol) and diisopropylethylamine (132 ml, 757 mmol) in dichloromethane (1.5 1) was cooled to 0 °C and a solution of methansulfonyl chloride (43.1 ml, 555 mmol) in dichloromethane (150 mL) was added dropwise over a period of 1 h. The mixture was stirred at room temperature for 2 h and then concentrated. The residue was re- dissolved in DMF (1.2 1) and sodium azide (39.4 g, 606 mmol) was added. The mixture was stirred at room temperature for 18 h. Water was added and the mixture was extracted with heptane/ethyl acetate (3: 1). The organic layer was washed with water then brine, dried over magnesium sulfate then concentrated to give intermediate 114A (165 g, 93%). - -
H NMR (400MHz, CDC13) δ [ppm] = 7.28-7.48 (m, 5H), 6.34 (s, 1H), 5.42 (s, 2H), 4.32-4.44 (m, 4H), 2.45 (s, 3H).
Intermediate 115A - (2-(Benzyloxy)-6-methyl-4-(2,2,2-trifluoroethoxy)pyridine-3- yl)methanamine
Figure imgf000121_0001
A mixture of intermediate 114A (165 g, 468 mmol) and 5% Pd/C (8 g) in methanol was stirred at 50 C under 50 bar of hydrogen for 7 h. The mixture was filtered through celite and concentrated. The resulting yellow oil was triturated with diethyl ether/heptanes (1: 1) to give intermediate 115 A (110 g, 72%) as a white solid.
¾ NMR (400MHz, CDCI3) δ [ppm] = 7.27-7.47 (m, 5H), 6.29 (s, 1H), 5.42 (s, 2H), 4.39 (q, 2H), 3.84 (s, 2H), 2.41 (s, 3H), 1.70 (br. s., 2H).
Intermediate 116A - 3-(Aminomethyl)-6-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ol hydrochloride salt
Figure imgf000121_0002
To a solution of intermediate 115A (55 g, 164 mmol) in dioxane (500 ml) was added 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.
¾ NMR (400MHz, DMSO-d6) δ [ppm]
(br.s, 2H), 3.68 (m, 2H), 2.18 (s, 3H).
Synthesis of 3-(Aminomethyl)-4-(l,l-difluoropropyl)-6-methylpyridin-2(lH)-one - - hydrochloride - Intermediate 120A (Scheme I)
Figure imgf000122_0001
To a solution of 2,2-difluorobutanoic acid (CAS 2366-62-3, 12.4 g, 100 mmol) in dichloromethane (300 ml) was added triethylamine (14.0 ml, 100 mmol) dropwise followed by methyl chloroformate (8.0 ml, 100 mmol) dropwise at 0 °C (effervescence was observed). The mixture was stirred at room temperature for 1 h then at reflux for 1 h. Water (200 ml) and 2M aqueous hydrochloric acid (100 ml) were added. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution (100 ml), dried over sodium sulfate and concentrated to give intermediate 117A (9.7 g, 70%).
H NMR (300 MHz, CDC13) δ [ppm] = 3.87 (s, 3H), 2.10 (m, 2H), 1.03 (t, 3H).
Intermediate 118A - 5,5-Difluoroheptane-2,4-dione
Figure imgf000122_0002
- -
To a suspension of sodium hydride (24.0 g, 600 mmol) in tetrahydrofuran (500 ml) was added a solution of intermediate 117A (61.5 g, 446 mmol) in anhydrous acetone (45 ml) dropwise, at -10 °C, under argon. The mixture was allowed to warm to 0 °C (effervescence was observed) and stirred for 1 h. The reaction mixture was quenched by the addition of water (500 ml). Diethyl ether (500 ml) and 2M aqueous HCI (500 ml) were added and the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution (100 ml), dried over sodium sulfate and concentrated to give intermediate 118A (35.3 g, 48%) which was used in the subsequent reaction without further purification.
Intermediate 119 A 4-(l,l-Difluoropropyl)-6-methyl-2-oxo-l,2-dihydropyridine-3-
Figure imgf000123_0001
To a hot solution of cyanoacetamide (19.3 g, 230 mmol) in IMS (1.5 1) was added intermediate 118A (35.3 g, 216 mmol), followed by triethylamine (16.0 ml, 115 mmol), and the mixture was stirred at reflux overnight. The mixture was then concentrated. Water (500 ml) was added to the residue and the resulting solids were collected, washed with water and dried to give intermediate 119A (45.9 g, 100%). ¾ NMR (400 MHz, DMSO-d6) δ [ppm] = 6.33 (s, 1H), 2.29 (s, 3H), 2.18 (m, 2H), 0.91 (t, 3H). 19F NMR (400 MHz, DMSO-d6) δ [ppm] = -98.14 (t, 2F).
13C NMR (100 MHz, DMSO-d6) δ [ppm] = 161.60, 155.24, 155.10, 122.00 (t), 115.16, 102.73, 96.50, 30.45 (t), 19.93, 6.69.
Intermediate 120A - 3-(Aminomethyl)-4-(l,l-difluoropropyl)-6-methylpyridin-2(lH)- hydrochloride
Figure imgf000123_0002
To a solution of intermediate 119A (55.2 g, 260 mmol) in methanol (1.0 1) was added concentrated aqueous hydrochloric acid (25 ml) followed by palladium hydroxide (10.0 g), and the mixture was stirred under hydrogen (28 bar) at room temperature for 7 d. The mixture was then stirred at 55 °C - - for 2 d, then at 60 °C for a further 5 d. The mixture was then filtered and fresh catalyst was added to the filtrate. The mixture was then stirred under hydrogen (28 bar) at 60 °C for 18 h. The mixture was then cooled, filtered and the filtrate concentrated. The crude product was purified by recrystallization from methanol/isopropanol, followed by recrystallization from concentrated hydrochloric acid in ethanol to give intermediate 120A (10.9 g, 20%).
¾ NMR (400 MHz, DMSO-d6) δ [ppm] = 8.14 (bs, 3H), 6.14 (s, 1H), 3.81 (s, 2H), 2.23 (s, 3H), 2.16 (m, 2H), 0.98 (t, 3H).
19F NMR (400 MHz, DMSO-d6) δ [ppm] = -94.95 (m, 2F).
13C NMR (100 MHz, DMSO-d6) δ [ppm] = 163.58, 147.91 (t), 147.50, 123.46, 118.01, 102.02, 35.70, 31.55 (t), 19.15, 6.85.
Synthesis of 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(lH) -one hydrochloride salt - 132A (Scheme K)
The synthesis of 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(lH)-one is described in WO2013120104 and was used with slight adaptions:
Figure imgf000124_0001
127A 128A
Figure imgf000124_0002
Scheme K
Intermediate 127A - 2-amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile - -
Figure imgf000125_0001
To a solution of malononitrile (30 g, 1.82 mol) in tetrahydrofurane (300 ml) was added sodium hydride (10.9 g, 1.82 mol) below 10 °C very carefully under a nitrogen atmosphere and then stirred for 0.5 h at 0 °C. Then 4-methyleneoxetan-2-one (38.18 g, 1.82 mol) was added dropwise below 0 °C and then the reaction was stirred at -10 °C for 1 h. The 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.
Intermediate 128A - 2, 4-dihydroxy-6-methylnicotinonitrile
Figure imgf000125_0002
A solution of 2-amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile (intermediate 127A, 60 g, 1.60 mol) in 10 % HC1 solution (800 ml) was refluxed for 5 hours with intensive stirring. After cooling to 18°C, the mixture was filtered, the filter cake was washed with water (800 ml) and ethanol (800 ml), methyl iert-butyl ether (800 ml) and dried in vacuo to give 2,4-dihydroxy-6- methylnicotinonitrile (intermediate 128A, combined yield from 4 batches: 105 g, 58% yield) as yellow powder, which was used in the next step without purification.
Intermediate 129A - 2, 4-dichloro-6-methylnicotinonitrile
Figure imgf000125_0003
To a solution of 2,4-dihydroxy-6-methylnicotinonitrile (intermediate 128A, 30 g, 599.49 mmol) in POCls (90 ml) was added DMF (730 mg, 29.97 mmol), then the mixture was heated at 95°C for 3 h. The mixture was concentrated in vacuo; the residue was dissolved in ethyl acetate (3 1) and neutralized by saturated aqueous sodium bicarbonate solution. Then the mixture was filtered and the organic layer was separated and dried over Na2SC>4, filtered and concentrated in vacuo to give 2,4-dichloro-6-methylnicotinonitrile (intermediate 129A, combined yield from 3 batches: 90 g, 80% yield) as brown solid. - -
H NMR (400 MHz, methanol-d4) δ [ppm] = 7.60 (s, 1 H), 2.58 (s, 3 H). Intermediate 130A - 2,4-dimethoxy-6-methylnicotinonitrile
Figure imgf000126_0001
To a solution of 2 4-dichloro-6-methylnicotinonitrile (intermediate 129A, 20 g, 427.73 mmol) in methanol (200 ml) was added sodium methanolate (11.55 g, 875.44 mmol) and stirred at 80 °C for 4 h. After cooling to 18 °C, the reaction was neutralized by acetic acid. The solvent was removed in vacuo and the residue was washed with water (800 ml) and methyl iert-butyl ether (800 ml). The resulting solid was concentrated in tetrahydrofuran (400 ml) to give 2,4-dimefhoxy-6- methylnicotinonitrile (intermediate 130A, combined yield from 4 batches: 72 g, 94% yield) as dark-yellow solid. H NMR (400 MHz, methanol-d4) δ [ppm] = 6.73 (s, 1 H), 3.99-4.00 (2 overlapping s, 6 H), 2.48(s, 3 H).
Intermediate 131A - tert-butyl((2,4-dimethoxy-6-methylpyridin -3-yl) methyl)carbamate
CH3
Figure imgf000126_0002
To a solution of 2,4-dimethoxy-6-methylnicotinonitrile (intermediate 130A, 5 g, 224.48 mmol) in the mixture of tetrahydrofuran (80 ml) and methanol (80 ml) was added Raney Nickel (5 g), triethylamine (15 g, 1.19 mol) and di-ieri-butyl dicarbonate (18.37 g, 673.44 mmol). Then the mixture was stirred under an atmosphere of hydrogen at 25 °C for 16 h. The reaction was concentrated to give ieri-butyl((2,4-dimethoxy-6-methylpyridin-3-yl)methyl)carbamate (intermediate 131A, combined yield from 8 batches: 54.4 g, 86% yield) as yellow solid.
H NMR (400 MHz, methanol-d4) δ [ppm] = 6.57 (s, 1 H), 4.21 (s, 2 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 2.41 (s, 3 H), 1.45 (s, 9 H). - -
Intermediate 132A 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(lH)-one hydrochloride
Figure imgf000127_0001
ieri-Butyl((2,4-dimethoxy-6-methylpyridin-3-yl)methyl)carbamate (intermediate 131A, 20 g, 10.63 mmol) was dissolved in 4N aqueous hydrochloric acid (400 ml) and refluxed at 110 °C for 5 h. Then the reaction was concentrated in vacuo. The residue was dissolved in ethanol (200 ml) and stirred for 15 min, filtered and washed with methyl ieri-butyl ether (200 ml). The mixture was concentrated in vacuo to give 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(lH)-one hydrochloride (intermediate 132A, combined yield from 2 batches: 22 g, 76% yield) as white solid.
H NMR (400 MHz, DMSO-d6) δ [ppm] = 11.76 (s, 1 H), 7.98 (br. s, 2 H), 6.20 (s, 1 H), 3.85 (s, 3 H), 3.73-3.72 (d, 2 H), 2.23 (s, 3 H). Synthesis of 3-(aniinoniethyl)-4-(difluoromethoxy)-6-methylpyridin-2(lH)-one hydrochloride salt - 137A (Scheme L)
The synthesis of 3-(aminomethyl)-4-(difluoromethoxy)-6- methylpyridin-2(lH)-one is described in WO2013120104 and was used with slight adaptions:
Figure imgf000127_0002
129A 133A 134A
Figure imgf000127_0003
135A 136A 137A
Scheme L - -
Intermediate 133A - 2-chloro-4-hydroxy-6-methylnicotinonitrile
Figure imgf000128_0001
A solution of 2,4-dichloro-6-methylnicotinonitrile (150 g, 3.21 mol) and potassium acetate (236.13 g, 9.64 mol) in DMF (700 ml) was stirred at 80 °C for 12 h under nitrogen after which target compound was detected and the starting material was consumed (based on TLC analysis). Then the mixture was concentrated in high vacuum to remove most of DMF and then dissolved in ethyl acetate (10 1) and filtered to remove the salt. The organic layer was washed with water (3x 800 ml) and dried over sodium sulfate, filtered and concentrated in vacuo to give 2-chloro-4-hydroxy-6- methylnicotinonitrile (intermediate 133A, combined yield from 4 batches: 300 g, 49% yield) as brown oil which was used in the following step without further purification.
Intermediate 134A - 4-hydroxy-2-methoxy-6-methylnicotinonitrile
Figure imgf000128_0002
A mixture of 2-chloro-4-hydroxy-6-methylnicotinonitrile (intermediate 133A, 100 g, 1.78 mol) and sodium methanolate (160.22 g, 8.91 mol) in methanol (500 ml) was stirred at 80 °C for 12 h under nitrogen. Then the reaction mixture was acidified with IN aqueous hydrochloric acid to pH=2~3 and then concentrated in vacuo to remove most methanol. The residue was extracted with ethyl acetate (1 1) and water (1 1), the organic layer was dried with sodium sulfate, filtered and concentrated in vacuo to give 4-hydroxy-2-methoxy-6-methylnicotinonitrile (intermediate 134A, combined yield from 3 batches: 120 g, 41 % yield) as dark yellow solid, which was used in the subsequent step without further purification. Intermediate 135A - 4-(difluoromethoxy)-2-methoxy-6-methylnicotino nitrile
Figure imgf000128_0003
To a solution of 4-hydroxy-2-methoxy-6-methylnicotinonitrile (intermediate 134A, 60 g, 731.0 - - mmol) in DMF (400 ml) was added sodium hydride (26.32 g, 2.2 mol) portionwise at 0 °C under nitrogen and the mixture was stirred for 30 min and then ethyl 2-chloro-2,2-difluoroacetate (CAS 383-62-0, 185.42 g, 2.34 mol) was added dropwise with vigorous stirring over the course of 30 min. Then the reaction was warmed to 80 °C and was stirred for 12 h under nitrogen. Then the reaction was quenched with saturated aqueous sodium carbonate solution, extracted with ethyl acetate (2 1) and water (2 1), the organic layer was dried with sodium sulfate and filtered and concentrated. The residue was purified by column chromatography on silica gel (petrol ether/ethyl acetate = 80/1) to give 4-(difluoromethoxy)-2-methoxy-6-methylnicotinonitrile (intermediate 135A, combined yield from 2 batches: 21 g, 13% yield) as a yellow solid.
¾ NMR (400 MHz, CDC13) δ [ppm] = 6.70 (t, 1 H), 6.67 (s, 1 H), 4.05 (s, 3 H), 2.52 (s, 3 H).
Intermediate 136A - ter^butyl((4-(difluoromethoxy)-2-methoxy-6-methylpyridin-3- yl)methyl)carbamate
Figure imgf000129_0001
To a solution of 4-(difluoromethoxy)-2-methoxy-6-methylnicotinonitrile (intermediate 135A, 1.40 g, 98.1 mmol) and di-ieri-butyl dicarbonate (2.14 g, 147.15 mmol), triethylamine (992.67 mg, 147.15 mmol) in tetrahydrofuran (30 ml) was added Raney-Nickel (1.12 g) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (2 bar) at 30 C for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give ieri-butyl((4-(difluoromethoxy)-2-methoxy-6-methylpyridin-3- yl)methyl)carbamate (intermediate 136A, combined yield from 15 batches: 23 g, 74% yield) as a yellow oil which was used without further purification.
Intermediate 137A - 3-(aminomethyl)-4-(difluoromethoxy)-6- methylpyridin-2(lH)-one hydrochloride
Figure imgf000129_0002
HCI - -
A solution of ier^butyl((4-(difluoromethoxy)-2-methoxy-6-methylpyridin-3-yl)methyl)carbamate (intermediate 136A, 12 g, 50.26 mmol) in 4N aqueous hydrochloric acid (120 ml) was stirred at 120 °C for 4 h. The formed precipitate was filtered off and dried in high vacuum, washed with ethanol (200 ml), filtered and dried again in vacuo to give 3-(aminomethyl)-4-(difluoromefhoxy)-6- methylpyridin-2(lH)-one hydrochloride (intermediate 137A, combined yield from 2 batches: 18.1 g, 66%) as a white solid.
¾ NMR (400 MHz, CDC13) δ [ppm] = 12.21 (s, 1 H), 8.15 (br. s, 3 H), 7.41 (t, 1 H), 6.18 (s, 1 H, 3.76-3.75 (d, 2 H), 2.26 (s, 3 H).
Synthesis of 3-(aminomethyl)-6-benzyl-4-methylpyridin-2(lH) -one hydrochloride salt - 147A - and 3-(aminomethyl)-4-benzyl-6-methylpyridin-2(lH) -one hydrochloride - 148A (Scheme M)
The synthesis of 3-(aminomethyl)-6-benzyl-4-methylpyridin-2(lH) -one is described in WO2011140324 and was used with slight adaptions:
Figure imgf000130_0001
145A 147A
Scheme M - -
Intermediate 142A - (Z?)-5-phenylpent-3-en-2-one
Figure imgf000131_0001
To a mixture of sodium amide (228.07 g, 5.85 mol) in tetrahydrofuran (2 1) under nitrogen at -5 °C was added ethyl 2 -phenyl acetate (300.00 g, 1.83 mol) and acetone (106.11 g, 1.83 mol). The mixture was stirred at 20 °C for 12 h. Then the mixture was acidified to pH 4.0-5.0 with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate (3x 2 1). The combined organic phases were washed with brine (2 2x 1), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petrol ether/ethyl acetate 100: 1 to 20: 1) to afford (£)-5-phenylpent-3-en-2-one (150.00 g, 936.27 mmol, 51% yield) as orange oil.
¾ NMR (400 MHz, CDC13) δ [ppm] = 7.33-7.35 (m, 5 H), 4.13-4.14 (m, 2 H), 3.60 (s, 2 H), 2.05 (d, 3 H).
Intermediate 143A - 4-benzyl-6-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile and 6- benzyl-4-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile
Figure imgf000131_0002
A solution of (£)-5-phenylpent-3-en-2-one (intermediate 142A, 150.00 g, 936.27 mmol) and 2- cyanoacetamide (78.72 g, 936.27 mmol) in ethanol (1 1) was heated to 75 °C. Piperidine (79.72 g, 936.27 mmol) was added and the reaction mixture was heated to 80 °C for 30 min. The reaction was slowly quenched with water (500 ml) and stirred for 20 min. The mixture was filtered and concentrated to give the products 4-benzyl-6-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile and 6-benzyl-4-methyl-2-oxo- l,2-dihydropyridine-3-carbonitrile (70.00 g, 312 mmol, 33% yield) in an approximately 1.5: 1 mixture as yellow-green solid. This mixture was used in the subsequent reaction without further purification.
Intermediate 144A - 3-(aminomethyl)-4-benzyl-6-methylpyridin-2(lH)- one and 3- (aminomethyl)-6-benzyl-4-methylpyridin-2(lH)-one - -
Figure imgf000132_0001
To a solution of 4-benzyl-6-methyl-2-oxo- l,2-dihydropyridine-3-carbonitrile and 6-benzyl- 4- methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (intermediate 143A, 5.0 g, 219.29 mmol) in DMF (100 ml) was added Raney-Nickel (5 g) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (3.5 bar) at 50 °C for 12 h. TLC showed the starting material was consumed completely. The reaction mixture was filtered and the filtrate was concentrated to give a mixture of crude 3-(aminomethyl)- 4- benzyl-6-methylpyridin-2(lH)-one and 3-(aminomethyl)-6-benzyl-4-methylpyridin-2(lH)- one (combined yield from 28 batches: 160.00 g ) as brown oil. This mixture was used in the subsequent step without further purification.
Intermediate 145A - tert-butyl ((4-benzyl-6-methyl-2-oxo-l,2-dihydropyridin -3- yl)methyl)carbamate
Figure imgf000132_0002
To a solution of 3-(aminomethyl)-4-benzyl-6-methylpyridin-2(lH)-one and 3-(aminomethyl) -6- benzyl-4-methylpyridin-2(lH)-one (intermediate 144A, 80.00 g, 350.44 mmol) in dichloromethane (800 ml) was added triethylamine (35.46 g, 350.43 mmol) and di-ieri-butyl dicarbonate (42.06 g, 192.74 mmol) under nitrogen at 0 °C. The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was quenched with 1 N aqueous hydrochloric acidl (300 ml); the mixture was extracted with dichloromethane (3x 500 ml). The combined organic layers were washed with brine (500 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Separation of the two regioisomeric products was accomplished by preparative HPLC to yield the pure product ieri-butyl ((4-benzyl-6-methyl-2-oxo- l,2-dihydropyridin-3-yl)methyl)carbamate (combined yield from two batches: 7.4 g) as yellow solid. - -
H NMR (400 MHz, CDC13) δ [ppm] = 7.16 - 7.33 (m, 5 H), 5.89 (s, 1 H), 5.67 (br. s, 1 H), 4.28 (d, 2 H), 4.07 (s, 2 H), 2.25 (s, 3 H), 1.43 (s, 9 H).
Intermediate 147A - 3-(aminomethyl)-4-benzyl-6-methylpyridin-2(lH) -one hydrochloride salt
Figure imgf000133_0001
A solution of ieri-butyl ((4-benzyl-6-methyl-2-oxo- l,2-dihydropyridin-3-yl) methyl)carbamate (intermediate 145A, 7.40 g, 31.57 mmol) in hydrochloric acid (4 N in ethyl acetate, 100 ml) was stirred at 20 °C for 3 h. Then the reaction was filtered and the filter cake was dried in vacuo to give the crude product 3-(aminomethyl)-4-benzyl-6-methyl pyridin-2(lH)-one hydrochloride (intermediate 147A, 6.00 g) as yellow solid. ¾ NMR (400 MHz, DMSO-d6) δ [ppm] = 11.93 (s, 1 H), 8.061 (br. s, 3 H), 7.29-7.33 (m, 2 H), 7.19-7.24 (m, 3 H), 5.87 (s, 1 H), 3.94 (s, 2 H), 3.85 (d, 2 H), 2.13 (s,3 H).
Synthesis of rac-ethyl {methyl(oxido)[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]- 6-sulfanylidene}carbamate - 150A (Scheme N)
Figure imgf000133_0002
149A 150A
Scheme N
Intermediate 149A - rac-ethyl [(4-bromophenyl)(methyl)oxido- 6-sulfanylidene]carbamate - -
Figure imgf000134_0001
To a suspension of rac-l-bromo-4-(methylsulfinyl)benzene (CAS 934-71-4, 100.0 g, 0.456 mol), ethyl carbamate (77.0 g, 0.864 mol), magnesium oxide (73.4 g, 1.821 mol) and dirhodium tetraacetate (4.7 g, 10.63 mmol) in dichloromethane (1.5 1) was added (diacetoxyiodo)benzene (CAS 3240-34-4 , 221.5 g, 0.688 mol) carefully under nitrogen. The mixture was stirred at room temperature for 7 d. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient of ethyl acetate in petroleum ether) to give the title compound (95.0 g, 68.0% of theory) as a white solid.
¾ NMR (400 MHz, CDC13) δ [ppm] = 7.87 - 7.85 (m, 2H), 7.76 - 7.74 (m, 2H), 4.13 - 4.08 (m, 2H), 3.30 (s, 3H), 1.28 - 1.22 (m, 3H).
Intermediate 150A - rac-ethyl {methyl(oxido)[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]- -sulfanylidene}carbamate
Figure imgf000134_0002
To a solution of intermediate 149A (95.0 g, 0.310 mol) in anhydrous dioxane (1.5 1) was added 4,4,4',4',5,5,5,,5,-octamethyl-2,2,-bi(l,3,2- dioxaborolane) (95.0 g, 0.374 mol), potassium acetate (61.0 g, 0.622 mol) and [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS 95464- 05-4, 7.0 g, 9.57 mmol ) under nitrogen. After the addition, the mixture was stirred at 80 °C for 18 h. The mixture was filtered and to the filtrate was added acetic acid (18.0 g, 0.30 mol) and pinacol (18.0 g, 0.152 mol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 20: 1 ~ 5: 1) to give the crude, which was washed by petroleum ether/ethyl acetate (2 x 100 ml, petroleum ether/ethyl acetate = 1: 10) to give the title compound (87.0 g) as a white solid. - -
¾ NMR (400 MHz, methanol-d4) δ [ppm] = 8.04 - 7.97 (m, 4H), 4.13 - 4.06 (m, 2H), 3.30 (s, 3H), 1.36 (s, 12H), 1.25 - 1.21 (m, 3H). Synthesis of rac-ethyl {methyl(oxido)[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]- 6-sulfanylidene}carbamate - 152A (Scheme O)
Figure imgf000135_0001
151 A 152A
Scheme O
Intermediate 151A - rac- ethyl [(3-bromophenyl)(methyl)oxido- 6-sulfanylidene]carbamate
Figure imgf000135_0002
To a suspension of rac-l-bromo-3-(methylsulfinyl)benzene (CAS 29959-92-0, 55.0 g, 0.251 mol), ethyl carbamate (45.0 g, 0.505 mol), magnesium oxide (40.3 g, 1.0 mol) and dirhodium tetraacetate (2.6 g, 7.6 mmol) in dichloromethane (600 ml) was added (diacetoxyiodo)benzene (CAS 3240-34- 4, 122.0 g, 0.378 mol) carefully under nitrogen. The mixture was stirred at room temperature for 5 d. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude, which was purified by column chromatography on silica gel (gradient of ethyl acetate in petroleum ether) to give rac-ethyl[(3-bromophenyl)(methyl)oxido-lambda6- sulfanylidene] carbamate (55.0 g, 81.4% of theory) as white solid.
¾ NMR (400 MHz, CDC13) δ = 8.15 - 8.14 (m, 1H), 7.94 - 7.92 (m, 1H), 7.81 - 7.80 (m, 1H), 7.51 - 7.47 (m, 1H), 4.13 - 4.08 (m, 2H), 3.32 (s, 3H), 1.25 (t, 3H). Intermediate 152A: rac-ethyl {methyl(oxido)[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]- 6-sulfanylidene}carbamate - -
Figure imgf000136_0001
To a solution of ethyl [(3-bromophenyl)(methyl)oxido-lambda6-sulfanylidene]carbamate (intermediate 151A, 55.0 g, 0.18 mol) in anhydrous dioxane (600 ml) was added 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi( 1,3,2- dioxaborolane) (53.0 g, 0.209 mol), potassium acetate (35.3 g, 0.34 mol) and [l, -Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS 95464-05-4, 4.0 g, 5.47 mmol ) under nitrogen. After the addition, the mixture was stirred at 80 °C for 4 h. The mixture was filtered and to the filtrate was added acetic acid (20.0 g, 0.33 mol) and pinacol (30.0 g, 0.253 mol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated and purified by chromatography on silica gel (gradient of ethyl acetate in petroleum ether) to give the crude, which was washed with petroleum ether/ethyl acetate (2 x 100 ml, petroleum ether: ethyl acetate = 1: 10) to give rac-ethyl {methyl(oxido)[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-lambda6-sulfanylidene} carbamate (35.0 g) as white solid. H NMR (400 MHz, methanol-d4) δ [ppm] = 8.40 (s, 1H), 8.09 - 8.07 (m, 1H), 7.61 - 7.58 (m, 1H), 4.13 - 4.07 (m, 2H), 3.32 (s, 3H), 1.35 (s, 12H), 1.25 - 1.22 (m, 3H).
Synthesis of 3-(aminomethyl)-4-isopropoxy-6-methylpyridin-2(lH)-one hydrochloride - 157A (Scheme P)
Figure imgf000136_0002
Scheme P - -
ethyl 2-(benzyloxy)-4-isopropoxy-6-methylnicotinate
Figure imgf000137_0001
To a solution of ethyl 2-(benzyloxy)-4-hydroxy-6-methylnicotinate (intermediate 111A, 2 g, 6.96 mmol), and potassium carbonate (2.89 g, 20.9 mmol) in DMF (60 ml) was added 2-iodopropane (0.76 ml, 7.66 mmol), and the reaction was stirred at room temperature for 12 h. Then, another 0.5 ml of 2-iodopropane were added and the mixture was stirred for 24 h. After this, the reaction mixture was filtered through a pad of Celite. The Celite was washed with ethyl acetate, and the combined filtrates were concentrated. The residue was treated with dichloromethane, and the resulting precipitate was filtered off and washed with dichloromethane. The combined filtrates were concentrated in vacuo to yield the title compound as a yellow oil (2.1 g, 90%),
H-NMR (400MHz, DMSO-d6) δ [ppm] = 1.16 - 1.28 (m, 9H), 2.37 (s, 3H), 4.22 (q, 2H), 4.74 (spt, 1H), 5.35 (s, 2H), 6.75 (s, 1H), 7.23 - 7.43 (m, 5H).
MS (ESI): [M + H]+ = 330.2.
Intermediate 154A - [2-(benzyloxy)-4-isopropoxy-6-methylpyridin-3-yl]methanol
Figure imgf000137_0002
To a solution of ethyl 2-(benzyloxy)-4-isopropoxy-6-methylnicotinate (intermediate 153A, 2.1 g, 6.38 mmol) in toluene (30 ml) was added sodium bis(2-methoxyethoxy)aluminum hydride (1.98 g, 6.38 mmol), and the reaction mixture was stirred at 80 °C for 12 h, after which additional sodium bis(2-methoxyethoxy)aluminum hydride was added and stirred at 80 °C for further 2 h. The reaction was then cooled to 0 °C and 2N aqueous sodium hydroxide was added. The organic phase was separated, washed with brine, dried with sodium sulfate and concentrated. The residue was stirred in hexane, filtered and dried to give [2-(benzyloxy)-4-isopropoxy-6-methylpyridin-3- - - yl]methanol (1.6 g, 87%).
^-NMR (400MHz, DMSO-d6) δ [ppm]= 1.28 (d, 6H), 2.33 (s, 3H), 4.30 (t, 1H), 4.41 (d, 2H), 4.68 (spt, 1H), 5.33 (s, 2H), 6.62 (s, 1H), 7.24 - 7.41 (m, 3H), 7.43 - 7.52 (m, 2H).
MS (ESI): [M + H]+ = 288,1.
Intermediate 155A [2-(benzyloxy)-4-isopropoxy-6-methylpyridin-3-yl]methyl methanesulfonate
Figure imgf000138_0001
To a solution of [2-(benzyloxy)-4-isopropoxy-6-methylpyridin-3-yl]methanol (intermediate 154A, 1.6 g, 5.57 mmol) in dichloromethane (40 ml) was added N-ethyl-diisopropylamine 1.26 ml, 7.24 mmol), and methanesulfonyl chloride (0.7 g, 6.13 mmol) at 0 °C. The cooling bath was removed and the reaction was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and used directly in the following step. -(azidomethyl)-2-(benzyloxy)-4-isopropoxy-6-methylpyridine
Figure imgf000138_0002
To a solution of crude [2-(benzyloxy)-4-isopropoxy-6-methylpyridin-3-yl]methyl methanesulfonate (Intermediate 155A, 2.03 g) in DMF (60 ml) was added N-ethyl-diisopropylamine (1.26 ml, 7.22 mmol), followed by sodium azide (0.4 g, 6.11 mmol). The mixture was stirred at room temperature for 2 h. Then, 1 N aqueous sodium hydroxide was added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was used without purification in the following step. - -
Intermediate 157A 3-(aminomethyl)-4-isopropoxy-6-methylpyridin-2(lH)-one hydrochloride
Figure imgf000139_0001
To a solution of crude 3-(azidomethyl)-2-(benzyloxy)-4-isopropoxy-6-methylpyridine (intermediate 156A, 1.5 g) in ethanol (50 ml) was added glacial acetic acid (0.55 ml) and palladium dihydroxide on charcoal (20%) (400 mg). The reaction was put under hydrogen atmosphere at 40.12 bar and stirred for 24 h at 23 °C. The same amount of palladium catalyst was added and the hydrogenation was continued at 40.1 bar for further 24 h at 23 °C. The mixture was filtrated, the filter cake was washed with methanol (40 ml) and the filtrate was concentrated in vacuo. The residue was dissolved in ethanol, triturated with hydrochloric acid (4 N in dioxane) and concentrated, re-dissolved and concentrated several times from ethanol, to yield 3-(aminomethyl)- 4-isopropoxy-6-methylpyridin-2(lH)-one hydrochloride (760 mg, 58% over 3 steps).
H-NMR (400MHz, DMSO-d6) δ [ppm]= 1.29 (d, 6H), 2.20 (s, 3H), 3.71 (q, 2H), 4.61 - 4.84 (m, 1H), 6.19 (s, 1H), 7.94 (br. s., 3H), 11.71 (br. s., 1H). Synthesis of 3-(Aminomethyl)-4-ethoxy-6-methylpyridin-2(lH)-one - 162A
(Scheme R)
Figure imgf000139_0002
160A 1 61 A 162A
Scheme R - -
Intermediate 158A - Ethyl 2-(benzyloxy)-4-(cyclobutylmethoxy)-6-methylnicotinate
Figure imgf000140_0001
A mixture of intermediate 103A (2.0 g, 6.96 mmol), potassium carbonate (2.89 g, 20.9 mmol) and (bromomethyl)cyclobutane (11.4 g, 7.66 mmol) in DMF (60 mL) was stirred at room temperature under an argon atmosphere for 18 h. The mixture was filtered over celite and the celite cake was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was mixed with dichloromethane (0.60 1). The solids were filtered and washed with dichloromethane. The filtrate was concentrated in vacuo to give intermediate 158A, 1.62 g (65 %) as yellow oil.
¾-NMR (400MHz, DMSO-d6): δ [ppm]= 1.21 (t, 3H), 1.72 - 1.94 (m, 4H), 1.95 - 2.07 (m, 2H), 2.37 (s, 3H), 2.59 - 2.71 (m, 1H), 4.04 (d, 2H), 4.22 (q, 2H), 5.36 (s, 2H), 6.74 (s, 1H), 7.26 - 7.32 (m, 1H), 7.33 - 7.42 (m, 4H).
MS (ESI): [M + H]+ = 356.2.
Intermediate 159A - [2-(benzyloxy)-4-(cyclobutylmethoxy)-6-methylpyridin-3-yl]methanol
Figure imgf000140_0002
To sodium bis(2-methoxyethoxy)aluminum dihydride (1.54 ml; 65% in toluene, 5.1 mmol) in toluene (1 1) was slowly added intermediate 158A (1.8 g, 5.1 mmol) in toluene (30 ml) at room temperature. The temperature rose to 30 °C and the mixture was stirred at room temperature for 12 h under an argon atmosphere; A further portion of sodium bis(2-methoxyethoxy)aluminum dihydride (1.54 ml, 5.1 mmol) was added slowly to the reaction mixture, then the reaction mixture was heated at 80 °C (oil bath temperature) for 2 h. The reaction mixture was cooled to 5 °C in an - - ice bath, and aqueous sodium hydroxide (2 M) was added dropwise. The organic partition was collected and washed with brine (2 x 20 mL), dried over sodium sulfate, filtered and concentrated to give a crude yellow solid. The crude product was suspended in hexane and filtered to yield intermediate 105A, 1.1 g (44 %).
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.79 - 1.96 (m, 4H), 2.01 - 2.13 (m, 2H), 2.34 (s, 3H), 2.62 - 2.80 (m, 1H), 4.01 (d, 2H), 4.44 (br. s., 2H), 5.34 (s, 2H), 6.62 (s, 1H), 7.21 - 7.41 (m, 4H), 7.46 (m, 1H). MS (ESI): [M + H]+ = 314.2.
[2- (benzyloxy) -4- (cyclobutylmethoxy)- 6-methylpyridin-3-yl] methyl
Figure imgf000141_0001
To an ice-cooled solution of intermediate 159A (1.1 g, 3.5 mmol) in dichloromethane (40 ml) was added A^ -diisopropylefhylamine (0.80 ml, 4.56 mmol), followed by methanesulfonyl chloride (0.30 ml, 3.86 mmol) being added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The solvent was removed in vacuo (water bath 20 °C) to yield intermediate 160A, which was used in the next step without purification.
Intermediate 161A - 3-(azidomethyl)-2-(benzyloxy)-4-(cyclobutylmethoxy)-6-methylpyridine
Figure imgf000141_0002
To intermediate 160A (1.37 g, crude product from the previous reaction) in DMF (40 ml) was added diisopropylethylamine (0.79 ml, 4.55 mmol), followed by sodium azide (0.25 g, 3.85 mmol), - - and the reaction mixture was stirred under argon at room temperature for 2 h. The reaction mixture was quenched with dilute sodium hydroxide solution (40 ml, 1 M) and extracted with ethyl acetate. The organic layer was collected and washed with brine solution, dried over sodium sulfate, filtered and the solution was concentrated in vacuo, to yield intermediate 107A (1 g crude), which was used in the next step without purification.
Intermediate 162A - 3-(aminomethyl)-4-(cyclobutylmethoxy)-6-methylpyridin-2(lH)-one hydrochloride
Figure imgf000142_0001
To intermediate 161A (crude material from the previous reaction) in an autoclave was added ethanol (50 ml) and acetic acid (0.34 ml; 5.91 mmol) followed by palladium hydroxide (20% on charcoal, 207 mg, 0.3 mmol). The autoclave was pressurized with hydrogen (40 bar) and the reaction mixture was stirred for 42 h at room temperature. A further portion of palladium hydroxide was added (210 mg) and the reaction mixture was pressurized with hydrogen (40 bar) and stirred for 20 h. The reaction mixture was filtered through celite, washed with methanol and the solvent removed in vacuo. The residue was triturated with hydrochloric acid (4N in dioxane) and concentrated in vacuo. The crude material was then redissolved in ethanol and concentrated several times to yield after final concentration intermediate 162A (657 mg, 72% over three steps).
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.81 - 1.91 (m, 4H), 2.00 - 2.09 (m, 2H), 2.21 (s, 3H), 2.63 - 2.75 (m, 1H), 3.73 (m, 2H), 4.05 (d, 2H), 6.19 (s, 1H), 7.86 (br. s., 2H), 11.74 (br. s., 1H).
- -
Intermediate 201A - 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]- l-isopropylimidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000143_0001
6 g 7-Chloro-l-(propan-2-yl)imidazo[l,5-a]pyridine-5-carboxylic acid (intermediate 8A, 25.1 mmol), 5.04 g 3-(aminomethyl)-4-ethoxy-6-methylpyridin-2(lH)-on (intermediate 108A, 27.65 mmol) and 12.4 g 0-(7-azabenzotriazol-l-yl)-/V,A',/V',/V'-tetramethyluronium hexafluorophosphate (HATU, 32.68 mmol) were dissolved in 180 ml anhydrous DMF and treated with 10.9 ml N,N- diisopropylethylamine (62.85 mmol, 2.5 eq.). The resulting mixture was stirred at room temperature overnight. The mixture was then poured into water and the solid material was filtered off. The filter cake was triturated with methanol, filtered and the solid was dried in vacuo to yield 4.5 g (46%) of the target compound.
¾ NMR (400 MHz, DMSO-d6) δ [ppm] = 11.44 (br. s, 1 H), 8.77 (s, 1 H), 8.69 (t, 1 H), 7.91 (s, 1 H), 7.08 (s, 1 H), 6.08 (s, 1 H), 4.28 (d, 2 H), 4.08 (q, 2 H), 2.17 (s, 3 H), 1.23 - 1.27 (m, 9 H).
MS (ESI): [M + H]+ = 403.
Intermediate 202A - 7-chloro-l-isopropyl-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3- yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000143_0002
600 mg 7-Chloro- l-(propan-2-yl)imidazo[l,5-a]pyridine-5-carboxylic acid (intermediate 8A, 2.5 mmol), 498 mg 3-(aminomethyl)-6-methyl-4-propylpyridin-2(lH)-one hydrochloride (intermediate 102A, 2.7 mmol) and 1.15 g 0-(7-azabenzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate (HATU, 3.02 mmol) were dissolved in 12 ml anhydrous DMF and treated with 1.09 ml A^ -diisopropylethylamine (6.28 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then poured into water and the solid material was filtered off to yield 718 mg (72%) of the target compound.
¾ NMR (400 MHz, DMSO) δ [ppm] = 11.53 (br. s, 1 H), 8.91 (t, 1 H), 8.81 (s, 1 H), 7.94 (s, 1 H), 7.12 (s, 1 H), 5.89 (s, 1 H), 4.34 (d, 2 H), 2.12 (s, 3 H), 1.44 - 1.57 (m, 2 H), 1.20 - 1.28 (d, 6 H), 0.88 (t, 3 H) (3 H obscured by solvent signal).
MS (ESI): [M + H]+ = 403.
Intermediate 203A - 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]- l-isopropyl-3-methylimidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000144_0001
265 mg Lithium 7-chloro-3-methyl-l-(propan-2-yl)imidazo[l,5-a]pyridine-5-carboxylate (intermediate 12A, 1.025 mmol) were dissolved in 5ml anhydrous DMF. 178 μΐ N V- diisopropylethylamine (6.28 mmol) and 389,59 mg 0-(7-azabenzotriazol-l-yl)-A',/V,/V',/V'- tetramethyluronium hexafluorophosphate (HATU, 3.02 mmol) were added 205 mg 3- (aminomethyl)-4-ethoxy-6-methylpyridin-2(lH)-one (intermediate 108A, 1,13 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. 10 ml water was added. The mixture was extracted with ethyl acetate (3 x 50 ml) and the combined organic layers were washed with brine, dried over sodium sulphate, filtered and the solvent was removed in vacuo. The crude product was dissolved into a minimum volume of hot ethyl acetate and cooled to room temperature to yield a yellow precipitate which was collected and washed with diethyl ether to yield 363 mg (42%) of the title compound as a yellow solid.
H NMR (400 MHz, methanol-d4) δ [ppm] = 1.29 (d, 6H), 1.40 (t, 3H), 2.29 (s, 3H), 2.52 (s, 3H), 3.24 (sept, 1H), 4.18 (q, 2H), 4.44 (s, 2H), 6.22 (s, 1H), 6.65 (d, 1H), 7.58 (d, 1H) (2 H obscured by solvent signal). - -
MS (ESI): [M + H]+ = 417
Intermediate 204A - rac-l-sec-butyl-7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2- dihydropyridin-3-yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000145_0001
200 mg rac-l-sec-butyl-7-chloroimidazo[l,5-a]pyridine-5-carboxylic acid (intermediate 19A, 0.79 mmol) were dissolved in 7.5ml anhydrous dimethylformamide. 414 μΐ N,N-diisopropylethylamine (2.37 mmol) and 451.4 mg 0-(7-azabenzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate (HATU, 1.19 mmol) were added 216 mg 3-(aminomethyl)-4-ethoxy-6- methylpyridin-2(lH)-one (intermediate 108A, 1.5 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude was purified by flash chromatography on a NH-Silica Phase with dichloromethane 100% to dichloromethane/ methanol 80%/20% as eluent to yield 230.8 mg (70%) of the title compound.
^-NMR (400MHz, DMSO-d6) δ [ppm]= 0.72 (t, 3H), 1.21 - 1.30 (m, 6H), 1.54 - 1.74 (m, 2H), 2.18 (s, 3H), 3.06 (sxt, 1H), 4.09 (q, 2H), 4.29 (d, 2H), 6.09 (s, 1H), 7.08 (d, 1H), 7.90 (d, 1H), 8.70 (t, 1H), 8.80 (s, 1H), 11.46 (s, 1H).
MS (ESI): [M + H]+ = 417.1
The following intermediates were prepared in analogy to intermediates 201A, 202A, 203A, and 204A by amide coupling of the respective carboxylic acids (intermediate 8A or intermediate 19A) derivatives with respective aminomethylpyridone derivatives, which are described above. - -
0.90 (m, (s,
(br.
(d, (br.
Figure imgf000146_0001
- -
(d, (s, 2H),
(t,
(t,
(d, (d, IH), (s,
Figure imgf000147_0001
- -
Figure imgf000148_0001
Intermediates 205.1 A and 205.2A where obtained from separation of enantiomers of Intermediate 205A by chiral SFC:
System: Sepiatec: Prep SFCIOO,
Column: Chiralpak ID 5μιη 250x20 mm
Solvent: C02 / 2-Propanol 77/23
flow: 80 ml/min
pressure( outlet): 150 bar
temperature: 40°C
detection: UV 254 nm
fraction Rt in min - -
Figure imgf000149_0003
Figure imgf000149_0001
Analytic chiral SFC:
Figure imgf000149_0004
Rt: 4.77 min
Figure imgf000149_0002
Analytic chiral SFC:
System: Agilent: 1260 AS, MWD, Aurora SFC-Modul:
Column: Chiralpak ID 5μιη 100x4.6 mm
Solvent: C02 / 2-Propanol 77/23 - -
Figure imgf000150_0002
Rt: 6.15 min
Intermediate 213A - 7-chloro-l-cyclopentyl-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin- 3-yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000150_0001
160 mg 7-chloro-l-cyclopentylimidazo[l,5-a]pyridine-5-carbonyl chloride (intermediate 27A, 0.79 mmol, 1 eq) were dissolved in 7.5 ml anhydrous dichloromethane. N,N-diisopropylethylamine (344 μΐ; 1.98 mmol) and 451.4 mg 3-(aminomethyl)-4-ethoxy-6-methylpyridin-2(lH)-one (intermediate 108A) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with dichloromethane. The remaining precipitate was filtered to provide 60 mg (25%) of the title compound as a solid. The dichloromethane layer was purified by flash chromatography to yield further 60 mg (25%).
¾-NMR (400MHz, DMSO-d6) δ [ppm]= 1.26 (t, 3H), 1.57 - 1.69 (m, 2H), 1.78 (br. s., 4H), 1.89 - 2.01 (m, 2H), 2.18 (s, 3H), 3.38 - 3.46 (m, 1H), 4.09 (q, 2H), 4.29 (d, 2H), 6.09 (s, 1H), 7.08 (s, 1H), 7.89 (s, 1H), 8.66 - 8.73 (m, 1H), 8.79 (s, 1H), 11.45 (br. s, 1H). MS (ESI): [M + H]+ = 429.2
The following intermediates were prepared in analogy to intermediate 212A by amide coupling of the respective carboxylic acid chloride (intermediate 27 A) with respective aminomethylpyridone derivatives, which are described above. - -
Figure imgf000151_0001
- -
Figure imgf000152_0001
- -
Figure imgf000153_0002
220A - 7-chloro-l-cyclopentyl-N-{[6-methyl-2-oxo-4-(2,2,2-trifluoroethoxy)-l,2- dihydropyridin-3-yl]methyl}imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000153_0001
100 mg 7-chloro-l-cyclopentylimidazo[l,5-a]pyridine-5-carboxylic acid (intermediate 26A, 0.378 mmol), 133.9 mg 3-(aminomethyl)-6-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2(lH)-one hydrochloride (1 : 1) (intermediate 116A, 0.49 mmol, 1.3 eq.) and 186.7 mg 0-(7-azabenzotriazol-l- yl A^ '-tetramethyluronium hexafluorophosphate (HATU, 0.49 mmol, 1.3 eq.) were dissolved in 2.14 mL anhydrous dimethylformamide and treated with 0.197 mL N,N- diisopropylethylamine (1.133 mmol, 3 eq.). The resulting mixture was stirred at room temperature overnight. The mixture was filtered and purified by preparative HPLC (condition 1) to yield 75 mg (41%) of the title compound. ¾-NMR (400MHz, DMSO-d6) δ [ppm]= 1.61 - 1.69 (m, 2H), 1.70 - 1.85 (m, 4H), 1.93 - 2.01 (m, 2H), 2.20 (s, 3H), 3.42 - 3.50 (m, 1H), 4.31 (d, 2H), 4.82 (q, 2H), 6.19 (s, 1H), 7.06 - 7.08 (m, 1H), 7.16 (d, 1H), 7.95 (d, 1H), 8.96 (s, 1H), 11.66 (s, 1H). - -
MS (ESI): [M + H]+ = 483.
Intermediate 221A - l-isopropyl-7 6-(morpholin-4-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5- carboxylic acid
Figure imgf000154_0001
A mixture of 7-chloro-l-(propan-2-yl)imidazo[l,5-a]pyridine-5-carboxylic acid, (intermediate 8A, 1 g, 4.19 mmol), [6-(morpholin-4-yl)pyridin-3-yl]boronic acid, 1.74 g (8.38 mmol), and sodium carbonate (0.88 g, 8.38 mmol) in 1,2-dimethoxy ethane (12 ml), ethanol (4 ml) and water (4 ml) was degassed by bubbling argon for 20 mins, then tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol) was added. The mixture was heated in a Biotage Initiator® microwave oven at 140 °C for 60 minutes. The mixture was partitioned between water and ethyl acetate. The aquous layer was acidified using concentrated aqueous hydrogen chloride and adjusted to pH 8 by adding saturated sodium bicarbonate solution. The resulting solid was collected by filtration to give the crude product. Sequential trituration (two times) from hot methanol gave the desired pure product (0.78 g, 50%). A small sample was solved in warm DMSO for NMR analysis.
1H NMR (400 MHz, DMSO-d6) [ppm]= 1.28 (d, 6H), 3.43-3.48 (m, 5H), 3.66-3.68 (m, 4H), 6.88 (d, 1H), 7.76 (s, 1H), 8.01 (d, 1H), 8.13 (s, 1H), 8.55 (s, 1H), 9.02 (s, 1H).
MS (ESI): m/z = (M+H)+ 367.
Intermediate 222A - 7-chloro-N-{[4-(cyclobutylmethoxy)-6-methyl-2-oxo-l,2-dihydropyridin- 3-yl]methyl}-l-isopropylimidazo[l,5-a]pyridine-5-carboxamide
- -
Figure imgf000155_0001
260 mg 7-chloro-l-isopropylimidazo[l,5-a]pyridine-5-carboxylic acid (intermediate 8A, 1.09 mmol), 291 mg 3-(aminomethyl)-4-(cyclobutylmethoxy)-6-methylpyridin-2(lH)-one hydrochloride (intermediate 162A, 1.1 mmol) and 538.5 mg 0-(7-azabenzotriazol-l-yl)-/V,A',/V',/V'- tetramethyluronium hexafluorophosphate (HATU, 1.4 mmol) were dissolved in 2.7 mL anhydrous dimethylformamide and treated with 0.57 mL N,N-diisopropylethylamine (3.27 mmol). The resulting mixture was stirred at room temperature overnight. To the mixture was added water and the resulting mixture was extracted with ethyl acetate. The organic phasesd were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, gradient of methanol in dichloromethane) to yeld 190 mg (40%) of the title compound.
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.26 (d, 6H), 1.75 - 1.86 (m, 4H), 1.89 - 2.01 (m, 2H), 2.18 (s, 3H), 2.61 - 2.70 (m, 1H), 3.32 - 3.41 (m, 1H, overlain by water signal), 4.00 (d, 2H), 4.30 (d, 2H), 6.11 (s, 1H), 7.18 (s, 1H), 7.98 (s, 1H), 8.72 (t, 1H), 8.97 (br. s., 1H), 11.47 (br. s., 1H).
MS (ESI): [M + H]+ = 443.2. Intermediate 223A - 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]- l-(tetrahydro-2H-pyran-4-yl)imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000155_0002
- -
100 mg 7-chloro-l-(tetrahydro-2H-pyran-4-yl)imidazo[l,5-a]pyridine-5-carboxylic acid (intermediate 33A, 0.36 mmol), 78 mg 3-(Aminomethyl)-4-ethoxy-6-methylpyridin-2(lH)-one (intermediate 108A, 0.43 mmol) and 176 mg 0-(7-azabenzotriazol-l-yl)-N,NN',N - tetramethyluronium hexafluorophosphate (HATU, 0.46 mmol) were dissolved in 3 ml anhydrous DMF and treated with 155 μΐ A^/V-diisopropylefhylamine (0.89 mmol). The resulting mixture was heatet in a microwave oven at 110 °C for 1 h. The mixture was then poured into water and the solid material was filtered off to yield 79 mg (50%) of the target compound.
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.26 (t, 3H), 1.61 - 1.71 (m, 2H), 1.78 - 1.96 (m, 2H), 2.14 - 2.21 (s, 3H), 3.18 - 3.30 (m, 1H, overlain by water signal), 3.41 - 3.52 (m, 2H), 3.94 (dd, 2H), 4.09 (q, 2H), 4.29 (d, 2H), 6.09 (s, 1H), 7.10 (d, 1H), 7.98 (d, 1H), 8.71 (t, 1H), 8.81 (s, 1H), 11.45 (br. s., 1H).
MS (ESI): [M + H]+ = 445
The following intermediates were prepared in analogy to intermediate 223A by amide coupling of the respective carboxylic acid (intermediate 33A) with respective aminomethylpyridone derivatives, which are described above.
Figure imgf000157_0001
- -
7-chloro-N-
33A, { [4-
137A, (difluoromet
reaction hoxy)-6- 1H-NMR (400MHz, DMSO- was methyl-2- Y d6): δ [ppm]= 1.61 - 1.69 (m, carried oxo-1,2- 2H), 1.79 - 1.94 (m, 2H), 2.21 out at dihydropyrid rVH (s, 3H), 3.22 - 3.29 (m, IH, room in-3- °-vNH ° overlain by water signal), 3.42 temperatu yl]methyl}- - 3.51 (m, 2H), 3.94 (dd, 2H), re 1- 4.30 (d, 2H), 6.09 (s, 1H), 7.12 overnight (tetrahydro- (d, IH), 7.30 (t, IH), 7.99 (d, instead 2H-pyran-4- IH), 8.80 (s, IH), 8.87 (t, IH), under yl)imidazo[l 11.92 (s, IH).
microwav ,5- e heating. a]pyridine-5- carboxamide
- -
Example 1 - N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-7-[3-fluoro-4- (morpholin-4-yl)phenyl]-l-isopropylimidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000159_0001
100 mg (0.25mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 83.9 mg (0.27 mmol) 4-[2- fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]morpholine and 29 mg (25 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.25 ml (0.5 mmol) aqueous sodium carbonate solution (2N), 1.5 ml toluene und 1.5 ml 1,2-dimethoxy ethane was added and the resulting mixture heated for 45 min to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in dimethylformamide, filtered and purified by HPLC (preparative HPLC conditions 1) to yield 37 mg (26%) of the target compound. H NMR (300 MHz, DMSO-d6) δ [ppm] = 1.24 (t, 3 H), 1.29 (d, 6 H), 2.17 (s, 3 H), 3.04 (m, 4 H), 3.46 (sept., 1 H), 3.75 (m, 4 H), 4.08 (q, 2 H), 4.33 (d, 2 H), 6.09 (s, 1 H), 7.09 (t, 1 H), 7.43 (s, 1 H), 7.62 (dd, 1 H), 7.72 (dd, 1 H), 8.03 (s, 1 H), 8.72 (t, 1 H), 8.83 (s, 1 H), 11.46 (s, 1 H).
LCMS (conditions 2.2): Rt 0,87min; MS (ESI): [M + H]+ = 546.3.
Example 2 - N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l-isopropyl-7-[6- (4-methylpiperazin-l-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide - -
Figure imgf000160_0001
150 mg (0.37 mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 124.2 mg (0.41 mmol) 1- methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and 43 mg (37 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.37 ml (0.75 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 2 ml toluene were added and the resulting mixture heated for lh to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by silica gel column chromatography (eluent: gradient of methanol in dichloromethane) to yield 92 mg of the slightly impure target compound. Further purification by preparative HPLC (see subsequent box for details) provided 49 mg (24%) of the target compound in pure form.
Figure imgf000160_0002
H NMR (300 MHz, DMSO-d6) δ [ppm] = 1.24 (t, 3 H), 1.29 (d, 6 H), 2.17 (s, 3 H), 2.21 (s, 3 H), 2.38-2.41 (m, 4 H), 3.43 (m, IH), 3.51-3.54 (m, 4 H), 4.08 (q, 2H), 4.33 (d, 2 H), 6.08 (s, 1 H), 6.91 (d ,1 H), 7.44 (s, 1 H), 7.95 (s, 1 H), 8.01 (dd, IH), 8.59 (d, IH), 8.69 (t, 1 H), 8.82 (s, 1 H), 11.45 (s, 1 H).
LCMS (conditions 2.2): Rt 0.51min; MS (ESI): [M + H]+ = 544.2.
Example 3 N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l-isopropyl-7-[2- (morpholin-4-yl)pyrimidin-5-yl]imidazo[l,5-a]pyridine-5-carboxamide - -
Figure imgf000161_0001
100 mg (0.25mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 79,5 mg (0.27 mmol) 4-[5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine and 29 mg (25 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.25 ml (0.5 mmol) aqueous sodium carbonate solution (2N), 0.8 ml ethanol und 1.5 ml 1,2-dimethoxy ethane was added and the resulting mixture heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue re- dissolved in DMSO, filtered and purified by HPLC (preparative HPLC conditions 1) to yield 37.5 mg (28%) of the target compound.
¾ NMR (400 MHz, DMSO-d6) δ [ppm] = 1.23 (t, 3 H), 1.29 (d, 6 H), 2.17 (s, 3 H), 3.43 (sept, 1 H), 3.67-3.75 (m, 8 H), 4.09 (q, 2 H), 4.34 (d, 2 H), 6.08 (s, 1 H), 7.46 (s, 1 H), 8.04 (s, 1 H), 8.61 (t, 1 H), 8.86 (s, 1 H), 8.88 (s, 2 H), 11.44 (s, 1 H).
LCMS (conditions 2.1): Rt 0,9 min; MS (ESI): [M + H]+ = 532.
Example 4 N- [(4-ethoxy-6-methyl-2-oxo- l,2-dihydropyridin-3-yl)methyl] -7-{3- [(ethylsulfonyl)-amino]phenyl}-l-isopropylimidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000161_0002
100 mg (0.25mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- - - isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 62.5 mg (0.27 mmol) { 3- [(ethylsulfonyl)amino]phenyl}boronic acid and 29 mg (25 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.25 ml (0.5 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxy ethane was added and the resulting mixture heated for lh to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue re- dissolved in dimethylsulf oxide, filtered and purified by HPLC (preparative HPLC conditions 1) to yield 50 mg (36%) of the target compound. ¾ NMR (400 MHz, DMSO-d6) δ [ppm] = 1.22 (t, 3 H), 1.26 (q, 3 H), 1.32 (d, 6 H), 2.17 (s, 3 H), 3.14 (q, 2 H), 3.44 (sept., 1 H), 4.1 (q, 2 H), 4.35 (dd, 2 H), 6.09 (s, 1 H), 7.24 (d, 1 H), 7.37 (s, 1 H), 7.43 (t, 1 H), 7.54 (d, 1 H), 7.92 (s, 1 H), 8.77 (t, 1 H), 8.82 (s, 1 H), 9.84 (s, 1 H), 1 1.46 (s, 1 H)
LCMS (condition 2.3): Rt 0,94 min; MS (ESI): [M + H]+ = 552.
The following example compounds were synthesized in analogy to example compounds 1 to 4 by Suzuki coupling of intermediate 201A with the respective commercially available boronic acids (or their pinacolate esters) employing a palladium catalyst in the presence of a base in a suitable solvent system under microwave heating (1 10 to 140 °C). Temperature and reaction time were individually modified in order to achieve maximum turnover of starting material. The target compounds were in general isolated by preparative HPLC conditions, for example preparative HPLC conditions 1 or 2.
Figure imgf000162_0001
- -
Figure imgf000163_0001
- -
Figure imgf000164_0001
- -
Figure imgf000165_0001
- -
Figure imgf000166_0001
- -
Figure imgf000167_0001
- -
Figure imgf000168_0001
Figure imgf000169_0001
- -
Figure imgf000170_0001
- -
Figure imgf000171_0001
- -
Figure imgf000172_0001
Example 40 rac-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l-isopropyl-7- [4-(S-methylsulfonimidoyl)phenyl]imidazo[l,5-a]pyridine-5-carboxamide - -
Figure imgf000173_0001
Step 1)
100 mg (0.224 mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 95 mg (0.268 mmol) rac- ethyl {methyl(oxido)[4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl]-lambda6- sulfanylidene} carbamate (intermediate 152A) and 26 mg (22 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 1 ml ethanol, 1 ml 1,2-dimethoxyethane and 0.22 ml (0.45 mmol) aqueous sodium carbonate solution (2N), were added and the resulting mixture heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by silica gel column chromatography (eluent: gradient of ethyl acetate in hexane) to yield 100 mg (71%) of the title compound. MS (ESI): [M + H]+ = 594.
Step 2)
To a solution of the product of step 1 (100 mg, 0.17 mmol) in ethanol (3 ml) was added a solution of sodium ethanolate in ethanol (0.23 ml, 0.61 mmol) and the reaction was stirred at 70 °C overnight. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (conditions 1) to yield 25 mg (29%) of rac-N-[(4-ethoxy-6-methyl-2-oxo-l,2- dihydropyridin-3-yl)methyl]-l-isopropyl-7-[4-(S-methylsulfonimidoyl)phenyl]imidazo[l,5- a]pyridine-5-carboxamide. ^-NMR (400MHz, DMSO-d6): δ [ppm] = 1.25 (t, 3H), 1.32 (d, 6H), 2.18 (s, 3H), 3.10 (s, 3H), 3.50 (dt, 1H), 4.10 (q, 2H), 4.26 (br. s., 1H), 4.35 (d, 2H), 6.10 (s, 1H), 7.52 (d, 1H), 7.99 (d, 2H), 8.07 (d, 2H), 8.20 (s, 1H), 8.77 (t, 1H), 8.88 (s, 1H).
MS (ESI): [M + H]+ = 522. - -
Example 41 rac-N (4-ethoxy-6-methyl-2-oxo ,2-dihydropyridin-3-yl)methyl]-l-isopropyl-7- [3-(S-methylsulfonimidoyl)phenyl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000174_0001
Step 1) 100 mg (0.224 mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl]-l-isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 95 mg (0.268 mmol) rac-efhyl {methyl(oxido)[3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl]-lambda6- sulfanylidene} carbamate (intermediate 152A) and 26 mg (22 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 1 ml ethanol, 1 ml 1,2-dimethoxyethane and 0.22 ml (0.45 mmol) aqueous sodium carbonate solution (2N), were added and the resulting mixture heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by silica gel column chromatography (eluent: gradient of ethyl acetate in hexane) to yield 100 mg (71 %) of the title compound.
MS (ESI): [M + H]+ = 594.
Step 2)
To a solution of the product of step 1 (100 mg, 0.17 mmol) in ethanol (3 ml) was added a solution of sodium ethanolate in ethanol (0.23 ml, 0.61 mmol) and the reaction was stirred at 70 °C for 3 days. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (conditions 1) to yield 25 mg (29%) of rac-N-[(4-ethoxy-6-methyl-2-oxo-l,2- dihydropyridin-3-yl)methyl]-l-isopropyl-7-[4-(S-methylsulfonimidoyl)phenyl]imidazo[l,5- a]pyridine-5-carboxamide.
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.26 (t, 3H), 1.32 (d, 6H), 2.18 (s, 3H), 3.16 (s, 3H), 3.51 (m, 1H), 4.10 (q, 2H), 4.30 (s, 1H), 4.35 (d, 2H), 6.09 (s, 1H), 7.47 (d, 1H), 7.69 (t, 1H), 7.91 (d, 1H), 8.10 (d, 1H), 8.17 (s, 1H), 8.33 (s, 1H), 8.80 (t, 1H), 8.84 (s, 1H), 11.46 (br. s., 1H).
MS (ESI): [M + H]+ = 522. - -
Example 42 N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l-isopropyl-7-[6- (morpholin-4-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000175_0001
100 mg (0.25 mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 79.2 mg (0.27 mmol) 4-[5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine, 0.25 ml (0.50 mmol) aqueous sodium carbonate solution (2N), 29 mg (25 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 1 ml ethanol und 2 ml toluene was added and the resulting mixture heated for 45 min to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC (conditions 1) provided 24 mg (18%) of the target compound in pure form.
H-NMR (300MHz, DMSO-d6): d [ppm]= 1.25 (t, 3H), 1.30 (d, 6H), 2.18 (s, 3H), 3.39 - 3.47 (m, 1H), 3.48 - 3.53 (m, 4H), 3.68 - 3.75 (m, 4H), 4.09 (q, 2H), 4.34 (d, 2H), 6.10 (s, 1H), 6.94 (d, 1H), 7.46 (s, 1H), 7.98 (s, 1H), 8.06 (dd, 1H), 8.64 (d, 1H), 8.70 (t, 1H), 8.83 (s, 1H), 11.47 (br. s., 1H).
MS (ESI): [M + H]+ = 531.
Example 43 N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l-isopropyl-7-[4- (morpholin-4-yl)phenyl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000176_0001
100 mg (0.25 mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 50.9 mg (0.25 mmol) [4- (morpholin-4-yl)phenyl]boronic acid, 0.22 ml (0.50 mmol) aqueous solution of sodium carbonate (2N), 26 mg (22 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 1.5 ml ethanol und 1.5 ml 1,2-dimethoxyethane was added and the resulting mixture heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC (see box below) provided 22 mg (18%) of the target compound in pure form.
Figure imgf000176_0002
H-NMR (400MHz, DMSO-d6): d [ppm]= 1.25 (t, 3H), 1.30 (d, 6H), 2.18 (s, 3H), 3.11 - 3.21 (m, 4H), 3.44 (spt, 1H), 3.71 - 3.80 (m, 4H), 4.09 (q, 2H), 4.33 (d, 2H), 6.09 (s, 1H), 6.96 - 7.06 (m, 2H), 7.43 (d, 1H), 7.67 - 7.76 (m, 2H), 7.87 - 7.94 (m, 1H), 8.75 (t, 1H), 8.80 (s, 1H), 11.46 (s, 1H).
MS (ESI): [M + H]+ = 530.
Example 44 - 7-[4-(dimethylcarbamoyl)phenyl]-N-[(4-ethoxy-6-methyl-2-oxo-l,2- dihydropyridin-3-yl)methyl] -isopropyliinidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000177_0001
100 mg (0.25 mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 52.7 mg (0.273 mmol) [4- (dimethylcarbamoyl)phenyl]boronic acid and 28.7 mg (25 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.25 ml (0.50 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxy ethane were added and the resulting mixture heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC (condition 1) provided 57.7 mg (45%) of the target compound in pure form.
^-NMR (300MHz, DMSO-d6): δ [ppm]= 1.25 (t, 3H), 1.31 (d, 6H), 2.18 (s, 3H), 2.90 - 3.07 (m, 6H), 3.49 (spt, 1H), 4.09 (q, 2H), 4.34 (d, 2H), 6.09 (s, 1H), 7.46 - 7.55 (m, 3H), 7.91 (d, 2H), 8.13 (s, 1H), 8.78 (t, 1H), 8.88 (s, 1H), 11.47 (s, 1H).
MS (ESI): [M + H]+ = 516.
Example 45 - tert-butyl 4-[5-(5-{[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl]carbamoyl}-l-isopropylimidazo[l,5-a]pyridin-7-yl)pyridin-2-yl]piperazine-l- carboxylate
Figure imgf000178_0001
200 mg (0.5 mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 212.6 mg (0.546 mmol) tert- butyl 4-[5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine- 1 -carboxylate and 57.4 mg (50 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.5 ml (1.0 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 2 ml toluene were added and the resulting mixture heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by silica gel column chromatography (eluent: gradient of dichloromethane and dichloromethane/methanol) to yield 162 mg (52%) of the target compound.
¾-NMR (400MHz, DMSO-d6): δ [ppm]= 1.26 (t, 3H), 1.30 (d, 6H), 1.43 (s, 9H), 2.18 (s, 3H), 3.40 - 3.48 (m, 5H), 3.52 - 3.59 (m, 4H), 4.09 (q, 2H), 4.34 (d, 2H), 6.09 (s, 1H), 6.94 (d, 1H), 7.45 (d, 1H), 7.96 (d, 1H), 8.05 (dd, 1H), 8.63 (d, 1H), 8.69 (t, 1H), 8.83 (s, 1H), 11.45 (s, 1H).
MS (ESI+): [M + H]+ = 631.
Example 46 - N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l-isopropyl-7-[6- (piperazin-l-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide - -
Figure imgf000179_0001
130 mg (0,206 mmol) tert-butyl 4-[5-(5-{ [(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl] carbamoyl }- 1 -isopropylimidazo[ 1 ,5-a]pyridin-7-yl)pyridin-2-yl]piperazine- 1 - carboxylate (Example 45) were dissolved in dichloromethane (5 ml). 0.16 ml (2.064 mmol) trifluoroacetic acid was added. The reaction stirred at room temperature over night. The mixture was concentrated. The residue was purified by preparative HPLC (condition 1) to provided 54 mg (49%) of the target compound. ¾-NMR (300MHz, DMSO-d6): δ [ppm]= 1.25 (t, 3H), 1.31 (d, 6H), 2.18 (s, 3H), 3.17 - 3.26 (m, 4H), 3.42 - 3.52 (m, 1H), 3.73 - 3.81 (m, 4H), 4.09 (q, 2H), 4.34 (d, 2H), 6.10 (s, 1H), 7.04 (d, 1H), 7.49 (s, 1H), 8.02 (s, 1H), 8.12 (dd, 1H), 8.68 (d, 1H), 8.72 (br. t, 1H), 8.76 - 8.85 (m, 1H), 8.91 (br. s, 1H), 11.47 (br. s, 1H). MS (ESI): [M + H]+ = 530.
Example 47 - N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l-isopropyl-7-{4- [(4-methylpiperazin-l-yl)carbonyl]phenyl}imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000180_0001
100 mg (0.25 mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 201A), 90.2 mg (0.273 mmol) (4- methylpiperazin-l-yl)[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methanone and 28.7 mg (25 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.25 ml (0.50 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxyethane were added and the resulting mixture heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC (condition 1) provided 52.4 mg (37%) of the target compound in pure form.
¾-NMR (300MHz, DMSO-d6): δ [ppm]= 1.22 - 1.28 (m, 3H), 1.31 (d, 6H), 1.76 - 1.95 (m, 4H), 2.18 (s, 3H), 3.39 - 3.55 (m, 5H), 4.09 (q, 2H), 4.34 (d, 2H), 6.10 (s, IH), 7.51 (s, IH), 7.61 (d, 2H), 7.91 (d, 2H), 8.13 (s, IH), 8.78 (d, IH), 8.88 (s, IH), 11.47 (s, IH) (3 H obscured by solvent signal).
MS (ESI): [M + H]+ = 571.5.
Example 48 - l-isopropyl-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl]-7-[6- (morpholin-4-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide - -
Figure imgf000181_0001
Example 48 was independently prepared by two methods: Method 48-1
100 mg (0.25mmol) 7-chloro-l-isopropyl-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3- yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide (intermediate 202A), 86.9 mg (0.3 mmol) 4-[5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine, 0.25 ml (0.5 mmol) aqueous sodium carbonate solution (2N), 29 mg (25 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.5 ml ethanol und 1.5 ml 1,2- toluene was added and the resulting mixture heated for 45 min to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was filtered, concentrated in vacuo and the residue re- dissolved in dimethylformamide, filtered and purified by HPLC (for HPLC conditions see box below) to yield 20 mg (15%) of the target compound.
Figure imgf000181_0002
Method 48-11
To a solution of l-isopropyl-7-[6-(morpholin-4-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5- carboxylic acid (intermediate 221A) (135 mg, 0.37 mmol) and N-ethyldiisopropylamine (289 μΐ, 1.66 mmol) in DMF (1.5 ml) were subsequently added 0-(7-azabenzotriazol-l-yl)-/V,A',/V',/V'- tetramethyluronium hexafluorophosphate (HATU, 211 mg, 0.55 mmol), and 3-(aminomethyl)-6- methyl-4-propylpyridin-2(lH)-one hydrochloride (intermediate 102A, 120 mg, 0.55 mmol), and the mixture was stirred for 12 h at room temperature. The reaction mixture was then partitioned between water and ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, and the - - combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was pre purified by chromatography (Biotage KP-Sil, dichloromethane, methanol), to obtain l-isopropyl-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl]-7- [6-(morpholin-4-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide (157 mg, 54%).
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.88 (t, 3H), 1.30 (d, 6H), 1.52 (m, 2H), 2.13 (s, 3H), 3.43 - 3.54 (m, 5H), 3.67 - 3.77 (m, 4H), 4.40 (d, 2H), 5.92 (s, 1H), 6.94 (d, 1H), 7.55 (s, 1H), 8.03 (s, 1H), 8.06 (dd, 1H), 8.65 (d, 1H), 8.95 (m, 2H), 11.56 (br. s., 1H), (2 H obscured by solvent signal).
LCMS (Methode 2): Rt 0.83 min; MS (ESI): [M + H]+ = 529.
The following example compounds were synthesized in analogy to example compound 48 by Suzuki coupling (Method 48-1) of intermediate 202A or intermediate 212A with the respective commercially available boronic acids (or their pinacolate esters) employing a palladium catalyst in the presence of a base in a suitable solvent system under microwave heating (usually 110 °C). The reaction time and temperature was individually adapted in order to achieve maximum turnover of starting material. The target compounds were in general isolated by preparative HPLC, for example preparative HPLC conditions 1 or 2.
Example Name Structure Analytical data
1-isopropyl-N-
¾-NMR (400MHz, DMSO-
[(6-methyl-2- d6): δ [ppm]= 0.89 (t, 3H), oxo-4-propyl-
1.30 (d, 6H), 1.52 (sxt, 2H),
1,2-
2.13 (s, 3H), 3.38 - 3.49 (m, dihydropyridin-
1H), 3.68 (d, 4H), 3.75 (d,
3-yl)methyl]-7- Γ T
49 4H), 4.40 (d, 2H), 5.92 (s, 1H),
[2-(morpholin-
7.50 - 7.52 (m, 1H), 8.07 (d,
4-yl)pyrimidin-
1H), 8.84 - 8.88 (m, 2H), 8.89 5-
(s, 2H), 11.57 (br. s, 1H). yl]imidazo[l,5-
(2 H obscured by solvent a]pyridine-5- signal).
carboxamide
MS (ESI): [M + H]+ = 530.3 H),
H), H),
H),
(2
(m,
8.88 (s,
Figure imgf000183_0001
Figure imgf000184_0001
- -
(m, 3H), 6.63 (d,
by
5.92 (d,
(2
1.53
(t, (d,
Figure imgf000185_0001
- -
Figure imgf000186_0001
- -
Figure imgf000187_0001
- -
3.45 (d,
(t,
5.91
(s,
Figure imgf000188_0001
Example Name Structure Analytical data
¾-NMR (400MHz, DMSO-
7-(3,4- d6): δ [ppm]= 0.89 (t, 3H), dimethoxypheny
1.30 (d, 6H), 1.53 (sxt, 2H), l)- l-isopropyl-
2.13 (s, 3H), 3.48 (spt, IH),
N-[(6-methyl-2-
3.80 (s, 3H), 3.87 (s, 3H), 4.41 oxo-4-propyl- r I
¾vNH ° (d, 2H), 5.92 (s, IH), 7.05 (d,
1,2-
65 IH), 7.32 - 7.38 (m, 2H), 7.44 dihydropyridin-
(d, IH), 7.98 (d, IH), 8.78 (s,
3-
O H3C 3 IH), 8.96 (t, IH), 11.53 (s, IH) yl)methyl]imida H3C (2 H obscured by solvent zo[l,5- signal).
a]pyridine-5-
LCMS (conditions 2.5): carboxamide
Figure imgf000189_0001
MS (ESI): [M + H]+ = 503.3
¾-NMR (400MHz, DMSO- l-isopropyl-7- d6): δ [ppm]= 0.89 (t, 3H),
[4-(2-
1.30 (d, 6H), 1.53 (sxt, 2H), methoxyethoxy)
2.14 (s, 3H), 3.32 (s, 3H), 3.44 phenyl]-N-[(6-
(spt, IH), 3.66 - 3.70 (m, 2H), methyl-2-oxo-4-
4.12 - 4.16 (m, 2H), 4.41 (d, propyl-1,2-
66 2H), 5.92 (s, IH), 7.04 (d, 2H), dihydropyridin-
7.47 (d, IH), 7.76 (d, 2H),
3-
Figure imgf000189_0002
7.95 (d, IH), 8.81 (s, IH), 8.96 yl)methyl]imida
(t, IH), 1 1.53 (s, IH) (2 H zo[l,5- obscured by solvent signal). a]pyridine-5-
LCMS (conditions 2.5): carboxamide
Figure imgf000189_0003
MS (ESI): [M + H]+ = 517.3 l-isopropyl-7- ¾-NMR (400MHz, DMSO-
(4-methoxy-2,5- d6): δ [ppm]= 0.89 (t, 3H), dimethylphenyl) 1.28 (d, 6H), 1.51 (sxt, 2H),
67 -N-[(6-methyl- 2.1 1 (s, 3H), 2.14 (s, 3H), 2.27
2-oxo-4-propyl- (s, 3H), 3.33 - 3.41 (m, IH),
1,2- 3.81 (s, 3H), 4.37 (d, 2H), 5.89 dihydropyridin-
Figure imgf000189_0004
(s, 1H), 6.87 (s, lH), 7.10 (s,
3- lH), 7.14 (d, 1H), 7.58 (d,
Figure imgf000190_0001
Figure imgf000191_0001
- -
Figure imgf000192_0001
- -
(2
(m,
5.92 (d, IH), (2
(m, (s, 2H), (s,
Figure imgf000193_0001
Figure imgf000194_0001
- -
Figure imgf000195_0001
- -
Figure imgf000196_0002
Example 84 - 7-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-l-isopropyl-N-[(6-methyl-2-oxo-4- propyl-l,2-dihydropyridin-3-yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000196_0001
Step 1 - 1 -isopropyl-N- [(6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl] -7-(6- { 2- [(trimethylsilyl)oxy]propan-2-yl}pyridin-3-yl)imidazo[l,5-a]pyridine-5-carboxamide - -
Figure imgf000197_0001
To a solution of 7-chloro-l-isopropyl-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3- yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide (intermediate 202A) (250 mg, 0.62 mmol) and 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-{2-[(trimethylsilyl)oxy]propan-2-yl }pyridine (241 mg, 0.75 mmol) in tetrahydrofuran (10 ml) under an atmosphere of nitrogen was added potassium phosphate (0.5 M, 4.2 ml), followed by a solution of (2'-aminobiphenyl-2- yl)(chloro)dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)palladium (2nd generation Ruphos precatalyst) (98 mg, 125 mmol) in tetrahydrofuran (0.5 ml), and the reaction was stirred at 50 °C for 2 h. Water was added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken to the next step without purification.
LCMS (conditions 2.4): Rt 1.40 min; MS (ESI): [M + H]+ = 574.5.
Step 2
To a solution of crude l-isopropyl-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl]- 7-(6-{2-[(trimethylsilyl)oxy]propan-2-yl}pyridin-3-yl)imidazo[l,5-a]pyridine-5-carboxamide (crude from the previous step) in dichloromethane (10 ml) was added formic acid (5 ml) and the mixture was stirred for 1 h at room temperature. The mixture was the concentrated and pre-purified by chromatography (Biotage KP-NH, dichloromethane, methanol). After HPLC purification (preparative conditions 1), 7-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]- l-isopropyl-N-[(6-methyl-2- oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide (229 mg, 73%) was obtained.
^-NMR (400MHz, DMSO-d6): d [ppm] = 0.89 (t, 3H), 1.34 (d, 6H), 1.45 - 1.59 (m, 8H), 2.14 (s, 3H), 3.59 (dt, 1H), 4.42 (d, 2H), 5.93 (s, 1H), 7.80 (d, 2H), 8.30 (dd, 1H), 8.34 (s, 1H), 8.98 (d, 1H), 9.05 (t, 1H), 9.37 (br. s., 1H), 11.58 (br. s., 1H). (2 H obscured by solvent signal)
LCMS (conditions 2.4): Rt 0.88 min; MS (ESI): [M + H]+ = 502 - -
The following examples were prepared as described for example 48, method 48-11, by amide coupling of intermediate 221A with the respective aminomethylpyridone derivatives, which are described above.
Figure imgf000199_0001
Example 89 - N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l-isopropyl-3- methyl-7 6-(4-methylpiperazin-l-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide - -
Figure imgf000200_0001
80 mg (0.19 mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropyl-3-methylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 203A, 68.82 mg, 0.23 mmol) l-methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and 22 mg (19 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.192 ml (0.384 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxyethane were added and the resulting mixture heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC (Preparative HPLC conditions 2 (basic)) provided 60.7 mg (52%) of the target compound in pure form.
¾-NMR (300MHz, DMSO-d6): δ [ppm]= 1.22 - 1.34 (m, 9H), 2.17 (s, 3H), 2.22 (s, 3H), 2.37 - 2.43 (m, 4H), 2.46 (s, 3H), 3.35 - 3.44 (m, 1H), 3.48 - 3.57 (m, 4H), 4.10 (q, 2H), 4.29 (d, 2H), 6.08 (s, 1H), 6.86 - 6.93 (m, 2H), 7.78 (d, 1H), 7.94 (dd, 1H), 8.51 (d, 1H), 8.67 (t, 1H), 11.44 (s, 1H).
MS (ESI): [M + H]+ = 558.4.
The following example compounds were synthesized in analogy to example compound 89 by Suzuki coupling of intermediate intermediate 203A with the respective commercially available boronic acids (or their pinacolate esters) employing a palladium catalyst in the presence of a base in suitable solvent system under microwave heating (usually 110 °C). The reaction time and temperature was individually adapted in order to achieve maximum turnover of starting material. The target compounds were in general isolated by preparative HPLC conditions, for example preparative HPLC conditions 1 or 2. - -
Figure imgf000201_0001
- -
Figure imgf000202_0002
Example 93 -N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l-isopropyl-3- methyl-7-[6-(piperazin-l-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000202_0001
Step 1)
100 mg (0.24 mmol) 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- isopropyl-3-methylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 203A), 112,06 mg (0.29 mmol) tert-butyl 4- [5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine- 1 - carboxylate and 27.7 mg (24 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.24 ml (0.48 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxy ethane were added and the resulting mixture heated for lh to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography using dichloromethane and dichloromethane/methanol as eluent to provide 100 mg (64%) of the target compound in pure form.
^-NMR (300MHz, DMSO-d6): δ [ppm]= 1.24 - 1.31 (m, 9H), 1.43 (s, 9H), 2.17 (s, 3H), 2.47 (s, 3H), 3.40 - 3.48 (m, 4H), 3.50 - 3.59 (m, 4H), 4.10 (q, 2H), 4.29 (d, 2H), 6.09 (s, 1H), 6.87 - 6.96 (m, 2H), 7.80 (d, 1H), 7.98 (dd, 1H), 8.53 (d, 1H), 8.69 (t, 1H), 11.47 (s, 1H).
MS (ESI): [M + H]+ = 644.
Step 2)
100 mg (0,155 mmol) tert-butyl 4-[5-(5-{ [(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl] carbamoyl }- 1 -isopropyl-3-methylimidazo[ l,5-a]pyridin-7-yl)pyridin-2-yl]piperazine- 1 - carboxylate were dissolved in dichloromethane (2 ml)/ methanol (2 ml). 5 ml (729.2 mmol) 4 N - - hydrochloric acid in dioxane were added. The reaction stirred at room temperature over night. The mixture was concentrated. The residue was extracted with water and diethyl ether. The aqueous layer was adjusted to pH 9 with aqueous sodium bicarbonate solution and extracted with ethyl acetate/ tetrahydrofurane. Organic and aqueous layer were concentrated to remove the organic solvent. The aqueous suspension was filtered, washed with water and dried in vacuo to give 50.9 mg (60%) of the pure compound as a solid.
^-NMR (400MHz, DMSO-d6): δ [ppm]= 1.21 - 1.34 (m, 9H), 2.17 (s, 3H), 2.47 (s, 3H), 2.75 - 2.82 (m, 4H), 3.41 - 3.49 (m, 5H), 4.11 (q, 2H), 4.29 (d, 2H), 6.08 (s, 1H), 6.81 - 6.91 (m, 3H), 7.77 (s, 1H), 7.92 (dd, 1H), 8.50 (s, 1H), 8.63 - 8.70 (m, 1H), 11.42 (br. s, 1H).
MS (ESI): [M + H]+ = 544.
Example 94 - rac-l-sec-butyl-7-(4-methoxyphenyl)-N-[(6-methyl-2-oxo-4-propyl-l,2- dihydropyridin-3-yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000203_0001
100 mg (0.241 mmol) rac-l-sec-butyl-7-chloro-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydropyridin- 3-yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide (intermediate 205A), 54.9 mg (0.36 mmol) (4- methoxyphenyl)boronic acid and 27.8 mg (24 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.241 ml (0.482 mmol) aqueous sodium carbonate solution (2N), 1.0 ml ethanol und 1.5 ml toluene were added and the resulting mixture heated for 30 min to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (see box below) to provide 34.5 mg (29%) of the target compound in pure form.
System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO,
DAD 2996, SQD 3100
Column: XBrigde CI 8 5μιη 100x30 mm - -
Figure imgf000204_0002
¾-NMR (400MHz, DMSO-d6): δ [ppm]= 0.76 (t, 3H), 0.89 (t, 3H), 1.11 (s, 2H), 1.28 (d, 3H), 1.52 (sxt, 2H), 1.59 - 1.78 (m, 2H), 2.13 (s, 3H), 3.19 (sxt, 1H), 3.80 (s, 3H), 4.41 (d, 2H), 5.92 (s, 1H), 7.03 (d, 2H), 7.46 (d, 1H), 7.77 (d, 2H), 7.93 (s, 1H), 8.82 (s, 1H), 8.97 (t, 1H), 11.50 - 11.58 (m, 1H).
MS (ESI): [M + H]+ = 487.3
Example 95 - rac -sec-butyl-N (4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]- 7 6-(4-methylpiperazin-l-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000204_0001
50 mg (0.12 mmol) rac-l-sec-butyl-7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide (intermediate 204A), 64.4 mg (0.216 mmol) 1- methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and 20.8 mg (18 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.12 ml (0.24 mmol) aqueous sodium carbonate solution (2N), 0.75 ml ethanol und 0.75 ml toluene were added and the resulting mixture heated for 30 min to 130 °C in a Biotage Initiator® microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (Preparative HPLC conditions 1) to provide 38.2 mg (57%) of the target compound in pure form.
H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.76 (t, 3H), 1.22 - 1.30 (m, 6H), 1.59 - 1.78 (m, 2H), - -
2.18 (s, 3H), 2.23 (s, 3H), 2.39 - 2.45 (m, 4H), 3.12 - 3.22 (m, 1H), 3.51 - 3.57 (m, 4H), 4.10 (q, 2H), 4.34 (d, 2H), 6.09 (s, 1H), 6.92 (d, 1H), 7.44 (d, 1H), 7.93 (d, 1H), 8.01 (dd, 1H), 8.59 - 8.62 (m, 1H), 8.69 (t, 1H), 8.83 (s, 1H), 11.45 (br. s, 1H). MS (ESI): [M + H]+ = 558.3
The following example compounds were synthesized in analogy to example 95 by Suzuki coupling of intermediates 204A, 205A, 206A, 207A, 208A, 209A, 210A, or 211A, with the respective commercially available boronic acids (or their pinacolate esters) employing a palladium catalyst in the presence of a base in a suitable solvent system under microwave heating (usually 110 °C). The reaction time and temperature was individually adapted in order to achieve maximum turnover of starting material. The target compounds were in general isolated by preparative HPLC conditions, for example preparative HPLC conditions 1 or 2.
Figure imgf000205_0001
- -
Figure imgf000206_0001
- -
Example Name Structure Analytical data
¾-NMR (500MHz, DMSO- rac-l-sec-butyl- d6): δ [ppm]= 0.76 (t, 3H), N-[(6-methyl-2- 1.28 (d, 3H), 1.60 - 1.77 (m, oxo-4-propyl-l,2- 2H), 2.20 (s, 3H), 2.23 (s, 3H), dihydropyridin-3- 2.41 (t, 4H), 3.18 (sxt, IH), yl)methyl]-7-[6- 3.54 (t, 4H), 3.82 (s, 3H), 4.31
98 (4- (d, 2H), 6.13 (s, 1H), 6.92 (d, methylpiperazin- IH), 7.45 (d, IH), 7.94 (d, l-yl)pyridin-3- IH), 8.02 (dd, IH), 8.61 (d,
Figure imgf000207_0001
yl]imidazo[l,5- IH), 8.70 (t, IH), 8.83 (s, IH), a] pyridine- 5- 11.49 (br. s, IH). carboxamide LCMS (conditions 2.5):
Figure imgf000207_0002
MS (ESI): [M + H]+ = 544
¾-NMR (500MHz, DMSO- rac-l-sec-butyl- d6): δ [ppm]= 0.77 (t, 3H), N-[(4-methoxy-6- 1.29 (d, 3H), 1.60 - 1.78 (m, methyl-2-oxo-l,2- 2H), 2.20 (s, 3H), 3.18 (sxt, dihydropyridin-3- IH), 3.80 (s, 3H), 3.82 (s, 3H),
99 yl)methyl]-7-(4- 4.32 (d, 2H), 6.12 (s, IH), 7.03 methoxyphenyl)i (d, 2H), 7.42 (d, IH), 7.77 (d, midazo[l,5- 2H), 7.92 (d, IH), 8.75 (t, IH), a] pyridine- 5- 8.82 (s, IH), 11.48 (s, IH).
Figure imgf000207_0003
carboxamide LCMS (conditions 2.5):
Rt 0.93 min MS (ESI): [M + H]+ = 475 rac-l-sec-butyl- ¾-NMR (500MHz, DMSO-
N-{ [4- d6): δ [ppm]= 0.76 (t, 3H), (difluoromethoxy) 1.28 (d, 3H), 1.60 - 1.77 (m, -6-methyl-2-oxo- 2H), 2.21 (s, 3H), 2.24 (s, 3H),
100 1,2- 2.42 (t, 4H), 3.18 (sxt, 2H), dihydropyridin-3- 3.55 (t, 4H), 4.35 (d, 2H), 6.09 yl]methyl}-7-[6- (s, IH), 6.93 (d, IH), 7.46 - (4-
Figure imgf000207_0004
7.48 (m, IH), 7.95 (d, IH), methylpiperazin- 8.01 (dd, IH), 8.60 (d, IH), l-yl)pyridin-3- 8.81 (s, IH), 8.86 (t, IH), - -
Figure imgf000208_0001
- -
(m, 3H), 4.48 (d,
(m, 2H), 7.03 (d, IH), H
(m, (t, IH),
Figure imgf000209_0001
- -
Example Name Structure Analytical data
l-yl)pyridin-3- 8.59 (d, IH), 8.78 - 8.83 (m, yl]imidazo[l,5- 2H), 12.12 (br. s, IH) (2 H a] pyridine- 5- obscured by solvent signal). carboxamide LCMS (conditions 2.5):
Rt 0.75 min
MS (ESI): [M + H]+ = 592.34 rac-l-sec-butyl- H-NMR (500MHz, DMSO-
N-{ [4- d6): δ [ppm]= 0.77 (s, 3H), (difluoromethoxy) 1.28 (d, 3H), 1.61 - 1.80 (m, -6-methyl-2-oxo- 2H), 2.21 (s, 3H), 3.18 (sxt, 1,2- 1H), 3.81 (s, 3H), 4.35 (d, 2H),
106 dihydropyridin-3- 6.09 (s, IH), 7.03 (d, 2H), 7.35 yl]methyl}-7-(4- (t, IH), 7.45 (d, IH), 7.76 (d, methoxyphenyl)i 2H), 7.93 (d, IH), 8.80 (s, IH), midazo[l,5- 8.91 (t, IH), 11.91 (br. s, IH).
Figure imgf000210_0001
a] pyridine- 5- LCMS (conditions 2.5): carboxamide Rt 0.99 min
MS (ESI): [M + H]+ = 511.29
H-NMR (400MHz, rac-l-sec-butyl-7- CHLOROFORM-d): δ [ppm]= (4- 0.83 (t, 3H), 1.41 (d, 3H), 1.71 methoxyphenyl) - - 1.92 (m, 2H), 2.21 (s, 3H), N-{ [6-methyl-2- 3.09 (sxt, IH), 3.82 (s, 3H), oxo-4-(2,2,2- 4.50 (q, 2H), 4.66 (d, 2H),
107 trifluoroethoxy)- 5.83 (s, IH), 6.90 (d, 2H), 7.23
1,2- - 7.26 (m, IH), 7.49 (d, 2H), dihydropyridin-3- 7.60 (d, IH), 8.25 (br. s, IH), yl] methyl Jimidaz 9.09 (br. s., IH), 12.38 (br. s,
Figure imgf000210_0002
o[l,5-a]pyridine- IH). 5-carboxamide LCMS (conditions 2.5):
Rt 1.02 min
MS (ESI): [M + H]+ = 543.29 - -
1.61 (m, (s, IH),
-
(m, 6H), 7.31 (d,
Figure imgf000211_0001
- -
Figure imgf000212_0001
- -
Figure imgf000213_0002
Example 114 - rac-l-sec-butyl-N-{[4-(l,l-difluoropropyl)-6-methyl-2-oxo-l,2-dihydropyridin- 3-yl]methyl}-7 6-(piperazin-l-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000213_0001
Step 1)
80 mg (0.18 mmol) rac-l-sec-butyl-7-chloro-N-{ [4-(l,l-difluoropropyl)-6-methyl-2-oxo-l,2- dihydropyridin-3-yl]methyl }imidazo[l,5-a]pyridine-5-carboxamide (intermediate 209A), 90 mg (0.23 mmol) ieri-butyl 4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine- 1-carboxylate and 21 mg (18 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.22 ml (0.44 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxy ethane were added and the resulting mixture heated for 30 min to 130 °C in a Biotage Initiator® microwave oven. The reaction mixture was concentrated in vacuo and the residue was extracted with water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product (120 mg) was used directly in the following step.
LCMS (Methode 2.4): Rt = 1.22min - -
MS (ESI): [M + H]+ = 678.5
Step 2)
120 mg crude rac-tert-butyl 4-{5-[l-sec-butyl-5-({ [4-(l,l-difluoropropyl)-6-methyl-2-oxo-l,2- dihydropyridin-3-yl]methyl }carbamoyl)imidazo[l,5-a]pyridin-7-yl]pyridin-2-yl}piperazine-l- carboxylate (crude product from previous step) were dissolved in tetrahydrofuran (10 ml) and methanol (5 ml). Then, hydrochloric acid in dioxane (4 N, 5 ml, 729.2 mmol) was added. The reaction mixture was stirred at room temperature over night. The mixture was concentrated and purified by preparative HPLC (conditions 1) to give 3.3 mg (3%) of the pure compound as a solid.
¾-NMR (500MHz, DMSO-d6): δ [ppm]= 0.76 (t, 3H), 0.98 (t, 3H), 1.28 (d, 3H), 1.60 - 1.80 (m, 2H), 2.18 - 2.31 (m, 5H), 2.85 (t, 4H), 3.14 - 3.21 (m, 1H), 3.51 (t, 4H), 4.41 (d, 2H), 6.11 (s, 1H), 6.92 (d, 1H), 7.44 (d, 1H), 7.95 (d, 1H), 8.00 (dd, 1H), 8.18 (s, 1H), 8.60 (d, 1H), 8.78 - 8.81 (m, 1H) (2H not visible)
MS (ESI): [M + H]+ = 578.3
The following example was synthesized in analogy to example 114:
Figure imgf000214_0001
- -
Example 116- l-cyclopentyl-N (4-methoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]- 7-(4-methoxyphenyl)imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000215_0001
50 mg (0.117 mmol) 7-chloro-l-cyclopentyl-N-[(4-ethoxy-6-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide (intermediate 213A), 31.88 mg (0.21 mmol) (4- methoxyphenyl)boronic acid and 20.2 mg (17 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.117 ml (0.233 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxyethane were added and the resulting mixture heated for 30 min to 130 °C in a Biotage Initiator® microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (conditions 1) to provide 23.6 mg (37%) of the target compound in pure form.
^-NMR (400MHz, DMSO-d6): δ [ppm]= 1.25 (t, 3H), 1.61 - 1.72 (m, 2H), 1.76 - 1.87 (m, 4H), 1.94 - 2.04 (m, 2H), 2.18 (s, 3H), 3.53 (quin, 1H), 3.80 (s, 3H), 4.09 (q, 2H), 4.34 (d, 2H), 6.09 (s, 1H), 7.02 (d, 2H), 7.43 (d, 1H), 7.77 (d, 2H), 7.93 (d, 1H), 8.74 (t, 1H), 8.82 (s, 1H), 11.45 (s, 1H).
LCMS (conditions 2.5): Rt = 1.02 min; MS (ESI): [M + H]+ = 501.32 Example 117 - l-cyclopentyl-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl]-7- [6-(4-methylpiperazin-l-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000215_0002
- -
50 mg (0.117 mmol) 7-chloro-l-cyclopentyl-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3- yl)methyl]imidazo[l,5-a]pyridine-5-carboxamide (intermediate 214A), 63.9 mg (0.21 mmol) 1- methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and 20.3 mg (18 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.117 ml (0.233 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxyethane were added and the resulting mixture heated for 30 min to 130 °C in a Biotage Initiator® microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (conditions 1) to provide 28.8 mg (38%) of the target compound in pure form.
¾-NMR (400MHz, DMSO-d6): δ [ppm]= 0.89 (t, 3H), 1.52 (sxt, 2H), 1.62 - 1.71 (m, 2H), 1.75 - 1.88 (m, 4H), 1.94 - 2.04 (m, 2H), 2.14 (s, 3H), 2.23 (s, 3H), 2.42 (t, 4H), 3.49 - 3.58 (m, 5H), 4.40 (d, 2H), 5.92 (s, 1H), 6.93 (d, 1H), 7.49 (d, 1H), 7.96 (d, 1H), 8.02 (dd, 1H), 8.61 (d, 1H), 8.82 (s, 1H), 8.91 (t, 1H), 11.54 (s, 1H) ) (3 H obscured by solvent signal).
LCMS (conditions 2.5): Rt = 0.79 min; MS (ESI): [M + H]+ = 568.38
The following example compounds were synthesized in analogy to example compounds 116 and 117 by Suzuki coupling of intermediates 213A, 214A, 215A, 216A, 217A, 218A, 219A, or 220A with the respective commercially available boronic acids (or their pinacolate esters) employing a palladium catalyst in the presence of a base in a suitable solvent system under microwave heating (usually 110 °C). The reaction time and temperature was individually adapted in order to achieve maximum turnover of starting material. The target compounds were in general isolated by preparative HPLC, for example preparative HPLC conditions 1 or 2.
Example Name Structure Analytical data
1-cyclopentyl-N- ¾-NMR (400MHz, DMSO-
{ [4- d6): δ [ppm]= 1.61 - 1.72 (m,
(methoxy methyl) - 2H), 1.75 - 1.87 (m, 4H), 1.94
6-methyl-2-oxo- rV" - 2.04 (m, 2H), 2.17 (s, 3H),
118 1,2- 3.48 - 3.58 (m, 1H), 3.80 (s, dihydropyridin-3- 3H), 4.36 (d, 2H), 4.47 (s, 2H), yl]methyl}-7-(4- 6.10 (s, 1H), 7.03 (d, 2H), 7.48 methoxyphenyl)i (d, 1H), 7.77 (d, 2H), 7.95 (d, midazo[l,5- 1H), 8.80 (s, 1H), 8.99 (t, 1H), a] pyridine- 5- 11.69 (s, 1H) (3 H obscured by - -
Example Name Structure Analytical data
carboxamide solvent signal).
LCMS (conditions 2.5):
Figure imgf000217_0001
MS (ESI): [M + H]+ = 501.32
^-NMR (400MHz, DMSO- d6): δ [ppm]= 1.61 - 1.72 (m,
1-cyclopentyl-N- 2H), 1.76 - 1.87 (m, 4H), 1.95 [(4-methoxy-6- - 2.04 (m, 2H), 2.20 (s, 3H), methyl-2-oxo-l,2- ■f-W "- 3.53 (quin, IH), 3.80 (s, 3H), dihydropyridin-3- (d, 2H), 6.12
119 yl)methyl]-7-(4- nr 3.81 (s, 3H), 4.31
(s, IH), 7.03 (d, 2H), 7.43 (d, methoxyphenyl)i
IH), 7.77 (d, 2H), 7.93 (d, midazo[l,5- IH), 8.74 (t, IH), 8.81 (s, IH), a] pyridine- 5- 1 1.48 (s, IH).
carboxamide
LCM s 2.5):
Figure imgf000217_0002
MS (ESI): [M + H]+ = 487.3
¾-NMR (400MHz, DMSO-
1-cyclopentyl-N- d6): δ [ppm]= 0.97 (s, 3H),
{ [4-(l,l- 1.62 - 1.71 (m, 2H), 1.76 - difluoropropyl)-6- 1.87 (m, 4H), 1.94 - 2.03 (m, methyl-2-oxo-l,2- 2H), 2.16 - 2.31 (m, 8H), 3.48 dihydropyridin-3- - 3.60 (m, 5H), 4.41 (d, 2H), yl]methyl}-7-[6- r i 6.1 1 (s, 1H), 6.51 (s, IH), 6.94
120
(4- (d, IH), 7.44 (d, IH), 7.97 (d, methylpiperazin- IH), 8.01 (dd, IH), 8.60 (d, l-yl)pyridin-3- IH), 8.77 - 8.82 (m, IH), yl]imidazo[l,5- 12.1 1 (br. s, IH). (4 H a] pyridine- 5- obscured by solvent signal). carboxamide LCMS (conditions 2.5):
Figure imgf000217_0003
MS (ESI): [M + H]+ = 604.35
Figure imgf000219_0001
- -
- (m,
7.03 (d, IH),
(m, 1.93 (s, 2H), 7.07
(m, 1.94
(d,
Figure imgf000220_0001
- -
Example Name Structure Analytical data
a] pyridine- 5- IH), 8.69 (t, IH), 8.83 (s, IH), carboxamide 1 1.49 (br. s, IH).
LCMS (conditions 2.5):
Rt 0.64 min MS (ESI): [M + H]+ = 556.35
^-NMR (400MHz, DMSO- d6): δ [ppm]= 1.63 - 1.72 (m,
N-[(4-benzyl-6- 2H), 1.75 - 1.86 (m, 4H), 1.94 methyl-2-oxo-l,2- - 2.03 (m, 2H), 2.1 1 (s, 3H), dihydropyridin-3- 2.23 (s, 3H), 2.41 (t, 4H), 3.49 yl)methyl]-l- - 3.58 (m, 5H), 3.95 (s, 2H), cyclopentyl-7-[6- 4.46 (d, 2H), 5.82 (s, IH), 6.94
129 (4- X (d, IH), 7.09 (sxt, IH), 7.20 methylpiperazin- (d, 4H), 7.43 (d, IH), 7.95 (d, l-yl)pyridin-3- 1 0 IH), 8.01 (dd, IH), 8.61 (d, yl]imidazo[l,5- IH), 8.79 (s, IH), 8.94 (t, IH), a] pyridine- 5- 1 1.62 (br. s, IH). carboxamide
LCMS (conditions 2.5):
Rt 0.80 min MS (ESI): [M + H]+ = 618
1-cyclopentyl-N- ¾-NMR (400MHz, DMSO-
{ [4- d6): δ [ppm]= 1.61 - 1.72 (m,
(difluoromethoxy) 2H), 1.76 - 1.86 (m, 4H), 1.94
-6-methyl-2-oxo- - 2.04 (m, 2H), 2.22 (d, 6H),
1,2- 2.37 - 2.43 (m, 4H), 3.47 - dihydropyridin-3- 3.59 (m, 5H), 4.35 (d, 2H),
130 yl]methyl}-7-[6- 6.09 (s, IH), 6.93 (d, 1H), 7.31
(4- (t, IH), 7.47 (d, IH), 7.97 (s, methylpiperazin- IH), 8.01 (dd, IH), 8.61 (d, l-yl)pyridin-3- IH), 8.80 (s, IH), 8.85 (t, IH), yl]imidazo[l,5- 1 1.91 (br. s, IH). a] pyridine- 5- LCMS (conditions 2.5): carboxamide Rt 0.70 min
MS (ESI): [M + H]+ = 592.41 - -
Figure imgf000222_0002
Example 132 - l-isopropyl-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl]-7- [6-(4-methylpiperazin-l-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide hydrochloride
Figure imgf000222_0001
l-isopropyl-N-[(6-methyl-2-oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl]-7-[2-(4- methylpiperazin-l-yl)pyrimidin-5-yl]imidazo[l,5-a]pyridine-5-carboxamide (example 71, 2.1 g, 4.1 mmol) was dissolved in dichloromethane (50 ml) and hydrogen chloride (4 N in dioxane, 10 ml, 40 mmol) was added. The solution was concentrated in vacuo, and to the residue was sequentially added dichloromethane, followed by concentration in vacuo; this procedure was performed three times. The residue was then dried under high vacuum to give the desired product, l-isopropyl-N-[(6-methyl-2-oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl]-7-[6-(4- methylpiperazin-l-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide hydrochloride (2.4 g). - -
Ή-NMR (400MHz, DMSO-d6): d [ppm]= 0.89 (t, 3H), 1.40 (d, 6H), 1.53 (dq, 2H), 2.15 (s, 3H), 2.52 - 2.56 (m, 2H, obscured by solvent signal), 2.79 (d, 3H), 2.99 - 3.19 (m, 2H), 3.35 - 3.43 (m, 2H), 3.51 (m, 2H), 3.75 (m, 1H), 4.40 - 4.44 (m, 2H, obscured by water signal), 4.49 - 4.57 (m, 2H, obscured by water signal), 5.95 (s, 1H), 7.19 (d, 1H), 7.97 - 8.11 (m, 1H), 8.28 (dd, 1H), 8.44 (s, 1H), 8.77 (d, 1H), 9.28 (t, 1H), 9.96 (s, 1H), 11.32 (br. s., 1H), 11.61 (br. s., 1H).
MS (ESI): [M + H]+ = 541.3 (parent compound)
Example 133 - N-{[4-(cyclobutylmethoxy)-6-methyl-2-oxo ,2-dihydropyridin-3-yl]methyl}-l- isopropyl-7 6-(4-methylpiperazin^-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000223_0001
80 mg (0.181 mmol) 7-chloro-N-{ [4-(cyclobutylmethoxy)-6-methyl-2-oxo-l,2-dihydropyridin-3- yl]methyl}-l-isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 222A), 71.2 mg (0.24 mmol) l-methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and 20.8 mg (18 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. Aqueous sodium carbonate solution (2N; 0.226 ml; 0.452 mmol), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxy ethane were added and the resulting mixture was heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (conditions 2) to provide 32 mg (31%) of the target compound in pure form.
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.30 (d, 6H), 1.72 - 1.86 (m, 4H), 1.88 - 2.00 (m, 2H), 2.18 (s, 3H), 2.22 (s, 3H), 2.40 (t, 4H), 2.57 - 2.66 (m, 1H), 3.44 (dt, 1H), 3.49 - 3.58 (m, 4H), 4.00 (d, 2H), 4.34 (d, 2H), 6.11 (s, 1H), 6.92 (d, 1H), 7.46 (d, 1H), 7.96 (d, 1H), 8.01 (dd, 1H), 8.60 (d, 1H), 8.68 (t, 1H), 8.84 (s, 1H), 11.48 (s, 1H).
MS (ESI): [M + H]+ = 584.5 - -
Example 134 - N-{[4-(cyclobutylmethoxy)-6-methyl-2-oxo-l,2-dihydropyridin-3-yl] isopropyl-7 6-(morpholin-4-yl)pyridin-3-yl]imidazo[l,5-a]pyridine-5-carboxamide
Figure imgf000224_0001
80 mg (0.181 mmol) 7-chloro-N-{ [4-(cyclobutylmethoxy)-6-methyl-2-oxo-l,2-dihydropyridin-3- yl]methyl}-l-isopropylimidazo[l,5-a]pyridine-5-carboxamide (intermediate 222A), 68.1 mg (0.24 mmol) 4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine and 20.8 mg (18 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. Aqueous sodium carbonate solution (2N; 0.226 ml; 0.452 mmol), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxy ethane were added and the resulting mixture was heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (conditions 2) to provide 33 mg (32%) of the target compound in pure form. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.30 (d, 6H), 1.69 - 1.85 (m, 4H), 1.88 - 2.00 (m, 2H), 2.18 (s, 3H), 2.56 - 2.66 (m, IH), 3.40 - 3.47 (m, IH), 3.48 - 3.54 (m, 4H), 3.66 - 3.76 (m, 4H), 4.00 (d, 2H), 4.34 (d, 2H), 6.11 (s, IH), 6.93 (d, IH), 7.47 (d, IH), 7.98 (d, IH), 8.05 (dd, IH), 8.64 (d, IH), 8.68 (t, IH), 8.85 (s, IH), 11.48 (s, IH). MS (ESI): [M + H]+ = 571.3
- -
Example 135 - N-[(4-methoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-7-[6-(4- methylpiperazin^-yl)pyridin-3-yl]-l-(tetrahydro-2H^yran-4-yl)iinidazo[l,5-a]pyridine-5-
Figure imgf000225_0001
90 mg (0.21 mmol) 7-chloro-N-[(4-methoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-l- (tetrahydro-2H-pyran-4-yl)imidazo[l,5-a]pyridine-5-carboxamide (intermediate 225A), 76.0 mg (0.25 mmol) l-methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and 24 mg (21 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. Aqueous sodium carbonate solution (2N; 0.26 ml; 0. 52 mmol), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxy ethane were added and the resulting mixture was heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (conditions 2) to provide 38 mg (31%) of the target compound in pure form.
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.70 (d, 2H), 1.92 (m, 2H), 2.19 (s, 3H), 2.22 (s, 3H), 2.37 - 2.43 (m, 4H), 3.44 - 3.62 (m, 7H), 3.81 (s, 3H), 3.97 (dd, 2H), 4.31 (d, 2H), 6.13 (s, 1H), 6.93 (d, 1H), 7.47 (d, 1H), 7.97 - 8.12 (m, 2H), 8.63 (d, 1H), 8.71 (t, 1H), 8.84 (s, 1H), 11.51 (br. s., 1H).
MS (ESI): [M + H]+ = 572.3
- -
Example 136 - N-{[4-(difluoromethoxy)-6-methyl-2-oxo-l,2-dihydropyridin-3-yl]
[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l-(tetrahydro-2H-pyran-4-yl)imidazo[l,5- a]pyridine-5-carboxamide trifluoroacetate
Figure imgf000226_0001
40 mg (86 μmol) 7-chloro-N-{ [4-(difluoromethoxy)-6-methyl-2-oxo-l,2-dihydropyridin-3- yl] methyl } - 1 -(tetrahydro-2H-pyran-4-yl)imidazo [ 1 ,5 - a] pyridine-5 -carboxamide (intermediate 226A), 31.2 mg (103 μιηοΐ) l-methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yljpiperazine and 9.9 mg (9 μιηοΐ) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. Aqueous sodium carbonate solution (2N; 0.107 ml; 0.214 mmol), 1.5 ml ethanol und 1.5 ml 1,2-dimethoxy ethane were added and the resulting mixture was heated for 1 h to 110 °C in a Biotage Initiator® microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (conditions 2) to yield 12 mg of impure product, which was further purified by preparative HPLC (conditions: see below) to provide 3 mg (6 %) of the trifluoroacetate salt of the target compound in pure form.
Conditions for final preparative HPLC:
Column: Waters XBrigde CI 8 5 μιη 100 x 30 mm;
Eluent: A: water + 0.2% vol. trifluoroacetic acid (99%); B: acetonitrile;
Gradient: 0.0-0.5 min 5% B, 0.51-5.5 min 5-50% B
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.71 (d, 2H), 1.87 - 2.01 (m, 2H), 2.22 (s, 3H), 2.86 (d, 3H), 3.04 - 3.22 (m, 5H), 3.40 - 3.57 (m, 6H, overlain by water signal), 3.99 (dd, 2H), 4.36 (d, 2H), 4.50 (d, 2H), 6.11 (s, 1H), 7.09 (d, 1H), 7.64 (br. s., 1H), 8.16 (dd, 1H), 8.20 (s, 1H), 8.72 (d, 1H), 8.97 (t, 1H), 9.15 (br. s., 1H), 9.73 (br. s., 1H).
MS (ESI): [M + H]+ = 608.2 Assays for profiling of Compounds of the present invention
A) Biochemical Assays Assay 1 - EZH2 wild type SPA assay
EZH2 wild type (wt) inhibitory activities of the compounds described in the present invention were quantified using a scintillation proximity assay (SPA) which measures methylation by the enzyme of the synthetic, biotinylated peptide ARTKQTAR-[Kme3]- STGGKAPRKQLATKAARKSAPATG-GVKKPHR-K(Btn)-Amin x TFA (Biosyntan) derived from Histone H3 and referred to from here on as H3(l-40)me3K9. The PRC2-EZH2 wt multiprotein complex used in the assay (composed by full length recombinant proteins Flag-EZH wt, SUZ12, EED and RbAp46/48) was purchased from Active Motif (Cat. No. 31387). In a typical assay 11 different concentrations of each compound (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 μΜ, 0.51 μΜ, 1.7 μΜ, 5.9 μΜ and 20 μΜ) were tested in duplicate within the same microti ter plate. To this end, 100-fold concentrated compound solutions (in DMSO) were previously prepared by serial dilution (1 :3.4) of 2 mM stocks in a clear low volume 384-well source microtiter plate (Greiner Bio-One), from which 50 nl of compounds were transferred into a white low volume test microtiter plate from the same supplier. Subsequently, 2.5 μΐ EZH2wt in aqueous assay buffer [50 mM Hepes pH 7.5 (Applichem), 2.75 mM dithiothreitol (DTT, Sigma), 0.01 % (w/v) bovine serum albumin (BSA, Sigma), 0.01 % (v/v) Pluronic (Sigma)] were added to the compounds in the test plate to a final enzyme concentration of typically ~ 0.7-1.0 ng/μΐ (this parameter was adjusted depending on the activity of the enzyme lot in order to be within the linear dynamic range of the assay). The samples were then incubated for 15 min at 22°C to allow pre-equilibration of the putative enzyme-inhibitor complexes before the start of the methylation reaction, which was initiated by the addition of 2.5 μΐ 2-fold concentrated solution (in assay buffer) of "cold" S-Adenosyl -L- Methionine (SAM, Sigma, final concentration: 0.875 μΜ), tritiated 3H-SAM (Perkin Elmer, final concentration: 0.125 μΜ) and H3(l-40)me3K9 peptide substrate (final concentration: 0.15 μΜ). The resulting mixture (5 μΐ final volume) was shortly centrifuged (2 min., 1500 rpm) and incubated at 22°C during 60 min. Thereupon the reaction was stopped by adding 3 μΐ of Streptavidin PS SPA imaging beads (Perkin Elmer, final concentration of 1.562 μg/μl) and "cold" SAM (AK Scientific, 250 μΜ final concentration) for non-specific binding reduction. Plates containing the stopped reaction were sealed with transparent adhesive foil (Perkin Elmer), centrifuged (2 min., 1500 rpm), and further incubated overnight at 4°C in order to allow the SPA signals to develop. Subsequently, the amount of product was evaluated by measuring the energy transfer from the β-particles emitted by the 3H-labeled substrate to the Europium scintillator co-polymerized in the polystyrene matrix of the PS imaging beads, using the standard settings for - - this purpose of a Viewlux (Perkin-Elmer) CCD plate imaging device (emission filter 613/55 (IFP). The resulting scintillation counts were taken as indicator for the amount of methylated peptide per well. The data were normalised using two sets of control wells (typically 16 each) for high- (= enzyme reaction with DMSO instead of test compound = 0 % = minimum inhibition) and low- (= all assay components without enzyme = 100 % = maximum inhibition) EZH2 wt activity. IC50 values were calculated by fitting the normalized inhibition data to a 4-parameter logistic equation.
Assay 2 - EZH2 Y641N SPA assay EZH2 Y641N inhibitory activities of the compounds described in the present invention were quantified using a scintillation proximity assay (SPA) which measures methylation by the enzyme of the synthetic, biotinylated peptide ARTKQTARKSTGGKAPRKQLATKAAR-K(Me2)- SAPATGGVKKPHR-K(Btn)-Amid x TFA (Biosyntan) derived from Histone H3 and referred to from here on as H3(l-40)me2K27. The human mutant PRC2- EZH2 Y641N multiprotein complex used in the assay (composed by full length recombinant proteins His-EZH Y641N, His-SUZ12, His-AEBP2, Flag-EED and His-RbAp48) was produced in-house by co-expression in Sf9 insect cells with N-terminal FLAG-tag and purification by affinity chromatography on an Anti-FLAG M2 (Sigma) column followed by a desalting step on a DS 26/10 column (GE Healthcare). In a typical assay 11 different concentrations of each compound (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 μΜ, 0.51 μΜ, 1.7 μΜ, 5.9 μΜ and 20 μΜ) were tested in duplicate within the same microti ter plate. To this end, 100-fold concentrated compound solutions (in DMSO) were previously prepared by serial dilution (1 :3.4) of 2 mM stocks in a clear low volume 384-well source microtiter plate (Greiner Bio-One), from which 50 nl of compounds were transferred into a white low volume test microtiter plate from the same supplier. Subsequently, 2.5 μΐ EZH2 Y641N in aqueous assay buffer [50 mM Hepes pH 7.5 (Applichem), 2.75 mM dithiothreitol (DTT, Sigma), 0.01 % (w/v) bovine serum albumin (BSA, Sigma), 0.01 % (v/v) Pluronic (Sigma)] were added to the compounds in the test plate to a final enzyme concentration of typically ~ 0.95 ng/μΐ (this parameter was adjusted depending on the activity of the enzyme lot in order to be within the linear dynamic range of the assay). The samples were then incubated for 15 min at 22°C to allow pre-equilibration of the putative enzyme-inhibitor complexes before the start of the methylation reaction, which was initiated by the addition of 2.5 μΐ 2-fold concentrated solution (in assay buffer) of "cold" S-adenosyl -L- Methionine (SAM, Sigma, final concentration: 0.875 μΜ), tritiated 3H-SAM (Perkin Elmer, final concentration: 0.125 μΜ) and H3(l-40)me2K27 peptide substrate (final concentration: 0.15 μΜ). The resulting mixture (5 μΐ final volume) was shortly centrifuged (2 min., 1500 rpm) and incubated at 22°C during 90 min. Thereupon the reaction was stopped by adding 3 μΐ of streptavidin PS SPA imaging beads (Perkin Elmer, final concentration of 1.562 μg/μl) and "cold" SAM (AK Scientific, 250 μΜ final concentration) for - - non-specific binding reduction. Plates containing the stopped reaction were sealed with transparent adhesive foil (Perkin Elmer), centrifuged (2 min., 1500 rpm), and further incubated overnight at 4°C in order to allow the SPA signals to develop. Subsequently, the amount of product was evaluated by measuring the energy transfer from the β-particles emitted by the 3H-labeled substrate to the Europium scintillator co-polymerized in the polystyrene matrix of the PS imaging beads, using the standard settings for this purpose of a Viewlux (Perkin-Elmer) CCD plate imaging device (emission filter 613/55 (IFP). The resulting scintillation counts were taken as indicator for the amount of methylated peptide per well. The data were normalised using two sets of control wells (typically 16 each) for high- (= enzyme reaction with DMSO instead of test compound = 0 % = minimum inhibition) and low- (= all assay components without enzyme = 100 % = maximum inhibition) EZH2 Y641N activity. IC50 values were calculated by fitting the normalized inhibition data to a 4-parameter logistic equation.
B) Cellular Assays
Assay 3 - H3K27me3 High Content Assay
Quantification of Histone H3 Lys27 Trimethylation (H3K27me3) after small molecule treatment of cancer cells
The H3K27me3-assay based on High-Content Analysis (HCA) enables the biological characterization of compounds inhibiting histone methyl transferase EZH2. By this assay, the substances are benchmarked on their cellular activity to modulate histone H3 modification levels on Lys 27 over broad inhibitor concentration ranges.
Cultivated cells of the human triple negative/basal-B breast adenocarcinoma tumor cell line MDA- MB-231 (ATCC HTB-26) were plated at a density of 2500 cells per well in a 384- well microtiter plate in 20 μΐ RPMI 1640 supplemented with 1% (v/v) glutamine, 1% (v/v) penicillin, 1% (v/v) streptomycin and 10% (v/v) fetal calf serum. After pre-incubation at 37°C overnight, test compounds solubilized in dimethyl sulfoxide (DMSO) were added at various concentrations (0 μΜ, as well as in the range of 0.005 μΜ - 30 μΜ; the final concentration of the solvent DMSO was 0.5% (v/v)). Cells were incubated at 37°C for 72h in the presence of test compounds. Thereafter, cells were fixed with 4% (v/v) paraformaldehyde in phosphate buffered saline (PBS) at room temperature for 12min, permeabilized using 0.5% (v/v) Triton XTM 100 in PBS and blocked with 1% (v/v) bovine serum albumin (BSA) in PBS. In the following, the cells were incubated with the histone-H3-specific H3K27me3 primary antibody (Cell Signaling #9733), followed by the species- specific fluorescent conjugated secondary antibody DyLight™488-conjugated goat anti-mouse - -
(Jackson Immuno Research #115-486-062) and Hoechst 33342 stain for chromatin staining and determination of total cell number. Primary antibodies were diluted in 1% (v/v) BS A/PBS containing 0.5% (v/v) Triton XTM 100 in PBS and the cells were incubated at 4°C for 16h after one hour blocking with the antibody diluent. Secondary antibodies were diluted in 0.5% (v/v) BSA/PBS containing 0.5% (v/v) Triton XTM 100 in PBS and 22 g/ml goat IgG (Jackson Immuno Research #005-000-003). After 15min blocking with secondary antibody diluent, the cells were incubated with the secondary antibodies at 37°C for lh. For chromatin staining, the cells were incubated for lOmin at room temperature using Hoechst at 4 g/ml. Antibodies and Hoechst 33342 were added at a volume of 20μ1 per well for 384-well microtiter plate. The cells were washed three times using PBS after each antibody or Hoechst 33342 incubation step. PBS was added and microtiter plates were stored at 4°C until analysis.
Image acquisition for cells was carried out using the confocal imaging system OPERA® (PerkinElmer). Images were captured using two channels: Hoechst 33342 stain (DNA) and DyLight™488 (H3K27me3 staining); and were analyzed using the MetaXpress® software (Molecular Devices). Exposure times were chosen for individual experiments to prevent saturation and allow for quantification in the linear range. A minimum of 1000 cells in 5 field views were analyzed per well using lOx water immersion objective with a two-fold binning. The image analysis routine was developed in MetaXpress®. The standardized image-analysis module "Count Nuclei" and the images of the DNA-channel were used for nuclei segmentation. The segmented nuclei were filtered for size, shape and signal intensity to exclude possible apoptotic and non-viable cells along with metaphase nuclei. These phenotypes result in overestimated antibody signals, due to their strong chromatin compaction. For further processing, binary object masks were calculated from the segmented and positively selected nuclei. The binary masks served as templates to be superimposed over the images of the H3K27me3 channel. The nuclear H3K27me3 average signal intensity was quantified for every image set. The assay raw data were further analyzed by four parameter logistic regression analysis using Genedata's Assay Analyzer and Condoseo software to determine the IC50 value for each tested compound.
- -
Activity Data for Compounds of the present invention
ICso [M]
ICso [M] ICso tM]
Y641N
Example # wt hEZH2 H3K27me3 hEZH2
(Assay 1) (Assay 3)
(Assay 2)
1 5.54 E-8 3.79 E-7 1.76 E-6
2 2.51 E-8 1.46 E-7 8.97 E-7
3 8.16 E-8 3.66 E-7 7.16 E-7
4 4.51 E-8 3.77 E-7 2.54 E-6
5 1.07 E-6 4.09 E-6 5.58 E-6
6 2.12 E-7
7 1.69 E-7 1.55 E-6 1.63 E-6
8 1.17 E-7 4.52 E-7 4.19 E-6
9 5.79 E-8 3.47 E-7 3.53 E-6
10 5.74 E-8 4.42 E-7 1.43 E-6
11 8.13 E-8 4.64 E-7 1.35 E-6
12 1.30 E-7 6.37 E-7 9.93 E-7
13 3.85 E-7 1.08 E-6
14 1.81 E-7 4.05 E-7 >5.00 E-6
15 1.90 E-7 1.28 E-6 5.39 E-6
16 3.98 E-7 4.53 E-6
17 1.15 E-7 6.96 E-7 2.62 E-6
18 9.78 E-8 6.94 E-7 6.39 E-6
19 1.64 E-7 6.15 E-7 2.01 E-6
20 9.80 E-8 5.98 E-7 1.55 E-6
21 6.20 E-8 7.28 E-7
22 4.61 E-7 3.07 E-6 >2.00 E-5
23 1.82 E-7 1.02 E-6
24 2.53 E-7 7.98 E-7
25 3.52 E-7 1.92 E-6 4.94 E-6
26 1.20 E-7 7.38 E-7
27 1.75 E-7 7.36 E-7
28 2.39 E-7 7.18 E-7
29 4.21 E-7 1.02 E-6 >4.30 E-5
30 7.80 E-7 1.26 E-6 -2.00 E-5
31 2.60 E-7 1.37 E-6 - -
ICso [M]
ICso [M] ICso tM]
Y641N
Example # wt hEZH2 H3K27me3 hEZH2
(Assay 1) (Assay 3)
(Assay 2)
32 1.21 E-7 1.46 E-6
33 5.47 E-7 3.55 E-6 5.93 E-6
34 2.33 E-7 1.76 E-6 2.00 E-5
35 1.69 E-7 1.84 E-6
36 2.54 E-6
37 7.40 E-7 2.75 E-6
38 1.51 E-7 2.94 E-6
39 8.82 E-7 3.04 E-6
40 4.79 E-8 3.42 E-7 1.25 E-5
41 4.47 E-8 3.68 E-7 2.10 E-6
42 4.75 E-8 3.44 E-7 7.44 E-7
43 6.77 E-8 5.53 E-7
44 6.12 E-8 5.11 E-7
45 1.22 E-7 1.14 E-6
46 2.18 E-8 1.38 E-7
47 3.38 E-8 2.72 E-7
48 2.20 E-8 3.30 E-7 7.04 E-7
49 1.95 E-8 4.07 E-7 6.81 E-8
50 3.41 E-8 5.52 E-7 1.05 E-6
51 6.42 E-8 8.52 E-7
52 6.39 E-7 1.84 E-5
53 1.40 E-8 1.63 E-7 1.00 E-6
54 7.44 E-8 1.65 E-6
55 3.04 E-8 6.12 E-7
56 7.11 E-8 1.75 E-6
57 7.10 E-8 1.60 E-6
58 1.65 E-7 5.40 E-6
59 4.30 E-7 1.71 E-5
60 5.75 E-8 1.02 E-6
61 1.51 E-7 2.61 E-6
62 4.51 E-8 7.18 E-7 3.58 E-6
63 9.11 E-8 1.91 E-6 1.00 E-5
64 6.49 E-8 9.64 E-7 6.65 E-6 - -
ICso [M]
ICso [M] ICso tM]
Y641N
Example # wt hEZH2 H3K27me3 hEZH2
(Assay 1) (Assay 3)
(Assay 2)
65 2.94 E-8 5.52 E-7 1.79 E-6
66 4.39 E-8 7.07 E-7 2.73 E-6
67 1.47 E-7 3.41 E-6
68 1.98 E-7 6.01 E-6
69 1.08 E-7 3.78 E-6
70 3.00 E-7 >2.00 E-5
71 1.05 E-8 1.99 E-7 4.60 E-8
72 2.04 E-8 3.98 E-7 1.29 E-6
73 3.22 E-8 3.08 E-7 2.97 E-6
74 1.86 E-8 3.81 E-7 1.79 E-6
75 5.55 E-8 9.07 E-7 5.09 E-6
76 8.27 E-8 9.61 E-7 2.15 E-6
77 3.62 E-8 3.57 E-7 3.64 E-6
78 2.55 E-8 4.84 E-7 1.84 E-7
79 1.18 E-8 1.68 E-7 1.14 E-7
80 2.46 E-8 2.70 E-7 3.34 E-7
81 3.57 E-8 6.45 E-7
82 6.39 E-9 1.02 E-7 5.19 E-8
83 9.77 E-9 2.43 E-7 4.98 E-8
84 1.95 E-8 4.02 E-7 4.12 E-7
85 1.87 E-8 2.34 E-7 1.55 E-6
86 5.56 E-8 1.02 E-6 1.00 E-6
87 2.99 E-8 6.23 E-7 2.16 E-6
88 3.17 E-8 1.23 E-7 4.00 E-6
89 2.92 E-8 2.57 E-7 8.82 E-7
90 4.59 E-8 5.81 E-7
91 3.02 E-7 2.29 E-6
92 7.12 E-8 9.06 E-7
93 2.53 E-8 2.14 E-7 5.62 E-6
94 7.48 E-8 1.09 E-6 3.35 E-6
95 3.60 E-8 3.10 E-7 1.29 E-6
96 9.71 E-8 9.04 E-7 2.91 E-6
97 1.07 E-8 1.02 E-7 6.03 E-7 - -
ICso [M]
ICso [M] ICso tM]
Y641N
Example # wt hEZH2 H3K27me3 hEZH2
(Assay 1) (Assay 3)
(Assay 2)
97.1 8.76 E-9 9.31 E-8 3.08 E-7
97.2 1.00 E-8 1.17 E-7 3.29 E-7
98 2.17 E-8 6.81 E-8 7.41 E-6
99 7.71 E-8 3.70 E-7 3.50 E-6
100 1.70 E-8 1.08 E-7 2.87 E-6
101 3.24 E-8 7.87 E-7 1.28 E-6
102 3.14 E-7 >2.00 E-5 1.24 E-5
103 1.06 E-7 6.00 E-7 2.41 E-6
104 4.59 E-7 3.31 E-6 1.24 E-5
105 2.29 E-8 2.50 E-7 7.58 E-7
106 8.86 E-8 7.01 E-7 2.18 E-6
107 2.12 E-7 2.61 E-6 9.32 E-6
108 1.22 E-7 2.66 E-6
109 4.09 E-7
110 3.80 E-8 3.92 E-7 1.15 E-6
111 5.08 E-8 7.45 E-7 1.33 E-6
112 4.18 E-8 5.68 E-7 7.30 E-7
113 3.83 E-8 3.66 E-7 4.07 E-6
114 1.94 E-8 2.77 E-7 1.79 E-6
115 8.13 E-9 7.61 E-8 6.64 E-7
116 1.39 E-7 1.75 E-6 6.07 E-6
117 2.17 E-8 2.10 E-7 2.05 E-6
118 5.30 E-7 5.88 E-6 >1.24 E-5
119 9.69 E-8 4.53 E-7 4.91 E-6
120 2.33 E-8 3.48 E-7 6.47 E-6
121 2.39 E-7 >2.00 E-5 >1.24 E-5
122 6.47 E-8 5.05 E-7 1.16 E-6
123 9.88 E-8 1.57 E-6 7.62 E-6
124 1.03 E-7 2.55 E-6 5.54 E-6
125 8.82 E-8 6.10 E-7 1.84 E-6
126 3.02 E-7 1.31 E-5
127 3.48 E-7 >2.00 E-5
128 5.36 E-8 2.21 E-7 8.54 E-7 - -
Figure imgf000235_0001
An empty field means "not determined yet"

Claims

Patent Claims
1. A compound of general formula (I)
Figure imgf000236_0001
in which
R1 represents a group selected from Ci-C6-alkyl-, C2-C6-alkenyl-, C3-C7-cycloalkyl-, (C3-C7- cycloalkyl)-(L1)-, 4- to 7-membered monocyclic heterocycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-(L1)-, Ci-C6-haloalkyl-, C2-C6-haloalkenyl-, Ci-C6-alkoxy-, Ci-Ce-haloalkoxy-, (Ci-C3-alkoxy)-(Ci-C3-alkyl-), -NR6R7 and phenyl-(Ci-C3-alkyl)-, wherein any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two or three substituent, each substituent independently selected from fluorine, hydroxy-, oxo, Ci-C3-alkyl-, C1-C3- haloalkyl-, Ci-C3-alkoxy-, Ci-C3-haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and - S(=0)2-R8, and 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-C3-alkyl-, Ci-C3-haloalkyl- and C1-C3- alkoxy- Ci-C3-haloalkoxy-;
R2 represents a Ci-C3-alkyl- group; R3 represents a hydrogen atom or a Ci-C3-alkyl- group; R4 represents a hydrogen atom or a group selected from Ci-Cs-alkyl-, (Ci-C3-alkoxy)-(Ci- C3-alkyl)-, C3-Cio-cycloalkyl-, 4- to 10-membered heterocycloalkyl- and phenyl-(Ci-C3-alkyl)-, wherein any C3-Cio-cycloalkyl- or 4- to 10-membered heterocycloalkyl- group is optionally substituted with one, two or three substituents, each substituent independently selected from fluorine, hydroxy-, oxo, Ci-C3-alkyl-, C1-C3- haloalkyl-, G-Cs-alkoxy-, Ci-Cs-haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and -S(=0)2-R8, and 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-C3-alkyl-, Ci-C3-haloalkyl- and C1-C3- alkoxy-, Ci-C3-haloalkoxy;
represents a group selected from phenyl-, naphthyl-, heteroaryl-, C3-Cio-cycloalkyl-, 4- to 10- membered heterocycloalkyl-, -NR6R10, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three , substituents, each substituent independently selected from R11; represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group; represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-Ce-alkyl-, G-Ce-haloalkyl-, hydroxy-(Ci-C6-alkyl)-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3- C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C3-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, Ci-C3-alkyl-, C1-C3- haloalkyl-, Ci-C3-alkoxy-, Ci-C3-haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and -S(=0)2R8, and wherein 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-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-, Ci- C2-haloalkoxy-,
R7, 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 group selected from Ci-C3-alkyl-, Ci-C3-haloalkyl-, -C(=0)-R8 and -C(=0)-OR9; 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-C2-alkyl-, trifluoromethyl- and C1-C2- alkoxy-, Ci-C2-haloalkoxy-; 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-C2-alkyl-, trifluoromethyl- and C1-C2- alkoxy-, Ci-C2-haloalkoxy; represents, independently for each occurrence, a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, wherein said groups 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-, Ci-C3-haloalkoxy-; 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-C6-alkyl)-, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-,
(Ci-C3-haloalkoxy)-(Ci-C3-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, C3-C7-cycloalkyl-(L3)-, 4- to 7-membered monocyclic heterocycloalkyl-(L3)-, phenyl-(L3)-, 5- to 6-membered monocyclic heteroaryl-(L3)-, -OR7, -C(=0)-R8, -C(=0)-OR9, -O- C(=0)-R8, -N(R6)-C(=0)-R7, -N(R6)-C(=0)-NR6R7, -NR6R7, -C(=0)-NR6R7, -SR8, - S(=0)-R8, -S(=0)2-R8, -N(R6)-S(=0)-R8, -S(=0)-NR6R7, -N(R6)-S(=0)2- R8, -S(=0)2-NR6R7, -S(=0)(=NR12)-R8 and -N=S(=0)(R6)-R8; 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, Ci-C3-alkyl-, C1-C3- haloalkyl-, C3-C6-cycloalkyl, cyclopropylmethyl-, Ci-C3-alkoxy-, C1-C3- haloalkoxy-, -C(=0)-R8, -C(=0)-OR9 and -S(=0)2-R8, and wherein 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-, C1-C3- haloalkyl- and Ci-C3-alkoxy-, Ci-C3-haloalkoxy, 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 -CH2-CH2-CH2-, - CH2-CH2-O-, -O-CH2-O-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-O- and
Figure imgf000239_0001
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, G-Ce-alkyl-, C3-C7-cycloalkyl-, phenyl-(Ci-C3-alkyl)- and -C(=0)-OR9;
L1 represents a group selected from -CH2-, -CH2-O- and -0-;
L2 represents a group selected from -CH=CH-, -C≡C-, -CH2- and -CH2CH2-;
L3 represents, independently for each occurrence, a group selected from -CH2- and -CH2CH2-; or an N-oxide, salt, tautomer, or stereoisomer of said compound, or a salt of said N-oxide tautomer, or stereoisomer.
2. The compound of general formula (I) according to claim 1,
in which represents a group selected from Ci-C t-aikyl-, C3-C6-cycloalkyl-, (C3-C6-cycloalkyl)-(L )-, 4- to 6-membered monocyclic heterocycloalkyl-, 4- to 6-membered monocyclic heterocycloalkyl-(L1)-, Ci-C4-fluoroalkyl-, C2-C4-fluoroalkenyl-, Ci-C t-aikoxy-, C1-C4- fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and phenyl-(Ci-C2-alkyl)-, wherein any C3-C6-cycloalkyl- or 4- to 6-membered monocyclic heterocycloalkyl- group is optionally substituted once with a Ci-C3-alkyl-, and wherein the phenyl group present in said phenyl-(Ci-C2-alkyl)- 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-; represents a Ci-C3-alkyl- group; represents a hydrogen atom or a methyl- group; 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 represents a group selected from phenyl-, naphthyl-, heteroaryl-, -NR6R10, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R11; represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group; represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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, Ci-C3-alkyl-, -C(=0)-R8 and - C(=0)-OR9, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, including the phenyl group present in said phenyl-(Ci-C2-alkyl)- 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-,
R7, 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 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-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 substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and C1-C2- alkoxy-; 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-;
R11 represents, independently for each occurrence, a halogen atom or a group selected from hydroxy-, cyano-, Ci-C t-aikyl-, Ci-C t-fluoroaikyl-, Ci-C4-fluoroalkoxy-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, -OR7, -C(=0)- R8, -C(=0)-OR9, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7,
-S(=0)-R8, -S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8, 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, Ci-C3-alkyl-, Ci-C3-alkoxy-, - C(=0)-R8, -C(=0)-OR9 and -S(=0)2-R8, and wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group is optionally substituted with one, two or three substituent, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-, or
two R11 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-;
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, Ci-C4-alkyl- and -C(=0)-OR9;
L1 represents a group selected from -CH2-O- and -0-;
L2 represents a group selected from -CH=CH-, -C≡C- and -CH2-; or an N-oxide, salt, tautomer, or stereoisomer of said compound, or a salt of said N-oxide, tautomer, or stereoisomer.
3. The compound of general formula (I) according to claim 1,
in which
R1 represents a group selected from Ci-C3-alkyl-, C3-C6-cycloalkyl-, (C3-C6-cycloalkyl)-(L1)- Ci-C3-fluoroalkyl-, C2-C3-fluoroalkenyl-, Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (C1-C2- alkoxy)-(Ci-C2-alkyl-) and benzyl-;
R2 represents a Ci-C3-alkyl- group;
R3 represents a hydrogen atom or a methyl- group; R4 represents a hydrogen atom or a group selected from Ci-C6-alkyl-, C3-C6-cycloalkyl- and 4- to 6-membered monocyclic heterocycloalkyl-;
R5 represents a group selected from phenyl-, naphthyl-, heteroaryl-, phenyl-(L2)- and heteroaryl-(L2)-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R11; R6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group;
R7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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 wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, and the phenyl group present in said phenyl-(Ci-C2-alkyl)- group is optionally substituted with one or two substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and Ci-C2-alkoxy-, or
R6 and R7, 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;
R8 represents, independently for each occurrence, a group selected from Ci-C4-alkyl- and benzyl-;
R9 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C t-alkyl- and benzyl-;
R11 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-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-, 5- to 6-membered monocyclic heteroaryl-, -OR7, -C(=0)- R8, -C(=0)-OR9, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7,
-S(=0)-R8, -S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8, 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, Ci-C2-alkyl-, -C(=0)-R8 and - C(=0)-OR9, and wherein 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 R11 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-.
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano-, Ci-C4-alkyl- and -C(=0)-OR9;
L1 represents a group selected from -CH2-O- and -0-;
L2 represents a group selected from -CH=CH-, -C≡C- and -CH2-; or an N-oxide, salt, or tautomer or stereoisomer of said compound, or a salt of said N-oxide or tautomer, or stereoisomer.
4. The compound of general formula (I) according to claim 1,
in which
R1 represents a group selected from Ci-C3-alkyl-, (C3-C6-cycloalkyl)-(L1)-, Ci-C3-fluoroalkyl- Ci-C3-alkoxy-, Ci-C3-fluoroalkoxy-, (Ci-C2-alkoxy)-(Ci-C2-alkyl-) and benzyl-;
R2 represents a methyl- group;
R3 represents a hydrogen atom or a methyl- group; R4 represents a group selected from C2-Cs-alkyl-, C3-C6-cycloalkyl- and 5- to 6-membered monocyclic heterocycloalkyl-;
R5 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 R11;
R6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group;
R7 represents, independently for each occurrence, a hydrogen atom or a group selected from Ci-C4-alkyl-, Ci-C4-fluoroalkyl-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-, phenyl-(Ci-C2-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 wherein any phenyl- or 5- to 6-membered monocyclic heteroaryl- group, including the phenyl group present in said phenyl-(Ci-C2-alkyl)- group, is optionally substituted with one or two substituents, each substituent independently selected from fluorine, chlorine, bromine, cyano-, Ci-C2-alkyl-, trifluoromethyl- and C1-C2- alkoxy-, or
R6 and R7, 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;
R8 represents, independently for each occurrence, a group selected from Ci-C4-alkyl- and benzyl-;
R9 represents a Ci-C2-alkyl- group, independently for each occurrence;
R11 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-fluoroalkyl-, O-C t-fluoroalkoxy-, hydroxy-(Ci-C4-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, C3-C7-cycloalkyl-, 4- to 7- membered monocyclic heterocycloalkyl-, -OR7, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7,
-S(=0)2-R8, -N(R6)-S(=0)2-R8, -S(=0)2-NR6R7 and -S(=0)(=NR12)-R8, wherein any C3-C7-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 tert- butoxycarbonyl- , or
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 -CH2-CH2-O-, -O-CH2-O- and -O-CH2-CH2-O-;
R12 represents, independently for each occurrence, a hydrogen atom or a group selected from cyano- and -C(=0)-OR9; L1 represents a -CH2-O- group; or an N-oxide, salt, tautomer, or stereoisomer of said compound, or a salt of said N-oxide tautomer, or stereoisomer.
5. The compound of general formula (I) according to claim 1,
in which
R1 represents a group selected from « -propyl-, cyclobutylmethoxy-, 1,1-difluoro-n-propyl-, methoxy-, ethoxy-, wo-propoxy-, difluoromethoxy-, 2,2,2-trifluoroethoxy- and benzyl-;
R2 represents a methyl- group;
R3 represents a hydrogen atom or a methyl- group;
R4 represents a group selected from Cs-C t-alkyl-, cyclopentyl- and tetrahydropyran-4-yl-;
R5 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 R11;
R6 represents, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group;
R7 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 R6 and R7, together with the nitrogen atom they are attached to, respresent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a methyl- group;
R represents, independently for each occurrence, a Ci-C3-alkyl- group;
R11 represents, independently for each occurrence, a fluoro atom, a chloro atom, or a group selected from cyano-, Ci-C3-alkyl-, hydroxy-(Ci-C4-alkyl)-, 4- to 7-membered monocyclic heterocycloalkyl-, -OR7, -N(R6)-C(=0)-R7, -NR6R7, -C(=0)-NR6R7, -S(=0)2-R8, -N(R6)- S(=0)2-R8, -S(=0)2-NR6R7 and-S(=0)(=NH)-R8, wherein any 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one or two substituents, each substituent independently selected from oxo and Ci-C2-alkyl-; or an N-oxide, salt, tautomer, or stereoisomer of said compound, or a salt of said N-oxide tautomer, or stereoisomer.
6. A method of preparing a compound of general formula (I) according to any one of claims 1 to 5, in which method an intermediate compound of formula (IV),
Figure imgf000246_0001
( IV ) in which R1, R2, R3, and R4 are as defined in any one of claims 1 to 5; is allowed to react with a compound of formula (V) :
R-0
,B-R
R-0
( V ) in which R5 is as defined in any one of claims 1 to 5, and in which R represents a hydrogen atom or a Ci-C3-alkyl- group, or R-R together represent a -C2-C6-alkylene- group, thus providing a compound of general formula (I) :
Figure imgf000247_0001
in which R , R , R , R , and R are as defined in any one of claims 1 to 5.
A method of preparing a compound of general formula (I) according to any one of claims 1 to 5, in which method an intermediate compound of formula (VI):
Figure imgf000247_0002
( VI ) in which R3, R4, and R5 are as defined in any one of claims 1 to 5; is allowed to react with a compound of formula (II):
Figure imgf000247_0003
in which R1 and R2 are as defined in any one of claims 1 to 5; thus providing a compound of general formula (I):
Figure imgf000248_0001
(I)
in which R1, R2, R3, R4, and R5 are as defined in any one of claims 1 to 5.
8. A compound of formula (IV):
Figure imgf000248_0002
(IV)
in which R1, R2, R3, and R4 are as defined in any one of claims 1 to 5.
9. A compound of formula (VI):
Figure imgf000248_0003
(VI)
in which R3, R4, and R5 are as defined in any one of claims 1 to 5.
10. A compound of formula (IV) according to claim 8 for use in the preparation of a compound of general formula (I) according to any one of claims 1 to 5.
11. A compound of formula (VI) according to claim 9 for use in the preparation of a compound of general formula (I) according to any one of claims 1 to 5. 12. A compound of general formula (I) according to claim 1 for use in the treatment of diseases.
13. A compound for use according to claim 12, wherein the disease is cancer.
14. A compound for use according to claim 13, wherein the cancer disease is 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.
15. A compound for use according to claim 14, wherein the cancer disease is Breast Cancer.
16. Combination comprising one or more first active ingredients selected from a compound of general formula (I) according to any of claims 1 to 5, and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and target- specific anticancer agents.
17. Pharmaceutical composition comprising a compound of general formula (I) according to claim 1 to 5 together with one or more pharmaceutically acceptable excipients. 18. Pharmaceutical composition according to claim 17 for use according to claims 12 to 15.
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