WO2016202898A1 - Glucose transport inhibitors - Google Patents

Glucose transport inhibitors Download PDF

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Publication number
WO2016202898A1
WO2016202898A1 PCT/EP2016/063823 EP2016063823W WO2016202898A1 WO 2016202898 A1 WO2016202898 A1 WO 2016202898A1 EP 2016063823 W EP2016063823 W EP 2016063823W WO 2016202898 A1 WO2016202898 A1 WO 2016202898A1
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Prior art keywords
pyrazol
methyl
carboxamide
dimethyl
quinoline
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PCT/EP2016/063823
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French (fr)
Inventor
Iring Heisler
Thomas Müller
Bernd Buchmann
Arwed Cleve
Holger Siebeneicher
Marcus Koppitz
Dirk Schneider
Marcus Bauser
Melanie HEROULT
Roland Neuhaus
Heike Petrul
Maria QUANZ-SCHÖFFEL
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Bayer Pharma Aktiengesellschaft
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Publication of WO2016202898A1 publication Critical patent/WO2016202898A1/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
    • C07D401/14—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 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • 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
    • C07D401/02—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 containing two hetero rings
    • C07D401/06—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 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/02—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 containing two hetero rings
    • C07D401/12—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 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to chemical compounds that selectively inhibit glucose transporter 1 (GLUT1), to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
  • GLUT1 glucose transporter 1
  • Glucose is an essential substrate for metabolism in most cells. Because glucose is a polar molecule, transport through biological membranes requires specific transport proteins. Transport of glucose through the apical membrane of intestinal and kidney epithelial cells depends on the presence of secondary active Na + /glucose symporters, SGLT-1 and SGLT-2, which concentrate glucose inside the cells, using the energy provided by co-transport of Na + ions down their electrochemical gradient.
  • glucose carriers protein symbol GLUT, gene symbol SLC2 for Solute Carrier Family 2
  • transport facilitators major facilitator superfamily
  • organic anion and cation transporters yeast hexose transporter
  • plant hexose/proton symporters bacterial sugar/proton symporters.
  • Basal glucose transporters GLUTs
  • GLUTs function as glucose channels and are required for maintaining the basic glucose needs of cells. These GLUTs are constitutively expressed and functional in cells and are not regulated by (or sensitive to) insulin.
  • GLUT proteins contain 12 transmembrane domains and transport glucose by facilitating diffusion, an energy-independent process.
  • GLUT1 transports glucose into cells probably by altemating its conformation.
  • GLUT1 exposes a single substrate-binding site toward either the outside or the inside of the cell. Binding of glucose to one site triggers a conformational change, releasing glucose to the other side of the membrane.
  • Results of transgenic and knockout animal studies support an important role for these transporters in the control of glucose utilization, glucose storage and glucose sensing.
  • the GLUT proteins differ in their kinetics and are tailored to the needs of the cell types they serve.
  • GLUT1 is a high affinity glucose transporter
  • GLUT1 expression was also found to be significantly higher than that of any other glucose transporters.
  • Evidence indicates that cancer cells are more sensitive to glucose deprivation than normal cells. Numerous studies strongly suggest that basal glucose transport inhibition induces apoptosis and blocks cancer cell growth. Anti- angiogenesis has been shown to be a very effective way to restrict cancer growth and cause cancer ablation.
  • GLUT1 is the most highly expressed hexose transporter in ErbB2- and PyVMT-induced mouse mammary carcinoma models, and that reducing the level of GLUT1 using shRNA or Cre/lox results in reduced glucose usage, reduced growth on plastic and in soft agar, and impaired tumor growth in nude mice (Christian D. Young et al., PLoS ONE, August 2011, Volume 6, Issue 8, e23205, 1-12). Therefore, inhibition of GLUT1 represents a promising approach for the treatment of proliferative disorders including solid tumours such as carcinomas and sarcomas and leukaemias and lymphoid malignancies or other disorders associated with uncontrolled cellular proliferation.
  • WO2011/119866(A1) discloses composition and methods for glucose transport inhibition
  • WO2012/051117(A2) and WO2013/155338(A2) disclose substituted benzamides as GLUT1 inhibitors.
  • Compounds showing a certain structural similarity to the compounds of the present invention are disclosed in prior art.
  • WO97/36881(A1) discloses arylheteroaryl-containing compounds which inhibit farnesyl-protein transferase.
  • WO00/07996(A2) discloses pyrazole estrogen receptor agonist and antagonist compounds.
  • WO01/21160(A2) discloses carboxamide derivatives as inhibitors of herpesviridae.
  • WO03/037274(A2) and WO2004/099154(A2) disclose pyrazole-amides as inhibitors of sodium channels.
  • WO2004/098528(A2) discloses pyrazole derived compounds as inhibitors of p38 kinase.
  • WO2006/132197(A1) discloses heterocyclic compounds as inhibitors of 11 - hydroxysteroid dehydrogenase type 1.
  • WO2006/062249(A1) discloses compounds for the prevention, therapy or improvement of a disease to which the activation of a thrombopoietin receptor is effective.
  • WO2008/126899(A1) discloses 5-membered heterocyclic compounds as inhibitors of xanthine oxidase.
  • WO2008/008286(A2) discloses substituted pyrazoles as ghrelin receptor antagonists.
  • WO2009/025793(A2) discloses compounds that function as bitter taste blockers.
  • WO2009/027393(A2) and WO2010/034737(A1) disclose pyrazole compounds for controlling invertebrate pests.
  • WO2009/099193(A1) discloses compounds having inhibitory action on melanin production.
  • WO2009/119880(A1) discloses pyrazole derivatives having an androgen receptor antagonistic action.
  • WO2011/050305(A1) and WO2011/050316(A1) disclose pyrazole compounds as allosteric modulators of mGluR4 receptor activity.
  • WO2011/126903(A2) discloses multisubstituted aromatic compounds including substituted pyrazolyl as thrombin inhibitors.
  • WO2004/110350(A2) discloses compounds modulating amyloid beta.
  • WO2009/055917(A1) discloses inhibitors of histone deacetylase.
  • WO02/23986(A1) discloses 4-acylaminopyrazole derivatives exhibiting fungicidal activities.
  • WO03/051833(A2) discloses heteroaryl substituted pyrazole compounds as mGluR5 modulators.
  • WO2009/076454(A2) discloses compounds which modulate the activity of store- operated calcium channels.
  • WO99/32454(A1) discloses nitrogen containing heteroaromatics with ortho-substituted P1 groups as factor Xa inhibitors.
  • WO2004/037248(A2) and WO2004/043951(A1) disclose compounds as modulators of the peroxisome proliferator activated receptors.
  • WO 2013/109991(A1) discloses various heterocyclic compounds for the treatment of neurodegenerative diseases.
  • WO 2014031936(A2) discloses heterocyclic compounds as modulators of HIF pathway activity.
  • Several pyrazole carboxamide and 4-quinolinyl pyrazole carboxamide derivatives showing a certain similarity to the compounds of the present invention have been indexed in Chemical Abstracts without publication reference.
  • the present invention relates to compounds of general formula (I) :
  • R 3 represents a group selected from: aryl-, heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ; wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
  • aryl-, heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ; and wherein two -(L 2 )p-R 6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
  • R 4a represents a group selected from: aryl-, heteroaryl-;
  • R 4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C 1 -C 3 -alkyl-, cyano- ;
  • R 5 represents a group selected from:
  • R 5 represents
  • phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
  • R 7 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C 1 -C 4 -alkyl-, C 3 -C 7 -cycloalkyl- and benzyl-;
  • R 8a represents a hydrogen atom or a C 1 -C 6 -alkyl-, halo-C 1 -C 3 -alkyl-, cyano- C1-C4-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-,
  • (aryl)-(4- to 10-membered heterocycloalkyl)- group said C 1 -C 10 -alkyl-, C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(L 3 )-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L 3 )-, phenyl-, heteroaryl-, phenyl-(L 3 )-, (phenyl)-O-(L 3 )-, heteroaryl-(L 3 )-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R 8d ;
  • phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-; R 10 ,
  • R 16 R 16a
  • L 2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-;
  • L 3 represents a -C1-C6-alkylene- group;
  • p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for use in the treatment and prophylaxis of a disease.
  • the present invention relates to compounds of general formula (I) :
  • R 3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ; and wherein two -(L 2 )p-R 6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
  • R 5 represents a group selected from:
  • R 7 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C 1 -C 4 -alkyl-, C 3 -C 7 -cycloalkyl- and benzyl-;
  • R 9 represents a halogen atom or a group selected from:
  • phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R 10 , R 1
  • aryl-, heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 ) p -R 6 ; and wherein two -(L 2 ) p -R 6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
  • R 5 represents a group selected from:
  • phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-; R 10 , R 10a , R 10b , R 10c
  • compounds of the formula (I) are not: 4-Cinnolinecarboxamide, N-[1-[(3,5-dimethyl-4-isoxazolyl)methyl]-1H- pyrazol- 4-yl]-3-phenyl-4-cinnolinecarboxamide, CAS Registry-Nr.1024526-45-1;
  • the present invention relates to compounds of general formula (I-2) :
  • R 3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed; wherein said aryl-, heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 ) p -R 6 ; and wherein two -(L 2 )p-R 6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally form a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*,
  • R 4 represents a hydrogen atom or group selected from: C 1 -C 3 -alkyl-,
  • R 4a represents a group selected from: aryl-, heteroaryl-;
  • R 4b represents a hydrogen atom or a group selected from: C 1 -C 3 -alkoxy-, C1-C3-alkyl-, cyano- ; R 5a ,
  • phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
  • R 8a represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group;
  • (aryl)-(4- to 10-membered heterocycloalkyl)- group said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L 3 )-, C 3 -C 6 -alkenyl-, C 3 -C 6 -alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L 3 )-, phenyl-, heteroaryl-, phenyl-(L 3 )-, (phenyl)-O-(L 3 )-, heteroaryl-(L 3 )-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R 8d ;
  • R 16 R 16a
  • R 17 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-,
  • L 1 represents a group selected from: -C 1 -C 4 -alkylene-, ,
  • L 2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-;
  • L 3 represents a -C1-C6-alkylene- group;
  • p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for use in the treatment and prophylaxis of a disease.
  • the present invention relates to compounds of general formula (I-2):
  • R 3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed; wherein said aryl-, heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 ) p -R 6 ; and wherein two -(L 2 )p-R 6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally form a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*,
  • R 4a represents a group selected from:
  • phenyl- or naphthyl- wherein said phenyl- or naphthyl- group is optionally substituted, one or more times, identically or differently, with R 8d ,
  • furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, and benzocondensed derivative thereof is optionally substituted, one or more times, identically or differently, with R 8d ,
  • R 4b represents a hydrogen atom or a group selected from: C 1 -C 3 -alkoxy-, C1-C3-alkyl-, cyano- ;
  • phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, halo-C1-C3-alkyl-, C1-C3-alkoxy-;
  • R 5d represents a hydrogen atom or a fluorine atom
  • R 4 represents a hydrogen atom or group selected from: C 1 -C 3 -alkyl-,
  • R 8a represents a hydrogen atom or a C 1 -C 6 -alkyl-, halo-C 1 -C 3 -alkyl-, cyano- C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R 8b , R 8c
  • (aryl)-(4- to 10-membered heterocycloalkyl)- group said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L 3 )-, C 3 -C 6 -alkenyl-, C 3 -C 6 -alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L 3 )-, phenyl-, heteroaryl-, phenyl-(L 3 )-, (phenyl)-O-(L 3 )-, heteroaryl-(L 3 )-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R 8d ;
  • R 16 R 16a
  • R 17 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-,
  • R 18 represents a fluorine atom, a chlorine atom, a bromo atom, or a cyano or methyl- group
  • L 2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-;
  • L 3 represents a -C1-C6-alkylene- group;
  • p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
  • halogen atom or“halo-” is to be understood as meaning a fluorine, chlorine, bromine or iodine atom, also referred to as fluoro-, chloro-, bromo- and iodo-.
  • C 1 -C 10 -alkyl- is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. a methyl-, ethyl-, propyl-, butyl-, pentyl-, hexyl-, iso-propyl-, iso-butyl-, sec-butyl-, tert-butyl-, iso-pentyl-, 2-methylbutyl-, 1- methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-, neo-pentyl-, 1,1- dimethylpropyl-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1- methylpentyl-, 2-ethylbutyl-, 1-ethylbutyl-, 3,3-dimethylbuty
  • said group has 1, 2, 3, 4, 5 or 6 carbon atoms (“C 1 -C 6 - alkyl-”), more particularly 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl-”), e.g. a methyl-, ethyl-, propyl-, butyl-, iso-propyl-, iso-butyl-, sec-butyl-, tert-butyl- group, even more particularly 1, 2 or 3 carbon atoms (“C 1 -C 3 -alkyl-”), e.g. a methyl-, ethyl-, n-propyl- or iso-propyl- group.
  • “-C1-C8-alkylene-” is understood as preferably meaning a linear or branched, saturated, divalent hydrocarbon chain (or“tether”) having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g.–CH2- (“methylene” or“-C1-alkylene-”) or, for example -CH2-CH2- (“ethylene” or“-C2-alkylene-”), -CH2-CH2-CH2-, -C(H)(CH3)- CH 2 - or -C(CH3)2-) (“propylene” or“-C3-alkylene-”), or, for example–CH2-C(H)(CH3)- CH 2 -, –CH 2 -C(CH 3 ) 2 -), -CH 2 -CH 2 -CH 2 -CH 2 - (“butylene” or “-C4-alkylene-”),“-C5-alkylene-”, e.g.
  • alkylene tether has 1, 2, 3, 4, or 5 carbon atoms ("-C1-C5- alkylene-"), more particularly 1 or 2 carbon atoms ("-C 1 -C 2 -alkylene-"), or, 3, 4, or 5 carbon atoms("-C3-C5-alkylene-").
  • halo-C1-C4-alkyl- is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term“C1- C 4 -alkyl-” is defined supra, and in which one or more of the hydrogen atoms is replaced, identically or differently, by a halogen atom.
  • Preferred are halo-C1- C 3 -alkyl- groups.
  • said halogen atom is F, resulting in a group also referred to as“fluoro-C1-C3-alkyl-”.
  • Said halo-C1-C3-alkyl- group or fluoro-C1-C3- alkyl- group is, for example, –CF 3 , -CHF 2 , -CH 2 F, -CF 2 CF 3 , or -CH 2 CF 3 .
  • Particularly preferred is–CF3, also referred to as“trifluoromethyl-“.
  • the term“cyano-C1-C4-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term“C 1 -C 4 -alkyl-” is defined supra, and in which one or more of the hydrogen atoms is replaced by a cyano group.
  • Said cyano-C1-C4-alkyl- group is, for example, -CH 2 CN, -CH 2 CH 2 -CN, -C(CN)H-CH 3 , -C(CN)H-CH 2 CN, or -CH2CH2CH2CH2-CN.
  • the term“hydroxy-C1-C4-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term“C1-C4-alkyl-” is defined supra, and in which one or more of the hydrogen atoms is replaced by a hydroxy group with the proviso that not more than one hydrogen atom attached to a single carbon atom is being replaced.
  • hydroxy-C1-C3-alkyl- groups Preferred are hydroxy-C1-C3-alkyl- groups.
  • Said hydroxy-C1-C4-alkyl- group, or, preferably, hydroxy-C 1 -C 3 -alkyl- group is, for example, -CH 2 OH, -CH 2 CH 2 -OH, -C(OH)H-CH 3 , or -C(OH)H-CH2OH.
  • the term“C1-C4-alkoxy-” is to be understood as preferably meaning a linear or branched, saturated, monovalent group of formula–O-(C 1 -C 4 -alkyl-), in which the term “C1-C4-alkyl-” is defined supra, e.g.
  • halo-C 1 -C 4 -alkoxy- is to be understood as preferably meaning a linear or branched, saturated, monovalent C1-C4-alkoxy- group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, by a halogen atom.
  • halo-C1-C3-alkoxy-groups are preferred.
  • said halogen atom is F, resulting in a group also referred to as “fluoro-C1-C4-alkoxy-”, or, preferably“fluoro-C1-C3-alkoxy-”.
  • Said halo-C1-C4- alkoxy- group or fluoro-C1-C4-alkoxy- group is, for example,–OCF3, -OCHF2, - OCH2F, -OCF2CF3, or -OCH2CF3.
  • Particularly preferred is–OCF3, also referred to as“trifluoromethoxy-“.
  • C1-C3-alkoxy-C1-C3-alkyl- is to be understood as preferably meaning a linear or branched, saturated, monovalent C 1 -C 3 -alkyl- group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, by a C1-C3-alkoxy group, as defined supra, e.g. methoxyalkyl-, ethoxyalkyl-, propyloxyalkyl- or iso-propoxyalkyl-.
  • halo-C1-C3-alkoxy-C1-C3-alkyl- is to be understood as preferably meaning a linear or branched, saturated, monovalent C1-C3-alkoxy-C1-C3-alkyl- group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom.
  • said halogen atom is F, resulting in a group also referred to as “fluoro-C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-”.
  • Said halo-C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl- group or fluoro-C1-C3-alkoxy-C1-C3-alkyl- group is, for example,–CH2CH2OCF3, -CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 2 F, -CH 2 CH 2 OCF 2 CF 3 , or -CH 2 CH 2 OCH 2 CF 3 .
  • C 2 -C 6 -alkenyl- is to be understood as preferably meaning 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, particularly 3, 4, 5 or 6 carbon atoms (“C3-C6-alkenyl-”), more particularly 2 or 4 carbon atoms (“C2-C4-alkenyl-”), or 3 or 4 carbon atoms (“C3-C4-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.
  • Said alkenyl- group is, for example, a vinyl-, allyl-, (E)-2-methylvinyl-, (Z)-2-methylvinyl-, homoallyl-, (E)-but-2-enyl-, (Z)-but-2-enyl-, (E)-but-1-enyl-, (Z)-but-1-enyl-, pent-4-enyl-, (E)-pent-3-enyl-, (Z)-pent-3-enyl-, (E)-pent-2-enyl-, (Z)-pent-2-enyl-, (E)-pent-1-enyl-, (Z)-pent-1-enyl-, hex-5-enyl-, (E)-hex-4-enyl-, (Z)-hex-4-enyl-, (E)-hex-3-enyl-, (Z)-hex-3-enyl-, (E)-hex-2
  • said group is vinyl- or allyl-.
  • the term“C 2 -C 6 -alkynyl-” is to be understood as preferably meaning 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, particularly 3, 4, 5 or 6 carbon atoms (“C 3 -C 6 -alkynyl-”), more particularly 2 or 4 carbon atoms (“C2-C4-alkynyl-”), or 3 or 4 carbon atoms (“C3-C4-alkynyl-”).
  • Said C2-C6-alkynyl- group is, for example, ethynyl-, prop-1-ynyl-, prop-2-ynyl-, but-1-ynyl-, but-2-ynyl-, but-3-ynyl-, pent-1-ynyl-, pent-2-ynyl-, pent-3-ynyl-, pent-4-ynyl-, hex-1-ynyl-, hex-2-ynyl-, hex-3-ynyl-, hex-4-ynyl-, hex-5-ynyl-, 1-methylprop-2-ynyl-, 2-methylbut-3-ynyl-, 1-methylbut-3-ynyl-, 1-methylbut-2-ynyl-, 3-methylbut-1-ynyl-, 1-ethylprop-2-ynyl-, 3-methylpent-4-ynyl-, 2-methylpent-4
  • alkynyl- group is ethynyl-, prop-1-ynyl-, or prop-2-ynyl-.
  • C3-C7-cycloalkyl- is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms.
  • Said C 3 -C 7 -cycloalkyl- group is for example a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- ring.
  • said ring contains 3, 4, 5 or 6 carbon atoms (“C 3 -C 6 -cycloalkyl-”), more particularly, said ring contains 5 or 6 carbon atoms (“C5-C6-cycloalkyl-”).
  • Said heterospirocycloalkyl- group is, 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-, or azaspiro[5.5]decyl-.
  • Said heterobicycoalkyl- group is, 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-, or azabicyclo[4.4.0]decyl-.
  • heterocycloalkyl- group is, for example,
  • 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-,
  • said 4- to 10-membered heterocycloalkyl- can contain 3, 4, 5 or 6 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a“4- to 7-membered heterocycloalkyl-”), more particularly said heterocycloalkyl- can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a “5- to 6-membered heterocycloalkyl-”).
  • said heterocycloalkyl- can be a 4-membered ring, such as an azetidinyl-, oxetanyl-, or a 5-membered ring, such as tetrahydrofuranyl-, pyrrolidinyl-, imidazolidinyl-, pyrazolidinyl-, or a 6-membered ring, such as tetrahydropyranyl-, piperidinyl-, morpholinyl-, dithianyl-, thiomorpholinyl-, piperazinyl-, or trithianyl-, or a 7-membered ring, such as a diazepanyl- ring, for example.
  • 4-membered ring such as an azetidinyl-, oxetanyl-, or a 5-membered ring, such as tetrahydrofuranyl-, pyrrolidinyl-, imidazolidinyl
  • aryl- is to be understood as preferably meaning a monovalent, aromatic, mono-, or bi- or tricyclic hydrocarbon ring system having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a“C 6 -C 14 -aryl-” group), particularly a group having 6 carbon atoms (a“C6-aryl-” group), e.g. a phenyl- group; or a group having 9 carbon atoms (a“C 9 -aryl-” group), e.g. an indanyl- or indenyl- group, or a group having 10 carbon atoms (a“C10-aryl-” group), e.g.
  • a tetralinyl-, dihydronaphthyl-, or naphthyl- group or a biphenyl- group (a“C 12 -aryl-” group), or a group having 13 carbon atoms, (a“C13-aryl-” group), e.g. a fluorenyl- group, or a group having 14 carbon atoms, (a“C14-aryl-” group), e.g. an anthracenyl- group.
  • the aryl- group is a phenyl- group.
  • heteroaryl- is understood as preferably meaning an“aryl-“ group as defined supra, in which at least one of the carbon ring atoms is replaced by a heteroatom selected from oxygen, nitrogen, and sulphur.
  • The“heteroaryl-“ group contains 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a“5- to 14-membered heteroaryl-” group), particularly 5 or 6 or 9 or 10 ring atoms (a “5- to 10-membered heteroaryl-” group), more particularly 5 or 6 ring atoms (a “5- to 6-membered heteroaryl-” group).
  • heteroaryl- is selected from thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, thia-4H-pyrazolyl-, tetrazolyl- etc., and benzo derivatives thereof, such as, for example, benzofuranyl-, benzothienyl-, benzoxazolyl-, benzisoxazolyl-, benzimidazolyl-, benzotriazolyl-, benzothiadiazolyl-, indazolyl-, indolyl-, isoindolyl-, etc.; or pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, tria
  • “5- to 6-membered heteroaryl-” is selected from thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, thia-4H-pyrazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, etc.
  • “5-membered heteroaryl-” is selected from thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, thia-4H-pyrazolyl-, tetrazolyl-, etc..
  • the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • the term pyridyl- includes pyridin-2-yl-, pyridin-3-yl-, and pyridin-4-yl-; or the term thienyl- includes thien-2-yl- and thien-3-yl-.
  • the heteroaryl- group is a pyridyl- group.
  • the term“C1-C6”, as used throughout this text, e.g. in the context of the definition of “C 1 -C 6 -alkyl-” is to be understood as meaning an alkyl- group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term“C 1 -C 6 ” is to be interpreted as any sub-range comprised therein, e.g. C1-C6 , C2-C5 , C3-C4 ,
  • 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 finite 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 “C 3 -C 7 ” is to be interpreted as any sub-range comprised therein, e.g. C 3 -C 6 , C 4 - C5 , C3-C5 , C3-C4 , C4-C6, C5-C7 ; particularly C3-C6.
  • 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.
  • the leaving group as used herein is suitable for nucleophilic aliphatic and/or aromatic substitution, e.g.
  • halogen atom in particular chloro-, bromo- or iodo-, or a group selected from methanesulfonyloxy-, p-toluenesulfonyloxy-, trifluoromethanesulfonyloxy-, nonafluorobutanesulfonyloxy-, (4-bromo-benzene)sulfonyloxy-, (4-nitro-benzene)sulfonyloxy-, (2-nitro-benzene)-sulfonyloxy-, (4-isopropyl-benzene)sulfonyloxy-, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy-, (2,4,6-trimethyl-benzene)sulfonyloxy-, (4-tert-butyl-benzene)sulfonyloxy-, benzenesulfonyloxy-, and (4-meth
  • the term“protective group” is a protective group attached to a nitrogen in intermediates used for the preparation of compounds of the general formula (I-2). Such groups are introduced e.g. by chemical modification of the respective amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for amino groups are descibed for example in T.W. Greene and P.G.M.
  • said groups can be selected from substituted sulfonyl groups, such as mesyl-, tosyl- or phenylsulfonyl-, acyl groups such as benzoyl-, acetyl- or tetrahydropyranoyl-, or carbamate based groups, such as tert.-butoxycarbonyl- (Boc), or can include silicon, as in e.g. 2-(trimethylsilyl)ethoxymethyl- (SEM).
  • substituted sulfonyl groups such as mesyl-, tosyl- or phenylsulfonyl-
  • acyl groups such as benzoyl-, acetyl- or tetrahydropyranoyl-, or carbamate based groups, such as tert.-butoxycarbonyl- (Boc)
  • silicon as in e.g. 2-(trimethylsilyl)ethoxymethyl- (SEM).
  • substituents of the compounds of the general formulae of the present invention is understood as meaning“one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times”.
  • 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 compounds of this invention 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.
  • 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.
  • Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations are included within the scope of the present invention.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the 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. In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
  • 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), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I, respectively.
  • Certain isotopic variations of a compound of the invention for example, those in which one or more radioactive isotopes such as 3 H or 14 C are incorporated, 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. 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.
  • 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 state of the art method, such as chromatography, especially chiral chromatography, for example. Further, 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 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 relates to useful forms of 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 contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • polar solvents in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • 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.
  • the compounds of the present invention can exist in free form, e.g. as a free base, or as 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 a relatively non-toxic, 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.
  • 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 polymorphs, or as a mixture of more than one polymorphs, in any ratio. In one aspect, the present invention relates to compounds of general formula (I) :
  • R 3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ; and wherein two -(L 2 )p-R 6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
  • R 9 represents a halogen atom or a group selected from:
  • phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-; R 10 , R 10a , R 10b , R 10c
  • R 10a and R 10b together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R 12 ;
  • L 1 represents a group selected from: -C1-C4-alkylene-,
  • the invention relates to compounds of formula (I), supra, wherein R 1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl- or cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 1 represents a C1-C3-alkyl- or halo-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 1 represents a C 1 -C 3 -alkyl- or fluoro-C 1 -C 3 -alkyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 1 represents a C 1 -C 3 -alkyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 1 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group, with the proviso that at least one of R 1 and R 2 is different from hydrogen.
  • the invention relates to compounds of formula (I), supra, wherein R 2 represents a C1-C3-alkyl-, halo-C1-C3-alkyl- or cyano- group.
  • the invention relates to compounds of formula (I), supra, wherein R 2 represents a C 1 -C 3 -alkyl- or halo-C 1 -C 3 -alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 2 represents a C1-C3-alkyl- or fluoro-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 2 represents a C1-C3-alkyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 2 represents a C 1 -C 3 -alkyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 2 represents a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 2 represents a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 2 represents a hydrogen atom or a methyl- group, with the proviso that at least one of R 1 and R 2 is different from hydrogen. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 2 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 2 represents a trifluoromethyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 1 represents a methyl-, ethyl- or trifluoromethyl- group, and wherein R 2 represents a C 1 -C 3 -alkyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 1 represents a methyl- or trifluoromethyl- group, and wherein R 2 represents a C1-C3-alkyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 1 represents a methyl- or trifluoromethyl- group, and wherein R 2 represents a methyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 1 represents a methyl- group and R 2 represents a methyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: aryl- and heteroaryl-; wherein said group is substituted, one or more times, identically or differently, with–(L 2 ) p -R 6 , and wherein two -(L 2 ) p -R 6 groups, if being present ortho to each other on said aryl- or heteroaryl- group optionally represent a bridge selected from: *-C 3 -C 5 -alkylene-*, *-O(CH 2 ) 2 O-*, *-O(CH2)O-*, *-O(CF2)O-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: aryl- and heteroaryl-; wherein said group is substituted, one or more times, identically or differently,
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 ) p -R 6 ;
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ;
  • two -(L 2 ) p -R 6 groups, if being present ortho to each other on a phenyl- or heteroaryl- group optionally represent a bridge selected from: *-C 3 -C 4 -alkylene-*, *-O(CH 2 ) 2 O-*, *-O(CH 2 )O-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ;
  • two -(L 2 ) p -R 6 groups, if being present ortho to each other on a phenyl- or heteroaryl- group optionally represent a bridge selected from: *-C3- C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- group,
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R 6 ,
  • R 1 represents a methyl- group
  • R 2 represents a methyl- group
  • R 4 represents a hydrogen atom
  • L 1 represents a -CH2- group.
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl–;
  • phenyl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with–(L 2 ) p -R 6 ;
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl–; wherein said phenyl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ;
  • two -(L 2 ) p -R 6 groups, if being present ortho to each other on a phenyl- heteroaryl- group optionally represent a bridge selected from: *-C3-C4- alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- group,
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl-;
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl-;
  • phenyl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with R 6 ,
  • R 1 represents a methyl- group
  • R 2 represents a methyl- group
  • R 4 represents a hydrogen atom
  • L 1 represents a -CH2- group.
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a phenyl- group ;
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R 6 ,
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a heteroaryl- group ; wherein said heteroaryl- group is optionally substituted, one or more times, identically or differently, with R 6 .
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a 5- to 6-membered heteroaryl- group ;
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl-;
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, heteroaryl-;
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, oxadiazolyl-, pyrazolyl- isoxazolyl-, thiazolyl-, oxazolyl-, imidazolyl-, tetrazolyl-, pyridyl- and imidazo[1,2a]pyridyl-;
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: phenyl-, oxadiazolyl-, pyrazolyl- isoxazolyl-, thiazolyl-, oxazolyl-, imidazolyl-, tetrazolyl-, pyridyl- and imidazo[1,2a]pyridyl-;
  • the invention relates to compounds of formula (I), supra, wherein R 3 represents a group selected from: ,
  • the invention relates to compounds of formula (I), supra, wherein R 4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L 2 )-, hydroxy-C1-C3-alkyl-, aryl-(L 2 )-, heteroaryl-(L 2 )-, and wherein L 2 represents -CH2- or -CH2CH2-.
  • the invention relates to compounds of formula (I), supra, wherein R 4 represents a hydrogen atom or group selected from: C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-(L 2 )-, hydroxy-C 1 -C 3 -alkyl-, phenyl-(L 2 )-, and wherein L 2 represents -CH2- or -CH2CH2-.
  • the invention relates to compounds of formula (I), supra, wherein R 4 represents a hydrogen atom or group selected from: C 1 -C 3 -alkyl-, phenyl-(L 2 )-, and wherein L 2 represents -CH 2 - or -CH 2 CH 2 -.
  • the invention relates to compounds of formula (I), supra, wherein R 4 represents a hydrogen atom or group selected from: C 1 -C 3 -alkyl-, phenyl-(L 2 )-, and wherein L 2 represents -CH 2 -.
  • the invention relates to compounds of formula (I), supra, wherein R 4 represents a hydrogen atom or a C1-C3-alkyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 4 represents a C 1 -C 3 -alkyl-group.
  • the invention relates to compounds of formula (I), supra, wherein R 4 represents a hydrogen atom.
  • the invention relates to compounds of formula (I), supra, wherein R 5 represents a group selected from:
  • the invention relates to compounds of formula (I), supra, wherein R 5 represents a group selected from:
  • the invention relates to compounds of formula (I), supra, wherein R 5 represents a group selected from:
  • the invention relates to compounds of formula (I), supra, wherein R 5 represents a group selected from:
  • the invention relates to compounds of formula (I), supra, wherein R 5 represents a group selected from:
  • the invention relates to compounds of formula (I), supra, wherein R 5 represents a group selected from:
  • the invention relates to compounds of formula (I), supra, wherein R 5 represents a group selected from: * * * * * *
  • the invention relates to compounds of
  • the invention relates to compounds of formula (I), supra, wherein R 5 represents a group selected from: * * * , * , wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 5 represents a group selected from:
  • R 6 represents a group selected from: C 1 -C 4 -alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C1-C3-alkyl-, C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl-
  • the invention relates to compounds of formula (I), supra, wherein R 6 represents a -CN group.
  • the invention relates to compounds of formula (I), supra, wherein R 6 represents a -CN group, and in which compounds R 1 represents a methyl- group, R 2 represents a methyl- group, R 4 represents a hydrogen atom and L 1 represents a -CH 2 - group.
  • the invention relates to compounds of formula (I), supra, wherein R 7 represents a hydrogen atom or a C1-C4-alkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 7 represents a hydrogen atom or a C 1 -C 4 -alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 7 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 7 represents a C1-C4-alkyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 7 represents a hydrogen atom or a C1-C2-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 7 represents a C 1 -C 2 -alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 7 represents a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R 7 represents a methyl- group.
  • said 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C 1 -C 3 -alkyl-, fluoro-C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-.
  • said 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: fluoro-, cyano-, C 1 -C 2 -alkyl-, C 1 -C 2 -alkoxy-.
  • said 5- membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: fluoro-, cyano-, C 1 -C 2 -alkyl-, C 1 -C 2 -alkoxy-,
  • said 5-membered heteroaryl- group being optionally substituted one or more times with a methyl- group
  • the invention relates to compounds of formula (I), supra, wherein R 9 represents a bromine atom or a trifluoromethyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 10 , R 10a , R 10b , R 10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl;
  • R 10a and R 10b together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R 12 .
  • the invention relates to compounds of formula (I), supra, wherein R 10 , R 10a , R 10b , R 10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-,C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-.
  • the invention relates to compounds of formula (I), supra, wherein R 10a and R 10b , together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 12 .
  • the invention relates to compounds of formula (I), supra, wherein R 10 , R 10a , R 10b , R 10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, hydroxy-C1- C3-alkyl-.
  • the invention relates to compounds of formula (I), supra, wherein R 10 , R 10a , R 10b , R 10c represent, independently from each other, a hydrogen atom or a C1-C3-alkyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 10 , R 10a , R 10b , R 10c represent, independently from each other, a hydrogen atom or a methyl- or an ethyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 10 , R 10a , R 10b , R 10c represent, independently from each other, a hydrogen atom or a methyl- group.
  • the invention relates to compounds of formula (I), supra, wherein R 12 represents a fluorine atom or a cyano, hydroxy, oxo, C 1 -C 3 -alkyl-, trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group.
  • the invention relates to compounds of formula (I), supra, wherein L 1 represents a group selected from: -C 1 -C 4 -alkylene-, -C(phenyl)(H)-, -CH 2 -CH 2 -O-.
  • the invention relates to compounds of formula (I), supra, wherein L 1 represents a group selected from: -C 1 -C 4 -alkylene-, -CH 2 -CH 2 -O-.
  • the invention relates to compounds of formula (I), supra, wherein L 1 represents a -C1-C4-alkylene- group.
  • the invention relates to compounds of formula (I), supra, wherein L 1 represents a -C1-C3-alkylene- group.
  • the invention relates to compounds of formula (I), supra, wherein L 1 represents a group selected from: In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L 1 represents a group selected from: –CH2-, -C(CH3)(H)-,–CH2–CH2-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L 1 represents a group selected from: In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L 1 represents a -C(CH 3 )(H)- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L 1 represents a–CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L 2 represents a group selected from: –
  • the invention relates to compounds of formula (I), supra, wherein L 2 represents a–CH2- group.
  • the invention relates to compounds of formula (I), supra, wherein p represents an integer of 0 or 1.
  • the invention relates to compounds of formula (I), supra, wherein p represents an integer of 1.
  • the invention relates to compounds of formula (I), supra, wherein p represents an integer of 0.
  • the invention relates to compounds of formula (I), supra, wherein p represents an integer of 1.
  • the invention relates to compounds of formula (I), supra, wherein R 1 represents a methyl- group, R 2 represents a methyl- group, R 4 represents a hydrogen atom and L 1 represents a -CH2- group. More preferred embodiments of compounds of the present invention are described below with respect to formula (I). Said preferred embodiments are to be understood as not including the following compounds:
  • the present invention relates to compounds of general formula (I) :
  • R 1 represents a C1-C3-alkyl- or trifluoromethyl- group
  • R 2 represents a C1-C3-alkyl- group
  • R 3 represents a group selected from: aryl-, heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • R 4 represents a hydrogen atom or a C1-C3-alkyl-group
  • R 5 represents a group selected from:
  • said 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
  • L 1 represents a group selected from:–CH2-,–CH2–CH2-; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (I) :
  • R 1 represents a methyl- or trifluoromethyl- group
  • R 2 represents a methyl- group
  • R 3 represents a group selected from: phenyl-, heteroaryl-;
  • R 4 represents a hydrogen atom
  • R 5 represents a group selected from:
  • R 7 represents a hydrogen atom or a C 1 -C 2 -alkyl- group;
  • R 9 represents a halogen atom or a group selected from:
  • the present invention relates to compounds of general formula (I) :
  • R 1 represents a methyl- or trifluoromethyl- group
  • R 2 represents a methyl- group
  • R 3 represents a group: * ,
  • R 4 represents a hydrogen atom
  • R 5 represents a group selected from:
  • R 7 represents a hydrogen atom or a C 1 -C 2 -alkyl- group
  • R 9 represents a halogen atom or a group selected from:
  • R 10 represents a hydrogen atom or a methyl- or an ethyl- group
  • L 1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (I) :
  • R 1 represents a methyl- or trifluoromethyl- group
  • R 2 represents a methyl- group
  • R 3 represents a group selected from: phenyl-, heteroaryl-;
  • R 4 represents a hydrogen atom
  • R 5 represents a group selected from:
  • the present invention relates to compounds of general formula (I) :
  • R 1 represents a methyl- or trifluoromethyl- group
  • R 2 represents a methyl- group
  • R 3 represents a group selected from: phenyl-, heteroaryl-;
  • R 4 represents a hydrogen atom
  • R 5 represents a group selected from:
  • L 1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (I) :
  • R 1 represents a methyl- or trifluoromethyl- group
  • R 2 represents a methyl- group
  • R 3 represents a group: * ,
  • R 4 represents a hydrogen atom
  • R 5 represents a group selected from:
  • the present invention relates to compounds of general formula (I) :
  • R 1 represents a methyl- or trifluoromethyl- group
  • R 2 represents a methyl- group
  • R 3 represents a group: * ,
  • R 4 represents a hydrogen atom
  • R 5 represents a group selected from: * * ,
  • the present invention relates to compounds of general formula (I) :
  • R 1 represents a methyl- or trifluoromethyl- group
  • R 2 represents a methyl- group
  • R 3 represents a group selected from: ,
  • R 4 represents a hydrogen atom
  • R 5 represents a group selected from: , ,
  • L 1 represents a–CH 2 - group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (I-2) :
  • R 3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ; and wherein two -(L 2 )p-R 6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally form a bridge selected from: *-C 3 -C 8 -alkylene-*, *-O(CH 2 ) 2 O-*, *-O(CH 2 )O-*, *-O(CF 2 )O-*,
  • R 4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
  • R 4a represents a group selected from: aryl-, heteroaryl-;
  • R 4b represents a hydrogen atom or a group selected from: C 1 -C 3 -alkoxy-, C1-C3-alkyl-, cyano- ; R 5a ,
  • phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-;
  • R 8a represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C 1 -C 4 -alkyl-, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-, C 3 -C 7 -cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R 8b , R 8c
  • (aryl)-(4- to 10-membered heterocycloalkyl)- group said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L 3 )-, C 3 -C 6 -alkenyl-, C 3 -C 6 -alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L 3 )-, phenyl-, heteroaryl-, phenyl-(L 3 )-, (phenyl)-O-(L 3 )-, heteroaryl-(L 3 )-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R 8d ;
  • R 16 R 16a
  • L 2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-;
  • L 3 represents a -C1-C6-alkylene- group;
  • p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same,
  • the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl- or cyano- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a C1-C3-alkyl- or halo-C1-C3-alkyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a C 1 -C 3 -alkyl- or fluoro-C 1 -C 3 -alkyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a C1-C3-alkyl- or trifluoromethyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group, with the proviso that at least one of R 1 and R 2 is different from hydrogen. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a methyl- or trifluoromethyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 2 represents a C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl- or cyano- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 2 represents a C 1 -C 3 -alkyl- or halo-C 1 -C 3 -alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 2 represents a C1-C3-alkyl- or fluoro-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 2 represents a C1-C3-alkyl- or trifluoromethyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 2 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 2 represents a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 2 represents a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 2 represents a hydrogen atom or a methyl- group, with the proviso that at least one of R 1 and R 2 is different from hydrogen.
  • the invention relates to compounds of formula (I-2), supra, wherein R 2 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 2 represents a trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a methyl-, ethyl- or trifluoromethyl- group, and wherein R 2 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a methyl- or trifluoromethyl- group, and wherein R 2 represents a C1-C3-alkyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a methyl- or trifluoromethyl- group, and wherein R 2 represents a methyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a methyl- group and R 2 represents a methyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a C 1 -C 3 -alkyl- group and R 2 represents a hydrogen atom.
  • the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a hydrogen atom and R 2 represents a C 1 -C 3 -alkyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a methyl- group and R 2 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a hydrogen atom and R 2 represents a methyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: aryl- and heteroaryl-; wherein said group is substituted, one or more times, identically or differently, with–(L 2 ) p -R 6 , and wherein two -(L 2 ) p -R 6 groups, if being present ortho to each other on said aryl- or heteroaryl- group optionally represent a bridge selected from: *-C 3 -C 5 -alkylene-*, *-O(CH 2 ) 2 O-*, *-O(CH2)O-*, *-O(CF2)O-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group.
  • the invention relates to compounds of formula (I- 2), supra, wherein R 3 represents a group selected from: aryl- and heteroaryl-; wherein said group is substituted, one or more times, identically or differently,
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 ) p -R 6 ;
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ;
  • two -(L 2 ) p -R 6 groups if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, 5- to 6-membered heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ;
  • two -(L 2 )p-R 6 groups if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C 3 -C 4 -alkylene-*, *-O(CH 2 ) 2 O-*, *-O(CH 2 )O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group,
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R 6 , and in which compounds R 1 represents a methyl- group, R 2 represents a methyl- group, R 4b represents a hydrogen atom, R 4 represents a hydrogen atom and L 1 represents a -CH 2 - group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl– and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 ) p -R 6 ;
  • two -(L 2 )p-R 6 groups if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ;
  • two -(L 2 ) p -R 6 groups if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group,
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- ;
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- ;
  • phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R 6 ,
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a phenyl-group;
  • phenyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ;
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 )p-R 6 ;
  • two -(L 2 ) p -R 6 groups if being present ortho to each other on a phenyl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- group,
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R 6 .
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R 6 ,
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl-, oxadiazolyl-, pyrazolyl-, isoxazolyl-, pyridyl-, and piperidinyl-; wherein said phenyl-, oxadiazolyl-, pyrazolyl-, isoxazolyl-, pyridyl-, and piperidinyl- group is optionally substituted, one or more times, identically or differently, with R 6 .
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl- and pyridyl-;
  • phenyl- and pyridyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: C1-C3-alkoxy-, -CN, halo-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl- and pyridyl-;
  • phenyl- and pyridyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: methoxy-, -CN, fluoro-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from: phenyl- and pyridyl-;
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a phenyl- group; wherein said phenyl- group is substituted once with a group selected from: methoxy-, -CN, fluoro-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a pyridyl- group; wherein said pyridyl- group is substituted once with a methoxy- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a phenyl- group; wherein said phenyl- group is substituted once with a group selected from: methoxy-, -CN.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a phenyl- group; wherein said phenyl- group is substituted once with a–CN group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a phenyl- group; wherein said phenyl- group is substituted once with a methoxy- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 3 represents a group selected from:
  • phenyl- wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R 8d ,
  • the invention relates to compounds of formula (I-2), supra, wherein R 4a represents a group selected from:
  • phenyl- wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R 8d ,
  • the invention relates to compounds of formula (I-2), supra, wherein R 4a represents a group selected from:
  • phenyl- wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R 8d ,
  • furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl- group is optionally substituted, one or two times, identically or differently, with R 8d ,
  • the invention relates to compounds of formula (I-2), supra, wherein R 4a represents a group selected from:
  • the invention relates to compounds of formula (I- 2), supra, wherein R 4a represents a group which is unsubstituted and is selected from:
  • R 4a represents a triazolyl- group which is once substituted with methyl-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 4a represents a group which is unsubstituted and is selected from:
  • R 4a represents a triazolyl- group which is once substituted with methyl-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 4a represents a group which is unsubstituted and is selected from:
  • R 4a represents a triazolyl- group which is once substituted with methyl-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 4a represents a group which is unsubstituted and is selected from: *
  • the invention relates to compounds of formula (I-2), supra, wherein R 4a represents a group which is unsubstituted and is selected from:
  • R 4a represents a triazolyl- group which is once substituted with methyl-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 4a represents a group which is unsubstituted and is selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 4b represents a hydrogen atom or a group selected from: C 1 -C 3 -alkoxy-, C 1 -C 3 -alkyl-, cyano-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 4b represents a hydrogen atom or a C1-C3-alkyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 4b represents a hydrogen atom.
  • the invention relates to compounds of formula (I- 2), supra, wherein R 5a
  • R 5b , R 5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a , R 5b , R 5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a
  • R 5b , R 5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a
  • R 5b , R 5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a
  • R 5b , R 5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a
  • R 5b , R 5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a
  • R 5b , R 5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a
  • R 5b , R 5c independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a
  • R 5b , R 5c independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from:
  • R 1 represents a methyl- group
  • R 2 represents a methyl- group
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a , R 5b , R 5c independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom or a group selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a
  • R 5b , R 5c independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom or a group selected from:
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a
  • R 5c , R 5d independently from each other represent a hydrogen atom.
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a represents a hydrogen atom.
  • the invention relates to compounds of formula (I-2), supra, wherein R 5b represents a hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 5c represents a hydrogen atom.
  • the invention relates to compounds of formula (I-2), supra, wherein R 5d represents a hydrogen atom.
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a , R 5c , R 5d independently from each other represent a hydrogen atom, and in which compounds R 5b represents a hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 5a
  • R 5c , R 5d independently from each other represent a hydrogen atom, and in which compounds R 5b represents a hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-,
  • R 1 represents a methyl- group
  • R 2 represents a methyl- group
  • R 4b represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • the invention relates to compounds of formula (I-2), supra, wherein R 4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L 2 )-, hydroxy-C1-C3-alkyl-, aryl-(L 2 )-, heteroaryl-(L 2 )-, and wherein L 2 represents -CH 2 - or -CH 2 CH 2 -.
  • the invention relates to compounds of formula (I-2), supra, wherein R 4 represents a hydrogen atom or group selected from: C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-(L 2 )-, hydroxy-C 1 -C 3 -alkyl-, phenyl-(L 2 )-, and wherein L 2 represents -CH2- or -CH2CH2-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 4 represents a hydrogen atom or group selected from: C 1 -C 3 -alkyl-, phenyl-(L 2 )-, and wherein L 2 represents -CH 2 - or -CH 2 CH 2 -.
  • the invention relates to compounds of formula (I-2), supra, wherein R 4 represents a hydrogen atom or group selected from: C 1 -C 3 -alkyl-, phenyl-(L 2 )-, and wherein L 2 represents -CH 2 -.
  • the invention relates to compounds of formula (I-2), supra, wherein R 4 represents a hydrogen atom or a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 4 represents a C 1 -C 3 -alkyl-group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 4 represents a hydrogen atom.
  • R 6 represents a group selected from: oxo, C 1 -C 4 -alkyl-, fluoro-C 1 -C 3 -alkyl-,
  • R 1 represents a methyl- group
  • R 2 represents a methyl- group
  • the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a group selected from: methyl-, ethyl-, methoxy-, -CN, fluoro-, chloro-,
  • the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a C1-C3-alkoxy-, -CN or halo- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a methoxy-, -CN or fluoro- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a -CN group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a C 1 -C 3 -alkoxy- or a -CN group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a methoxy- group or a
  • the invention relates to compounds of formula (I-2), supra, wherein R 6 represents halo-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a fluorine atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a C1-C3-alkoxy- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a methoxy- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a methoxy- group or a
  • the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a -CN group, and in which compounds R 1 represents a methyl- group and R 2 represents a methyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 6 represents a methoxy- group, and in which compounds R 1 represents a methyl- group and R 2 represents a methyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 8a represents C 1 -C 4 -alkyl-, fluoro-C 1 -C 3 -alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl- or benzyl- group.
  • R 8a represents a hydrogen atom or a C1-C6-alkyl-, C3-C7-cycloalkyl- or benzyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 8a represents a hydrogen atom or a C1-C6-alkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 8a represents a hydrogen atom or a C1-C6-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 8a represents a hydrogen atom or a C 1 -C 4 -alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 8a represents a hydrogen atom.
  • the invention relates to compounds of formula (I-2), supra, wherein R 8a represents a C1-C4-alkyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , independently from each other, represent a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(L 3 )-, C 3 -C 6 -alkenyl-, C 3 -C 6 -alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L 3 )-, phenyl-, heteroaryl-, phenyl-(L 3 )-, (phenyl)-O-(L 3 )-, heteroaryl-(L 3 )-, or
  • R 8b and R 8c together with the nitrogen atom they are attached to, represent a 4- to 10-membered heterocycloalkyl- group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 8d ,
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , independently from each other, represent a hydrogen atom, or a C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, (C3-C7-cycloalkyl)-(L 3 )-, 4- to 7-membered heterocycloalkyl-, (4- to 7- membered heterocycloalkyl)-(L 3 )-, phenyl-, 5- to 6-membered heteroaryl-, phenyl-(L 3 )-, (phenyl)-O-(L 3 )- or 5- to 6-membered heteroaryl-(L 3 )- group;
  • R 8b and R 8c together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 8d .
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , independently from each other, represent a hydrogen atom, or a C1-C6-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L 3 )-, 4- to 7-membered heterocycloalkyl-, (4- to 7- membered heterocycloalkyl)-(L 3 )-, phenyl-, 5- to 6-membered heteroaryl-, phenyl-(L 3 )-, (phenyl)-O-(L 3 )- or 5- to 6-membered heteroaryl-(L 3 )- group;
  • R 8b and R 8c together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 8d ,
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, phenyl- or 5- to 6-membered heteroaryl- group; said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R 8d ;
  • R 8b and R 8c together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 8d .
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, phenyl- or 5- to 6-membered heteroaryl- group; said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R 8d .
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 8d .
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , independently from each other, represent a hydrogen atom, or a C 1 -C 4 -alkyl-, C 3 -C 7 -cycloalkyl- or 4- to 7- membered heterocycloalkyl- group;
  • R 8b and R 8c together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 8d .
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7- membered heterocycloalkyl- group;
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , independently from each other, represent a hydrogen atom, or a C 1 -C 2 -alkyl-, cyclopropyl- or 5- to 6-membered heterocycloalkyl- group;
  • R 8b and R 8c together with the nitrogen atom they are attached to, represent a 5- to 6-membered heterocycloalkyl- group, said 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 8d .
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , independently from each other, represent a hydrogen atom, or a C 1 -C 2 -alkyl-, cyclopropyl- or 5- to 6-membered heterocycloalkyl- group;
  • the invention relates to compounds of formula (I-2), supra, wherein R 8b and R 8c , together with the nitrogen atom they are attached to, represent a 5- to 6-membered heterocycloalkyl- group, said 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 8d .
  • R 8d represents a halogen atom, or an oxo, C1-C3-alkyl-, fluoro-C1-C3-alkyl-,
  • R 8d represents a halogen atom, or a, C 1 -C 2 -alkyl-, fluoro-C 1 -C
  • R 1 represents a methyl- group
  • R 2 represents a methyl- group
  • R 4b represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • the invention relates to compounds of formula (I-2), supra, wherein R 8d represents a methyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 14 , R 14a , R 14b , R 14c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl;
  • R 14a and R 14b together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R 17 .
  • the invention relates to compounds of formula (I-2), supra, wherein R 14 , R 14a , R 14b , R 14c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C 1 -C 3 -alkyl-,C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-, C 3 -C 7 -cycloalkyl-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 14a and R 14b , together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 17 .
  • the invention relates to compounds of formula (I-2), supra, wherein R 14 , R 14a , R 14b , R 14c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, hydroxy-C1- C3-alkyl-.
  • the invention relates to compounds of formula (I-2), supra, wherein R 14 , R 14a , R 14b , R 14c represent, independently from each other, a hydrogen atom or a C1-C3-alkyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 14 , R 14a , R 14b , R 14c represent, independently from each other, a hydrogen atom or a methyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 17 represents a fluorine atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein R 18 represents a fluorine atom, a chlorine atom, or a cyano or methyl- group.
  • the invention relates to compounds of formula (I-2), supra, wherein L 1 represents a group selected from: -C 1 -C 4 -alkylene-, -C(phenyl)(H)-, -CH 2 -CH 2 -O-.
  • the invention relates to compounds of formula (I-2), supra, wherein L 1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH2-O-.
  • the invention relates to compounds of formula (I-2), supra, wherein L 1 represents a -C 1 -C 4 -alkylene- group.
  • the invention relates to compounds of formula (I-2), supra, wherein L 1 represents a -C1-C3-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L 1 represents a group selected from: In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L 1 represents a group selected from: –CH 2 -, -C(CH 3 )(H)-,–CH 2 –CH 2 -.
  • the invention relates to compounds of formula (I-2), supra, wherein L 1 represents a group selected from: In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L 1 represents a -C(CH3)(H)- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L 1 represents a–CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L 2 represents a group selected from: In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L 2 represents a–CH2- group.
  • the invention relates to compounds of formula (I-2), supra, wherein L 3 represents a -C 1 -C 4 -alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L 3 represents a -C 1 -C 3 -alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L 3 represents a -C1-C2-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L 3 represents a -CH2- or -CH2-CH2- group.
  • the invention relates to compounds of formula (I-2), supra, wherein p represents an integer of 0 or 1. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein p represents an integer of 1. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein p represents an integer of 0. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R 1 represents a methyl- group, wherein R 2 represents a methyl- group, R 4b represents a hydrogen atom, R 4 represents a hydrogen atom, and wherein L 1 represents a–CH 2 - group. More preferred embodiments of compounds of the present invention are described below with respect to formula (I-2). Said preferred embodiments are to be understood as not including the following compounds:
  • R 1 represents a hydrogen atom, or a C1-C3-alkyl-, fluoro-C1-C3-alkyl- or cyano group
  • R 2 represents a hydrogen atom, or a C 1 -C 3 -alkyl-, fluoro-C 1 -C 3 -alkyl- or cyano- group
  • R 3 represents a group selected from: phenyl-, 5- to 6-membered
  • heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- wherein said phenyl-, 5- to 6-membered heteroaryl-, C 5 -C 6 -cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L 2 ) p -R 6 ;
  • R 4a represents a group selected from:
  • phenyl- wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R 8d ,
  • furanyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, oxadiazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl-, benzofuranyl-, benzothienyl-, quinolinyl- and isoquinolinyl- group is optionally substituted, one or two times, identically or differently, with R 8d ,
  • R 4b represents a hydrogen atom or a C1-C3-alkyl-group
  • phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-;
  • R 5d represents a hydrogen atom;
  • R 4 represents a hydrogen atom or a C 1 -C 3 -alkyl- group;
  • R 6 represents a group selected from: oxo,
  • R 8a represents a hydrogen atom or a C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl- or
  • R 17 represents a a fluoro atom or a cyano, hydroxy, oxo, C 1 -C 3 -alkyl-,
  • R 18 represents a fluorine atom, a chlorine atom, a bromo atom, or a cyano or methyl- group
  • L 1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH2-O-
  • L 2 represents a group selected from:–CH2-,–CH2–CH2 -
  • p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not: N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
  • the present invention relates to compounds of general formula (I-2) :
  • R 1 represents a hydrogen atom, or a C1-C3-alkyl- or trifluoromethyl- group
  • R 2 represents a hydrogen atom, or a C1-C3-alkyl- or trifluoromethyl- group, with the proviso that at least one of R 1 and R 2 is different from hydrogen
  • R 3 represents a group selected from: phenyl-, 5- to 6-membered
  • 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R 6 ;
  • R 4a represents a group selected from:
  • phenyl- wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R 8d ,
  • furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl- groupgroup is optionally substituted, one or two times, identically or differently, with R 8d , thienyl- which is unsubstituted,
  • R 4b represents a hydrogen atom
  • R 5d represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 6 represents a group selected from: C 1 -C 4 -alkyl-, C 1 -C 3 -alkoxy-,
  • R 8a represents a hydrogen atom or a C1-C4-alkyl- group
  • R 18 represents a fluorine atom, a chlorine atom, or a cyano or methyl- group
  • L 1 represents a group selected from:–CH 2 -,–CH 2 –CH 2 -; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
  • the present invention relates to compounds of general formula (I-2) :
  • R 1 represents a C1-C3-methyl- or trifluoromethyl- group
  • R 2 represents a methyl- group
  • R 3 represents a group selected from: phenyl- and pyridyl-;
  • phenyl- and pyridyl- group is optionally substituted, one or more times, identically or differently, with a group selected from:
  • R 4a represents a group selected from:
  • phenyl- wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R 8d ,
  • furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl- groupgroup is optionally substituted, one or two times, identically or differently, with R 8d , thienyl- which is unsubstituted,
  • R 4b represents a hydrogen atom
  • R 5d represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 18 represents a fluorine atom, a chlorine atom, or a cyano or methyl- group
  • L 1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
  • the present invention relates to compounds of general formula (I-2) :
  • R 1 represents a C 1 -C 3 -methyl- or trifluoromethyl- group
  • R 2 represents a methyl- group
  • R 3 represents a group selected from: phenyl-, 5- to 6-membered
  • 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R 6 ;
  • R 4a represents a group group which is unsubstituted and is selected from: phenyl-,
  • R 4a represents a triazolyl- group which is once substituted with methyl-.
  • R 4b represents a hydrogen atom;
  • R 5d represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 6 represents a group selected from: C1-C4-alkyl-, C1-C3-alkoxy-,
  • R 8a represents a hydrogen atom or a C1-C4-alkyl- group
  • R 8b represents a hydrogen atom or a C1-C4-alkyl- group
  • R 8b and R 8c together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R 8d ;
  • the present invention relates to compounds of general formula (I-2) :
  • R 1 represents a C 1 -C 3 -methyl- or trifluoromethyl- group
  • R 2 represents a methyl- group
  • R 3 represents a group selected from: phenyl- and pyridyl-;
  • phenyl- and pyridyl- group is optionally substituted, one or more times, identically or differently, with a group selected from:
  • R 4a represents a group group which is unsubstituted and is selected from: phenyl-,
  • R 4a represents a triazolyl- group which is once substituted with methyl-.
  • R 4b represents a hydrogen atom;
  • R 5d represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • L 1 represents a–CH 2 - group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
  • the present invention relates to compounds of general formula (I-2) :
  • R 1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group
  • R 2 represents a hydrogen atom, or a methyl- group
  • R 3 represents a group selected from:
  • R 4a represents a group selected from:
  • R 4b represents a hydrogen atom
  • R 5b represents hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-
  • R 5d represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • L 1 represents a group selected from:–CH 2 -,–CH 2 –CH 2 -; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
  • the present invention relates to compounds of general formula (I-2) :
  • R 1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group
  • R 2 represents a hydrogen atom, or a methyl- group
  • R 3 represents a group selected from: * , *
  • R 4a represents a group selected from:
  • R 4b represents a hydrogen atom
  • R 5b represents hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-
  • R 5d represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • L 1 represents a group selected from:–CH 2 -,–CH 2 –CH 2 -; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
  • the present invention relates to compounds of general formula (I-2) :
  • R 1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group
  • R 2 represents a hydrogen atom, or a methyl- group
  • R 3 represents a group selected from: * ,
  • R 4a represents a group selected from:
  • R 4b represents a hydrogen atom
  • 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 formula (I), in which method an intermediate compound of general formula (II) :
  • the present invention relates to a method of preparing compounds of formula (I-2), in which method an intermediate compound of general formula (II) :
  • the present invention relates to a method of preparing compounds of formula (I-2), in which method an intermediate compound of general formula (XI-2) :
  • the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), particularly in the methods described herein.
  • the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), particularly in the methods described herein.
  • the present invention covers compounds of general formula (III- 2):
  • the present invention covers the use of the intermediate compounds of general formula (XI-2):
  • compositions containing one or more compounds of the present invention can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.
  • a pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the present invention relates also to such combinations.
  • the compounds of this invention can be combined with known anti-hyper- proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.
  • Preferred additional pharmaceutical agents are: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmol
  • Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ.
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
  • the compounds of the invention may also be administered in combination with protein therapeutics.
  • Such protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonistic monoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1, bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1 + ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, rinfabate, AS-1402, B43
  • Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
  • cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to: (1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone, (2) provide for the administration of lesser amounts of the administered chemotherapeutic agents, (3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans, (5) provide for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments, (7) provide a longer time for tumor progression, and/or (8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
  • Another particular aspect of the present invention is the use of a compound of general formula (I-2), described supra, or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.
  • Another particular aspect of the present invention is the use of a compound of general formula (I-2) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth. Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.
  • the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper- proliferative disorders.
  • Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder.
  • Hyper- proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias. Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small- intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to AIDS- related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • General synthesis of compounds of general formula (I) of the present invention The following paragraphs outline a variety of synthetic approaches suitable to prepare compounds of the general formula (I), and intermediates useful for their synthesis.
  • 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 (O-(7-azabenzotriazol-1- yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), TBTU (O- (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), or EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with HOBt (1-hydroxy-1H-benzotriazole hydrate), in the presence of a base such as an aliphatic or aromatic tertiary amine, preferably a tertiary
  • Preferred herein is the performance of said carboxamide coupling reaction using O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) as a coupling agent, in the presence of N,N- diisopropylethylamine as a base, and in dimethylsulfoxide as a solvent, within a temperature range from 0°C to 50°C.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • Also preferred herein is the performance of said carboxamide coupling reaction using O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) as a coupling agent, in the presence of N,N-diisopropylethylamine as a base, and in tetrahydrofuran as a solvent, within a temperature range from 0°C to 50°C.
  • TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate
  • Also preferred herein is the performance of said carboxamide coupling reaction using benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as a coupling agent, in the presence of N,N-diisopropylethylamine as a base, and in tetrahydrofuran as a solvent, within a temperature range from 0°C to 50°C.
  • PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
  • Scheme 1 Preparation of compounds of general formula (I) from 4-aminopyrazole derivatives of formula (II) and carboxylic acids of formula (III).
  • 4-Aminopyrazole intermediates of formula (II) can be prepared using synthetic methods described in more detail as according to Scheme 3 shown below.
  • Heterocyclic carboxylic acid derivatives of formula (III) are well known to the person skilled in the art, and can be approached by a multitude of known synthetic approaches well described in a plethora of monographies and scientific articles. Many of said methods are also illustrated in the experimental section, infra.
  • Heterocyclic carboxylic acids of formula (III) are also commercially available in some structural variety.
  • R 4 groups different from hydrogen can also be introduced subsequently to said carboxamide coupling reaction by means of deprotonating the resulting compounds of formula (Ia), in which R 1 , R 2 , R 3 , R 5 and L 1 are as defined for the compounds of general formula (I), with a base such as an alkali metal hydride, preferably sodium hydride, followed by reaction with a compound of the formula (IV), in which LG represents a leaving group, preferably chloro, bromo, or iodo, and in which R 4 is as defined for the compounds of general formula (I) but different from hydrogen, to give compounds of formula (Ib), as outlined in Scheme 2.
  • a base such as an alkali metal hydride, preferably sodium hydride
  • said nitropyrazole intermediates of formula (VII) are formed as mixtures of regioisomers, as a result of the tautomery featured by the pyrazole core.
  • Said mixtures can be separated into pure regioisomers by methods known to the person skilled in the art, such as column chromatography on silica gel, or by preparative HPLC, either directly following the reaction, or on a later or final stage.
  • Said compounds of formula (VII) can subsequently be reduced, using reduction methods well known to the person skilled in the art, to give primary amines of formula (IIa).
  • Said reduction methods encompass the use of palladium catalysed hydrogenation, using elemental hydrogen or alternative hydrogen sources such as ammonium formiate, and the use of zinc dust or powdered iron in the presence of acetic acid, or the use of tin (II) chloride e.g. in ethanol as a solvent.
  • the latter reagents are preferably used if the substrate contains functional groups vulnerable to catalytic hydrogenation, such as cyano-, bromo or chloro, in particular if attached to an aromatic ring.
  • 1 Scheme 3 Preparation of amino pyrazoles of formula (IIa) from compounds of formula (V). 4-Nitropyrazoles of the formula (V) are well known to the person skilled in the art (see e.g.
  • nitro group can be introduced into pyrazole derivatives lacking subsitution at C-4, by treating 3,5-disubstituted pyrazoles with sulfuric and nitric acid, to give 4-nitropyrazoles of formula (V).
  • R 4 groups different from hydrogen can be either be introduced at later stage, as outlined in Scheme 2, or they may be introduced into primary amines by means of reductive amination reactions well known to the person skilled in the art, e.g. by reaction of said primary amines of formula (IIa) with suitable aldehydes or ketones, followed by reduction e.g. with sodium cyanoborohydride.
  • Participation of the pyrazole ring NH in said carboxamide coupling reaction may give rise to the formation of intermediate compounds of formula (IX) as regioisomeric mixtures with the corresponding N1 amides.
  • intermediate compounds of formula (IX) can be removed by separation techniques well known to the person skilled in the art, e.g. preparative HPLC either immediately after the coupling, or, preferably, after conversion into the compounds of general formula (I).
  • Said intermediate compounds of formula (IX) can be converted into the compounds of general formula (I) by reaction with compounds of the formula (VI), in which R 3 and L 1 are as defined for the compounds of general formula (I), and in which LG represents a leaving group, preferably chloro, bromo, or iodo, in the presence of a suitable inorganic base, such as an alkali carbonate, preferably cesium carbonate or an alkali hydride, such as sodium hydride, or an organic base, such as potassium tert.-butoxide or 1,8- diazabicyclo[5.4.0]undec-7-ene.
  • a suitable inorganic base such as an alkali carbonate, preferably cesium carbonate or an alkali hydride, such as sodium hydride
  • an organic base such as potassium tert.-butoxide or 1,8- diazabicyclo[5.4.0]undec-7-ene.
  • Said coupling reaction can be performed by reaction of compounds of the formulae (II-2) and (III-2) in the presence of a suitable coupling reagent, such as HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium tetrafluoroborate), PyBOP (benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate), or EDC (1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with HOBt (1-hydroxy-1H-benzotriazole hydrate), in the presence of a base such as an aliphatic or aromatic tertiary amine, preferably a terti
  • Preferred herein is the performance of said carboxamide coupling reaction using O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) as a coupling agent, in the presence of N,N- diisopropylethylamine as a base, and in dimethylsulfoxide as a solvent, within a temperature range from 0°C to 50°C.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • Also preferred herein is the performance of said carboxamide coupling reaction using O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) as a coupling agent, in the presence of N,N-diisopropylethylamine as a base, and in tetrahydrofuran as a solvent, within a temperature range from 0°C to 50°C.
  • TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate
  • Also preferred herein is the performance of said carboxamide coupling reaction using benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as a coupling agent, in the presence of N,N-diisopropylethylamine as a base, and in tetrahydrofuran as a solvent, within a temperature range from 0°C to 50°C.
  • PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
  • Scheme 5 Preparation of compounds of general formula (I-2) from 4-aminopyrazole derivatives of formula (II-2) and carboxylic acids of formula (III-2).
  • 4-Aminopyrazole intermediates and quinazoline-4-carboxylic acid derivatives of formulae (II-2) and (III-2) can be prepared using synthetic methods described in more detail as according to the Schemes shown below.
  • Certain quinazoline-4- carboxylic acids are also commercially available in some structural variety.
  • R 4 groups different from hydrogen can also be introduced subsequently to said carboxamide coupling reaction by means of deprotonating the resulting compounds of formula (Ia-2), in which R 1 , R 2 , R 3 , R 4a , R 4b , R 5a , R 5b , R 5c , R 5d and L 1 are as defined for the compounds of general formula (I-2), with a base such as an alkali metal hydride, preferably sodium hydride, followed by reaction with a compound of the formula (IV-2), in which LG represents a leaving group, preferably chloro, bromo, or iodo, and in which R 4 is as defined for the compounds of general formula (I-2) but different from hydrogen, to give compounds of formula (Ib-2), as outlined in Scheme 6.
  • a base such as an alkali metal hydride, preferably sodium hydride
  • said nitropyrazole intermediates of formula (VII-2) are formed as mixtures of regioisomers, as a result of the tautomery featured by the pyrazole core. Said mixtures can be separated into pure regioisomers by methods known to the person skilled in the art, such as column chromatography on silica gel, or by preparative HPLC, either directly following the reaction, or on a later or final stage.
  • Said compounds of formula (VII-2) can subsequently be reduced, using reduction methods well known to the person skilled in the art, to give primary amines of formula (IIa-2).
  • Said reduction methods encompass the use of palladium catalysed hydrogenation, using elemental hydrogen or alternative hydrogen sources such as ammonium formiate, and the use of zinc dust or powdered iron in the presence of acetic acid, or the use of tin (II) chloride e.g. in ethanol as a solvent.
  • the latter reagents are preferably used if the substrate contains functional groups vulnerable to catalytic hydrogenation, such as cyano-, bromo or chloro, in particular if attached to an aromatic ring.
  • the nitro group can be introduced into pyrazole derivatives lacking subsitution at C-4, by treating 3,5-disubstituted pyrazoles with sulfuric and nitric acid, to give 4-nitropyrazoles of formula (V-2).
  • R 4 groups different from hydrogen can be either be introduced at later stage, as outlined in Scheme 2, or they may be introduced into primary amines by means of reductive amination reactions well known to the person skilled in the art, e.g. by reaction of said primary amines of formula (IIa-2) with suitable aldehydes or ketones, followed by reduction e.g. with sodium cyanoborohydride.
  • Quinoline-4-carboxylic acid derivatives of formula (III-2), if not commercially available, can be prepared readily from indole-2,3-dione precursors (see e.g. Monatshefte für Chemie 2013,p. 391; Chinese Chemical Letters 2010, p. 35; The Pfitzinger Reaction.
  • Scheme 8 Preparation of quinoline-4-carboxylic acid derivatives of formula (III-2) from indole-2,3-diones of formula (VIII-2).
  • Indole-2,3-diones of formula (VIII-2) are well known to the person skilled in the art and are either commercially available or can be prepared by methods described e.g. in Chinese Chemical Letters, 2013, p. 929; J. Med. Chem. 2006, p. 4638.
  • Carbonyl compounds of formula (IX-2) can be purchased commercially in wide structural variety.
  • certain compounds of general formula (I-2) can be prepared, according to Scheme 9, from quinoline-4-carboxylic acid derivatives of formula (X-2), in which G represents a group selected from a chlorine atom, a bromine atom, a iodine atom or a [(trifluoromethyl)sulfonyl]oxy- group, and in which R 4b , R 5a , R 5b , R 5c and R 5d are as defined for the compounds of general formula (I-2) but different from G, which can be reacted with 4-aminopyrazole derivatives of formula (II-2), in which R 1 , R 2 , R 3 , R 4 and L 1 are as defined for the compounds of general formula (I-2), in a carboxamide (or peptide) coupling reaction well known to the person skilled in the art, as discussed supra with regard to Scheme 5, to give carboxamide derivatives of formula (XI-2).
  • G represents a group selected from a chlorine atom, a bromine
  • Said coupling reaction can be performed by reaction of compounds of the formulae (X-2) and (II-2) in the presence of a suitable coupling reagent, such as HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
  • TBTU O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium tetrafluoroborate
  • PyBOP benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate
  • EDC 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with HOBt (1-hydroxy-1H-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(C1-C4-alkyl)3, in an appropriate solvent.
  • a base such as an aliphatic or aromatic tertiary amine, preferably a tertiary aliphatic amine of the formula N(C1-C4-alkyl)3, in an appropriate solvent.
  • Said carboxamide derivatives of formula (XI-2) can be subjected to a palladium catalyzed Suzuki coupling, which is well known to the person skilled in the art, by reacting with a boronic acid or a boronic ester of formula (XII-2), in which R 4a is as defined for the compounds of general formula (I-2), and in which the R B groups represent hydrogen atoms, C1-C3-alkyl- groups, or together represent a–C(CH3)2-C(CH3)2- group, in the presence of a palladium catalyst, such as [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II), and in the presence of a base, such as sodium carbonate, to give compounds of formula (I-2).
  • a palladium catalyst such as [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II)
  • a base such as sodium carbonate
  • Quinoline-4-carboxylic acid derivatives of formula (X-2) are known to the person skilled in the art and are commercially available in many cases.
  • Boronic acids and boronic esters, as well their use in Suzuki couplings, are also well known to the person skilled in the art, for a review on boronic acids 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.
  • Scheme 9 Alternative preparation of certain compounds of general formula (I- 2) from quinoline-4-carboxylic acid derivatives of formula (X-2).
  • Participation of the pyrazole ring NH in said carboxamide coupling reaction may give rise to the formation of intermediate compounds of formula (XV-2) as regioisomeric mixtures with the corresponding N1 amides.
  • These can be removed by separation techniques well known to the person skilled in the art, e.g. preparative HPLC either immediately after the coupling, or, preferably, after conversion into the compounds of general formula (I-2).
  • Said intermediate compounds of formula (XV-2) can be converted into the compounds of general formula (I-2) by reaction with compounds of the formula (VI-2), in which R 3 and L 1 are as defined for the compounds of general formula (I-2), and in which LG represents a leaving group, preferably chloro, bromo, or iodo, in the presence of a suitable inorganic base, such as an alkali carbonate, preferably cesium carbonate or an alkali hydride, such as sodium hydride, or an organic base, such as potassium tert.-butoxide or 1,8- diazabicyclo[5.4.0]undec-7-ene.
  • a suitable inorganic base such as an alkali carbonate, preferably cesium carbonate or an alkali hydride, such as sodium hydride
  • an organic base such as potassium tert.-butoxide or 1,8- diazabicyclo[5.4.0]undec-7-ene.
  • Method 4 System: Waters autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5 ⁇ m 100x30 mm;
  • ⁇ 1 intensity 1
  • ⁇ 2 intensity 2
  • ... intensity i
  • a 1 H-NMR peaklist is similar to a classical 1 H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1 H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities.
  • the peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%).
  • Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints".
  • An expert who calculates the peaks of the target compounds by known methods can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1 H- NMR interpretation.

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Abstract

The present invention relates to chemical compounds that selectively inhibit glucose transporter 1 (GLUT1), to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.

Description

GLUCOSE TRANSPORT INHIBITORS The present invention relates to chemical compounds that selectively inhibit glucose transporter 1 (GLUT1), to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
BACKGROUND OF THE INVENTION
Glucose is an essential substrate for metabolism in most cells. Because glucose is a polar molecule, transport through biological membranes requires specific transport proteins. Transport of glucose through the apical membrane of intestinal and kidney epithelial cells depends on the presence of secondary active Na+/glucose symporters, SGLT-1 and SGLT-2, which concentrate glucose inside the cells, using the energy provided by co-transport of Na+ ions down their electrochemical gradient. Facilitated diffusion of glucose through the cellular membrane is otherwise catalyzed by glucose carriers (protein symbol GLUT, gene symbol SLC2 for Solute Carrier Family 2) that belong to a superfamily of transport facilitators (major facilitator superfamily) including organic anion and cation transporters, yeast hexose transporter, plant hexose/proton symporters, and bacterial sugar/proton symporters. Basal glucose transporters (GLUTs) function as glucose channels and are required for maintaining the basic glucose needs of cells. These GLUTs are constitutively expressed and functional in cells and are not regulated by (or sensitive to) insulin. All cells use both glycolysis and oxidative phosphorylation in mitochondria but rely overwhelmingly on oxidative phosphorylation when oxygen is abundant, switching to glycolysis at times of oxygen deprivation (hypoxia), as it occurs in cancer. In glycolysis, glucose is converted to pyruvate and two ATP molecules are generated in the process. Cancer cells, because of their faster proliferation rates, are predominantly in a hypoxic (low oxygen) state. Therefore, cancer cells use glycolysis (lactate formation) as their predominant glucose metabolism pathway. Such a glycolytic switch not only gives cancer higher potentials for metastasis and invasiveness, but also increases cancer's vulnerability to external interference in glycolysis. The reduction of basal glucose transport is likely to restrict glucose supply to cancer cells, leading to glucose deprivation that forces cancer cells to slow down growth or to starve.
All known GLUT proteins contain 12 transmembrane domains and transport glucose by facilitating diffusion, an energy-independent process. GLUT1 transports glucose into cells probably by altemating its conformation. According to this model, GLUT1 exposes a single substrate-binding site toward either the outside or the inside of the cell. Binding of glucose to one site triggers a conformational change, releasing glucose to the other side of the membrane. Results of transgenic and knockout animal studies support an important role for these transporters in the control of glucose utilization, glucose storage and glucose sensing. The GLUT proteins differ in their kinetics and are tailored to the needs of the cell types they serve. Although more than one GLUT protein may be expressed by a particular cell type, cancers frequently overexpress GLUT1, which is a high affinity glucose transporter, and its expression level is correlated with invasiveness and metastasis potentials of cancers, indicating the importance of upregulation of glucose transport in cancer cell growth and in the severity of cancer malignancy. GLUT1 expression was also found to be significantly higher than that of any other glucose transporters. Evidence indicates that cancer cells are more sensitive to glucose deprivation than normal cells. Numerous studies strongly suggest that basal glucose transport inhibition induces apoptosis and blocks cancer cell growth. Anti- angiogenesis has been shown to be a very effective way to restrict cancer growth and cause cancer ablation. Reduced GLUT1 expression following transfection of GLUT1 antisense cDNA into cancer cell lines has been shown to suppress cell growth in vitro and tumor growth in vivo, and to reduce in vitro invasiveness of cells (Noguchi Y. et al. Cancer Lett 154(2), 2000, 175–182; Ito S. et al. J Natl Cancer Inst 94(14), 2002, 1080–1091). It has been demonstrated that GLUT1 is the most highly expressed hexose transporter in ErbB2- and PyVMT-induced mouse mammary carcinoma models, and that reducing the level of GLUT1 using shRNA or Cre/lox results in reduced glucose usage, reduced growth on plastic and in soft agar, and impaired tumor growth in nude mice (Christian D. Young et al., PLoS ONE, August 2011, Volume 6, Issue 8, e23205, 1-12). Therefore, inhibition of GLUT1 represents a promising approach for the treatment of proliferative disorders including solid tumours such as carcinomas and sarcomas and leukaemias and lymphoid malignancies or other disorders associated with uncontrolled cellular proliferation. Different compounds have been disclosed in prior art which show an inhibitory effect on GLUT1. For example, WO2011/119866(A1) discloses composition and methods for glucose transport inhibition; WO2012/051117(A2) and WO2013/155338(A2) disclose substituted benzamides as GLUT1 inhibitors. Compounds showing a certain structural similarity to the compounds of the present invention are disclosed in prior art. WO97/36881(A1) discloses arylheteroaryl-containing compounds which inhibit farnesyl-protein transferase. WO00/07996(A2) discloses pyrazole estrogen receptor agonist and antagonist compounds. WO01/21160(A2) discloses carboxamide derivatives as inhibitors of herpesviridae. WO03/037274(A2) and WO2004/099154(A2) disclose pyrazole-amides as inhibitors of sodium channels. WO2004/098528(A2) discloses pyrazole derived compounds as inhibitors of p38 kinase. WO2006/132197(A1) discloses heterocyclic compounds as inhibitors of 11 - hydroxysteroid dehydrogenase type 1. WO2006/062249(A1) discloses compounds for the prevention, therapy or improvement of a disease to which the activation of a thrombopoietin receptor is effective. WO2008/126899(A1) discloses 5-membered heterocyclic compounds as inhibitors of xanthine oxidase. WO2008/008286(A2) discloses substituted pyrazoles as ghrelin receptor antagonists. WO2009/025793(A2) discloses compounds that function as bitter taste blockers. WO2009/027393(A2) and WO2010/034737(A1) disclose pyrazole compounds for controlling invertebrate pests. WO2009/099193(A1) discloses compounds having inhibitory action on melanin production. WO2009/119880(A1) discloses pyrazole derivatives having an androgen receptor antagonistic action. WO2011/050305(A1) and WO2011/050316(A1) disclose pyrazole compounds as allosteric modulators of mGluR4 receptor activity. WO2011/126903(A2) discloses multisubstituted aromatic compounds including substituted pyrazolyl as thrombin inhibitors. WO2004/110350(A2) discloses compounds modulating amyloid beta. WO2009/055917(A1) discloses inhibitors of histone deacetylase. WO02/23986(A1) discloses 4-acylaminopyrazole derivatives exhibiting fungicidal activities. WO03/051833(A2) discloses heteroaryl substituted pyrazole compounds as mGluR5 modulators. WO2009/076454(A2) discloses compounds which modulate the activity of store- operated calcium channels. WO99/32454(A1) discloses nitrogen containing heteroaromatics with ortho-substituted P1 groups as factor Xa inhibitors. WO2004/037248(A2) and WO2004/043951(A1) disclose compounds as modulators of the peroxisome proliferator activated receptors. WO 2013/109991(A1) discloses various heterocyclic compounds for the treatment of neurodegenerative diseases. WO 2014031936(A2) discloses heterocyclic compounds as modulators of HIF pathway activity. Several pyrazole carboxamide and 4-quinolinyl pyrazole carboxamide derivatives showing a certain similarity to the compounds of the present invention have been indexed in Chemical Abstracts without publication reference. Selected examples of such compounds are listed below: 4-Cinnolinecarboxamide, N-[1-[(3,5-dimethyl-4-isoxazolyl)methyl]-1H- pyrazol- 4-yl]-3-phenyl-4-cinnolinecarboxamide, CAS Registry-Nr.1024526-45-1;
Isoxazolo[5,4-b]pyridine-4-carboxamide, 3,6-dimethyl-N-[1-(phenylmethyl)-1H- pyrazol-4-yl]- CAS Registry-Nr.1626778-45-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-1H- pyrazol-4-yl]-3,6-dimethyl-1-phenyl-, hydrochloride (1:1); CAS Registry-Nr. 1432030-01-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1-(1-methylethyl)-N-[1- (phenylmethyl)-1H-pyrazol-4-yl]-6-(2-thienyl)-, CAS Registry-Nr.1302712-02-2; 1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1,3-dimethyl-6-(1-methylethyl)-N- [1-(3-pyridinylmethyl)-1H-pyrazol-4-yl]-, CAS Registry-Nr. 1295087-01-2;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 6-cyclopropyl-N-[1-[(2- fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]- 1,3-dimethyl-, CAS Registry-Nr.1179485-80-3;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-3,5- dimethyl-1H-pyrazol-4-yl]-3,6-dimethyl-1- phenyl-, CAS Registry-Nr. 1179467-28-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-3,5- dimethyl-1H-pyrazol-4-yl]-1,3,6- trimethyl-, CAS Registry-Nr.1179381-50-0; Isoxazolo[5,4-b]pyridine-4-carboxamide, N-[3,5-dimethyl-1-(phenylmethyl)-1H- pyrazol-4-yl]-3-(4-methoxyphenyl)-6- methyl-, CAS Registry-Nr. 1174881-46-9; 1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[3,5-dimethyl-1-[(3- methylphenyl)methyl]-1H-pyrazol-4-yl]-1,6-dimethyl-, CAS Registry- Nr.1174856-57-5;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1-butyl-N-[3,5-dimethyl-1- (phenylmethyl)-1H-pyrazol-4-yl]-3,6-dimethyl-, CAS Registry-Nr.1005577-44-5; 1-Naphthalenecarboxamide, N-[1-[(2-chlorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-; CAS Registry-Nr. 1171567-34-2
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 3,6-dicyclopropyl-N-[1-[(1,3- dimethyl-1H-pyrazol-4-yl)methyl]-1H-pyrazol-4- yl]-1-methyl-, CAS Registry- Nr.1005685-96-0;
N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide, CAS Registry-Nr. 515847-18-4,
N-[1-[(3,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- pyridinyl)-4-quinolinecarboxamide, CAS Registry-Nr. 901635-45-8,
2-(3,4-Dimethoxyphenyl)-N-[1-[(4-fluorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-4-quinolinecarboxamide, CAS Registry-Nr. 901608-74-0,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide, CAS Registry-Nr. 901608-46-6,
6-Bromo-N-[3,5-dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide, CAS Registry-Nr. 901608-88-6,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide hydrochloride (1:1) , CAS Registry-Nr. 1052514-07-4, 2-(3-Chlorophenyl)-N-[1-[(2,4-dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl]-4-quinolinecarboxamide, CAS Registry-Nr. 1005860-92-3,
N-[1-[(2,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide, CAS Registry-Nr. 894603-03-3,
and
N-[3,5-Dimethyl-1-(phenylmethyl)-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide, CAS Registry-Nr. 1006142-46-6. No therapeutic application has been disclosed hitherto for these compounds. So, the state of the art described above either does not specifically disclose the compounds of general formula (I) of the present invention, or does not disclose their pharmacological activity.
DESCRIPTION of the INVENTION In one aspect, the present invention relates to compounds of general formula (I) :
Figure imgf000008_0001
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ; wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
*-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R4a represents a group selected from: aryl-, heteroaryl-;
wherein said aryl- and heteroaryl - group is optionally substituted, one or more times, identically or differently, with R8d; R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; R5 represents a group selected from:
* *
Figure imgf000009_0001
, * * * * *
Figure imgf000010_0001
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule;
or
R5 represents
Figure imgf000010_0002
wherein * represents the point of attachment to the rest of the molecule; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from: cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-,
halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14,
-N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c,
-N(R14a)C(=O)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14,
-S(=O)2N(R14a)R14b or -S(=O)(=NR14a)R14b ,
said phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a,
-C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a, -S(=O)(=NR15)-R14, phenyl-, 5- to 6-membered heteroaryl-; R7 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl- and benzyl-;
R8 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl-, benzyl-, -C(=O)R10, -C(=O)OR10, -C(=O)N(R10a)R10b, -S(=O)2R10; R8a represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-,
C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8b, R8c
represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4-to 10-membered heterocycloalkyl-,
(4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group; said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R8d;
or
R8b and 8c, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl-group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d; R8d represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -NO2, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b,
,
Figure imgf000012_0001
-O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14, -S(=O) 4b
2N(R14a)R1 , -S(=O)(=NR14a)R14b or a tetrazolyl- group; or
two R8d groups present ortho to each other on a phenyl- or heteroaryl- ring form a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R14a)(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- ring; R9 represents a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b or -S(=O)(=NR11)-R10 ,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R10,
Figure imgf000013_0001
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-;
or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group; R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; R14, R14a, R14b, R14c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, said C1-C3-alkyl- group being optionally substituted once with -N(R16)R16a; or
R14a and R14b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R17; R15 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b or -C(=O)O-R14 group; R16, R16a
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group,
or,
R16, R16a,
together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group; R17 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R14 or -C(=O)O-R14 group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-,
-C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R14a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; L3 represents a -C1-C6-alkylene- group; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for use in the treatment and prophylaxis of a disease.
In another aspect, the present invention relates to compounds of general formula (I) :
Figure imgf000015_0001
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
*-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R5 represents a group selected from:
* *
Figure imgf000016_0001
, *
Figure imgf000017_0001
, * * * * *
Figure imgf000017_0002
,
*
* * * ,
Figure imgf000017_0003
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4- alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R10, - C(=O)-O-R10, -C(=O)N(R10a)R10b, -N(R10a)R10b, -S(=O) 0
2R1 , -S(=O)(=NR11)-R10, phenyl-, 5- to 6-membered heteroaryl-; R7 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl- and benzyl-; R8 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl-, benzyl-, -C(=O)R10, -C(=O)OR10, -C(=O)N(R10a)R10b, -S(=O)2R10; R9 represents a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b,
,
Figure imgf000018_0001
-O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b or -S(=O)(=NR11)-R10 ,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R10, R1
Figure imgf000018_0002
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-;
or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group; R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for use in the treatment and prophylaxis of a disease. In another aspect, the present invention relates to compounds of general formula (I):
Figure imgf000019_0001
(I)
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group, with the proviso that at least one of R1 and R2 is different from hydrogen; represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-,
Figure imgf000020_0001
and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
*-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R5 represents a group selected from:
* *
,
Figure imgf000020_0002
* * * * *
Figure imgf000021_0001
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4- alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R10, - C(=O)-O-R10, -C(=O)N(R10a)R10b, -N(R10a)R10b, -S(=O)2R10, -S(=O)(=NR11)-R10, phenyl-, 5- to 6-membered heteroaryl-; R7 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl- and benzyl-; R9 represents a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b,
Figure imgf000021_0002
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R10, R10a, R10b, R10c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-;
or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group; R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same,
with the proviso that compounds of the formula (I) are not: 4-Cinnolinecarboxamide, N-[1-[(3,5-dimethyl-4-isoxazolyl)methyl]-1H- pyrazol- 4-yl]-3-phenyl-4-cinnolinecarboxamide, CAS Registry-Nr.1024526-45-1;
Isoxazolo[5,4-b]pyridine-4-carboxamide, 3,6-dimethyl-N-[1-(phenylmethyl)-1H- pyrazol-4-yl]- CAS Registry-Nr.1626778-45-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-1H- pyrazol-4-yl]-3,6-dimethyl-1-phenyl-, hydrochloride (1:1); CAS Registry-Nr. 1432030-01-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1-(1-methylethyl)-N-[1- (phenylmethyl)-1H-pyrazol-4-yl]-6-(2-thienyl)-, CAS Registry-Nr.1302712-02-2; 1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1,3-dimethyl-6-(1-methylethyl)-N- [1-(3-pyridinylmethyl)-1H-pyrazol-4-yl]-, CAS Registry-Nr. 1295087-01-2;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 6-cyclopropyl-N-[1-[(2- fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]- 1,3-dimethyl-, CAS Registry-Nr.1179485-80-3;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-3,5- dimethyl-1H-pyrazol-4-yl]-3,6-dimethyl-1- phenyl-, CAS Registry-Nr. 1179467-28-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-3,5- dimethyl-1H-pyrazol-4-yl]-1,3,6- trimethyl-, CAS Registry-Nr.1179381-50-0; Isoxazolo[5,4-b]pyridine-4-carboxamide, N-[3,5-dimethyl-1-(phenylmethyl)-1H- pyrazol-4-yl]-3-(4-methoxyphenyl)-6- methyl-, CAS Registry-Nr. 1174881-46-9;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[3,5-dimethyl-1-[(3- methylphenyl)methyl]-1H-pyrazol-4-yl]-1,6-dimethyl-, CAS Registry- Nr.1174856-57-5;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1-butyl-N-[3,5-dimethyl-1- (phenylmethyl)-1H-pyrazol-4-yl]-3,6-dimethyl-, CAS Registry-Nr.1005577-44-5; 1-Naphthalenecarboxamide, N-[1-[(2-chlorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-; CAS Registry-Nr. 1171567-34-2 1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 3,6-dicyclopropyl-N-[1-[(1,3- dimethyl-1H-pyrazol-4-yl)methyl]-1H-pyrazol-4- yl]-1-methyl-, CAS Registry- Nr.1005685-96-0.
In another aspect, the present invention relates to compounds of general formula (I-2) :
Figure imgf000024_0001
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed; wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally form a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*,
*-CH2C(R14a)(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*,
*-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R4a represents a group selected from: aryl-, heteroaryl-;
wherein said aryl- and heteroaryl - group is optionally substituted, one or more times, identically or differently, with R8d; R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; R5a,
Figure imgf000025_0001
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-,
halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14,
-N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c,
-N(R14a)C(=O)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14,
-S(=O)2N(R14a)R14b or -S(=O)(=NR14a)R14b ,
said phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-;
R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a,
-C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a, -S(=O)(=NR15)-R14, phenyl-, 5- to 6-membered heteroaryl-; R8a represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8b, R8c
represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4-to 10-membered heterocycloalkyl-,
(4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group; said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R8d;
or
R8b and 8c, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl-group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d; R8d represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -NO2, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14, -S(=O)2N(R14a)R14b, -S(=O)(=NR14a)R14b or a tetrazolyl- group; or
two R8d groups present ortho to each other on a phenyl- or heteroaryl- ring form a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R14a)(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- ring; R14, R14a, R14b, R14c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, said C1-C3-alkyl- group being optionally substituted once with -N(R16)R16a; or
R14a and R14b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R17; R15 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b or -C(=O)O-R14 group; R16, R16a
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group,
or,
R16, R16a,
together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group; R17 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-,
trifluoromethyl-, -C(=O)R14 or -C(=O)O-R14 group; L1 represents a group selected from: -C1-C4-alkylene-,
Figure imgf000028_0001
,
-C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R14a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; L3 represents a -C1-C6-alkylene- group; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for use in the treatment and prophylaxis of a disease. In another aspect, the present invention relates to compounds of general formula (I-2):
Figure imgf000029_0001
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed; wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally form a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*,
*-CH2C(R14a)(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*,
*-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4a represents a group selected from:
phenyl- or naphthyl-, wherein said phenyl- or naphthyl- group is optionally substituted, one or more times, identically or differently, with R8d,
furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, and benzocondensed derivatives thereof,
wherein said furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, and benzocondensed derivative thereof is optionally substituted, one or more times, identically or differently, with R8d,
thienyl- which is unsubstituted,
thienyl- which is substituted once with R18, and which is optionally substituted, one or more times, identically or differently, with R8d, and pyrazolyl- which is unsubstituted; R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; R5a, R5
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-,
halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14,
-N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(R14a)C(=O)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14,
-S(=O)2N(R14a)R14b or -S(=O)(=NR14a)R14b ,
said phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, halo-C1-C3-alkyl-, C1-C3-alkoxy-;
Figure imgf000031_0001
R5d represents a hydrogen atom or a fluorine atom; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a,
-C(=O)N(R8b)R8b, -N(R14a)R14b, -S(=O)2R8a, -S(=O)(=NR15)-R14, phenyl-, 5- to 6-membered heteroaryl-; R8a represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8b, R8c
represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4-to 10-membered heterocycloalkyl-,
(4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group; said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R8d;
or
R8b and R8c, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl-group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d; R8d represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -NO2, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14, -S(=O)2N(R14a)R14b, -S(=O)(=NR14a)R14b or a tetrazolyl- group; R14, R
Figure imgf000033_0001
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, said C1-C3-alkyl- group being optionally substituted once with -N(R16)R16a; or
R14a and R14b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R17; R15 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b or -C(=O)O-R14 group; R16, R16a
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group,
or,
R16, R16a,
together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group; R17 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-,
trifluoromethyl-, -C(=O)R14 or -C(=O)O-R14 group; R18 represents a fluorine atom, a chlorine atom, a bromo atom, or a cyano or methyl- group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-,
-C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R14a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; L3 represents a -C1-C6-alkylene- group; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
N-[1-[(3,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- pyridinyl)-4-quinolinecarboxamide,
2-(3,4-Dimethoxyphenyl)-N-[1-[(4-fluorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
6-Bromo-N-[3,5-dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide hydrochloride (1:1) ,
2-(3-Chlorophenyl)-N-[1-[(2,4-dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl]-4-quinolinecarboxamide, N-[1-[(2,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-(phenylmethyl)-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide.
The terms as mentioned in the present text have preferably the following meanings : The term“halogen atom” or“halo-” is to be understood as meaning a fluorine, chlorine, bromine or iodine atom, also referred to as fluoro-, chloro-, bromo- and iodo-. The term“oxo” is to be understood as preferably meaning an oxygen atom attached to an atom featuring suitable bonding valence, such as a saturated carbon atom or a sulfur atom, by a double bond, resulting in the formation e.g. of a carbonyl group -C(=O)- or a sulfonyl group .
Figure imgf000035_0001
The term“C1-C10-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. a methyl-, ethyl-, propyl-, butyl-, pentyl-, hexyl-, iso-propyl-, iso-butyl-, sec-butyl-, tert-butyl-, iso-pentyl-, 2-methylbutyl-, 1- methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-, neo-pentyl-, 1,1- dimethylpropyl-, 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-, heptyl-, octyl-, nonyl- or decyl- group, or an isomer thereof. Particularly, said group has 1, 2, 3, 4, 5 or 6 carbon atoms (“C1-C6- alkyl-”), more particularly 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl-”), e.g. a methyl-, ethyl-, propyl-, butyl-, iso-propyl-, iso-butyl-, sec-butyl-, tert-butyl- group, even more particularly 1, 2 or 3 carbon atoms (“C1-C3-alkyl-”), e.g. a methyl-, ethyl-, n-propyl- or iso-propyl- group. The term“-C1-C8-alkylene-” is understood as preferably meaning a linear or branched, saturated, divalent hydrocarbon chain (or“tether”) having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g.–CH2- (“methylene” or“-C1-alkylene-”) or, for example -CH2-CH2- (“ethylene” or“-C2-alkylene-”), -CH2-CH2-CH2-, -C(H)(CH3)- CH2- or -C(CH3)2-) (“propylene” or“-C3-alkylene-”), or, for example–CH2-C(H)(CH3)- CH2-, –CH2-C(CH3)2-), -CH2-CH2-CH2-CH2- (“butylene” or “-C4-alkylene-”),“-C5-alkylene-”, e.g. -CH2-CH2-CH2-CH2-CH2- (“n-pentylene”), or “-C6-alkylene-”, e.g. –CH2-CH2-CH2-CH2-CH2-CH2- (“n-hexylene”) group. Particularly, said alkylene tether has 1, 2, 3, 4, or 5 carbon atoms ("-C1-C5- alkylene-"), more particularly 1 or 2 carbon atoms ("-C1-C2-alkylene-"), or, 3, 4, or 5 carbon atoms("-C3-C5-alkylene-"). The term“halo-C1-C4-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term“C1- C4-alkyl-” is defined supra, and in which one or more of the hydrogen atoms is replaced, identically or differently, by a halogen atom. Preferred are halo-C1- C3-alkyl- groups. Particularly, said halogen atom is F, resulting in a group also referred to as“fluoro-C1-C3-alkyl-”. Said halo-C1-C3-alkyl- group or fluoro-C1-C3- alkyl- group is, for example, –CF3, -CHF2, -CH2F, -CF2CF3, or -CH2CF3. Particularly preferred is–CF3, also referred to as“trifluoromethyl-“. The term“cyano-C1-C4-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term“C1-C4-alkyl-” is defined supra, and in which one or more of the hydrogen atoms is replaced by a cyano group. Said cyano-C1-C4-alkyl- group is, for example, -CH2CN, -CH2CH2-CN, -C(CN)H-CH3, -C(CN)H-CH2CN, or -CH2CH2CH2CH2-CN. The term“hydroxy-C1-C4-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term“C1-C4-alkyl-” is defined supra, and in which one or more of the hydrogen atoms is replaced by a hydroxy group with the proviso that not more than one hydrogen atom attached to a single carbon atom is being replaced. Preferred are hydroxy-C1-C3-alkyl- groups. Said hydroxy-C1-C4-alkyl- group, or, preferably, hydroxy-C1-C3-alkyl- group is, for example, -CH2OH, -CH2CH2-OH, -C(OH)H-CH3, or -C(OH)H-CH2OH. The term“C1-C4-alkoxy-” is to be understood as preferably meaning a linear or branched, saturated, monovalent group of formula–O-(C1-C4-alkyl-), in which the term “C1-C4-alkyl-” is defined supra, e.g. a methoxy-, ethoxy-, n-propoxy-, iso-propoxy-, n-butoxy-, tert-butoxy. Preferred are C1-C3-alkoxy- groups. The term“halo-C1-C4-alkoxy-” is to be understood as preferably meaning a linear or branched, saturated, monovalent C1-C4-alkoxy- group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, by a halogen atom. Preferred are halo-C1-C3-alkoxy-groups. Particularly, said halogen atom is F, resulting in a group also referred to as “fluoro-C1-C4-alkoxy-”, or, preferably“fluoro-C1-C3-alkoxy-”. Said halo-C1-C4- alkoxy- group or fluoro-C1-C4-alkoxy- group is, for example,–OCF3, -OCHF2, - OCH2F, -OCF2CF3, or -OCH2CF3. Particularly preferred is–OCF3, also referred to as“trifluoromethoxy-“. The term“C1-C3-alkoxy-C1-C3-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent C1-C3-alkyl- group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, by a C1-C3-alkoxy group, as defined supra, e.g. methoxyalkyl-, ethoxyalkyl-, propyloxyalkyl- or iso-propoxyalkyl-. The term“halo-C1-C3-alkoxy-C1-C3-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent C1-C3-alkoxy-C1-C3-alkyl- group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F, resulting in a group also referred to as “fluoro-C1-C3-alkoxy-C1-C3-alkyl-”. Said halo-C1-C3-alkoxy-C1-C3-alkyl- group or fluoro-C1-C3-alkoxy-C1-C3-alkyl- group is, for example,–CH2CH2OCF3, -CH2CH2OCHF2, -CH2CH2OCH2F, -CH2CH2OCF2CF3, or -CH2CH2OCH2CF3. The term“C2-C6-alkenyl-” is to be understood as preferably meaning 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, particularly 3, 4, 5 or 6 carbon atoms (“C3-C6-alkenyl-”), more particularly 2 or 4 carbon atoms (“C2-C4-alkenyl-”), or 3 or 4 carbon atoms (“C3-C4-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. Said alkenyl- group is, for example, a vinyl-, allyl-, (E)-2-methylvinyl-, (Z)-2-methylvinyl-, homoallyl-, (E)-but-2-enyl-, (Z)-but-2-enyl-, (E)-but-1-enyl-, (Z)-but-1-enyl-, pent-4-enyl-, (E)-pent-3-enyl-, (Z)-pent-3-enyl-, (E)-pent-2-enyl-, (Z)-pent-2-enyl-, (E)-pent-1-enyl-, (Z)-pent-1-enyl-, hex-5-enyl-, (E)-hex-4-enyl-, (Z)-hex-4-enyl-, (E)-hex-3-enyl-, (Z)-hex-3-enyl-, (E)-hex-2-enyl-, (Z)-hex-2-enyl-, (E)-hex-1-enyl-, (Z)-hex-1-enyl-, iso-propenyl-, 2-methylprop-2-enyl-, 1-methylprop-2-enyl-, 2-methylprop-1-enyl-, (E)-1-methylprop-1-enyl-, (Z)-1-methylprop-1-enyl-, 3-methylbut-3-enyl-, 2-methylbut-3-enyl-, 1-methylbut-3-enyl-, 3-methylbut-2-enyl-, (E)-2-methylbut-2-enyl-, (Z)-2-methylbut-2-enyl-, (E)-1-methylbut-2-enyl-, (Z)-1-methylbut-2-enyl-, (E)-3-methylbut-1-enyl-, (Z)-3-methylbut-1-enyl-, (E)-2-methylbut-1-enyl-, (Z)-2-methylbut-1-enyl-, (E)-1-methylbut-1-enyl-, (Z)-1-methylbut-1-enyl-, 1,1-dimethylprop-2-enyl-, 1-ethylprop-1-enyl-, 1-propylvinyl-, 1-isopropylvinyl-, 4-methylpent-4-enyl-, 3-methylpent-4-enyl-, 2-methylpent-4-enyl-, 1-methylpent-4-enyl-, 4-methylpent-3-enyl-, (E)-3-methylpent-3-enyl-, (Z)-3-methylpent-3-enyl-, (E)-2-methylpent-3-enyl-, (Z)-2-methylpent-3-enyl-, (E)-1-methylpent-3-enyl-, (Z)-1-methylpent-3-enyl-, (E)-4-methylpent-2-enyl-, (Z)-4-methylpent-2-enyl-, (E)-3-methylpent-2-enyl-, (Z)-3-methylpent-2-enyl-, (E)-2-methylpent-2-enyl-, (Z)-2-methylpent-2-enyl-, (E)-1-methylpent-2-enyl-, (Z)-1-methylpent-2-enyl-, (E)-4-methylpent-1-enyl-, (Z)-4-methylpent-1-enyl-, (E)-3-methylpent-1-enyl-, (Z)-3-methylpent-1-enyl-, (E)-2-methylpent-1-enyl-, (Z)-2-methylpent-1-enyl-, (E)-1-methylpent-1-enyl-, (Z)-1-methylpent-1-enyl-, 3-ethylbut-3-enyl-, 2-ethylbut-3-enyl-, 1-ethylbut-3-enyl-, (E)-3-ethylbut-2-enyl-, (Z)-3-ethylbut-2-enyl-, (E)-2-ethylbut-2-enyl-, (Z)-2-ethylbut-2-enyl-, (E)-1-ethylbut-2-enyl-, (Z)-1-ethylbut-2-enyl-, (E)-3-ethylbut-1-enyl-, (Z)-3-ethylbut-1-enyl-, 2-ethylbut-1-enyl-, (E)-1-ethylbut-1-enyl-, (Z)-1-ethylbut-1-enyl-, 2-propylprop-2-enyl-, 1-propylprop-2-enyl-, 2-isopropylprop-2-enyl-, 1-isopropylprop-2-enyl-, (E)-2-propylprop-1-enyl-, (Z)-2-propylprop-1-enyl-, (E)-1-propylprop-1-enyl-, (Z)-1-propylprop-1-enyl-, (E)-2-isopropylprop-1-enyl-, (Z)-2-isopropylprop-1-enyl-, (E)-1-isopropylprop-1-enyl-, (Z)-1-isopropylprop-1-enyl-, (E)-3,3-dimethylprop-1-enyl-, (Z)-3,3-dimethylprop-1-enyl-, 1-(1,1-dimethylethyl)ethenyl-, buta-1,3-dienyl-, penta-1,4-dienyl-, hexa-1,5-dienyl-, or methylhexadienyl- group. Particularly, said group is vinyl- or allyl-. The term“C2-C6-alkynyl-” is to be understood as preferably meaning 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, particularly 3, 4, 5 or 6 carbon atoms (“C3-C6-alkynyl-”), more particularly 2 or 4 carbon atoms (“C2-C4-alkynyl-”), or 3 or 4 carbon atoms (“C3-C4-alkynyl-”). Said C2-C6-alkynyl- group is, for example, ethynyl-, prop-1-ynyl-, prop-2-ynyl-, but-1-ynyl-, but-2-ynyl-, but-3-ynyl-, pent-1-ynyl-, pent-2-ynyl-, pent-3-ynyl-, pent-4-ynyl-, hex-1-ynyl-, hex-2-ynyl-, hex-3-ynyl-, hex-4-ynyl-, hex-5-ynyl-, 1-methylprop-2-ynyl-, 2-methylbut-3-ynyl-, 1-methylbut-3-ynyl-, 1-methylbut-2-ynyl-, 3-methylbut-1-ynyl-, 1-ethylprop-2-ynyl-, 3-methylpent-4-ynyl-, 2-methylpent-4-ynyl-, 1-methylpent-4-ynyl-, 2-methylpent-3-ynyl-, 1-methylpent-3-ynyl-, 4-methylpent-2-ynyl-, 1-methyl- pent-2-ynyl-, 4-methylpent-1-ynyl-, 3-methylpent-1-ynyl-, 2-ethylbut-3-ynyl-, 1-ethylbut-3-ynyl-, 1-ethylbut-2-ynyl-, 1-propylprop-2-ynyl-, 1-isopropylprop-2-ynyl-,
2,2-dimethylbut-3-ynyl-, 1,1-dimethylbut-3-ynyl-, 1,1-dimethylbut-2-ynyl-, or 3,3-dimethylbut-1-ynyl- group. Particularly, said alkynyl- group is ethynyl-, prop-1-ynyl-, or prop-2-ynyl-. The term“C3-C7-cycloalkyl-” is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms. Said C3-C7-cycloalkyl- group is for example a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- ring. Particularly, said ring contains 3, 4, 5 or 6 carbon atoms (“C3-C6-cycloalkyl-”), more particularly, said ring contains 5 or 6 carbon atoms (“C5-C6-cycloalkyl-”). The term“4- to 10-membered heterocycloalkyl-” is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from -O-, -S-, -S(=O)-, -S(=O)2-, -NRa-, in which Ra represents a hydrogen atom or a C1-C6-alkyl- or C3-C7-cycloalkyl- group; 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. The term "heterospirocycloalkyl-" is to be understood as meaning a saturated, monovalent 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 one or more heteroatom-containing groups selected from -O-, -S-, -S(=O)-, -S(=O)2-, -NRa-, in which Ra represents a hydrogen atom or a C1-C6-alkyl-- or C3-C7-cycloalkyl- group; 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. Said heterospirocycloalkyl- group is, 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-, or azaspiro[5.5]decyl-. 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 one or more heteroatom-containing groups selected from -O-, -S-, -S(=O)-, -S(=O)2-, -NRa-, in which Ra represents a hydrogen atom or a C1-C6-alkyl- or C3-C7-cycloalkyl- group; 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. Said heterobicycoalkyl- group is, 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-, or 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 one or more heteroatom-containing groups selected from -O-, -S-, - S(=O)-, -S(=O)2-, -NRa-, in which Ra represents a hydrogen atom, or a
C1-C6-alkyl- or C3-C7-cycloalkyl- group; 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. Said bridged
heterocycloalkyl- group is, 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, thiazabicyclo[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-. Particularly, said 4- to 10-membered heterocycloalkyl- can contain 3, 4, 5 or 6 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a“4- to 7-membered heterocycloalkyl-”), more particularly said heterocycloalkyl- can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a “5- to 6-membered heterocycloalkyl-”). Particularly, without being limited thereto, said heterocycloalkyl- can be a 4-membered ring, such as an azetidinyl-, oxetanyl-, or a 5-membered ring, such as tetrahydrofuranyl-, pyrrolidinyl-, imidazolidinyl-, pyrazolidinyl-, or a 6-membered ring, such as tetrahydropyranyl-, piperidinyl-, morpholinyl-, dithianyl-, thiomorpholinyl-, piperazinyl-, or trithianyl-, or a 7-membered ring, such as a diazepanyl- ring, for example. The term“aryl-” is to be understood as preferably meaning a monovalent, aromatic, mono-, or bi- or tricyclic hydrocarbon ring system having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a“C6-C14-aryl-” group), particularly a group having 6 carbon atoms (a“C6-aryl-” group), e.g. a phenyl- group; or a group having 9 carbon atoms (a“C9-aryl-” group), e.g. an indanyl- or indenyl- group, or a group having 10 carbon atoms (a“C10-aryl-” group), e.g. a tetralinyl-, dihydronaphthyl-, or naphthyl- group, or a biphenyl- group (a“C12-aryl-” group), or a group having 13 carbon atoms, (a“C13-aryl-” group), e.g. a fluorenyl- group, or a group having 14 carbon atoms, (a“C14-aryl-” group), e.g. an anthracenyl- group. Preferably, the aryl- group is a phenyl- group. The term“heteroaryl-” is understood as preferably meaning an“aryl-“ group as defined supra, in which at least one of the carbon ring atoms is replaced by a heteroatom selected from oxygen, nitrogen, and sulphur. The“heteroaryl-“ group contains 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a“5- to 14-membered heteroaryl-” group), particularly 5 or 6 or 9 or 10 ring atoms (a “5- to 10-membered heteroaryl-” group), more particularly 5 or 6 ring atoms (a “5- to 6-membered heteroaryl-” group). Particularly, heteroaryl- is selected from thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, thia-4H-pyrazolyl-, tetrazolyl- etc., and benzo derivatives thereof, such as, for example, benzofuranyl-, benzothienyl-, benzoxazolyl-, benzisoxazolyl-, benzimidazolyl-, benzotriazolyl-, benzothiadiazolyl-, indazolyl-, indolyl-, isoindolyl-, etc.; or pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, etc., and benzo derivatives thereof, such as, for example, quinolinyl-, quinazolinyl-, isoquinolinyl-, etc.; or azocinyl-, indolizinyl-, purinyl-, etc., and benzo derivatives thereof; or cinnolinyl-, phthalazinyl-, quinazolinyl-, quinoxalinyl-, naphthpyridinyl-, pteridinyl-, carbazolyl-, acridinyl-, phenazinyl- , phenothiazinyl-, phenoxazinyl-, xanthenyl-, or oxepinyl-, and further bi- or tricyclic heteroaryl- groups featuring heteroatoms in more than one rings such as pyrrolopyrazolyl-, imidazopyrazolyl-, thienopyrrolyl-, pyrrolooxazolyl-, pyrrolopyridyl-, thienopyrimidyl-, imidazopyrimidyl-, imidazopyridazinyl-, imidazopyridyl-, thiazolopyridyl-, pyrazolopyridyl-, pyrrolotriazinyl-, etc.. Furthermore, “5- to 6-membered heteroaryl-” is selected from thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, thia-4H-pyrazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, etc..
Furthermore,“5-membered heteroaryl-” is selected from thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, thia-4H-pyrazolyl-, tetrazolyl-, etc.. In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals 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-; or the term thienyl- includes thien-2-yl- and thien-3-yl-. Preferably, the heteroaryl- group is a pyridyl- group. The term“C1-C6”, as used throughout this text, e.g. in the context of the definition of “C1-C6-alkyl-” is to be understood as meaning an alkyl- group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term“C1-C6” is to be interpreted as any sub-range comprised therein, e.g. C1-C6 , C2-C5 , C3-C4 ,
C1-C2 , C1-C3 , C1-C4 , C1-C5 , C1-C6 ; particularly C1-C2 , C1-C3 , C1-C4 , C1-C5 , C1-C6 ; more particularly C1-C4 ; in the case of“C1-C3-haloalkyl-” or“halo-C1-C3-alkoxy- ” even more particularly 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 finite number of carbon atoms of 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 any sub-range comprised therein, e.g. C2-C6 , C3-C5 , C3-C4 , C2-C3 , C2-C4 , C2-C5 ; particularly 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 finite 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 any sub-range comprised therein, e.g. C3-C6 , C4- C5 , C3-C5 , C3-C4 , C4-C6, C5-C7 ; particularly C3-C6. 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. The leaving group as used herein is suitable for nucleophilic aliphatic and/or aromatic substitution, e.g. a halogen atom, in particular chloro-, bromo- or iodo-, or a group selected from methanesulfonyloxy-, p-toluenesulfonyloxy-, trifluoromethanesulfonyloxy-, nonafluorobutanesulfonyloxy-, (4-bromo-benzene)sulfonyloxy-, (4-nitro-benzene)sulfonyloxy-, (2-nitro-benzene)-sulfonyloxy-, (4-isopropyl-benzene)sulfonyloxy-, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy-, (2,4,6-trimethyl-benzene)sulfonyloxy-, (4-tert-butyl-benzene)sulfonyloxy-, benzenesulfonyloxy-, and (4-methoxy-benzene)sulfonyloxy-. As used herein, the term“protective group” is a protective group attached to a nitrogen in intermediates used for the preparation of compounds of the general formula (I-2). Such groups are introduced e.g. by chemical modification of the respective amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for amino groups are descibed for example in T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999; more specifically, said groups can be selected from substituted sulfonyl groups, such as mesyl-, tosyl- or phenylsulfonyl-, acyl groups such as benzoyl-, acetyl- or tetrahydropyranoyl-, or carbamate based groups, such as tert.-butoxycarbonyl- (Boc), or can include silicon, as in e.g. 2-(trimethylsilyl)ethoxymethyl- (SEM). As used herein, the term“one or more times”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning“one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times”. 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 compounds of this invention 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. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations are included within the scope of the present invention. Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art. The 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 order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976). 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), 11C, 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 129I and 131I, respectively. 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. 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 state of the art method, such as chromatography, especially chiral chromatography, for example. 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
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. 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 relates to useful forms of 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 contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. 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. Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as 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 a relatively non-toxic, 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. 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 polymorphs, or as a mixture of more than one polymorphs, in any ratio. In one aspect, the present invention relates to compounds of general formula (I) :
Figure imgf000051_0001
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
*-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R5 represents a group selected from:
* *
* *
Figure imgf000052_0001
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4- alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R10, - C(=O)-O-R10, -C(=O)N(R10a)R10b, -N(R10a)R10b, -S(=O)2R10, -S(=O)(=NR11)-R10, phenyl-, 5- to 6-membered heteroaryl-; R7 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl- and benzyl-;
R8 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl-, benzyl-, -C(=O)R10, -C(=O)OR10, -C(=O)N(R10a)R10b, -S(=O)2R10; R9 represents a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b or -S(=O)(=NR11)-R10 ,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R10, R10a, R10b, R10c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-;
or
R10a and R10b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group; R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In a preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a C1-C3-alkyl-, fluoro-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl- or cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a C1-C3-alkyl- or halo-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a C1-C3-alkyl- or fluoro-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a C1-C3-alkyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group, with the proviso that at least one of R1 and R2 is different from hydrogen. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a trifluoromethyl- group. In a preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a C1-C3-alkyl-, fluoro-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a C1-C3-alkyl-, halo-C1-C3-alkyl- or cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a C1-C3-alkyl- or halo-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a C1-C3-alkyl- or fluoro-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a C1-C3-alkyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a hydrogen atom or a methyl- group, with the proviso that at least one of R1 and R2 is different from hydrogen. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R2 represents a trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a methyl-, ethyl- or trifluoromethyl- group, and wherein R2 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a methyl- or trifluoromethyl- group, and wherein R2 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a methyl- or trifluoromethyl- group, and wherein R2 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a methyl- group and R2 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: aryl- and heteroaryl-; wherein said group is substituted, one or more times, identically or differently, with–(L2)p-R6, and wherein two -(L2)p-R6 groups, if being present ortho to each other on said aryl- or heteroaryl- group optionally represent a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group. In a preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: aryl- and heteroaryl-; wherein said group is substituted, one or more times, identically or differently,
Figure imgf000058_0001
In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or heteroaryl- group optionally represent a bridge selected from: *-C3- C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or heteroaryl- group optionally represent a bridge selected from: *-C3- C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- group,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl–;
wherein said phenyl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- heteroaryl- group optionally represent a bridge selected from: *-C3-C4- alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl–; wherein said phenyl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- heteroaryl- group optionally represent a bridge selected from: *-C3-C4- alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- group,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl-;
wherein said phenyl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with R6. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl-;
wherein said phenyl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with R6,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a phenyl- group ;
wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R6. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R6,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a heteroaryl- group ; wherein said heteroaryl- group is optionally substituted, one or more times, identically or differently, with R6. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a 5- to 6-membered heteroaryl- group ;
wherein said 5- to 6-membered heteroaryl- group is optionally substituted, one or more times, identically or differently, with R6. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl-;
wherein said phenyl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with a group selected from: C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, C1-C2-alkoxy-C1-C2-alkyl-, -CN, halo-, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, heteroaryl-;
wherein said phenyl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with a group selected from: methyl-, ethyl-, cyclopropyl-, morpholinyl-, methoxymethyl-, -CN, fluoro-, - C(=O)N(H)CH3. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, oxadiazolyl-, pyrazolyl- isoxazolyl-, thiazolyl-, oxazolyl-, imidazolyl-, tetrazolyl-, pyridyl- and imidazo[1,2a]pyridyl-;
wherein said phenyl-, oxadiazolyl-, pyrazolyl- isoxazolyl-, thiazolyl-, oxazolyl-, imidazolyl-, tetrazolyl-, pyridyl- and imidazo[1,2a]pyridyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, halo-, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from: phenyl-, oxadiazolyl-, pyrazolyl- isoxazolyl-, thiazolyl-, oxazolyl-, imidazolyl-, tetrazolyl-, pyridyl- and imidazo[1,2a]pyridyl-;
wherein said phenyl-, oxadiazolyl-, pyrazolyl- isoxazolyl-, thiazolyl-, oxazolyl-, imidazolyl-, tetrazolyl-, pyridyl- and imidazo[1,2a]pyridyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: methyl-, ethyl-, cyclopropyl-, morpholinyl-, methoxymethyl-, - CN, fluoro-, -C(=O)N(H)CH3. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group selected from:
Figure imgf000063_0001
,
,
,
Figure imgf000064_0001
wherein * represents the point of attachment to L1. In a particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a group:
Figure imgf000064_0002
wherein * represents the point of attachment to L1. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R4 represents a hydrogen atom or a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R4 represents a C1-C3-alkyl-group. In a particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R4 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R5 represents a group selected from:
* *
Figure imgf000065_0001
,
wherein said group is optionally substituted, one or more times, identically or differently, with R9; and wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R5 represents a group selected from:
* *
Figure imgf000066_0001
,
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R5 represents a group selected from:
* *
Figure imgf000066_0002
,
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R5 represents a group selected from:
* *
Figure imgf000066_0003
,
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R5 represents a group selected from:
* * * *
Figure imgf000067_0001
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R5 represents a group:
*
Figure imgf000067_0002
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R5 represents a group selected from:
* * * *
Figure imgf000067_0003
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R5 represents a group selected from: * * * *
Figure imgf000068_0001
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of
Figure imgf000068_0002
* * * * ,
Figure imgf000069_0001
,
* *
Figure imgf000069_0002
,
* *
,
Figure imgf000069_0003
,
* *
Figure imgf000069_0004
, wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R5 represents a group selected from: * * *
Figure imgf000070_0001
, *
Figure imgf000070_0002
, wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R5 represents a group selected from:
* *
Figure imgf000070_0003
wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R6 represents a group selected from: oxo, C1-C4- alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-, C1-C2-alkoxy-C1-C2-alkyl-, cyano-C1-C3-alkyl-, C1-C3- alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R10, -C(=O)-O-R10, -C(=O)N(R10a)R10b, -N(R10a)R10b and -S(=O)2R10. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R6 represents a group selected from: C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C1-C3-alkyl-, C1-C2-alkoxy-C1-C2-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo- and -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R6 represents a group selected from: C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C1-C3-alkyl-, C1-C2-alkoxy-C1-C2-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo- and -C(=O)N(R10a)R10b,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R6 represents a group selected from: C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, C1-C2-alkoxy-C1-C2-alkyl-, -CN, halo-, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R6 represents a group selected from: C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, C1-C2-alkoxy-C1-C2-alkyl-, -CN, halo-, -C(=O)N(R10a)R10b,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R6 represents a group selected from: methyl-, ethyl-, cyclopropyl-, morpholinyl-, methoxymethyl-, -CN, fluoro-, - C(=O)N(H)CH3. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R6 represents a group selected from methyl-, ethyl- , cyclopropyl-, morpholinyl-, methoxymethyl-, -CN, fluoro-, -C(=O)N(H)CH3,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R6 represents a -CN group. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R6 represents a -CN group, and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R7 represents a hydrogen atom or a C1-C4-alkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R7 represents a hydrogen atom or a C1-C4-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R7 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R7 represents a C1-C4-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R7 represents a hydrogen atom or a C1-C2-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R7 represents a C1-C2-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R7 represents a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R7 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a halogen atom or a group selected from: cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, 5- to 6-membered heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -OR10, -S(=O)2R10, -S(=O)2N(H)R10,
said 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a halogen atom or a group selected from: cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, 5- to 6-membered heteroaryl-, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -OR10,
said 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: fluoro-, cyano-, C1-C2-alkyl-, C1-C2-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a halogen atom or a group selected from: cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, 5- membered heteroaryl-, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -OR10,
said 5- membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: fluoro-, cyano-, C1-C2-alkyl-, C1-C2-alkoxy-,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a halogen atom or a group selected from: C1-C3-alkyl-, trifluoromethyl-, C1-C3-alkoxy-, 5-membered heteroaryl-, -C(=O)N(H)R10, -C(=O)OR10,
said 5-membered heteroaryl- group being optionally substituted one or more times with a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a halogen atom or a group selected from: C1-C3-alkyl-, trifluoromethyl-, C1-C3-alkoxy-, 5-membered heteroaryl-, -C(=O)N(H)R10, -C(=O)OR10,
said 5-membered heteroaryl- group being optionally substituted one or more times with a methyl- group,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a bromine atom or a group selected from: trifluoromethyl-, methoxy-,isoxazolyl-, -C(=O)NH2,
Figure imgf000074_0001
said isoxazolyl- group being optionally substituted one or more times with a methyl- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a bromine atom or a group selected from: trifluoromethyl-, -C(=O)NH2. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a bromine atom or a trifluoromethyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a group selected from: trifluoromethyl-, -C(=O)NH2. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a trifluoromethyl-, group. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R9 represents a -C(=O)NH2 group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl;
or R10a and R10b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-,C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R10a and R10b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R12. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, hydroxy-C1- C3-alkyl-. In a particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or a C1-C3-alkyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or a methyl- or an ethyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R11 represents a hydrogen atom or a cyano-, C1-C3- alkyl-, -C(=O)R10, or -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R11 represents a hydrogen atom or a cyano-, -C(=O)R10, or -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R11 represents a hydrogen atom or a cyano- or -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R11 represents a -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R11 represents a cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R11 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R12 represents a fluorine atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, - CH2-C(=O)-N(R10a)-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L1 represents a group selected from: -C1-C4-alkylene-, -C(phenyl)(H)-, -CH2-CH2-O-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH2-O-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L1 represents a -C1-C4-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L1 represents a -C1-C3-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L1 represents a group selected from:
Figure imgf000078_0001
In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L1 represents a group selected from: –CH2-, -C(CH3)(H)-,–CH2–CH2-. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L1 represents a group selected from:
Figure imgf000078_0002
In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L1 represents a -C(CH3)(H)- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L1 represents a–CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L2 represents a group selected from: –
Figure imgf000079_0001
In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein L2 represents a–CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein p represents an integer of 0 or 1. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein p represents an integer of 1. In a particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein p represents an integer of 0. In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein p represents an integer of 1. In a particularly preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R1 represents a methyl- group, R2 represents a methyl- group, R4 represents a hydrogen atom and L1 represents a -CH2- group. More preferred embodiments of compounds of the present invention are described below with respect to formula (I). Said preferred embodiments are to be understood as not including the following compounds:
4-Cinnolinecarboxamide, N-[1-[(3,5-dimethyl-4-isoxazolyl)methyl]-1H- pyrazol- 4-yl]-3-phenyl-4-cinnolinecarboxamide, CAS Registry-Nr.1024526-45-1;
Isoxazolo[5,4-b]pyridine-4-carboxamide, 3,6-dimethyl-N-[1-(phenylmethyl)-1H- pyrazol-4-yl]- CAS Registry-Nr.1626778-45-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-1H- pyrazol-4-yl]-3,6-dimethyl-1-phenyl-, hydrochloride (1:1); CAS Registry-Nr. 1432030-01-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1-(1-methylethyl)-N-[1- (phenylmethyl)-1H-pyrazol-4-yl]-6-(2-thienyl)-, CAS Registry-Nr.1302712-02-2; 1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1,3-dimethyl-6-(1-methylethyl)-N- [1-(3-pyridinylmethyl)-1H-pyrazol-4-yl]-, CAS Registry-Nr. 1295087-01-2;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 6-cyclopropyl-N-[1-[(2- fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]- 1,3-dimethyl-, CAS Registry-Nr.1179485-80-3;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-3,5- dimethyl-1H-pyrazol-4-yl]-3,6-dimethyl-1- phenyl-, CAS Registry-Nr. 1179467-28-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-3,5- dimethyl-1H-pyrazol-4-yl]-1,3,6- trimethyl-, CAS Registry-Nr.1179381-50-0; Isoxazolo[5,4-b]pyridine-4-carboxamide, N-[3,5-dimethyl-1-(phenylmethyl)-1H- pyrazol-4-yl]-3-(4-methoxyphenyl)-6- methyl-, CAS Registry-Nr. 1174881-46-9;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[3,5-dimethyl-1-[(3- methylphenyl)methyl]-1H-pyrazol-4-yl]-1,6-dimethyl-, CAS Registry- Nr.1174856-57-5;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1-butyl-N-[3,5-dimethyl-1- (phenylmethyl)-1H-pyrazol-4-yl]-3,6-dimethyl-, CAS Registry-Nr.1005577-44-5; 1-Naphthalenecarboxamide, N-[1-[(2-chlorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-; CAS Registry-Nr. 1171567-34-2
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 3,6-dicyclopropyl-N-[1-[(1,3- dimethyl-1H-pyrazol-4-yl)methyl]-1H-pyrazol-4- yl]-1-methyl-, CAS Registry- Nr.1005685-96-0.
It is to be understood that the present invention relates to any sub- combination within any embodiment of compounds of general formula (I), supra. Some further examples of combinations are given hereinafter. However, the invention is not limited to these combinations.
In a preferred embodiment, the present invention relates to compounds of general formula (I) :
Figure imgf000081_0001
(I)
in which :
R1 represents a C1-C3-alkyl- or trifluoromethyl- group; R2 represents a C1-C3-alkyl- group, R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6; R4 represents a hydrogen atom or a C1-C3-alkyl-group; R5 represents a group selected from:
* *
* *
Figure imgf000082_0001
wherein said group is optionally substituted, one or more times, identically or differently, with R9; and wherein * represents the point of attachment to the rest of the molecule; R6 represents a group selected from: oxo, C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3- alkyl-, C1-C2-alkoxy-C1-C2-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R10, -C(=O)-O-R10, -C(=O)N(R10a)R10b, -N(R10a)R10b and -S(=O)2R10; R7 represents a hydrogen atom or a C1-C4-alkyl- group; R9 represents a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, 5- to 6-membered heteroaryl-, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -OR10,
said 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
fluoro-, cyano-, C1-C2-alkyl-, C1-C2-alkoxy-; R10, R
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group; L1 represents a group selected from:–CH2-,–CH2–CH2-; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (I) :
Figure imgf000084_0001
in which :
R1 represents a methyl- or trifluoromethyl- group; R2 represents a methyl- group, R3 represents a group selected from: phenyl-, heteroaryl-;
wherein said phenyl-, and heteroaryl- is optionally substituted, one or more times, identically or differently, with R6; R4 represents a hydrogen atom; R5 represents a group selected from:
* *
* *
Figure imgf000084_0002
* * * * *
Figure imgf000085_0001
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule; R6 represents a group selected from: C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, C1-C2-alkoxy-C1-C2-alkyl-, -CN, halo-, -C(=O)N(R10a)R10b; R7 represents a hydrogen atom or a C1-C2-alkyl- group; R9 represents a halogen atom or a group selected from:
C1-C3-alkyl-, trifluoromethyl-, C1-C3-alkoxy-, 5-membered heteroaryl-, -C(=O)N(H)R10, -C(=O)OR10,
said 5-membered heteroaryl- group being optionally substituted one or more times with a methyl- group; R10, R10a, R10b
represent, independently from each other, a hydrogen atom or a methyl- or an ethyl- group; L1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In a particularly preferred embodiment, the present invention relates to compounds of general formula (I) :
Figure imgf000086_0001
in which :
R1 represents a methyl- or trifluoromethyl- group; R2 represents a methyl- group, R3 represents a group: *
Figure imgf000086_0002
,
wherein * represents the point of attachment to L1; R4 represents a hydrogen atom; R5 represents a group selected from:
* *
Figure imgf000086_0003
* * *
Figure imgf000087_0001
, * * * * *
Figure imgf000087_0002
, * * *
Figure imgf000087_0003
,
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule; R7 represents a hydrogen atom or a C1-C2-alkyl- group; R9 represents a halogen atom or a group selected from:
C1-C3-alkyl-, trifluoromethyl-, C1-C3-alkoxy-, 5-membered heteroaryl-, -C(=O)N(H)R10, -C(=O)OR10,
said 5-membered heteroaryl- group being optionally substituted one or more times with a methyl- group; R10 represents a hydrogen atom or a methyl- or an ethyl- group; L1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another particularly preferred embodiment, the present invention relates to compounds of general formula (I) :
Figure imgf000088_0001
in which :
R1 represents a methyl- or trifluoromethyl- group; R2 represents a methyl- group, R3 represents a group selected from: phenyl-, heteroaryl-;
wherein said phenyl-, and heteroaryl- is optionally substituted, one or more times, identically or differently, with R6; R4 represents a hydrogen atom; R5 represents a group selected from:
* * *
Figure imgf000088_0002
wherein * represents the point of attachment to the rest of the molecule; R6 represents a group selected from: C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, C1-C2-alkoxy-C1-C2-alkyl-, -CN, halo-, -C(=O)N(R10a)R10b; R10a, R10b
represent, independently from each other, a hydrogen atom or a methyl- or an ethyl- group; L1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another particularly preferred embodiment, the present invention relates to compounds of general formula (I) :
Figure imgf000089_0001
(I)
in which :
R1 represents a methyl- or trifluoromethyl- group; R2 represents a methyl- group, R3 represents a group selected from: phenyl-, heteroaryl-;
wherein said phenyl-, and heteroaryl- is optionally substituted, one or more times, identically or differently, with R6; R4 represents a hydrogen atom; R5 represents a group selected from:
* *
Figure imgf000090_0001
wherein * represents the point of attachment to the rest of the molecule; R6 represents a group selected from: C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, C1-C2-alkoxy-C1-C2-alkyl-, -CN, halo-, -C(=O)N(R10a)R10b;
represent, independently from each other, a hydrogen atom or a methyl- or an ethyl- group; L1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another particularly preferred embodiment, the present invention relates to compounds of general formula (I) :
Figure imgf000091_0001
in which :
R1 represents a methyl- or trifluoromethyl- group; R2 represents a methyl- group, R3 represents a group: *
Figure imgf000091_0002
,
wherein * represents the point of attachment to L1; R4 represents a hydrogen atom; R5 represents a group selected from:
* * *
Figure imgf000091_0003
, *
Figure imgf000091_0004
,
wherein * represents the point of attachment to the rest of the molecule; L1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another particularly preferred embodiment, the present invention relates to compounds of general formula (I) :
Figure imgf000092_0001
(I)
in which :
R1 represents a methyl- or trifluoromethyl- group; R2 represents a methyl- group, R3 represents a group: *
Figure imgf000092_0002
,
wherein * represents the point of attachment to L1; R4 represents a hydrogen atom; R5 represents a group selected from: * *
Figure imgf000093_0001
,
wherein * represents the point of attachment to the rest of the molecule; L1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another particularly preferred embodiment, the present invention relates to compounds of general formula (I) :
Figure imgf000093_0002
in which :
R1 represents a methyl- or trifluoromethyl- group; R2 represents a methyl- group, R3 represents a group selected from:
Figure imgf000093_0003
,
Figure imgf000094_0001
wherein * represents the point of attachment to L1; R4 represents a hydrogen atom;
R5 represents a group selected from: ,
Figure imgf000094_0002
Figure imgf000095_0001
Figure imgf000096_0001
,
* *
Figure imgf000096_0002
, wherein * represents the point of attachment to the rest of the molecule.
L1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another aspect, the present invention relates to compounds of general formula (I-2) :
Figure imgf000096_0003
in which : R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally form a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*,
*-CH2C(R14a)(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*,
*-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R4a represents a group selected from: aryl-, heteroaryl-;
wherein said aryl- and heteroaryl - group is optionally substituted, one or more times, identically or differently, with R8d; R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; R5a,
Figure imgf000098_0001
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-,
halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14,
-N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(R14a)C(=O)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14,
-S(=O)2N(R14a)R14b or -S(=O)(=NR14a)R14b ,
said phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-;
R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a,
-C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a, -S(=O)(=NR15)-R14, phenyl-, 5- to 6-membered heteroaryl-; R8a represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8b, R8c
represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4-to 10-membered heterocycloalkyl-,
(4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group; said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R8d;
or
R8b and 8c, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl-group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d; R8d represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -NO2, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14, -S(=O)2N(R14a)R14b, -S(=O)(=NR14a)R14b or a tetrazolyl- group; or two R8d groups present ortho to each other on a phenyl- or heteroaryl- ring form a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R14a)(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- ring; R14, R14a, R14b, R14c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, said C1-C3-alkyl- group being optionally substituted once with -N(R16)R16a; or
R14a and R14b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R17; R15 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b or -C(=O)O-R14 group; R16, R16a
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group,
or,
R16, R16a,
together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group; R17 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R14 or -C(=O)O-R14 group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-,
-C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R14a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; L3 represents a -C1-C6-alkylene- group; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, In a preferred embodiment, the invention relates to compounds of formula (I- 2), supra, wherein R1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl-, fluoro-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl- or cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl- or halo-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl- or fluoro-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group, with the proviso that at least one of R1 and R2 is different from hydrogen. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a trifluoromethyl- group. In a preferred embodiment, the invention relates to compounds of formula (I- 2), supra, wherein R2 represents a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a C1-C3-alkyl-, fluoro-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a C1-C3-alkyl-, halo-C1-C3-alkyl- or cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a C1-C3-alkyl- or halo-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a C1-C3-alkyl- or fluoro-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a C1-C3-alkyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a hydrogen atom or a methyl- group, with the proviso that at least one of R1 and R2 is different from hydrogen. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl-, ethyl- or trifluoromethyl- group, and wherein R2 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- or trifluoromethyl- group, and wherein R2 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- or trifluoromethyl- group, and wherein R2 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- group and R2 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl- group and R2 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a hydrogen atom and R2 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- group and R2 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a hydrogen atom and R2 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: aryl- and heteroaryl-; wherein said group is substituted, one or more times, identically or differently, with–(L2)p-R6, and wherein two -(L2)p-R6 groups, if being present ortho to each other on said aryl- or heteroaryl- group optionally represent a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group. In a preferred embodiment, the invention relates to compounds of formula (I- 2), supra, wherein R3 represents a group selected from: aryl- and heteroaryl-; wherein said group is substituted, one or more times, identically or differently,
Figure imgf000105_0001
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R14a)(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4b represents a hydrogen atom, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6, and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4b represents a hydrogen atom, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl– and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4b represents a hydrogen atom, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl- and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4b represents a hydrogen atom, R4 represents a hydrogen atom and L1 represents a -CH2- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a phenyl-group;
wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- group,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4b represents a hydrogen atom, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R6. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R6,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4b represents a hydrogen atom, R4 represents a hydrogen atom and L1 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, oxadiazolyl-, pyrazolyl-, isoxazolyl-, pyridyl-, and piperidinyl-; wherein said phenyl-, oxadiazolyl-, pyrazolyl-, isoxazolyl-, pyridyl-, and piperidinyl- group is optionally substituted, one or more times, identically or differently, with R6. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, oxadiazolyl-, pyrazolyl-, isoxazolyl-, pyridyl-, and piperidinyl-; wherein said phenyl-, oxadiazolyl-, pyrazolyl-, isoxazolyl-, pyridyl-, and piperidinyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: C1-C6-alkyl-, C1-C4-alkoxy-, -CN, halo-, -S(=O)2R8a. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, oxadiazolyl-, pyrazolyl-, isoxazolyl-, pyridyl-, and piperidinyl-; wherein said phenyl-, oxadiazolyl-, pyrazolyl-, isoxazolyl-, pyridyl-, and piperidinyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: C1-C3-alkyl-, C1-C3-alkoxy-, -CN, halo-, -S(=O)2R8a. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl-, oxadiazolyl-, pyrazolyl-, isoxazolyl-, pyridyl- and piperidinyl-; wherein said phenyl-, oxadiazolyl-, pyrazolyl-, isoxazolyl-, pyridyl- and piperidinyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: methyl-, ethyl-, methoxy-, -CN, fluoro-, chloro-, -S(=O)2-ethyl. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl- and pyridyl-;
wherein said phenyl- and pyridyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: C1-C3-alkoxy-, -CN, halo-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl- and pyridyl-;
wherein said phenyl- and pyridyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: methoxy-, -CN, fluoro-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from: phenyl- and pyridyl-;
wherein said phenyl- and pyridyl- group is substituted once with a group selected from: methoxy-, -CN, fluoro-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a phenyl- group; wherein said phenyl- group is substituted once with a group selected from: methoxy-, -CN, fluoro-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a pyridyl- group; wherein said pyridyl- group is substituted once with a methoxy- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a phenyl- group; wherein said phenyl- group is substituted once with a group selected from: methoxy-, -CN. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a phenyl- group; wherein said phenyl- group is substituted once with a–CN group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a phenyl- group; wherein said phenyl- group is substituted once with a methoxy- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from:
Figure imgf000113_0001
wherein * represents the point of attachment to L1. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from:
* , *
Figure imgf000114_0001
wherein * represents the point of attachment to L1. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a group selected from:
*
Figure imgf000114_0002
,
wherein * represents the point of attachment to L1. compounds of formula (I-2), supra, wherein R3 represents a group:
*
Figure imgf000114_0003
,
wherein * represents the point of attachment to L1. compounds of formula (I-2), supra, wherein R3 represents a group: *
Figure imgf000115_0001
,
wherein * represents the point of attachment to L1. In a preferred embodiment, the invention relates to compounds of formula (I- 2), supra, wherein R4a represents a group selected from:
phenyl-, wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R8d,
furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, and benzocondensed derivatives thereof, wherein said furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, and benzocondensed derivative thereof is optionally substituted, one or two times, identically or differently, with R8d,
thienyl- which is unsubstituted,
thienyl- which is substituted once with R18, and which is optionally substituted, one or two times, identically or differently, with R8d, and
pyrazolyl- which is unsubstituted. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group selected from:
phenyl-, wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R8d,
furanyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, oxadiazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl-, benzofuranyl-, benzothienyl-, quinolinyl- and isoquinolinyl-, wherein said furanyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, oxadiazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl-, benzofuranyl- , benzothienyl-, quinolinyl- and isoquinolinyl- group is optionally substituted, one or two times, identically or differently, with R8d,
thienyl- which is unsubstituted,
thienyl- which is substituted once with R18, and which is optionally substituted, one or two times, identically or differently, with R8d, and
pyrazolyl- which is unsubstituted. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group selected from:
phenyl-, wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R8d,
furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl-,
wherein said furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl- group is optionally substituted, one or two times, identically or differently, with R8d,
thienyl- which is unsubstituted,
thienyl- which is substituted once with R18, and which is optionally substituted once with R8d, and
pyrazolyl- which is unsubstituted. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group selected from:
*
Figure imgf000116_0001
,
Figure imgf000117_0001
,
Figure imgf000118_0001
wherein * represents the point of attachment to the rest of the molecule. In a preferred embodiment, the invention relates to compounds of formula (I- 2), supra, wherein R4a represents a group which is unsubstituted and is selected from:
phenyl-,
furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, and benzocondensed derivatives thereof, thienyl- and pyrazolyl-,
or
R4a represents a triazolyl- group which is once substituted with methyl-.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group which is unsubstituted and is selected from:
phenyl-,
furanyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, oxadiazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl-, benzofuranyl-, benzothienyl-, quinolinyl- and isoquinolinyl-, thienyl- and pyrazolyl-,
or
R4a represents a triazolyl- group which is once substituted with methyl-. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group which is unsubstituted and is selected from:
phenyl-,
furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, thienyl- and pyrazolyl-,
or
R4a represents a triazolyl- group which is once substituted with methyl-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group which is unsubstituted and is selected from: *
,
*
Figure imgf000120_0001
wherein * represents the point of attachment to the rest of the molecule. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group which is unsubstituted and is selected from:
phenyl-,
furanyl-, thiazolyl-, pyridyl-, thienyl- and pyrazolyl-,
or
R4a represents a triazolyl- group which is once substituted with methyl-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group which is unsubstituted and is selected from:
Figure imgf000120_0002
wherein * represents the point of attachment to the rest of the molecule. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4b represents a hydrogen atom or a C1-C3-alkyl- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4b represents a hydrogen atom. In a preferred embodiment, the invention relates to compounds of formula (I- 2), supra, wherein R5a
, R5b, R5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(R14a)C(=O)R14b,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a , R5b, R5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, 5- to 6-membered heteroaryl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, said phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from: cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(R14a)C(=O)R14b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, 5- to 6-membered heteroaryl-,
said phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, and in which compounds R1 represents a C1-C3-alkyl- group and R2 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from:
C1-C3-alkyl-, trifluoromethyl-, C1-C3-alkoxy-, trifluoromethoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from:
C1-C3-alkyl-, trifluoromethyl-, C1-C3-alkoxy-, trifluoromethoxy-,
and in which compounds R1 represents a methyl- group and R2 represents a methyl- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a , R5b, R5c independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom or a group selected from:
methyl-, methoxy-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom or a group selected from:
methyl-, methoxy-, and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4b represents a hydrogen atom and R4 represents a hydrogen atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5c, R5d independently from each other represent a hydrogen atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a represents a hydrogen atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5b represents a hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5c represents a hydrogen atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5d represents a hydrogen atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a , R5c, R5d independently from each other represent a hydrogen atom, and in which compounds R5b represents a hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5c, R5d independently from each other represent a hydrogen atom, and in which compounds R5b represents a hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4b represents a hydrogen atom and R4 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4 represents a hydrogen atom or a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4 represents a C1-C3-alkyl-group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: oxo, C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a, -C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a, phenyl-, 5- to 6-membered heteroaryl-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: oxo, C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a, -C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a
. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: oxo, C1-C4-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3- alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a, -C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a . In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: oxo, C1-C4-alkyl-, C1-C3-alkoxy-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a, -C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a
. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: C1-C4-alkyl-, C1-C3-alkoxy-, -CN, halo-, -S(=O)2R8a. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: C1-C4-alkyl-, C1-C3-alkoxy-, -CN, halo-, -S(=O)2R8a,
and in which compounds R1 represents a methyl- group and R2 represents a methyl- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: methyl-, ethyl-, methoxy-, -CN, fluoro-, chloro-,
Figure imgf000127_0001
In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: methyl-, ethyl-, methoxy-, -CN, fluoro-, chloro-, -S(=O)2-CH2CH3, and in which compounds R1 represents a methyl- group and R2 represents a methyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a C1-C3-alkoxy-, -CN or halo- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a methoxy-, -CN or fluoro- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a -CN group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a C1-C3-alkoxy- or a -CN group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a methoxy- group or a
-CN group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents halo-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a fluorine atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a C1-C3-alkoxy- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a methoxy- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a methoxy- group or a
-CN group,
and in which compounds R1 represents a methyl- group and R2 represents a methyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a -CN group, and in which compounds R1 represents a methyl- group and R2 represents a methyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a methoxy- group, and in which compounds R1 represents a methyl- group and R2 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a represents C1-C4-alkyl-, fluoro-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a represents a hydrogen atom or a C1-C6-alkyl-, C3-C7-cycloalkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a represents a hydrogen atom or a C1-C6-alkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a represents a hydrogen atom or a C1-C6-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a represents a hydrogen atom or a C1-C4-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a represents a C1-C4-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, independently from each other, represent a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group;
said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R8d;
or wherein R8b and R8c, together with the nitrogen atom they are attached to, represent a 4- to 10-membered heterocycloalkyl- group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d,
and in which compounds L3 represents a -CH2- or -CH2CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, independently from each other, represent a hydrogen atom, or a C1-C6-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, 4- to 7-membered heterocycloalkyl-, (4- to 7- membered heterocycloalkyl)-(L3)-, phenyl-, 5- to 6-membered heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)- or 5- to 6-membered heteroaryl-(L3)- group;
said C1-C6-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, 4- to 7-membered heterocycloalkyl-, (4- to 7-membered heterocycloalkyl)-(L3)-, phenyl-, 5- to 6-membered heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, and 5- to 6- membered heteroaryl-(L3)- group being optionally substituted one or more times, identically or differently, with R8d;
or wherein R8b and R8c, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, independently from each other, represent a hydrogen atom, or a C1-C6-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, 4- to 7-membered heterocycloalkyl-, (4- to 7- membered heterocycloalkyl)-(L3)-, phenyl-, 5- to 6-membered heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)- or 5- to 6-membered heteroaryl-(L3)- group;
said C1-C6-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, 4- to 7-membered heterocycloalkyl-, (4- to 7-membered heterocycloalkyl)-(L3)-, phenyl-, 5- to 6-membered heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, and 5- to 6- membered heteroaryl-(L3)- group being optionally substituted one or more times, identically or differently, with R8d;
or wherein R8b and R8c, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d,
and in which compounds L3 represents a -CH2- or -CH2CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, phenyl- or 5- to 6-membered heteroaryl- group; said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R8d;
or R8b and R8c, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, phenyl- or 5- to 6-membered heteroaryl- group; said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R8d. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7- membered heterocycloalkyl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl- and 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d;
or R8b and R8c, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7- membered heterocycloalkyl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl- and 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, independently from each other, represent a hydrogen atom, or a C1-C2-alkyl-, cyclopropyl- or 5- to 6-membered heterocycloalkyl- group;
said C1-C2-alkyl-, cyclopropyl- and 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d;
or R8b and R8c, together with the nitrogen atom they are attached to, represent a 5- to 6-membered heterocycloalkyl- group, said 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, independently from each other, represent a hydrogen atom, or a C1-C2-alkyl-, cyclopropyl- or 5- to 6-membered heterocycloalkyl- group;
said C1-C2-alkyl-, cyclopropyl- and 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8b and R8c, together with the nitrogen atom they are attached to, represent a 5- to 6-membered heterocycloalkyl- group, said 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8d represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -NO2, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -S(=O)2N(H)R14, -S(=O)2N(R14a)R14b or a tetrazolyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8d represents a halogen atom, or an oxo, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(H)S(=O)2R14, -OR14 or a -S(=O)2N(H)R14 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8d represents a halogen atom, or a, C1-C2-alkyl-, fluoro-C1-C2-alkyl-, hydroxy-C1-C2-alkyl-, C1-C2-alkoxy-C1-C2-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(H)S(=O)2R14, -OR14 or a -S(=O)2N(H)R14 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8d represents a halogen atom, or a, C1-C2-alkyl-, fluoro-C1-C2-alkyl-, hydroxy-C1-C2-alkyl-, C1-C2-alkoxy-C1-C2-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(H)S(=O)2R14, -OR14 or a -S(=O)2N(H)R14 group,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4b represents a hydrogen atom and R4 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8d represents a fluorine atom, a chlorine atom, or a C1-C2-alkyl-, hydroxymethyl-, methoxymethyl-, -CN, -C(=O)NH2, -N(CH3)2, -N(H)C(=O)CH3, -N(H)S(=O)2CH3, hydroxy-, methoxy-, ethoxy- or a -S(=O)2NH2 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8d represents a fluorine atom, a chlorine atom, or a C1-C2-alkyl-, hydroxymethyl-, methoxymethyl-, -CN, -C(=O)NH2, -N(CH3)2, -N(H)C(=O)CH3, -N(H)S(=O)2CH3, hydroxy-, methoxy-, ethoxy- or a -S(=O)2NH2 group,
and in which compounds R1 represents a methyl- group, R2 represents a methyl- group, R4b represents a hydrogen atom and R4 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8d represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R14, R14a, R14b, R14c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl;
or R14a and R14b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R17. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R14, R14a, R14b, R14c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-,C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R14a and R14b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R17. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R14, R14a, R14b, R14c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, hydroxy-C1- C3-alkyl-. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R14, R14a, R14b, R14c represent, independently from each other, a hydrogen atom or a C1-C3-alkyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R14, R14a, R14b, R14c represent, independently from each other, a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R15 represents a hydrogen atom or a cyano-, C1- C3-alkyl-, -C(=O)R14, or -C(=O)O-R14 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R15 represents a hydrogen atom or a cyano-, -C(=O)R14, or -C(=O)O-R14 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R15 represents a hydrogen atom or a cyano- or -C(=O)O-R14 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R15 represents a -C(=O)O-R14 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R15 represents a cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R15 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R16, R16a represent, independently from each other, a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R17 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R14 or -C(=O)O-R14 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R17 represents a fluorine atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R18 represents a fluorine atom, a chlorine atom, or a cyano or methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, - CH2-C(=O)-N(R14a)-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L1 represents a group selected from: -C1-C4-alkylene-, -C(phenyl)(H)-, -CH2-CH2-O-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH2-O-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L1 represents a -C1-C4-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L1 represents a -C1-C3-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L1 represents a group selected from:
Figure imgf000139_0001
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L1 represents a group selected from: –CH2-, -C(CH3)(H)-,–CH2–CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L1 represents a group selected from:
Figure imgf000139_0002
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L1 represents a -C(CH3)(H)- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L1 represents a–CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L2 represents a group selected from:
Figure imgf000139_0003
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L2 represents a–CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L3 represents a -C1-C4-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L3 represents a -C1-C3-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L3 represents a -C1-C2-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L3 represents a -CH2- or -CH2-CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein p represents an integer of 0 or 1. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein p represents an integer of 1. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein p represents an integer of 0. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- group, wherein R2 represents a methyl- group, R4b represents a hydrogen atom, R4 represents a hydrogen atom, and wherein L1 represents a–CH2- group. More preferred embodiments of compounds of the present invention are described below with respect to formula (I-2). Said preferred embodiments are to be understood as not including the following compounds:
N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide, N-[1-[(3,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- pyridinyl)-4-quinolinecarboxamide,
2-(3,4-Dimethoxyphenyl)-N-[1-[(4-fluorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
6-Bromo-N-[3,5-dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide hydrochloride (1:1) ,
2-(3-Chlorophenyl)-N-[1-[(2,4-dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl]-4-quinolinecarboxamide,
N-[1-[(2,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-(phenylmethyl)-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide. It is to be understood that the present invention relates to any sub- combination within any embodiment of compounds of general formula (I-2), supra. Some further examples of combinations are given hereinafter. However, the invention is not limited to these combinations. In a preferred embodiment, the present invention relates to compounds of general formula (I-2) :
Figure imgf000142_0001
(I-2)
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, fluoro-C1-C3-alkyl- or cyano group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, fluoro-C1-C3-alkyl- or cyano- group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: phenyl-, 5- to 6-membered
heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ; wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally form a bridge selected from:
*-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group; R4a represents a group selected from:
phenyl-, wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R8d,
furanyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, oxadiazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl-, benzofuranyl-, benzothienyl-, quinolinyl- and isoquinolinyl-,
wherein said furanyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, oxadiazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl-, benzofuranyl-, benzothienyl-, quinolinyl- and isoquinolinyl- group is optionally substituted, one or two times, identically or differently, with R8d,
thienyl- which is unsubstituted,
thienyl- which is substituted once with R18, and which is optionally substituted, one or two times, identically or differently, with R8d, and pyrazolyl- which is unsubstituted; R4b represents a hydrogen atom or a C1-C3-alkyl-group; R5a, R5b, R5c
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3- alkoxy-, phenyl-, heteroaryl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(R14a)C(=O)R14b,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-; R5d represents a hydrogen atom; R4 represents a hydrogen atom or a C1-C3-alkyl- group; R6 represents a group selected from: oxo,
C1-C4-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-,
cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a, -C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a; R8a represents a hydrogen atom or a C1-C6-alkyl-, C3-C7-cycloalkyl- or
benzyl- group; R8b, R8c
represent, independently from each other, a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl- or 5- to 6-membered heteroaryl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R8d;
or
R8b and R8c, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d; R8d represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -NO2, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -S(=O)2N(H)R14 or -S(=O)2N(R14a)R14b group; R14, R14a, R14b, R14c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-,C1- C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-;
or
R14a and R14b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R17; R17 represents a a fluoro atom or a cyano, hydroxy, oxo, C1-C3-alkyl-,
trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group; R18 represents a fluorine atom, a chlorine atom, a bromo atom, or a cyano or methyl- group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH2-O-; L2 represents a group selected from:–CH2-,–CH2–CH2 -; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not: N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
N-[1-[(3,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- pyridinyl)-4-quinolinecarboxamide,
2-(3,4-Dimethoxyphenyl)-N-[1-[(4-fluorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
6-Bromo-N-[3,5-dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide hydrochloride (1:1) ,
2-(3-Chlorophenyl)-N-[1-[(2,4-dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl]-4-quinolinecarboxamide,
N-[1-[(2,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-(phenylmethyl)-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide.
In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
Figure imgf000147_0001
(I-2)
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl- or trifluoromethyl- group; R2 represents a hydrogen atom, or a C1-C3-alkyl- or trifluoromethyl- group, with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: phenyl-, 5- to 6-membered
heteroaryl- and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl- and 5- to
6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6; R4a represents a group selected from:
phenyl-, wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R8d,
furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl-,
wherein said furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl- groupgroup is optionally substituted, one or two times, identically or differently, with R8d, thienyl- which is unsubstituted,
thienyl- which is substituted once with R18, and which is optionally substituted once with R8d, and
pyrazolyl- which is unsubstituted; R4b represents a hydrogen atom;
Figure imgf000148_0001
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3- alkoxy-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(R14a)C(=O)R14b; R5d represents a hydrogen atom; R4 represents a hydrogen atom; R6 represents a group selected from: C1-C4-alkyl-, C1-C3-alkoxy-,
C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -OH,
-CN, halo-, -C(=O)R8a, -C(=O)-O-R8a, -C(=O)N(R8b)R8c, -N(R14a)R14b,
-S(=O)2R8a; R8a represents a hydrogen atom or a C1-C4-alkyl- group; R8b, R8c
represent, independently from each other, a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7-membered heterocycloalkyl- group; said C1-C4-alkyl-, C3-C7-cycloalkyl- and 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d;
or
R8b and R8c, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d; R8d represents a halogen atom, or C1-C2-alkyl-, fluoro-C1-C2-alkyl-, hydroxy- C1-C2-alkyl-, C1-C2-alkoxy-C1-C2-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(H)S(=O)2R14, -OR14 or a -S(=O)2N(H)R14 group;
R14, R14a, R14b
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group; R18 represents a fluorine atom, a chlorine atom, or a cyano or methyl- group; L1 represents a group selected from:–CH2-,–CH2–CH2-; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide, N-[1-[(3,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- pyridinyl)-4-quinolinecarboxamide,
2-(3,4-Dimethoxyphenyl)-N-[1-[(4-fluorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
6-Bromo-N-[3,5-dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide hydrochloride (1:1) ,
2-(3-Chlorophenyl)-N-[1-[(2,4-dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl]-4-quinolinecarboxamide,
N-[1-[(2,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-(phenylmethyl)-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide.
In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
Figure imgf000150_0001
(I-2) in which :
R1 represents a C1-C3-methyl- or trifluoromethyl- group; R2 represents a methyl- group, R3 represents a group selected from: phenyl- and pyridyl-;
wherein said phenyl- and pyridyl- group is optionally substituted, one or more times, identically or differently, with a group selected from:
methoxy-, -CN, fluoro-; R4a represents a group selected from:
phenyl-, wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R8d,
furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl-,
wherein said furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl- groupgroup is optionally substituted, one or two times, identically or differently, with R8d, thienyl- which is unsubstituted,
thienyl- which is substituted once with R18, and which is optionally substituted once with R8d, and
pyrazolyl- which is unsubstituted; R4b represents a hydrogen atom;
Figure imgf000151_0001
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-; R5d represents a hydrogen atom; R4 represents a hydrogen atom; R8d represents a halogen atom, or C1-C2-alkyl-, fluoro-C1-C2-alkyl-, hydroxy- C1-C2-alkyl-, C1-C2-alkoxy-C1-C2-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(H)S(=O)2R14, -OR14 or a -S(=O)2N(H)R14 group;
R14, R14a, R14b
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group; R18 represents a fluorine atom, a chlorine atom, or a cyano or methyl- group; L1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
2-(3,4-Dimethoxyphenyl)-N-[1-[(4-fluorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-(phenylmethyl)-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide. In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
Figure imgf000153_0001
in which :
R1 represents a C1-C3-methyl- or trifluoromethyl- group; R2 represents a methyl- group, R3 represents a group selected from: phenyl-, 5- to 6-membered
heteroaryl- and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl- and 5- to
6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6; R4a represents a group group which is unsubstituted and is selected from: phenyl-,
furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, thienyl- and pyrazolyl-,
or
R4a represents a triazolyl- group which is once substituted with methyl-. R4b represents a hydrogen atom;
Figure imgf000154_0001
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-; R5d represents a hydrogen atom; R4 represents a hydrogen atom; R6 represents a group selected from: C1-C4-alkyl-, C1-C3-alkoxy-,
C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -OH,
-CN, halo-, -C(=O)R8a, -C(=O)-O-R8a, -C(=O)N(R8b)R8c, -N(R14a)R14b,
-S(=O) a
2R8 ; R8a represents a hydrogen atom or a C1-C4-alkyl- group; R8b, R8c
represent, independently from each other, a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7-membered heterocycloalkyl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl- and 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d;
or
R8b and R8c, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d; R8d represents a C1-C2-alkyl-, fluoro-C1-C2-alkyl-, -C(=O)R14, -OR14 or a -S(=O)2N(H)R14 group; R14, R
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group; L1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
N-[1-[(3,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
6-Bromo-N-[3,5-dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide hydrochloride (1:1) ,
N-[1-[(2,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide, N-[3,5-Dimethyl-1-(phenylmethyl)-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide. In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
Figure imgf000156_0001
(I-2)
in which :
R1 represents a C1-C3-methyl- or trifluoromethyl- group; R2 represents a methyl- group, R3 represents a group selected from: phenyl- and pyridyl-;
wherein said phenyl- and pyridyl- group is optionally substituted, one or more times, identically or differently, with a group selected from:
methoxy-, -CN, fluoro-; R4a represents a group group which is unsubstituted and is selected from: phenyl-,
furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, thienyl- and pyrazolyl-,
or R4a represents a triazolyl- group which is once substituted with methyl-. R4b represents a hydrogen atom; R5a, R5b, R5c
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-; R5d represents a hydrogen atom; R4 represents a hydrogen atom; L1 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
N-[3,5-Dimethyl-1-(phenylmethyl)-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide.
In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
Figure imgf000158_0001
(I-2)
in which :
R1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group; R2 represents a hydrogen atom, or a methyl- group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from:
Figure imgf000158_0002
,
Figure imgf000159_0001
wherein * represents the point of attachment to L1;
R4a represents a group selected from:
Figure imgf000159_0002
,
Figure imgf000160_0001
,
Figure imgf000161_0001
wherein * represents the point of attachment to the rest of the molecule; R4b represents a hydrogen atom; R5a, R5c
independently from each other represent a hydrogen atom; R5b represents hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-; R5d represents a hydrogen atom; R4 represents a hydrogen atom; L1 represents a group selected from:–CH2-,–CH2–CH2-; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
N-[3,5-Dimethyl-1-(phenylmethyl)-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide.
In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
Figure imgf000162_0001
(I-2)
in which :
R1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group; R2 represents a hydrogen atom, or a methyl- group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: * , *
Figure imgf000163_0001
wherein * represents the point of attachment to L1; R4a represents a group selected from:
Figure imgf000163_0002
wherein * represents the point of attachment to the rest of the molecule; R4b represents a hydrogen atom; R5a, R5c
independently from each other represent a hydrogen atom; R5b represents hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-; R5d represents a hydrogen atom; R4 represents a hydrogen atom; L1 represents a group selected from:–CH2-,–CH2–CH2-; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide. In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
Figure imgf000164_0001
in which :
R1 represents a hydrogen atom, or a methyl- or trifluoromethyl- group; R2 represents a hydrogen atom, or a methyl- group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: *
Figure imgf000165_0001
,
wherein * represents the point of attachment to L1; R4a represents a group selected from:
,
Figure imgf000165_0002
wherein * represents the point of attachment to the rest of the molecule; R4b represents a hydrogen atom; R5a, R5c
independently from each other represent a hydrogen atom; R5b represents hydrogen atom, a bromine atom or a group selected from: hydroxy-, methyl-, methoxy-; R5d represents a hydrogen atom; R4 represents a hydrogen atom; L1 represents a group selected from:–CH2-,–CH2–CH2-; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 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 formula (I), in which method an intermediate compound of general formula (II) :
Figure imgf000166_0001
in which R1, R2, R3, R4 and L1 are as defined for the compounds of general formula (I), supra; is allowed to react with a compound of general formula (III) :
Figure imgf000166_0002
(III) in which R5 is as defined for the compounds of general formula (I), supra, thus providing a compound of general formula (I) :
Figure imgf000167_0001
in which R1, R2, R3, R4, R5 and L1 are as defined for the compounds of general formula (I), supra. In another preferred embodiment, the present invention relates to a method of preparing compounds of formula (I-2), in which method an intermediate compound of general formula (II) :
(II)
in which R1, R2, R3, R4 and L1 are as defined for the compounds of general formula (I-2), supra; is allowed to react with a compound of general formula (III-2) :
Figure imgf000167_0003
(III-2) in which R4a, R4b, R5a, R5b, R5c, and R5d are as defined for the compounds of general formula (I-2), supra, thus providing a compound of general formula (I-2) :
Figure imgf000168_0001
(I-2) in which R1, R2, R3, R4a, R4b, R5a, R5b, R5b, R5d, R4 and L1 are as defined for the compounds of general formula (I-2), supra. In another preferred embodiment, the present invention relates to a method of preparing compounds of formula (I-2), in which method an intermediate compound of general formula (XI-2) :
Figure imgf000169_0001
(XI-2) in which G represents a group selected from a chlorine atom, a bromine atom, a iodine atom or a [(trifluoromethyl)sulfonyl]oxy- group, and in which R4b, R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-2), supra, but are different from G; is allowed to react with a compound of general formula (XII-2) :
Figure imgf000169_0002
(XII-2) in which R4a is as defined for the compounds of general formula (I-2), supra, and in which the RB groups represent hydrogen atoms, C1-C3-alkyl- groups, or together represent a–C(CH3)2-C(CH3)2- group; thus providing a compound of general formula (I-2) :
Figure imgf000170_0001
(I-2) in which R1, R2, R3, R4a, R4b, R5a, R5b, R5b, R5d, R4 and L1 are as defined for the compounds of general formula (I-2), supra.
In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), particularly in the methods described herein. In another preferred embodiment, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), particularly in the methods described herein. In particular, the present invention covers compounds of general formula (III- 2):
Figure imgf000171_0001
(III-2) in which R4a, R4b, R5a, R5b, R5c, and R5d are as defined for the compounds of general formula (I-2), supra. Furthermore, the present invention covers compounds of general formula (XI- 2):
Figure imgf000171_0002
(XI-2) in which G represents a group selected from a chlorine atom, a bromine atom, a iodine atom or a [(trifluoromethyl)sulfonyl]oxy- group, and in which R4b, R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-2), supra, but are different from G. In accordance with a further aspect, the present invention covers the use of the intermediate compounds of general formula (II):
Figure imgf000172_0001
in which R1, R2, R3, R4 and L1 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 accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula (II):
Figure imgf000172_0002
(II)
in which R1, R2, R3, R4 and L1 are as defined for the compounds of general formula (I-2), supra;
for the preparation of a compound of general formula (I-2) as defined supra. In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula (III-2):
Figure imgf000173_0001
(III-2) in which R4a, R4b, R5a, R5b, R5c, and R5d are as defined for the compounds of general formula (I-2), supra, for the preparation of a compound of general formula (I-2) as defined supra.
In another preferred embodiment, the present invention covers the use of the intermediate compounds of general formula (XI-2):
Figure imgf000173_0002
(XI-2) in which G represents a group selected from a chlorine atom, a bromine atom, a iodine atom or a [(trifluoromethyl)sulfonyl]oxy- group, and in which R4b, R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-2), supra, but are different from G; for the preparation of a compound of general formula (I-2) as defined supra. In another preferred embodiment, the present invention covers the use of the intermediate compounds of general formula (XII-2):
O R B
4a
R B O R B (XII-2) in which R4a is as defined for the compounds of general formula (I-2), supra, and in which the RB groups represent hydrogen atoms, C1-C3-alkyl- groups, or together represent a–C(CH3)2-C(CH3)2- group; for the preparation of a compound of general formula (I-2) as defined supra.
As one of ordinary skill in the art is aware of, the methods described above may comprise further steps like e.g. the introduction of a protective group and the cleavage of the protective group. This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated. The compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like. The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. The present invention relates also to such combinations. For example, the compounds of this invention can be combined with known anti-hyper- proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof. Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones. Preferred additional pharmaceutical agents are: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alfa, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polysaccharide-K, porfimer sodium, pralatrexate, prednimustine, procarbazine, quinagolide, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab, romidepsin, romiplostim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin. Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine. Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5- azacytidine cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5- fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine. Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan. The compounds of the invention may also be administered in combination with protein therapeutics. Such protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonistic monoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1, bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1 + ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, rinfabate, AS-1402, B43-genistein, L-19 based radioimmunotherapeutics, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine, APC- 8024, NGR-hTNF, rhH1.3, IGN-311, Endostatin, volociximab, PRO-1762, lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX- 321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab, alpha-particle- emitting radioisotope-llinked lintuzumab, EM-1421, HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7, Javelin - prostate cancer, Javelin - melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab, zalutumumab, cintredekin besudotox, WX- G250, Albuferon, aflibercept, denosumab, vaccine, CTP-37, efungumab, or 131I-chTNT-1/B. Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab. Generally, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to: (1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone, (2) provide for the administration of lesser amounts of the administered chemotherapeutic agents, (3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans, (5) provide for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments, (7) provide a longer time for tumor progression, and/or (8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
Another particular aspect of the present invention is the use of a compound of general formula (I-2), described supra, or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease. Another particular aspect of the present invention is the use of a compound of general formula (I-2) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease. The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth. Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.
The present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper- proliferative disorders. Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder. Hyper- proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias. Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor. Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small- intestine, and salivary gland cancers. Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers. Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS- related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system. Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention. The term“treating” or“treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma. Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight. Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests. General synthesis of compounds of general formula (I) of the present invention 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, in particular R1, R2, R4, as well as of the R6 group attached to R3 via -(L2)p- and substituents attached to R5, in particular R9, 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).
Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a “one-pot” reaction, as it is well-known to a person skilled in the art. Compounds of general formula (I) can be assembled from 4-aminopyrazole derivatives of formula (II), in which R1, R2, R3, R4 and L1 are as defined for the compounds of general formula (I), and heterocyclic carboxylic acid derivatives of formula (III), in which R5 is 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 1. 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 (O-(7-azabenzotriazol-1- yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), TBTU (O- (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), or EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with HOBt (1-hydroxy-1H-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(C1-C4-alkyl)3, in an appropriate solvent. Preferred herein is the performance of said carboxamide coupling reaction using O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) as a coupling agent, in the presence of N,N- diisopropylethylamine as a base, and in dimethylsulfoxide as a solvent, within a temperature range from 0°C to 50°C. Also preferred herein is the performance of said carboxamide coupling reaction using O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) as a coupling agent, in the presence of N,N-diisopropylethylamine as a base, and in tetrahydrofuran as a solvent, within a temperature range from 0°C to 50°C. Also preferred herein is the performance of said carboxamide coupling reaction using benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as a coupling agent, in the presence of N,N-diisopropylethylamine as a base, and in tetrahydrofuran as a solvent, within a temperature range from 0°C to 50°C. The preparation of amides from 4-aminopyrazole derivatives of formula (II), in which R1, R2, R3, R4 and L1 are as defined for the compounds of general formula (I), andheterocyclic carboxylic acid derivatives of formula (III), in which R5 is 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 said 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 4- aminopyrazole derivatives of formula (II).
Figure imgf000186_0001
Scheme 1: Preparation of compounds of general formula (I) from 4-aminopyrazole derivatives of formula (II) and carboxylic acids of formula (III). 4-Aminopyrazole intermediates of formula (II) can be prepared using synthetic methods described in more detail as according to Scheme 3 shown below. Heterocyclic carboxylic acid derivatives of formula (III) are well known to the person skilled in the art, and can be approached by a multitude of known synthetic approaches well described in a plethora of monographies and scientific articles. Many of said methods are also illustrated in the experimental section, infra. Heterocyclic carboxylic acids of formula (III) are also commercially available in some structural variety. If aminopyrazole derivatives of formula (II), in which R4 represents a hydrogen atom, have been employed in the carboxamide coupling reaction described supra, R4 groups different from hydrogen can also be introduced subsequently to said carboxamide coupling reaction by means of deprotonating the resulting compounds of formula (Ia), in which R1, R2, R3, R5 and L1 are as defined for the compounds of general formula (I), with a base such as an alkali metal hydride, preferably sodium hydride, followed by reaction with a compound of the formula (IV), in which LG represents a leaving group, preferably chloro, bromo, or iodo, and in which R4 is as defined for the compounds of general formula (I) but different from hydrogen, to give compounds of formula (Ib), as outlined in Scheme 2.
Figure imgf000188_0001
(Ia) (Ib; R4 H) Scheme 2: Preparation of compounds of formula (Ib) from compounds of formula (Ia). Compounds of formula (IV) are well known to the person skilled in the art and are readily commercially available. Intermediate 4-aminopyrazole derivatives of formula (II) are available e.g. by reaction of 4-nitropyrazole derivatives of the formula (V), in which R1 and R2 are as defined for the compounds of general formula (I), with compounds of the formula (VI), in which R3 and L1 are as defined for the compounds of general formula (I), and in which LG represents a leaving group, preferably chloro, bromo, or iodo, in the presence of a suitable base such as an alkali carbonate, preferably cesium carbonate, to give N-1-substituted nitropyrazole intermediates of formula (VII). As another suitable base, 1,8- diazabicyclo(5.4.0)undec-7-ene can be used to perform said alkylation reaction. Alternatively, the nitro group can be introduced after substitution of pyrazole N-1 with -L1-R3 described above.
In cases where R1 and R2 are different from each other, said nitropyrazole intermediates of formula (VII) are formed as mixtures of regioisomers, as a result of the tautomery featured by the pyrazole core. Said mixtures can be separated into pure regioisomers by methods known to the person skilled in the art, such as column chromatography on silica gel, or by preparative HPLC, either directly following the reaction, or on a later or final stage. Said compounds of formula (VII) can subsequently be reduced, using reduction methods well known to the person skilled in the art, to give primary amines of formula (IIa). Said reduction methods encompass the use of palladium catalysed hydrogenation, using elemental hydrogen or alternative hydrogen sources such as ammonium formiate, and the use of zinc dust or powdered iron in the presence of acetic acid, or the use of tin (II) chloride e.g. in ethanol as a solvent. The latter reagents are preferably used if the substrate contains functional groups vulnerable to catalytic hydrogenation, such as cyano-, bromo or chloro, in particular if attached to an aromatic ring. 1
Figure imgf000189_0001
Scheme 3: Preparation of amino pyrazoles of formula (IIa) from compounds of formula (V). 4-Nitropyrazoles of the formula (V) are well known to the person skilled in the art (see e.g. ethyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate see Journal of Organic Chemistry 1956, p.833; 3-methyl-4-nitro-1H-pyrazole-5-carbonitrile see Journal of Heterocyclic Chemistry 1970, p.863; 3-methyl-4-nitro-1H- pyrazole-5-carboxamide see Journal of Organic Chemistry 1956, p.833 or US4282361 (1981); N,3-dimethyl-4-nitro-1H-pyrazole-5-carboxamide see Chinese Chemical Letters 2012, p.669; N,N,3-trimethyl-4-nitro-1H-pyrazole-5- carboxamide see DE1945430 (1968)) and are also commercially available in certain cases (e.g. ethyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate at Fluorochem, Matrix, Oakwood; 3,5-dimethyl-4-nitro-1H-pyrazole at ABCR; 5- methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole at ABCR, Fluorochem, Matrix. In general, the nitro group can be introduced into pyrazole derivatives lacking subsitution at C-4, by treating 3,5-disubstituted pyrazoles with sulfuric and nitric acid, to give 4-nitropyrazoles of formula (V).
R4 groups different from hydrogen can be either be introduced at later stage, as outlined in Scheme 2, or they may be introduced into primary amines by means of reductive amination reactions well known to the person skilled in the art, e.g. by reaction of said primary amines of formula (IIa) with suitable aldehydes or ketones, followed by reduction e.g. with sodium cyanoborohydride.
A further alternative synthetic approach to the compounds of the general formula (I), which is particularly suitable for the preparation or multiple derivatives featuring different -L1-R3 moieties by introducing said -L1-R3 moieties on late stage, is outlined in Scheme 4. 4-Aminopyrazoles of formula (VIII), in which R1, R2 and R4 are as defined for the compounds of general formula (I), and heterocyclic carboxylic acid derivatives of formula (III), in which R5 is as defined for the compounds of general formula (I), are subjected to a carboxamide (or peptide) coupling reaction well known to the person skilled in the art, as discussed supra with regard to Scheme 1, to give intermediate compounds of formula (IX).
Participation of the pyrazole ring NH in said carboxamide coupling reaction may give rise to the formation of intermediate compounds of formula (IX) as regioisomeric mixtures with the corresponding N1 amides. These can be removed by separation techniques well known to the person skilled in the art, e.g. preparative HPLC either immediately after the coupling, or, preferably, after conversion into the compounds of general formula (I).
Said intermediate compounds of formula (IX) can be converted into the compounds of general formula (I) by reaction with compounds of the formula (VI), in which R3 and L1 are as defined for the compounds of general formula (I), and in which LG represents a leaving group, preferably chloro, bromo, or iodo, in the presence of a suitable inorganic base, such as an alkali carbonate, preferably cesium carbonate or an alkali hydride, such as sodium hydride, or an organic base, such as potassium tert.-butoxide or 1,8- diazabicyclo[5.4.0]undec-7-ene.
4-Aminopyrazoles of formula (VIII) are well known to the person skilled in the art and can be purchased commercially in many cases.
Figure imgf000191_0001
I
Scheme 4: Alternative preparation of compounds of general formula (I) from 4-aminopyrazole derivatives of formula (VIII) and carboxylic acids of formula (III).
General synthesis of compounds of general formula (I-2) of the present invention The following paragraphs outline a variety of synthetic approaches suitable to prepare compounds of the general formula (I-2), 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, in particular R1, R2, R4a, R4b, R5a, R5b, R5c, R5d or R4, as well as of the R6 group attached to R3 via -(L2)p-, 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).
Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a “one-pot” reaction, as it is well-known to a person skilled in the art. Compounds of general formula (I-2) can be assembled from 4-aminopyrazole derivatives of formula (II-2), in which R1, R2, R3, R4 and L1 are as defined for the compounds of general formula (I-2), and quinoline-4-carboxylic acid derivatives of formula (III-2), in which R4a, R4b, R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-2), by means of carboxamide (or peptide) coupling reaction well known to the person skilled in the art, according to Scheme 1. Said coupling reaction can be performed by reaction of compounds of the formulae (II-2) and (III-2) in the presence of a suitable coupling reagent, such as HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium tetrafluoroborate), PyBOP (benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate), or EDC (1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with HOBt (1-hydroxy-1H-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(C1-C4-alkyl)3, in an appropriate solvent. Preferred herein is the performance of said carboxamide coupling reaction using O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) as a coupling agent, in the presence of N,N- diisopropylethylamine as a base, and in dimethylsulfoxide as a solvent, within a temperature range from 0°C to 50°C. Also preferred herein is the performance of said carboxamide coupling reaction using O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) as a coupling agent, in the presence of N,N-diisopropylethylamine as a base, and in tetrahydrofuran as a solvent, within a temperature range from 0°C to 50°C. Also preferred herein is the performance of said carboxamide coupling reaction using benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as a coupling agent, in the presence of N,N-diisopropylethylamine as a base, and in tetrahydrofuran as a solvent, within a temperature range from 0°C to 50°C. The preparation of amides from 4-aminopyrazole derivatives of formula (II-2), in which R1, R2, R3, R4 and L1 are as defined for the compounds of general formula (I-2), and quinoline-4-carboxylic acid derivatives of formula (III-2), in which R4a, R4b, R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-2), can furthermore be accomplished, as well known to the person skilled in the art, by converting carboxylic acids of the formula (III-2) 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 4-aminopyrazole derivatives of formula (II-2).
Figure imgf000194_0001
Scheme 5: Preparation of compounds of general formula (I-2) from 4-aminopyrazole derivatives of formula (II-2) and carboxylic acids of formula (III-2). 4-Aminopyrazole intermediates and quinazoline-4-carboxylic acid derivatives of formulae (II-2) and (III-2) can be prepared using synthetic methods described in more detail as according to the Schemes shown below. Certain quinazoline-4- carboxylic acids are also commercially available in some structural variety. If aminopyrazole derivatives of formula (II-2), in which R4 represents a hydrogen atom, have been employed in the carboxamide coupling reaction described supra, R4 groups different from hydrogen can also be introduced subsequently to said carboxamide coupling reaction by means of deprotonating the resulting compounds of formula (Ia-2), in which R1, R2, R3, R4a, R4b, R5a, R5b, R5c, R5d and L1 are as defined for the compounds of general formula (I-2), with a base such as an alkali metal hydride, preferably sodium hydride, followed by reaction with a compound of the formula (IV-2), in which LG represents a leaving group, preferably chloro, bromo, or iodo, and in which R4 is as defined for the compounds of general formula (I-2) but different from hydrogen, to give compounds of formula (Ib-2), as outlined in Scheme 6.
Figure imgf000195_0001
Scheme 6: Preparation of compounds of formula (Ib-2) from compounds of formula (Ia-2). Compounds of formula (IV-2) are well known to the person skilled in the art and are readily commercially available. Intermediate 4-aminopyrazole derivatives of formula (II-2) are available e.g. by reaction of 4-nitropyrazole derivatives of the formula (V-2), in which R1 and R2 are as defined for the compounds of general formula (I-2), with compounds of the formula (VI-2), in which R3 and L1 are as defined for the compounds of general formula (I-2), and in which LG represents a leaving group, preferably chloro, bromo, or iodo, in the presence of a suitable base such as an alkali carbonate, preferably cesium carbonate, to give N-1-substituted nitropyrazole intermediates of formula (VII-2). As another suitable base, 1,8- diazabicyclo(5.4.0)undec-7-ene can be used to perform said alkylation reaction. Alternatively, the nitro group can be introduced after substitution of pyrazole N-1 with -L1-R3 described above.
In cases where R1 and R2 are different from each other, said nitropyrazole intermediates of formula (VII-2) are formed as mixtures of regioisomers, as a result of the tautomery featured by the pyrazole core. Said mixtures can be separated into pure regioisomers by methods known to the person skilled in the art, such as column chromatography on silica gel, or by preparative HPLC, either directly following the reaction, or on a later or final stage.
Said compounds of formula (VII-2) can subsequently be reduced, using reduction methods well known to the person skilled in the art, to give primary amines of formula (IIa-2). Said reduction methods encompass the use of palladium catalysed hydrogenation, using elemental hydrogen or alternative hydrogen sources such as ammonium formiate, and the use of zinc dust or powdered iron in the presence of acetic acid, or the use of tin (II) chloride e.g. in ethanol as a solvent. The latter reagents are preferably used if the substrate contains functional groups vulnerable to catalytic hydrogenation, such as cyano-, bromo or chloro, in particular if attached to an aromatic ring.
Figure imgf000197_0001
(VII-2) (IIa-2) Scheme 7: Preparation of amino pyrazoles of formula (IIa-2) from compounds of formula (V-2). 4-Nitropyrazoles of the formula (V-2) are well known to the person skilled in the art (see e.g. ethyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate see Journal of Organic Chemistry 1956, p.833; 3-methyl-4-nitro-1H-pyrazole-5-carbonitrile see Journal of Heterocyclic Chemistry 1970, p.863; 3-methyl-4-nitro-1H- pyrazole-5-carboxamide see Journal of Organic Chemistry 1956, p.833 or US4282361 (1981); N,3-dimethyl-4-nitro-1H-pyrazole-5-carboxamide see Chinese Chemical Letters 2012, p.669; N,N,3-trimethyl-4-nitro-1H-pyrazole-5- carboxamide see DE1945430 (1968)) and are also commercially available in certain cases (e.g. ethyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate at Fluorochem, Matrix, Oakwood; 3,5-dimethyl-4-nitro-1H-pyrazole at ABCR; 5- methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole at ABCR, Fluorochem, Matrix; 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole at ABCR, Fluorochem, Matrix; 3-methyl-4-nitro-1H-pyrazole at ABCR, Alfa, Apollo Scientific, Fluorochem). In general, the nitro group can be introduced into pyrazole derivatives lacking subsitution at C-4, by treating 3,5-disubstituted pyrazoles with sulfuric and nitric acid, to give 4-nitropyrazoles of formula (V-2). R4 groups different from hydrogen can be either be introduced at later stage, as outlined in Scheme 2, or they may be introduced into primary amines by means of reductive amination reactions well known to the person skilled in the art, e.g. by reaction of said primary amines of formula (IIa-2) with suitable aldehydes or ketones, followed by reduction e.g. with sodium cyanoborohydride. Quinoline-4-carboxylic acid derivatives of formula (III-2), if not commercially available, can be prepared readily from indole-2,3-dione precursors (see e.g. Monatshefte für Chemie 2013,p. 391; Chinese Chemical Letters 2010, p. 35; The Pfitzinger Reaction. (Review) in Chemistry of Heterocyclic Compounds, Vol 40 (2004), Issue 3, pp 257) of formula (VIII-2), in which R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-2), by reaction with carbonyl compounds of formula (IX-2), in which R4a and R4b are as defined for the compounds of general formula (I-2), in an aqueous buffered solvent e.g. comprising sodium hydroxide, sodium acetate, acetic acid and water, at an elevated temperature, to directly give compounds of formula (III-2), as outlined in Scheme 8.
Figure imgf000198_0001
Scheme 8: Preparation of quinoline-4-carboxylic acid derivatives of formula (III-2) from indole-2,3-diones of formula (VIII-2). Indole-2,3-diones of formula (VIII-2) are well known to the person skilled in the art and are either commercially available or can be prepared by methods described e.g. in Chinese Chemical Letters, 2013, p. 929; J. Med. Chem. 2006, p. 4638. Carbonyl compounds of formula (IX-2) can be purchased commercially in wide structural variety. In an alternative approach, certain compounds of general formula (I-2) can be prepared, according to Scheme 9, from quinoline-4-carboxylic acid derivatives of formula (X-2), in which G represents a group selected from a chlorine atom, a bromine atom, a iodine atom or a [(trifluoromethyl)sulfonyl]oxy- group, and in which R4b, R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-2) but different from G, which can be reacted with 4-aminopyrazole derivatives of formula (II-2), in which R1, R2, R3, R4 and L1 are as defined for the compounds of general formula (I-2), in a carboxamide (or peptide) coupling reaction well known to the person skilled in the art, as discussed supra with regard to Scheme 5, to give carboxamide derivatives of formula (XI-2). Said coupling reaction can be performed by reaction of compounds of the formulae (X-2) and (II-2) in the presence of a suitable coupling reagent, such as HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
hexafluorophosphate), TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium tetrafluoroborate), PyBOP (benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate), or EDC (1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with HOBt (1-hydroxy-1H-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(C1-C4-alkyl)3, in an appropriate solvent.
Said carboxamide derivatives of formula (XI-2) can be subjected to a palladium catalyzed Suzuki coupling, which is well known to the person skilled in the art, by reacting with a boronic acid or a boronic ester of formula (XII-2), in which R4a is as defined for the compounds of general formula (I-2), and in which the RB groups represent hydrogen atoms, C1-C3-alkyl- groups, or together represent a–C(CH3)2-C(CH3)2- group, in the presence of a palladium catalyst, such as [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II), and in the presence of a base, such as sodium carbonate, to give compounds of formula (I-2). Quinoline-4-carboxylic acid derivatives of formula (X-2) are known to the person skilled in the art and are commercially available in many cases. Boronic acids and boronic esters, as well their use in Suzuki couplings, are also well known to the person skilled in the art, for a review on boronic acids 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.
Figure imgf000200_0001
Scheme 9: Alternative preparation of certain compounds of general formula (I- 2) from quinoline-4-carboxylic acid derivatives of formula (X-2). A further alternative synthetic approach to the compounds of the general formula (I-2), which is particularly suitable for the preparation or multiple derivatives featuring different -L1-R3 moieties by introducing said -L1-R3 moieties on late stage, is outlined in Scheme 6. 4-Aminopyrazoles of formula (XIV-2), in which R1, R2 and R4 are as defined for the compounds of general formula (I-2), and quinoline-4-carboxylic acid derivatives of formula (III-2), in which R4a, R4b, R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-2), are subjected to a carboxamide (or peptide) coupling reaction well known to the person skilled in the art, as discussed supra with regard to Schemes 5 and 9, to give intermediate compounds of formula (XV-2).
Participation of the pyrazole ring NH in said carboxamide coupling reaction may give rise to the formation of intermediate compounds of formula (XV-2) as regioisomeric mixtures with the corresponding N1 amides. These can be removed by separation techniques well known to the person skilled in the art, e.g. preparative HPLC either immediately after the coupling, or, preferably, after conversion into the compounds of general formula (I-2).
Said intermediate compounds of formula (XV-2) can be converted into the compounds of general formula (I-2) by reaction with compounds of the formula (VI-2), in which R3 and L1 are as defined for the compounds of general formula (I-2), and in which LG represents a leaving group, preferably chloro, bromo, or iodo, in the presence of a suitable inorganic base, such as an alkali carbonate, preferably cesium carbonate or an alkali hydride, such as sodium hydride, or an organic base, such as potassium tert.-butoxide or 1,8- diazabicyclo[5.4.0]undec-7-ene.
4-Aminopyrazoles of formula (XIV-2) are well known to the person skilled in the art and can be purchased commercially in many cases.
Figure imgf000202_0001
Scheme 10: Alternative preparation of compounds of general formula (I-2) from 4-aminopyrazole derivatives of formula (XIV-2) and carboxylic acids of formula (III-2). Abbreviations
Figure imgf000202_0002
DLD1 colorectal adenocarcinoma cells isolated by D.L. Dexter CHO-K1 chinese hamster ovary K1 cells
H460 lung carcinoma cells
RCC renal cell carcinoma cells
VHL von Hippel-Lindau
DMEM Dulbecco’s modified eagle medium
FCS fetal calf serum
HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
HMPA Hexamethylphosphoramide
KRP Krbes-Ringer phosphate
HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
Xphos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
tetrafluoroborate
PyBOP Benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate
KP-Sil ready to use silica gel column
Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
wt.% weight %
Examples were analyzed and characterized by the following analytical methods to determine characteristic retention time and mass spectrum:
Figure imgf000203_0001
Flow: 0.8 mL/min
Temperature: 60 °C
Injection: 2.0 µL
Detection: DAD scan range 210-400 nm -> Peak table
ELSD
Method: MS ESI+, ESI- Switch -> diverse scan ranges possible
Method 1: UPLC (ACN-HCOOH)
Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.1% formic acid, eluent B: acetonitril; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 °C; injection: 2 µL; DAD scan: 210-400 nm; ELSD Method 2: UPLC (ACN-NH3)
Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.2% ammonia, eluent B: acetonitril; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 °C; injection: 2 µL; DAD scan: 210-400 nm; ELSD Method 3: System: Waters autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5µm 100x30 mm;
Solvent: A = H2O + 0.1% Vol. formic acid (99%), B = acetonitrile; Gradient: 0-8 min 10-100% B, 8-10 min 100% B; Flow: 50 mL/min; temperature: room temp.; Solution: Max. 250 mg / max. 2.5 mL DMSO o. DMF; Injection: 1 x 2.5 mL; Detection: DAD scan range 210–400 nm; MS ESI+, ESI-, scan range 160-1000 m/z. Method 4: System: Waters autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5µm 100x30 mm;
Solvent: A = H2O + 0.1% Vol. ammonia (99%), B = acetonitrile; Gradient: 0-8 min 10- 100% B, 8-10 min 100% B; Flow: 50 mL/min; temperature: room temp.; Solution: Max. 250 mg / max. 2.5 mL DMSO o. DMF; Injection: 1 x 2.5 mL; Detection: DAD scan range 210–400 nm; MS ESI+, ESI-, scan range 160-1000 m/z. Method 5: (prep. HPLC) System: Labomatic, Pump: HD-5000, Fraction Collector: LABOCOL Vario-4000, UV-Detector: Knauer UVD 2.1S; Column: Chromatorex C1810µm 125x30 mm; Solvent: A = water + + 0.1% Vol. formic acid (99%), B = Acetonitril; Flow: 150 mL/min; temperature: room temperature; Solution: Max. 250 mg / 2mL DMSO; Injektion: 2 x 2mL; Detection: UV 218 nm; Software: SCPA PrepCon5. Gradient: 0– 15 min 30 - 70 % B (for Rt (min): 1.10– 1.35) Method 6: System: Labomatic HD3000, AS-3000, Labcol Vario 4000 Plus, Knauer DAD 2600; Column: Waters XBrigde C18 5µ 150x50mm; Solvent: A: Wasser, Eluent B: Acetonitril; temperature: room temp.; detection: DAD at 254 nm a) Gradient: 0,00–1,00 min 54% B (50->150mL/min), 1,00–8,00 min 54% B (150mL/min)
b) Gradient: 0,00–1,00 min 55% B (50->150mL/min), 1,00–8,00 min 55% B (150mL/min)
c) Gradient: 0,00–1,00 min 52% B (50->150mL/min), 1,00–8,00 min 52% B (150mL/min)
d) Gradient: 0,00–1,00 min 30% B (50->150mL/min), 1,00–10,00 min 30-45% B (150mL/min), Column chromatography was performed on a Biotage® Isolera™ Spektra Four Flash Purification System. Whereever NMR peak forms are specified, they are stated as they appear in the spectra, possible higher order effects have not been considered. In cases were a signal is very broad or is partially or totally hidden by a solvent peak the total number of hydrogen atoms displayed in NMR spectra can differ from the number of hydrogen atoms present in the respective molecule. The 1H-NMR data of selected examples are listed in the form of 1H-NMR peaklists. For each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ1 (intensity1), δ2 (intensity2), ... , (intensityi), ... , δn (intensityn).
The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A 1H-NMR peaklist is similar to a classical 1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%). Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compounds by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1H- NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. Research Disclosure Database Number 605005, 2014, 01 Aug 2014, or http://www.researchdisclosure.com/searching-disclosures). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. Depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%. Yields in % reflect the purity of the desired product obtained if not stated otherwise; purities significantly below 90% were specified explicity if appropriate. If not stated otherwise, starting materials as mentioned in the protocols were purchased from commercial suppliers. The chemical names of the intermediates and examples were generated using the program ´ACD/Name batch version 12.01´ from ACD LABS, and were adapted if needed.
Intermediates– Section 1
Intermediate 1A-1
2-(trifluoromethyl)-1,8-naphthyridine-4-carboxylic acid
Figure imgf000207_0001
1 g (98% purity, 6.62 mmol) of 1H-pyrrolo[2,3-b]pyridine-2,3-dione (CAS-No. 5654-95- 5) was suspended in 3.8 mL water. 480 mg (85% purity, 7.28 mmol) potassium hydroxide, 760 µL (13 mmol) acetic acid and 760 mg (9.26 mmol) sodium acetate were added to adjust to pH 5. The solution was cooled to 10°C and 1.2 mL (13 mmol) 1,1,1-trifluoropropan-2-one was added rapidly. The mixture was heated for 2 h 45 min to 105°C. The reaction was stopped by the addition of 2 N aqueous hydrochloric acid solution and the resulting precipitate was isolated by filtration, washed with water and dried in a vacuum drying cabinet at 50°C overnight to obtain 653 mg (50% purity, 20% yield) of the desired title compound. 1H NMR (300 MHz, DMSO-d6): δ [ppm] = 7.79 (br. s., 1H), 7.91 (dd, 1H), 8.37 (s, 1H), 9.26 (dd, 1H), 9.32 (dd, 1H). The following intermediates shown in table 1 were prepared in analogy to intermediate 1A-1:
Table 1
Figure imgf000207_0002
Figure imgf000208_0001
Intermediate 3A-1
2-carbamoyl-1,8-naphthyridine-4-carboxylic acid
Intermediate 3A-1 Step 1: di 2,4-dicarboxylate
Figure imgf000208_0002
8.2 g (96% purity, 27.3 mmol) 2,4-dibromo-1,8-naphthyridine (CAS-No. 54569-27-6) were dissolved in 230 ml methanol in an autoclave. 516 mg (95% purity, 1.37 mmol) butyldi-1-adamantylphosphine, 310 mg (1.37 mmol) palladium(II) acetate, and 11 mL (82 mmol) triethylamine were added. The reaction mixture was flushed with carbon monoxide (CO) three times, submitted to a CO pressure of 12.43 bar, and stirred at room temperature for 30 minutes. The pressure was removed, the autoclave was evacuated to 0.06 bar, and again submitted to a CO pressure of 14.6 bar. The reaction was heated to 80°C overnight. For work-up the slurry was filtered over Celite®. The filtrate was evaporated and purified by flash chromatography yielding 1.82 g (95% purity, 26% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 4.01 (s, 3H), 4.03 (s, 3H), 7.88 (dd, 1H), 8.56 (s, 1H), 9.17 (dd, 1H), 9.30 (dd, 1H). The following intermediate shown in table 2 was prepared in analogy to intermediate 3A-1 Step 1:
Table 2
Figure imgf000209_0001
Intermediate 3A-1 Step 2: methyl 2-carbamoyl-1,8-naphthyridine-4-carboxylate
Figure imgf000210_0001
To a solution of 1.81 g (7.3 mmo me y , -naphthyridine-2,4-dicarboxylate (intermediate 3A-1 step 1) in 50 mL methanol was added 21 mL of a 7M solution of ammonia in methanol and stirred for 2.5 hour at room temperature. After cooling to 0°C the formed solid was isolated by filtration and dried. Using this methodology we obtained 1.71 g (80% purity, 81% yield) of the desired methyl 2-carbamoyl-1,8- naphthyridine-4-carboxylate. 1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 4.03 (s, 3H), 7.86 (dd, 1H), 7.98 (br. s., 1H), 8.45 (br. s., 1H), 8.65 (s, 1H), 9.18 (dd, 1H), 9.27 (dd, 1H). The following intermediates shown in table 3 were prepared in analogy to intermediate 3A-1 step 2:
Table 3
Figure imgf000210_0002
Starting
Inter- Compound name
materia Structure
mediate 1H-NMR data
l
methyl 2-carbamoyl-1,6- O O naphthyridine-4-carboxylate H3 C 1H-NMR (300 MHz, DMSO-d6) δ 9A-1 9A-1 N
[ppm]: 4.05 (s, 3H), 8.07 (br. s., Step 3 Step 2 O
N 1H), 8.09 (dd, 1H), 8.51 (br. s., 1H), NH2 8.61 (s, 1H), 8.92 (d, 1H), 10.10 (d,
1H)
methyl 2-carbamoyl-1,7- CH3 naphthyridine-4-carboxylate O O 1H-NMR (300 MHz, DMSO-d6) δ 10A-1 10A-1
[ppm]: 4.03 (s, 3H), 8.04 (br. s., Step 4 Step 3
N O
N 1H), 8.51 (br. s., 1H), 8.62 (dd, 1H), NH2 8.76 (s, 1H), 8.82 (d, 1H), 9.57 (d,
1H)
methyl 6-carbamoyl-3- CH3 methyl[1,2]oxazolo[5,4-b]pyridine- O O
H3 C 4-carboxylate
11A-1 11A-1
1H-NMR (400 MHz, DMSO-d6) δ Step 6 Step 5 N
NH O N 2 [ppm]: 2.70 (s, 3H), 4.00 (s, 3H),
O 8.00 (br. s., 1H), 8.43 (s, 1H), 8.48
(br. s., 1H)
methyl 6-carbamoyl-1H- CH3 pyrazolo[3,4-b]pyridine-4- O O
carboxylate
12A-1 12A-1 1H-NMR (400 MHz, DMSO-d6) δ Step 6 Step 5 N
N NH2 [ppm]: 4.02 (s, 3H), 7.86 (br. s., H N
O 1H), 8.11 (br. s., 1H), 8.34 (s, 1H),
8.51 (s, 1H), 13.44 (br. s., 1H)
Figure imgf000212_0001
Starting
Inter- Compound name
materia Structure
mediate 1H-NMR data
l
methyl 6-carbamoyl-3- CH3 methyl[1,2]thiazolo[5,4-b]pyridine- O O
H 4-carboxylate
21A-1 21A-1 3 C
1H-NMR (400 MHz, DMSO-d6) δ Step 6 Step 5 N
S NH
N 2 [ppm]: 2.72 (s, 3H), 4.03 (s, 3H), O 7.99 (br. s., 1H), 8.30 (s, 1H), 8.58
(br. s., 1H)
Intermediate 3A-1 Step 3: 2-carbamoyl-1,8-naphthyridine-4-carboxylic acid
Figure imgf000213_0001
To a solution of 1.71 g (80% purity, 5.92 mmol) methyl 2-carbamoyl-1,8- naphthyridine-4-carboxylate (intermediate 3A-1 step 2) in 130 mL methanol was added 53 mL of an aqueous solution of sodium hydroxide in water (1.0 M, 53 mmol). This mixture was stirred for 30 minutes at 25°C and then concentrated in vacuo. The residue was diluted with water and 10% aqueous sulfuric acid was added to adjust to pH 2. After stirring for additional 15 minutes the formed solid was isolated by filtration and dried in vacuo. Using this methodology we obtained 1.72 g (75% purity, 100% yield) of the desired 2-carbamoyl-1,8-naphthyridine-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 7.83 (dd, 1H), 7.95 (br. s., 1H), 8.41 (br. s., 1H), 8.61 (s, 1H), 9.24 (dd, 1H), 9.26 (dd, 1H). The following intermediates shown in table 4 were prepared in analogy to intermediate 3A-1 step 3:
Table 4
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Intermediate 4A-1
3-carbamoyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylic acid
Figure imgf000216_0002
To a mixture of 6.7 mL (21 wt.% solution in ethanol, 18 mmol) sodium ethoxide and 2.1 mL (15 mmol) diethyl oxalate, 1.6 mL (15 mmol) cyclohexanone was added dropwise. This mixture was stirred for 3 hours at 25°C before 1.2 ml (15 mmol) 2- cyanoacetamide was added. The reaction was stirred at 80°C for 2 hours and then concentrated in vacuo. The residue was taken up in 50 mL boiling water and 4 mL acetic acid. After stirring at 0°C the formed solid was isolated by filtration and dried in vacuo. Thus, 1.80 g (98% purity, 47% yield) of the desired title compound was obtained. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.31 (t, 3H), 1.67 (m, 4H), 2.34 (m, 2H), 2.62 (m, 2H), 4.40 (q, 2H), 12.70 (br. s., 1H). The following intermediate shown in table 5 was prepared in analogy to intermediate 4A-1 step 1:
Table 5
Figure imgf000217_0002
Intermediate 4A-1 Step 2: 3-carbamoyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-4- carboxylic acid was prepared in analogy to intermediate 3A-1 step 3, see table 4.
Intermediate 5A-1
2-oxo-1,2,5,6,7,8-hexahydroqui lic acid
Figure imgf000217_0001
A mixture of 1.3 g (5.3 mmol) ethyl 3-cyano-2-oxo-1,2,5,6,7,8-hexahydroquinoline-4- carboxylate (intermediate 4A-1 step 1) and 8.1 mL (6 M, 49 mmol) hydrochloric acid was stirred at 115°C overnight. After addition of further 2 mL 6 M hydrochloric acid the mixture was heated to 115°C for another night. The hot reaction was poured onto ice, and filtered. The residue was dried at 45°C in vacuo to yield 447 mg (95% purity, 42% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.65 (m, 4H), 2.49 (m, 4H), 6.34 (s, 1H), 11.76 (br. s., 1H), 13.12 (br. s., 1H) The following intermediate shown in table 6 was prepared in analogy to intermediate 5A-1:
Table 6
Figure imgf000218_0001
Intermediate 7A-1
2-carbamoyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acid
Figure imgf000219_0001
Intermediate 7A-1 Step 1: dimethyl (±)-7,7-dimethyl-5-oxo-1,4,5,6,7,8- hexahydroquinoline-2,4-dic
Figure imgf000219_0002
To a solution of 2.15 g (15.3 mmol) 5,5-dimethylcyclohexane-1,3-dione in 18 mL methanol, a solution of 558 mg (13.9 mmol) sodium hydroxide in 36 mL methanol, and a solution of 3.0 g (80% purity, 13.9 mmol) dimethyl (2E)-4-oxopent-2-enedioate (CAS-No.38256-25-6) in 18 mL methanol were added. This mixture was stirred for 3 hours at 25°C. Then, 5.37 g (69.7 mmol) ammonium acetate and 15 mL (260 mmol) acetic acid were added. The reaction was stirred at reflux overnight and then concentrated in vacuo. The residue was re-dissolved in water and extracted three times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and with brine, dried over sodium sulfate, filtered and evaporated. Thus, 2.56 g (70% purity, 44% yield) of the desired title compound was obtained. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.01 (s, 3H), 1.03 (s, 3H), 2.06 (d, 1H), 2.17 (d, 1H), 2.40 (s, 2H), 3.57 (s, 3H), 3.77 (s, 3H), 4.25 (d, 1H), 5.84 (dd, 1H), 8.85 (br. s., 1H).
Intermediate 7A-1 Step 2: dimethyl 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline- 2,4-dicarboxylate
Figure imgf000220_0001
A solution of 2.56 g (70% purity, 6.11 mmol) intermediate 7A-1 step 1 in 80 ml dichloromethane was heated with 4.25 g (48.9 mmol) manganese dioxide to reflux for one week. For work-up the slurry was filtered over Celite®. The filtrate was evaporated and purified by flash chromatography yielding 881 mg (95% purity, 49% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.04 (s, 6H), 2.68 (s, 2H), 3.12 (s, 2H), 3.85 (s, 3H), 3.91 (s, 3H), 7.98 (s, 1H).
Intermediate 7A-1 Steps 3 and 4 were prepared in analogy to intermediate 3A-1 steps 2 and 3, see also tables 3 and 4.
Intermediate 8A-1
2-(trifluoromethyl)-1,6-naphthyridine-4-carboxylic acid was prepared in analogy to intermediate 1A-1, see also table 1.
Intermediate 9A-1
2-carbamoyl-1,6-naphthyridine-4-carboxylic acid
Figure imgf000220_0002
Intermediate 9A-1 Step 1: 1,6-naphthyridine-2,4-dicarboxylic acid
Figure imgf000221_0001
500 mg (1.80 mmol) of ethyl {4-[(2,2-dimethylpropanoyl)amino]pyridin-3- yl}(oxo)acetate (CAS-No. 191338-94-0) was added to 4 mL (33% aqueous solution, 3.2 mmol) potassium hydroxide and stirred overnight at 80°C. To the slurry 5 mL (33% aqueous solution) potassium hydroxide were added, and after thorough stirring the solid was filtered off and rinsed with 33% aqueous potassium hydroxide solution. The solid was dissolved in water, and 10% aqueous sulfuric acid was added until a solid precipitated. The slurry was stirred for 15 minutes before the solid was filtered off and dried to yield 229 mg (97% purity, 57% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 8.12 (dd, 1H), 8.52 (s, 1H), 8.89 (d, 1H), 10.18 (d, 1H).
Intermediate 9A-1 Step 2: dimethyl 1,6-naphthyridine-2,4-dicarboxylate
H
Figure imgf000221_0002
3
229 mg (1.05 mmol) intermediate 9A-1 step 1 was heated with 1.1 mL (16 mmol) thionyl chloride to 80°C overnight and then concentrated in vacuo. The residue was taken up in 1.9 mL (48 mmol) methanol and heated to reflux for 2 hours. Then, the solution was evaporated. The residue was stirred with a small amount of methanol. The solid was filtered off and dried to yield 192 mg (95% purity, 71% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 4.01 (s, 3H), 4.06 (s, 3H), 8.24 (dd, 1H), 8.56 (s, 1H), 8.95 (d, 1H), 10.13 (d, 1H). The following intermediates shown in table 7 were prepared in analogy to intermediate 9A-1 step 2:
Table 7:
Figure imgf000222_0001
Intermediate 9A-1 Steps 3 and 4 were prepared in analogy to intermediate 3A-1 steps 2 and 3, see also tables 3 and 4.
Intermediate 10A-1
2-carbamoyl-1,7-naphthyridine-4-carboxylic acid
Figure imgf000223_0001
Intermediate 10A-1 Step 1: 1,7- iol
Figure imgf000223_0002
To 2.5 g (16.4 mmol) of methyl 3-aminopyridine-4-carboxylate (CAS-No. 55279-30-6) in 16 ml ethyl acetate, 3.69 g (32.9 mmol) potassium tert-butylate were added cautiously in a portion-wise manner. The reaction was stirred for 18 hours at 75°C in a nitrogen atmosphere. After cooling to room temperature, 50 mL water were added. The aqueous phase was extracted with ethyl acetate and acidified with 2 M aqueous hydrochloric acid to adjust to pH 6. The precipitate was filtered off and dried to yield 550 mg (95% purity, 20% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 5.90 (s, 1H), 7.64 (d, 1H), 8.29 (d, 1H), 8.61 (s, 1H), 11.48 (br. s., 1H), 11.75 (br. s., 1H).
Intermediate 10A-1 Step 2: 2,4-d hyridine
Figure imgf000223_0003
To 500 mg (3.08 mmol) of intermediate 10A-1 step 1 and 6.5 mL 1- methylpyrrolidinium trifluoromethanesulfonate, 2.92 g (10.2 mmol) phosphorous(V) oxybromide was added. The slurry was stirred overnight at 85°C. After cooling to room temperature, 50% aqueous sodium hydroxide and crushed ice were added. The precipitate was filtered off and dried to yield 260 mg (95% purity, 28% yield) of the desired title compound. 1H NMR (300 MHz, DMSO-d6): δ [ppm] = 7.99 (d, 1H), 8.50 (s, 1H), 8.81 (d, 1H), 9.38 (s, 1H).
Intermediate 10A-1 Steps 3, 4, and 5 were prepared in analogy to intermediate 3A-1 steps 1, 2, and 3, see also tables 2, 3 and 4.
Intermediate 11A-1
6-carbamoyl-3-methyl[1,2]oxazolo[5,4-b]pyridine-4-carboxylic acid
Figure imgf000224_0001
Intermediate 11A-1 Step 1: ethyl 6-hydroxy-3-methyl[1,2]oxazolo[5,4-b]pyridine-4- carboxylate
Figure imgf000224_0002
To a solution of 5.0 g (51.0 mmol) 3-methyl-1,2-oxazol-5-amine (CAS-No. 14678-02-5) in 19 mL water, a suspension of 10.7 g (51.0 mmol) sodium 1,4-diethoxy-1,4- dioxobut-2-en-2-olate (CAS-No. 40876-98-0) in 25 mL water was added, followed by 15 mL (262 mmol) acetic acid. The reaction was stirred at 85°C overnight, and then evaporated in vacuo. The residue was purified by flash chromatography to obtain 1.36 g (73% purity, 9% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.35 (t, 3H), 2.54 (s, 3H), 4.41 (q, 2H), 7.07 (s, 1H), 12.62 (br. s., 1H). The following intermediates shown in table 8 were prepared in analogy to intermediate 11A-1 step 1:
Table 8
Figure imgf000225_0001
Inter- Starting Compound name mediat Structure
material 1H-NMR data e
3-methyl- ethyl 6-hydroxy-3- 1,2-thiazol- methyl[1,2]thiazolo[5,4-b]pyridine-4- 21A-1 5-amine carboxylate
Step 1 hydro- 1H-NMR (400 MHz, DMSO-d6) δ [ppm]:
chloride 1.34 (t, 3H), 2.43 (s, 3H), 4.39 (q, (1:1)
Figure imgf000226_0001
2H), 6.60 (s, 1H), 12.80 (br. s., 1H)
Intermediate 11A-1 Step 2: ethyl 6-bromo-3-methyl[1,2]oxazolo[5,4-b]pyridine-4- carboxylate
Figure imgf000226_0002
To 1.36 g (73% purity, 4.59 mmol) intermediate 11A step 1 2.63 g (9.18 mmol) phosphorous(V) oxybromide was added. The reaction was heated to reflux for 6 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was cautiously added. The aqueous phase was extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to obtain a crude product, which was purified by flash chromatography to obtain 650 mg (95% purity, 47% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.39 (t, 3H), 2.66 (s, 3H), 4.45 (q, 2H), 8.01 (s, 1H).
The following intermediates shown in table 9 were prepared in analogy to intermediate 11A-1 step 2:
Table 9
Figure imgf000227_0001
Starting
Inter- Compound name
materia Structure
mediate 1H-NMR data
l
CH 3 ethyl 5-bromo[1,3]thiazolo[5,4- O O b]pyridine-7-carboxylate
20A-1 20A-1
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: Step 2 Step 1 N
1.36 (t, 3H), 4.44 (q, 2H), 8.07 (s, 1H), S N Br 9.70 (s, 1H)
ethyl 6-bromo-3- methyl[1,2]thiazolo[5,4-b]pyridine-4- 21A-1 21A-1 carboxylate
Step 2 Step 1 1H-NMR (400 MHz, DMSO-d6) δ [ppm]:
1.38 (t, 3H), 2.66 (s, 3H), 4.47 (q, 2H),
Figure imgf000228_0001
8.00 (s, 1H)
Intermediate 11A-1 Step 3: ethyl 6-cyano-3-methyl[1,2]oxazolo[5,4-b]pyridine-4- carboxylate
Figure imgf000228_0002
To a solution of 1.89 g (6.63 mmol) intermediate 11A-1 step 2 in 28 mL DMF 0.77 g (0.66 mmol) tetrakis(triphenylphosphine)palladium(0) and 856 mg (7.29 mmol) zinc cyanide were added. The reaction was heated to 150°C for 2 hours. After cooling down, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with water and with brine, dried over sodium sulfate, filtered and evaporated to obtain a crude product, which was purified by flash chromatography to obtain 800 mg (95% purity, 50% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.40 (t, 3H), 2.71 (s, 3H), 4.48 (q, 2H), 8.46 (s, 1H). The following intermediates shown in table 10 were prepared in analogy to intermediate 11A-1 step 3:
Table 10
Figure imgf000229_0001
Figure imgf000230_0001
Intermediate 11A-1 Step 4: 3-methyl[1,2]oxazolo[5,4-b]pyridine-4,6-dicarboxylic acid
Figure imgf000230_0002
To a solution of 800 mg (3.46 mmol) intermediate 11A-1 step 3 in 9.2 mL ethanol was added a solution of 2.49 g (62.3 mmol) sodium hydroxide in 18.4 mL water. This mixture was stirred for 1 hour at 50°C and then concentrated in vacuo. The residue was diluted with water and 10% aqueous sulfuric acid was added to adjust to pH 3. After stirring for additional 15 minutes the formed solid was isolated by filtration and dried in vacuo. Using this methodology we obtained 590 mg (95% purity, 73% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.71 (s, 3H), 8.38 (s, 1H). The following intermediates shown in table 11 were prepared in analogy to intermediate 11A-1 step 4:
Table 11
Figure imgf000231_0001
Starting
Inter- Compound name
materia Structure
mediate 1H-NMR data
l
O OH 3-methyl[1,2]thiazolo[5,4-b]pyridine- H3 C 4,6-dicarboxylic acid
21A-1 21A-1
N 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: Step 4 Step 3 O
S N 2.75 (s, 3H), 8.19 (s, 1H), 13.94 (br. s.,
OH 2H)
Intermediate 11A-1 Steps 5, 6, and 7: 6-carbamoyl-3-methyl[1,2]oxazolo[5,4- b]pyridine-4-carboxylic acid was prepared in analogy to intermediate 9A-1 step 2, intermediate 3A-1 step 2, and intermediate 3A-1 step 3, see tables 7, 3 and 4.
Intermediate 12A-1
6-carbamoyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid was prepared in analogy to intermediate 11A-1 steps 1, 2, 3, 4, intermediate 9A-1 step 2, intermediate 3A-1 steps 2, and 3, see tables 7, 3 and 4.
Intermediate 13A-1
6-carbamoyl-1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid was prepared in analogy to intermediate 11A-1 steps 1, 2, 3, 4, intermediate 9A-1 step 2, intermediate 3A-1 steps 2, and 3, see tables 7, 3 and 4.
Intermediate 14A-1
2-carbamoyl-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxylic acid
Figure imgf000233_0001
Intermediate 14A-1 Step 1: methyl 2-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine- 4-carboxylate
Figure imgf000233_0002
A solution of 1.86 g (10.4 mmol) intermediate 6A-1 step 2 in 80 mL methanol was heated with 1.7 mL (31.1 mmol) 10% aqueous sulfuric acid to reflux overnight and then concentrated in vacuo. Water was added. The aqueous phase was extracted three times with dichloromethane. The combined organic layer was evaporated to obtain a crude product which was purified by flash chromatography yielding 1.3 g (95% purity, 62% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.00 (tt, 2H), 2.74 (t, 2H), 2.87 (t, 2H), 3.81 (s, 3H), 6.59 (s, 1H), 12.02 (br. s., 1H).
The following intermediate shown in table 12 was prepared in analogy to intermediate 14A-1 step 1:
Table 12
Figure imgf000233_0003
Starting
Inter- Compound name
materia Structure
mediate 1H-NMR data
l
1H)
Intermediate 14A-1 Steps 2, 3, and 4: 6,7-dihydro-5H-cyclopenta[b]pyridine-2,4- dicarboxylic acid was prepared in analogy to intermediate 11A-1 steps 2, 3, and 4, see above.
Intermediate 14A-1 Step 5: dimethyl 6,7-dihydro-5H-cyclopenta[b]pyridine-2,4- dicarboxylate
Figure imgf000234_0001
A solution of 3.30 g (15% purity, 2.39 mmol) intermediate 14A-1 step 4 in 20 mL methanol was heated with 0.8 mL (15 mmol) 10% aqueous sulfuric acid to reflux overnight and then concentrated in vacuo. Water was added. The aqueous phase was extracted three times with dichloromethane. The combined organic layers were evaporated to obtain a crude product which was purified by flash chromatography yielding 400 mg (80% purity, 57% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.12 (tt, 2H), 3.03 (t, 2H), 3.26 (t, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 8.19 (s, 1H), 13.78 (br. s., 1H).
The following intermediates shown in table 13 were prepared in analogy to intermediate 14A-1 step 5:
Table 13
Figure imgf000235_0001
Intermediate 14A-1 Steps 6 and 7: 2-carbamoyl-6,7-dihydro-5H- cyclopenta[b]pyridine-4-carboxylic acid was prepared in analogy to intermediate 3A- 1 steps 2 and 3, see also tables 3 and 4.
Intermediate 15A-1
2-carbamoyl-5,6,7,8-tetrahydroquinoline-4-carboxylic acid was prepared in analogy to intermediate 14A-1 step 1 (see also table 12), intermediate 11A-1 steps 2, 3, 4 (see also tables 9, 10 and 11), intermediate 14A-1 step 5 (see also table 13), intermediate 3A steps 2, and 3 (see also tables 3 and 4). Intermediate 16A-1
2-carbamoylquinoline-5-carb
Figure imgf000236_0001
2.0 g (9.63 mmol) 2-chloroquinoline-5-carboxylic acid (CAS-No. 1092287-30-3) were suspended in 10 mL tetrahydrofuran and 100 mL (0.5 M, 50 mmol) ammonia in dioxane in an autoclave. 393 mg (482 µmol) [1,1'-Bis(diphenylphosphino)ferrocene]di- chloropalladium(II) dichloromethane adduct were added. The reaction mixture was flushed with carbon monoxide (CO) three times, submitted to a CO pressure of 14.05 bar, and stirred at room temperature for 30 minutes. The pressure was removed, and again a CO pressure of 13.83 bar was applied. The reaction was heated to 100°C for 24 hours. For work-up the slurry was filtered over Celite®. The filtrate was evaporated yielding 810 mg (75% purity, 29% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 7.84 (br. s., 1H), 7.94 (dd, 1H), 8.26 (d, 1H), 8.34 (m, 3H), 9.45 (d, 1H), 13.57 (br. s., 1H).
The following intermediates shown in table 14 were prepared in analogy to intermediate 16A-1:
Table 14
Figure imgf000236_0002
Figure imgf000237_0001
Intermediate 17A-1
3-carbamoylnaphthalene-1-car
Figure imgf000237_0002
Intermediate 17A-1 Step 1: methyl 3-carbamoylnaphthalene-1-carboxylate was prepared in analogy to intermediate 16A-1, see also table 14.
Intermediate 17A-1 Step 2: 3-c -1-carboxylic acid
Figure imgf000238_0001
To a solution of 200 mg (872 µmol) of intermediate 17A-1 step 1 in 5 mL methanol and 1 mL tetrahydrofuran was added a solution of 41.8 mg (1.75 mmol) lithium hydroxide in 9.2 mL water. This mixture was stirred for 90 minutes at 25°C. Then, 10% aqueous sulfuric acid was added to adjust to pH 4, and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated to obtain 140 mg (90% purity, 67% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.59 (br. s., 1H), 7.66 (m, 1H), 7.74 (m, 1H), 8.09 (d, 1H), 8.29 (br. s., 1H), 8.59 (d, 1H), 8.70 (d, 1H), 8.87 (d, 1H), 13.30 (br. s., 1H).
The following intermediates shown in table 15 were prepared in analogy to intermediate 17A-1 step 2:
Table 15
Figure imgf000238_0002
Figure imgf000239_0001
Intermediate 18A-1
7-carbamoylquinoline-5-carboxy
Figure imgf000239_0002
Intermediate 18A-1 Step 1: ethyl 7-bromoquinoline-5-carboxylate
Figure imgf000240_0001
A mixture of 5 g (21.7 mmol) methyl 3-amino-5-bromobenzoate (CAS-No. 706791-83- 5) with 7.97 mL (109 mmol) glycerine, 43.5 mL (612 mmol) 75% aqueous sulfuric acid, and 9 g (43.5 mmol) sodium 3-nitrobenzenesulfonate was heated to 100°C for 3 hours, and additionally to 140°C for 2 hours. The reaction mixture was then concentrated in vacuo. Water and a 50% aqueous ammonia solution were added until the pH turned basic. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and evaporated to obtain a crude product which was purified by flash chromatography yielding 2.45 g (40% yield) of the desired title compound accompanied by the regioisomer ethyl 5- bromoquinoline-7-carboxylate (55:45). 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.368 (5.68), 1.374 (7.40), 1.386 (12.43), 1.392 (16.00), 1.403 (6.01), 1.410 (7.60), 4.378 (1.76), 4.396 (6.04), 4.415 (9.43), 4.433 (7.82), 4.451 (2.16), 7.698 (2.70), 7.708 (2.76), 7.719 (2.72), 7.730 (2.81), 7.814 (1.63), 7.825 (1.95), 7.835 (1.80), 7.846 (2.05), 8.255 (4.40), 8.260 (4.70), 8.269 (0.55), 8.298 (3.40), 8.302 (3.89), 8.486 (2.63), 8.491 (2.98), 8.550 (1.10), 8.552 (1.53), 8.556 (1.47), 8.568 (2.28), 8.572 (4.71), 8.575 (2.85), 8.998 (2.19), 9.002 (2.51), 9.008 (2.27), 9.012 (2.45), 9.082 (1.74), 9.088 (3.57), 9.092 (2.16), 9.098 (1.81), 9.103 (2.37), 9.107 (1.84), 9.110 (1.73).
Intermediate 18A-1 Steps 2 and 3: 7-carbamoylquinoline-5-carboxylic acid was pre- pared in analogy to intermediates 16A-1 and 17A-1 step 2, see also tables 14 and 15.
Intermediate 19A-1
6-carbamoyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid was pre- pared in analogy to intermediate 11A-1 steps 1, 2, 3, 4 (see also tables 8, 9, 10, 11), intermediate 14A-1 step 5 (see also table 13), intermediate 3A-1 step 2 (see also table 3), and intermediate 17A-1 step 2 (see also table 15).
Intermediate 20A-1
5-carbamoyl[1,3]thiazolo[5,4-b]pyridine-7-carboxylic acid was prepared in analogy to intermediate 11A-1 steps 1, 2 (see also tables 8 and 9), intermediate 16A- 1 see also table 14), and intermediate 17A-1 step 2 (see also table 15).
Intermediate 21A-1
6-carbamoyl-3-methyl[1,2]thiazolo[5,4-b]pyridine-4-carboxylic acid was prepared in analogy to intermediate 11A-1 steps 1, 2, 3, 4 (see also tables 8, 9, 10, 11), intermediate 14A-1 step 5 (see also table 13), intermediate 3A-1 step 2 (see also table 3), and intermediate 17A-1 step 2 (see also table 15).
Intermediate 1B-1
1-(4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole
Figure imgf000242_0001
150 mg (1.06 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole (CAS-No. 14531-55-6) was dissolved in 5 mL acetonitrile and 158 µL (1.28 mmol) 1-(bromomethyl)-4-fluoroben- zene (CAS-No. 459-46-1) and 416 mg (1.28 mmol) cesium carbonate were added. The suspension was stirred at 60°C for 2 h. Afterwards the reaction mixture was filtered, the filtrate was evaporated and the residue partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted two further times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to obtain 259 mg (1.04 mmol, 98% yield) of the desired title compound after drying. 1H NMR (400 MHz, CDCl3): δ [ppm] = 2.55 (s, 3 H), 2.58 (s, 3 H), 5.23 (s, 2 H), 7.05 (m, 2 H), 7.13 - 7.19 (m, 2 H). The following intermediates shown in table 16 were prepared in analogy to intermediate 1B-1:
Table 16
Figure imgf000242_0002
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Intermediate 17B-1
3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-5-methyl-1,2-oxazole
Figure imgf000248_0001
6.72 g (47.6 mmol) 3,5-Dimethyl-4-nitro-1H-pyrazole were heated with 7.52 g (57.1 mmol) 3-(chloromethyl)-5-methyl-1,2-oxazole (CAS-No. 35166-37-1) and 8.53 mL (57.1 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene in 25 mL dimethylsulfoxide to 60°C overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried, filtered, and evaporated. The crude title compound (10 g) was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 2.37 (s, 3H), 2.39 (s, 3H), 2.61 (s, 3H), 5.42 (s, 2H), 6.16 (s, 1H).
Intermediate 18B-1
4-{4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-1,3-thiazol-2-yl}morpholine
Figure imgf000248_0002
At 0°C, 167 mg (1.18 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole were stirred with 331 mg (2.95 mmol) potassium tert-butylate in 8 mL DMF for 30 minutes. 310 mg (1.42 mmol) 4-[4-(Chloromethyl)-1,3-thiazol-2-yl]morpholine (CAS-No. 172649-58-0) were added and the mixture was stirred at 80°C overnight. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic phases were washed with brine, dried, filtered, and evaporated. The crude title compound (320 mg) was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 2.38 (s, 3H), 2.68 (s, 3H), 3.31 (m, 4H), 3.67 (m, 4H), 5.17 (s, 2H), 6.70 (s, 1H). The following intermediate shown in table 17 was prepared in analogy to intermediate 17B-1:
Table 17
Figure imgf000249_0001
Intermediate 20B-1
5-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-1-trityl-1H-tetrazole
Figure imgf000250_0001
1.34 g (6.00 mmol) 5-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-1H-tetrazole (intermediate 14B-1) were heated with 1.76 g (6.30 mmol) chlorotriphenylmethane and 0.88 mL (6.30 mmol) triethylamine in 25 mL dichloromethane to reflux overnight. A 10% aqueous citric acid solution and water were added to the reaction mixture, which was then extracted with dichloromethane. The combined organic phases were washed with brine, dried, filtered, and evaporated. Flash chromatography of the residue yielded 1.40 g (50% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 2.38 (s, 3H), 2.57 (s, 3H), 5.76 (s, 2H), 7.01 (m, 6H), 7.39 (m, 9H).
Intermediate 1C-1
1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine
Figure imgf000251_0001
9.33 g (37.43 mmol) 1-(4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (interme- diate 1B-1) was dissolved in 250 mL methanol and 1.99 g (1.87 mmol) palladium on carbon (10 wt.%) and 23.6 g (374.3 mmol) ammonium formiate were added. The reaction mixture was heated for 1 h at 80°C. Afterwards the suspension was filtered through Celite® and the filtrate was evaporated. The residue was partitioned between water and ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to obtain 7.29 g (33.25 mmol, 89% yield) of the desired title compound after drying. 1H NMR (300 MHz, CDCl3): δ [ppm] = 2.05 (s, 3 H), 2.20 (s, 3 H), 2.56 (br. s., 2 H), 5.13 (s, 2 H), 6.86 - 7.12 (m, 4 H).
Intermediate 2C-1
4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile
Figure imgf000251_0002
To a solution of 2.25 g (8.78 mmol) 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 2B-1) in 100 mL ethanol was added 50 mL water, 10 mL acetic acid and 2.01 g (30.7 mmol) zinc dust. This reaction mixture was stirred at 60°C for 2 hours. After cooling to 25°C the suspension was filtered through Celite®, washed with ethyl acetate and the complete filtrate was evaporated. To the residue was added 100 mL water and 30 mL of conc. aq. sodium carbonate. This aqueous phase was extracted three times with 100 mL ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to obtain a crude product, which was purified via a Biotage chromatography system (50g snap KP-Sil column, ethyl acetate / 0– 50% methanol) to obtain 1.77 g (89% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO-d6) δ [ppm] = 1.97 (s, 3H), 1.99 (s, 3H), 3.43 (br. s., 2H), 5.17 (s, 2H), 7.10 - 7.21 (m, 2H), 7.77 (d, 2H). The following intermediates shown in table 18 were prepared in analogy to intermediate 2C-1:
Table 18
Figure imgf000252_0001
Figure imgf000253_0001
Intermediate 6C-1
3-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-methyl-1,2,4-oxadiazole-5- carboxamide
Figure imgf000253_0002
To a solution of 590 mg (2.11 mmol) 3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1- yl)methyl]-N-methyl-1,2,4-oxadiazole-5-carboxamide (intermediate 6B-1) in 69 mL ethanol was added 2.38 g (10.5 mmol) stannous chloride dihydrate. This reaction mixture was stirred at reflux overnight. After cooling to 25°C the mixture was filtered over amino phase silica gel and evaporated. The resulting yellow solid (1.1 g) was heated to reflux in dichloromethane for 30 minutes. The slurry was filtered, and the filtrate was evaporated to yield 380 mg (58% yield) of the desired title compound which was used without further purification. 1H-NMR (400 MHz, CDCl3) δ [ppm] = 2.17 (s, 3H), 2.20 (s, 3H), 2.55 (br. s., 2H), 3.01 (d, 3H), 5.30 (s, 2H), 7.09 (br. s., 1H). The following intermediates shown in table 19 were prepared in analogy to intermediate 6C-1:
Table 19
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Inter- Starting Compound name
Structure
mediate material 1H-NMR data O 3,5-dimethyl-1-{[2-(morpholin-4-yl)-1,3- N S thiazol-4-yl]methyl}-1H-pyrazol-4- N amine
18C-1 18B-1
N N 1H NMR (300 MHz, DMSO-d6): δ [ppm] = H3C CH3
1.96 (s, 3H), 2.10 (s, 3H), 3.31 (m, 4H), NH2 3.68 (m, 4H), 4.87 (s, 2H), 6.26 (s, 1H) 1-(imidazo[1,2-a]pyridin-2-ylmethyl)- 3,5-dimethyl-1H-pyrazol-4-amine N N
19C-1 19B-1 1H-NMR (400 MHz, DMSO-d6) δ [ppm] =
N N 1.97 (s, 3H), 2.12 (s, 3H), 5.13 (s, 2H), H3C CH3 6.83 (m, 1H), 7.19 (m, 1H), 7.47 (d, NH2 1H), 7.53 (s, 1H), 8.46 (d, 1H)
Intermediate 1D-1
6-bromo-N-{3,5-dimethyl-1-[(1-trityl-1H-tetrazol-5-yl)methyl]-1H-pyrazol-4-yl}-2- (trifluoromethyl)-1,8-naphthyridine-4-carboxamide
Figure imgf000258_0001
213 mg (488 µmol) 3,5-dimethyl-1-[(1-trityl-1H-tetrazol-5-yl)methyl]-1H-pyrazol-4- amine (intermediate 14C-1) was dissolved in 15 mL dimethylsulfoxide and 131 mg (407 µmol) 6-bromo-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxylic acid (intermediate 2A-1), 85 µL (488 µmol) N,N-diisopropylethylamine and 186 mg (488 µmol) HATU were added. The reaction mixture was stirred for 16 h at 60°C. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, then dried, filtrated and evaporated to dryness. The residue was purified by preparative HPLC to obtain 96 mg (27% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 2.11 (s, 3H), 2.23 (s, 3H), 5.62 (s, 2H), 7.02 (m, 6H), 7.35 (m, 9H), 8.45 (s, 1H), 9.00 (d, 1H), 9.40 (d, 1H), 10.24 (s, 1H).
Example Compounds– Section 1
Example 1-1
N-[1-(4-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)-1,8- naphthyridine-4-carboxamide
Figure imgf000259_0001
364 mg (1.61 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate 2C-1) was dissolved in 8 mL dimethylsulfoxide and 325 mg (1.34 mmol) 2-(trifluoromethyl)-1,8-naphthyridine-4-carboxylic acid (intermediate 1A), 351 µL (2.01 mmol) N,N-diisopropylethylamine and 612 mg (1.61 mmol) HATU were added. The reaction mixture was stirred for 24 h at 60°C. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, then dried over sodium sulfate, filtrated and evaporated to dryness. The residue was purified by preparative HPLC to obtain 268 mg (44% yield) of the desired title compound. 1H NMR (300 MHz, CD3OD): δ [ppm] = 2.26 (s, 3H), 2.28 (s, 3H), 5.42 (s, 2H), 7.32 (d, 2H), 7.73 (d, 2H), 7.90 (dd, 1H), 8.30 (s, 1H), 8.92 (dd, 1H), 9.28 (dd, 1H). The following examples shown in table 20 were prepared in analogy to example 1-1, using the intermediates specified respectively:
Table 20
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Exa Starting Compound name
Structure
mple materials 1H-NMR data
(1.44), 7.694 (1.43), 8.080 (5.56), 8.089 (1.64), 8.096 (1.56), 8.367 (2.66), 8.373 (2.69), 8.387 (2.25), 8.393 (2.65), 9.002 (2.41), 9.004 (2.69), 9.007 (2.66), 9.010 (2.35),
10.131 (3.52).
N4-[1-(4-cyanobenzyl)-3,5-dimethyl- 1H-pyrazol-4-yl]-5,6,7,8- tetrahydroquinoline-2,4- dicarboxamide
1H-NMR (400 MHz, DMSO-d6) δ [ppm]:
1.788 (1.23), 1.802 (1.35), 1.807 (1.38), 1.850 (1.37), 1.855 (1.34), 1.869 (1.29), 2.083 (16.00), 2.108 54- 2C-1 (14.48), 2.518 (1.69), 2.523 (1.34), 1 15A-1 2.877 (1.22), 2.893 (2.44), 2.909
(1.35), 2.929 (1.43), 2.945 (2.51), 2.960 (1.23), 5.349 (5.68), 7.286 (3.74), 7.291 (1.54), 7.303 (1.59), 7.307 (4.04), 7.670 (1.44), 7.677
Figure imgf000288_0001
(1.47), 7.816 (5.22), 7.826 (5.11),
7.832 (1.69), 7.843 (1.77), 7.847 (4.59), 8.002 (1.46), 8.009 (1.45),
9.735 (3.32).
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Exa Starting Compound name
Structure
mple materials 1H-NMR data
(2.01), 8.092 (1.98), 8.095 (2.40), 8.110 (1.63), 8.113 (1.43), 8.297 (3.74), 8.310 (1.45), 8.312 (2.21), 8.319 (3.95), 8.334 (1.80), 8.389 (2.23), 8.395 (2.25), 8.405 (1.65), 8.410 (3.51), 8.415 (3.06), 8.905 (2.48), 8.927 (2.25), 9.074 (2.29), 9.079 (2.48), 9.081 (2.23), 9.957
(3.37).
N5-{1-[(5-cyanopyridin-2-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl}quinoline-2,5-dicarboxamide 1H-NMR (400 MHz, Acetone-d6) δ [ppm]: 2.438 (1.33), 5.727 (0.63), 7.460 (0.14), 7.480 (0.15), 7.938 (0.12), 7.955 (0.15), 7.959 (0.14), 60- 5C-1 7.977 (0.16), 8.124 (0.15), 8.130 1 16A-1 (1.02), 8.142 (0.14), 8.146 (0.12),
8.283 (0.10), 8.285 (0.16), 8.307 (0.30), 8.313 (0.18), 8.327 (0.15), 8.333 (0.17), 8.337 (0.28), 8.359 (0.29), 8.980 (0.13), 8.982 (0.16),
Figure imgf000292_0001
8.985 (0.16), 8.987 (0.15), 9.006
(0.17), 9.007 (0.18), 9.028 (0.16), 9.030 (0.16), 9.371 (0.10).
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Example 72-1
6-bromo-N-[3,5-dimethyl-1-(1H-tetrazol-5-ylmethyl)-1H-pyrazol-4-yl]-2- (trifluoromethyl)-1,8-naphthyridine-4-carboxamide
Figure imgf000299_0002
96 mg (130 µmol) 6-bromo-N-{3,5-dimethyl-1-[(1-trityl-1H-tetrazol-5-yl)methyl]-1H- pyrazol-4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide (intermediate 1D- 1) was dissolved in 20 mL methanol and 65 mg (260 µmol) pyridinium p- toluenesulfonate were added. The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was evaporated, diluted with brine and extracted three times with ethyl acetate. The combined organic layers were dried, filtrated and evaporated to dryness. The residue was purified by preparative HPLC to obtain 11 mg (17% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 2.10 (s, 3H), 2.31 (s, 3H), 5.48 (s, 2H), 8.44 (s, 1H), 8.99 (d, 1H), 9.40 (d, 1H), 10.25 (s, 1H).
Example 73-1
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-(3,5- dimethyl-1,2-oxazol-4-yl)-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
Figure imgf000300_0001
A mixture of 32 mg (55 µmol) 6-bromo-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluo- romethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide (example 3), 15.5 mg (110 µmol) (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid (CAS-No. 16114-47-9), 9 mg (11 µmol) [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladi- um(II), and 15 mg (110 µmol) sodium carbonate in 2 mL dioxan was heated for 45 minutes at 130°C in a microwave reactor. After cooling the mixture was purified by preparative HPLC to obtain 7 mg (21% yield) of the desired title compound. 1H NMR (400 MHz, CD3OD): δ [ppm] = 2.31 (s, 3H), 2.37 (s, 3H), 2.55 (s, 3H), 5.56 (s, 2H), 7.41 (d, 2H), 7.76 (d, 2H), 8.29 (s, 1H), 8.79 (d, 1H), 9.33 (s, 1H). Intermediates– Section 2
Intermediate 1A-2
2-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4- carboxamide
Figure imgf000301_0001
750 mg (3.42 mmol) 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (intermediate 1C-2) was dissolved in 20 ml tetrahydrofuran and 1.03 g (4.10 mmol) 2- bromoquinoline-4-carboxylic acid ([CAS-No. 15733-87-6], commercially available at e.g. Fluorochem, Combi-Blocks Inc.), 894 µL (5.13 mmol) N,N-diisopropylethylamine and 1.65 g (5.13 mmol) TBTU were added. The reaction mixture was stirred for 2 h at 25°C. Then the reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted two further times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane and under evaporation adsorbed on Isolute® HM-N (Biotage). The isolute was given on a Biotage SNAP cartridge (100 g; KP-Sil) preequilibrated with hexane and purified via column chromatography on silica gel (solvent: hexane/0– 100% ethyl acetate) to obtain 1.47 g (3.24 mmol, 95% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.14 (s, 3 H), 2.18 (s, 3 H), 5.24 (s, 2 H), 7.15 - 7.27 (m, 4 H), 7.77 (ddd, 1 H), 7.90 (ddd, 1 H), 7.94 (s, 1 H), 8.06 (d, 1 H), 8.16 (dd, 1 H), 10.02 (s, 1 H).
Intermediate 2A-2
2-bromo-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4- carboxamide
Figure imgf000302_0001
To a solution of 2.07 g (9.16 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 2C-2) in 41.5 mL DMSO was added 3.83 g (10.1 mmol) HATU, 3.19 mL N,N-diisopropylethylamine and 2.31 g (9.16 mmol) 2- bromoquinoline-4-carboxylic acid ([CAS-No. 15733-87-6], commercially available at e.g. Fluorochem, Combi-Blocks Inc.).The reaction mixture was stirred for 2 hours at 25°C. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous ammonium chloride, then dried over sodium sulfate, filtrated and evaporated to dryness. The residue was purified using three subsequent Biotage Chromatography system (50 g snap KP-Sil column, hexane / 0– 100% ethyl acetate, then ethyl acetate / 0– 10% methanol) to obtain 3.0 g (64% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.14 (s, 3H), 2.16 (s, 3H), 5.37 (s, 2H), 7.30 (d, 2H), 7.76 (ddd, 1H), 7.81 - 7.93 (m, 3H), 7.95 (s, 1H), 8.06 (d, 1H), 8.15 (d, 1H), 10.06 (s, 1H). Intermediate 1B-2
1-(4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole
Figure imgf000303_0001
150 mg (1.06 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole [CAS-No. 14531-55-6] was dissolved in 5 mL acetonitrile and 158 µL (1.28 mmol) 1-(bromomethyl)-4- fluorobenzene and 416 mg (1.28 mmol) cesium carbonate were added. The suspension was stirred at 60°C for 2 h. Afterwards the reaction mixture was filtered, the filtrate was evaporated and the residue partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted two further times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to obtain 259 mg (1.04 mmol, 98% yield) of the desired title compound after drying. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.55 (s, 3 H), 2.58 (s, 3 H), 5.23 (s, 2 H), 7.05 (m, 2 H), 7.13 - 7.19 (m, 2 H).
Intermediate 2B-2
4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile
Figure imgf000303_0002
In analogy to intermediate 1B-2, 6.0 g (42.5 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole and 10.0 g (51.0 mmol) 4-(bromomethyl)-benzonitrile were reacted to give after purification of the crude product via a Biotage chromatography system (100g snap KP-Sil column, hexane / 30– 100% ethyl acetate) 9.56 g (88% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.40 (s, 3H), 2.56 (s, 3H), 5.48 (s, 2H), 7.35 (d, 2H), 7.82 (d, 2H).
Intermediate 3B-2
2-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile
Figure imgf000304_0001
In analogy to intermediate 1B-2, 1.5 g (10.6 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole and 2.5 g (12.8 mmol) 2-(bromomethyl)-benzonitrile were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP- Sil column, hexane / 15– 100% ethyl acetate) 2.48 g (89% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.37 (s, 3H), 2.64 (s, 3H), 5.53 (s, 2H), 7.22 (d, 1H), 7.49 - 7.57 (m, 1H), 7.69 (td, 1H), 7.89 (dd, 1H).
Intermediate 4B-2
1-(4-methoxybenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole
Figure imgf000305_0001
In analogy to intermediate 1B-2, 1.5 g (10.6 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole and 2.56 g (12.8 mmol) 1-(bromomethyl)-4-methoxybenzene were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP-Sil column, hexane / 30– 100% ethyl acetate) 2.41 g (85% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.39 (s, 3H), 2.57 (s, 3H), 3.72 (s, 3H), 5.26 (s, 2H), 6.87 - 6.93 (m, 2H), 7.14 - 7.20 (m, 2H).
Intermediate 5B-2
4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile
Figure imgf000305_0002
In analogy to intermediate 1B-2, 4.30 g (22.0 mmol) 5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazole and 5.19 g (26.5 mmol) 4-(bromomethyl)benzonitrile were reacted to give after purification of the crude product via a Biotage chromatography system (100g snap KP-Sil column, hexane / 0– 70% ethyl acetate) 6.30 g (88% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.63 (s, 3H), 5.67 (s, 2H), 7.38 - 7.44 (m, 2H), 7.83 - 7.88 (m, 2H). Intermediate 6B-2
1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole
Figure imgf000306_0001
In analogy to intermediate 1B-2, 1.58 g (11.2 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole and 3.00 g (13.4 mmol) 4-(bromomethyl)-2-chloro-1-fluorobenzene were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP-Sil column, hexane / 0– 100% ethyl acetate, then ethyl acetate / 0– 45% methanol) 3.16 g (85% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.39 (s, 3H), 2.59 (s, 3H), 5.35 (s, 2H), 7.21 (ddd, 1H), 7.39 (t, 1H), 7.49 (dd, 1H).
Intermediate 7B-2
5-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile
Figure imgf000306_0002
In analogy to intermediate 1B-2, 2.98 g (21.1 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole and 5.00 g (25.4 mmol) 5-(bromomethyl)pyridine-2-carbonitrile were reacted to give after purification of the crude product via a Biotage chromatography system (100g snap KP-Sil column, hexane / 20– 100% ethyl acetate) 3.69 g (64% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.39 (s, 3H), 2.61 (s, 3H), 5.53 (s, 2H), 7.81 (dd, 1H), 8.02 (dd, 1H), 8.66 (d, 1H).
Intermediate 8B-2
3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-4-nitro-1H-pyrazole
Figure imgf000307_0001
In analogy to intermediate 1B-2, 0.90 g (6.38 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole and 1.00 g (7.66 mmol) 3-(chloromethyl)-1-methyl-1H-pyrazole were reacted to give after purification of the crude product via a Biotage chromatography system (25g snap KP-Sil column, hexane / 0– 100% ethyl acetate, then ethyl acetate / 0– 50% methanol) 1.28 g (83% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.37 (s, 3H), 2.62 (s, 3H), 3.77 (s, 3H), 5.24 (s, 2H), 6.13 (d, 1H), 7.61 (d, 1H).
Intermediate 9B-2
2-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]nicotinonitrile
Figure imgf000308_0001
In analogy to intermediate 1B-2, 1.49 g (10.6 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole and 2.50 g (12.7 mmol) 2-(bromomethyl)nicotinonitrile were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP- Sil column, hexane / 0– 100% ethyl acetate, then ethyl acetate / 0– 15% methanol) 2.16 g (75% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.36 (s, 3H), 2.63 (s, 3H), 5.69 (s, 2H), 7.57 (dd, 1H), 8.38 (dd, 1H), 8.75 (dd, 1H).
Intermediate 10B-2
1-(3-fluoro-4-methoxybenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole
Figure imgf000308_0002
In analogy to intermediate 1B-2, 1.07 g (7.61 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole and 2.00 g (9.13 mmol) 3-fluoro-4-methoxybenzylbromide were reacted to give after purification of the crude product via a Biotage chromatography system (25g snap KP- Sil column, hexane / 10– 100% ethyl acetate, then ethyl acetate / 0– 25% methanol) 2.09 g (93% yield) of the desired title compound. 1H-NMR (500 MHz, DMSO d6) δ (ppm) = 2.39 (s, 3H), 2.58 (s, 3H), 3.80 (s, 3H), 5.27 (s, 2H), 6.98 - 7.02 (m, 1H), 7.07 - 7.15 (m, 2H).
Intermediate 11B-2
2-methoxy-5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-
Figure imgf000309_0001
In analogy to intermediate 1B-2, 547 mg (2.80 mmol) 5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazole and 530 mg (3.36 mmol) 5-(chloromethyl)-2- methoxypyridine (Journal of Organic Chemistry, 2011, 8336) were reacted to give after purification of the crude product via a Biotage chromatography system (25g snap KP-Sil column, hexane / 10– 100% ethyl acetate, then ethyl acetate / 0– 25% methanol) 800 mg (81% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.69 (s, 3H), 3.83 (s, 3H), 5.48 (s, 2H), 6.82 (d, 1H), 7.63 (dd, 1H), 8.18 (d, 1H).
Intermediate 12B-2
4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-fluorobenzonitrile
Figure imgf000309_0002
In analogy to intermediate 1B-2, 934 mg (6.62 mmol) 3,5-dimethyl-4-nitro-1H- pyrazole and 1.70 g (7.94 mmol) 4-(bromomethyl)-3-fluorobenzonitrile ([CAS-No. 105942-09-4], commercially available at e.g. ABCR) were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP- Sil column, hexane / 0– 100% ethyl acetate) 1.84 g (91% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.38 (s, 3H), 2.63 (s, 3H), 5.50 (s, 2H), 7.31 (t, 1H), 7.70 (dd, 1H), 7.92 (dd, 1H).
Intermediate 13B-2
1-(4-methoxybenzyl)-5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole
Figure imgf000310_0001
In analogy to intermediate 1B-2, 5.0 g (25.6 mmol) 5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazole and 4.82 g (30.8 mmol) 1-(chloromethyl)-4- methoxybenzene were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP-Sil column, hexane / 0– 100% ethyl acetate) 6.7 g (79% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.65 (s, 3H), 3.73 (s, 3H), 5.45 (s, 2H), 6.93 (d, 2H), 7.22 (d, 2H).
Intermediate 14B-2
5-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-2-methoxypyridine
Figure imgf000311_0001
In analogy to intermediate 1B-2, in two experiment 187 mg (1.32 mmol) / 2.31 g (16.4 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole and 250 mg (1.59 mmol) / 3.10 g (19.7 mmol) 5-(chloromethyl)-2-methoxypyridine (Journal of Organic Chemistry, 2011, 8336) were reacted to give after two subsequent purifications of the combined crude products via a Biotage chromatography system (50g snap KP-Sil column, hexane / 10– 100% ethyl acetate, then ethyl acetate / 0– 25% methanol and secondly 50g snap KP- Sil column, hexane / 10– 100% ethyl acetate) 3.23 g (70% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.38 (s, 3H), 2.62 (s, 3H), 3.82 (s, 3H), 5.29 (s, 2H), 6.79 (d, 1H), 7.58 (dd, 1H), 8.13 (d, 1H).
Intermediate 15B-2
5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyridine-2-
Figure imgf000311_0002
In analogy to intermediate 1B-2, 2.48 g (12.7 mmol) 5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazole and 3.00 g (15.2 mmol) 5-(bromomethyl)pyridine-2- carbonitrile ([CAS-No. 308846-06-2], commercially avalaible e.g. Fluorochem, Apollo Scientific) were reacted to give after two subsequent purification of the crude product via a Biotage chromatography system (50g snap KP-Sil column, hexane / 0– 100% ethyl acetate, then ethyl acetate / 0– 25% methanol)) 2.46 g (60% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.68 (s, 3H), 5.73 (s, 2H), 7.90 (dd, 1H), 8.07 (d, 1H), 8.73 (d, 1H).
Intermediate 16B-2
3-fluoro-4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-
Figure imgf000312_0001
In analogy to intermediate 1B-2, 1.29 g (6.62 mmol) 5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazole and 1.70 g (7.94 mmol) 4-(bromomethyl)-3- fluorobenzonitrile ([CAS-No.105942-09-4], commercially available at e.g. ABCR) were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP-Sil column, hexane / 0– 100% ethyl) 1.89 g (78% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.68 (s, 3H), 5.70 (s, 2H), 7.43 (t, 1H), 7.73 (dd, 1H), 7.95 (dd, 1H).
Intermediate 17B-2 and 18B-2
4-[(3-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(5-methyl-4- nitro-1H-pyrazol-1-yl)methyl]benzonitrile
Figure imgf000313_0001
5.00 g (39.4 mmol) 3-methyl-4-nitro-1H-pyrazole was dissolved in 115 mL acetonitrile and 9.26 g (47.2 mmol) 4-(bromomethyl)-benzonitrile and 15.4 g (47.2 mmol) cesium carbonate were added. The suspension was stirred at 60°C for 3 h. Afterwards the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified via a Biotage chromatography system (100g snap KP-Sil column, hexane / 40– 100% ethyl acetate) to give 7.27 g (76% yield) of the desired title compounds as a mixture. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.39 / 2.59 (s, 3H), 5.42 / 5.55 (s, 2H), 7.35 / 7.47 (d, 2H), 7.80 - 7.85 (m, 2H), 8.29 / 8.99 (s, 1H).
Intermediate 19B-2
tert-butyl 4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1- yl]methyl}piperidine-1-carboxylate
Figure imgf000313_0002
2.38 g (11.98 mmol) 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole were heated with 4 g (14.38 mmol) tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (CAS-No. 158407-04-6) and 2.68 mL (17.97 mmol) 1,8-diazabicyclo(5.4.0)undec-7-ene in 29 mL DMSO to 80°C overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried, filtered, and evaporated. Flash chromatography yielded the title compound (3.67 g, 74% yield) as a light yellow oil. 1H NMR (300 MHz, CDCl3): δ (ppm) = 1.24 (dddd, 2H), 1.46 (s, 9H), 1.57 (br. d., 2H), 2.13 (m, 1H), 2.68 (s, 3H), 2.69 (m, 2H), 4.03 (d, 2H), 4.16 (m, 2H).
Intermediate 20B-2
3-ethyl-5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2,4-
Figure imgf000314_0001
In analogy to intermediate 19B-2, 2.22 g (11.4 mmol) 5-methyl-4-nitro-3-(trifluorome- thyl)-1H-pyrazole and 2.00 g (13.6 mmol) 5-(chloromethyl)-3-ethyl-1,2,4-oxadiazole (CAS-No. 50737-34-3) were reacted to give after purification of the crude product by flash chromatography 1.80 g (5.90 mmol, 52% yield) of the desired title compound. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.33 (t, 3H), 2.77 (s, 3H), 2.78 (q, 2H), 5.59 (s, 2H).
Intermediate 21B-2
5-methyl-3-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2- oxazole
Figure imgf000315_0001
In analogy to intermediate 19B-2, 6.15 g (31.5 mmol) 5-methyl-4-nitro-3-(trifluorome- thyl)-1H-pyrazole and 4.98 g (37.9 mmol) 3-(chloromethyl)-5-methyl-1,2-oxazole (CAS-No. 35166-37-1) were reacted to give after purification of the crude product by flash chromatography 8.55 g (26.5 mmol, 84% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.39 (s, 3H), 2.67 (s, 3H), 5.64 (s, 2H), 6.25 (s, 1H).
Intermediate 22B-2
5-ethyl-3-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2,4- oxadiazole
N
Figure imgf000315_0002
In analogy to intermediate 19B-2, 2.22 g (11.4 mmol) 5-methyl-4-nitro-3-(trifluorome- thyl)-1H-pyrazole and 2.00 g (13.6 mmol) 3-(chloromethyl)-5-ethyl-1,2,4-oxadiazole (CAS-No. 83227-01-4) were reacted to give after purification of the crude product by flash chromatography 2.35 g (7.30 mmol, 64% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 1.25 (t, 3H), 2.71 (s, 3H), 2.95 (q, 2H), 5.80 (s, 2H). Intermediate 23B-2
3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-5-methyl-1,2-oxazole
Figure imgf000316_0001
In analogy to intermediate 19B-2, 8.94 g (63.3 mmol) 3,5-dimethyl-4-nitro-1H- pyrazole and 10 g (76.0 mmol) 3-(chloromethyl)-5-methyl-1,2-oxazole (CAS-No. 35166-37-1) were reacted to give after purification of the crude product by flash chromatography 9.38 g (37.7 mmol, 60% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.37 (s, 3H), 2.39 (s, 3H), 2.61 (s, 3H), 5.42 (s, 2H), 6.16 (s, 1H).
Intermediate 24B-2
3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-4-methyl-1,2,5-oxadiazole
Figure imgf000316_0002
In analogy to intermediate 19B-2, 1.17 g (8.79 mmol) 3,5-dimethyl-4-nitro-1H- pyrazole and 1.03 g (7.32 mmol) 3-(chloromethyl)-4-methyl-1,2,5-oxadiazole (CAS- No. 62642-47-1) were reacted to give 1.72 g of the desired title compound as crude product which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.32 (s, 3H), 2.39 (s, 3H), 2.64 (s, 3H), 5.67 (s, 2H).
Intermediate 1C-2
1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine
Figure imgf000317_0001
9.33 g (37.43 mmol) 1-(4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (intermediate 1B-2) was dissolved in 250 mL methanol and 1.99 g (1.87 mmol) palladium on carbon (10 weight %) and 23.6 g (374.3 mmol) ammonium formiate were added. The reaction mixture was heated for 1 h at 80°C. Afterwards the suspension was filtered through Celite and the filtrate was evaporated. The residue was partitioned between water and ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to obtain 7.29 g (33.25 mmol, 89% yield) of the desired title compound after drying. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.05 (s, 3 H), 2.20 (s, 3 H), 2.56 (br. s., 2 H), 5.13 (s, 2 H), 6.86 - 7.12 (m, 4 H).
Intermediate 2C-2
4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile
Figure imgf000318_0001
To a solution of 2.25 g (8.78 mmol) 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 2B-2) in 100 mL ethanol was added 50 mL water, 10 mL acetic acid and 2.01 g (30.7 mmol) zinc dust. This reaction mixture was stirred at 60°C for 2 hours. After cooling to 25°C the suspension was filtered through Celite, washed with ethyl acetate and the complete filtrate was evaporated. To the residue was added 100 mL water and 30 mL of conc. aq. sodium carbonate. This aqueous phase was extracted three times with 100 mL ethyl acetate.The combined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to obtain a crude product, which was purified via a Biotage chromatography system (50g snap KP-Sil column, ethyl acetate / 0– 50% methanol) to obtain 1.77 g (89% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 1.97 (s, 3H), 1.99 (s, 3H), 3.43 (br. s., 2H), 5.17 (s, 2H), 7.10 - 7.21 (m, 2H), 7.77 (d, 2H).
Intermediate 3C-2
2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile
Figure imgf000318_0002
To a solution of 2.48 g (9.68 mmol) 2-[(3,5-dimethyl-4-nitro-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 3B-2) in 51 mL ethanol was added 10.9 g (48.4. mmol) stannous chloride dihydrate. This reaction mixture was stirred at reflux for 5 hours and then at 70°C for 20 hours. After cooling to 25°C the mixture was evaporated. To the residue was added 5M aq. sodium hydroxide solution to get a basic pH. This aqueous phase was extracted three times with 80 mL ethyl acetate.The combined organic layer was washed with water, brine, dried over sodium sulfate, filtered and evaporated to obtain a crude product, which was puruified via a Biotage chromatography system (50g snap KP-Sil column, ethyl acetate / 0– 35% methanol) to obtain 1.91 g (83% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 1.98 (s, 3H), 2.04 (s, 3H), 3.42 (br. s., 2H), 5.24 (s, 2H), 6.86 (d, 1H), 7.42 - 7.50 (m, 1H), 7.62 (td, 1H), 7.83 (dd, 1H).
Intermediate 4C-2
1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine
Figure imgf000319_0001
In analogy to intermediate 1C-2, 2.41 g (9.22 mmol) 1-(4-methoxybenzyl)-3,5- dimethyl-4-nitro-1H-pyrazole (intermediate 4B-2) were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP- Sil column, hexane / 20– 70% ethyl acetate) 2.35 g (105% calculated yield) of the desired, not completely pure compound, which was used without any further purification. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 1.98 (s, 6H), 3.65 (br. s., 2H), 3.70 (s, 3H), 4.97 (s, 2H), 6.84 (d, 2H), 6.99 (d, 2H). Intermediate 5C-2
4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile
Figure imgf000320_0001
In analogy to intermediate 2C-2, 3.20 g (10.3 mmol) 4-{[5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5B-2) were reacted to give after purification of the crude products via a Biotage chromatography system (50g snap KP-Sil column, hexane / 30– 80% ethyl acetate) 2.66 g (87% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.05 (s, 3H), 4.06 (s, 2H), 5.38 (s, 2H), 7.19 - 7.26 (m, 2H), 7.79 - 7.85 (m, 2H).
Intermediate 6C-2
1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine
Figure imgf000320_0002
In analogy to intermediate 3C-2, 1.50 g (5.29 mmol) 1-(3-chloro-4-fluorobenzyl)-3,5- dimethyl-4-nitro-1H-pyrazole (intermediate 6B-2 were reacted to give without further purification 1.24 g (74% yield) of the desired, not completely pure compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 1.99 (s, 6H), 3.40 (s, 2H), 5.06 (s, 2H), 7.01 (ddd, 1H), 7.20 (dd, 1H), 7.30 - 7.39 (m, 1H). Intermediate 7C-2
5-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile
Figure imgf000321_0001
In analogy to intermediate 2C-2, 3.69 g (14.3 mmol) 5-[(3,5-dimethyl-4-nitro-1H- pyrazol-1-yl)methyl]pyridine-2-carbonitrile (intermediate 7B-2) were reacted to give after purification of the crude products via a Biotage chromatography system (50g snap KP-Sil column, ethyl acetate / 0– 50% methanol) 1.00 g (28% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 1.98 (s, 3H), 2.02 (s, 3H), 3.71 (br. s., 2H), 5.23 (s, 2H), 7.55 (dd, 1H), 7.97 (d, 1H), 8.45 (d, 1H).
Intermediate 8C-2
3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4-amine
Figure imgf000321_0002
In analogy to intermediate 2C-2, 100m g (0.43 mmol) 3,5-dimethyl-1-[(1-methyl-1H- pyrazol-3-yl)methyl]-4-nitro-1H-pyrazole (intermediate 8B-2 were reacted to give after purification of the crude products via a Biotage chromatography system (10g snap KP-Sil column, ethyl acetate / 0– 100% methanol) 210 mg (241% calculated yield) of a crude product which contained the desired title compound and is used in the next step. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 1.94 (s, 3H), 2.05 (s, 3H), 3.74 (s, 3H), 4.92 (s, 2H), 5.88 (d, 1H), 7.53 (d, 2H).
Intermediate 9C-2
2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile
Figure imgf000322_0001
In analogy to intermediate 2C-2, 2.16 g (8.40 mmol) 2-[(3,5-dimethyl-4-nitro-1H- pyrazol-1-yl)methyl]nicotinonitrile (intermediate 9B-2) were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP- Sil column, hexane / 60– 100% ethyl acetate, then ethyl acetate / 0– 90% methanol) 1.11 g (52% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 1.91 (s, 3H), 2.13 (s, 3H), 3.61 (br. s., 2H), 5.31 (s, 2H), 7.51 (dd, 1H), 8.30 (dd, 1H), 8.74 (dd, 1H).
Intermediate 10C-2
1-(3-fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine
Figure imgf000322_0002
In analogy to intermediate 2C-2, in a first experiment of 100 mg (0.36 mmol) and in a second experiment 1.80 g (6.45 mmol) 1-(3-fluoro-4-methoxybenzyl)-3,5-dimethyl-4- nitro-1H-pyrazole (intermediate 10B-2) were reacted to give after purification of the combined crude product via a Biotage chromatography system (100g snap KP-Sil column, hexane / 80– 100% ethyl acetate, then ethyl acetate / 0– 50% methanol) 1.17 g (77% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 1.98 (s, 3H), 1.99 (s, 3H), 3.60 (br. s., 2H), 3.78 (s, 3H), 4.99 (s, 2H), 6.79 - 6.89 (m, 2H), 7.07 (t, 1H).
Intermediate 11C-2
1-[(6-methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-
Figure imgf000323_0001
In analogy to intermediate 2C-2, 800 mg (2.53 mmol) 2-methoxy-5-{[5-methyl-4-nitro- 3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyridine (intermediate 11B-2) were reacted to give after purification of the crude product via a Biotage chromatography system (25g snap KP-Sil column, hexane / 50– 100% ethyl acetate, then ethyl acetate / 0– 50% methanol) 610 mg (79% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.11 (s, 3H), 3.81 (s, 3H), 3.98 (s, 2H), 5.19 (s, 2H), 6.79 (d, 1H), 7.46 (dd, 1H), 8.03 (d, 1H).
Intermediate 12C-2
4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3-fluorobenzonitrile
Figure imgf000324_0001
In analogy to intermediate 2C-2, 1.84 g (6.71 mmol) 4-[(3,5-dimethyl-4-nitro-1H- pyrazol-1-yl)methyl]-3-fluorobenzonitrile (intermediate 12B-2) were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP-Sil column, hexane / 25– 100% ethyl acetate, then ethyl acetate / 0– 100% methanol) 1.24 g (72% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 1.98 (s, 3H), 2.02 (s, 3H), 3.47 (br. s., 2H), 5.19 (s, 2H), 6.86 (t, 1H), 7.62 (dd, 1H), 7.84 (dd, 1H).
Intermediate 13C-2
1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine
Figure imgf000324_0002
In analogy to intermediate 2C-2, in a first experiment 500 mg (1.59 mmol) and in a second experiment 6.20 g (19.7 mmol) 1-(4-methoxybenzyl)-5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazole (intermediate 13B-2) were reacted to give after purification of the combined crude products via a Biotage chromatography system (100g snap KP-Sil column, hexane / 80– 100% ethyl acetate, then ethyl acetate / 0– 50% methanol) 5.65 g (93% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.06 (s, 3H), 3.71 (s, 3H), 3.96 (br. s., 2H), 5.16 (s, 2H), 6.83 - 6.93 (m, 2H), 7.04 - 7.10 (m, 2H). Intermediate 14C-2
1-[(6-methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-amine
Figure imgf000325_0001
In analogy to intermediate 1C-2, 500 mg (1.91 mmol) 5-[(3,5-dimethyl-4-nitro-1H- pyrazol-1-yl)methyl]-2-methoxypyridine (intermediate 14B-2) were reacted to give after purification of the crude product via a Biotage chromatography system (10g snap KP-Sil column, hexane / 80– 100% ethyl acetate, then ethyl acetate / 0– 75% methanol) 214 mg (46% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 1.97 (s, 3H), 2.02 (s, 3H), 3.35 (s, 2H), 3.80 (s, 3H), 5.00 (s, 2H), 6.74 (d, 1H), 7.38 (dd, 1H), 7.94 (d, 1H).
Intermediate 15C-2
5-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyridine-2-
Figure imgf000325_0002
In analogy to intermediate 2C-2, 2.60 g (8.25 mmol) 5-{[5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyridine-2-carbonitrile (intermediate 15B-2) were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP-Sil column, hexane / 20– 100% ethyl acetate, then ethyl acetate / 0– 40% methanol) 670 mg (26% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.12 (s, 3H), 4.09 (s, 2H), 5.45 (s, 2H), 7.66 (dd, 1H), 8.03 (d, 1H), 8.57 (d, 1H).
Intermediate 16C-2
4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3- fluorobenzonitrile
Figure imgf000326_0001
NH2 In analogy to intermediate 2C-2, in a first experiment 250 mg (0.76 mmol) and in a second experiment 1.64 g (5.00 mmol) 3-fluoro-4-{[5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 16B-2) were reacted to give after purification of the combined crude products via a Biotage chromatography system (50g snap KP-Sil column, hexane / 25– 100% ethyl acetate, then ethyl acetate / 0– 100% methanol) 1.65 g (96% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.10 (s, 3H), 4.06 (s, 2H), 5.39 (s, 2H), 7.03 (t, 1H), 7.68 (dd, 1H), 7.89 (dd, 1H).
Intermediate 17C-2 and 18C-2
4-[(4-amino-3-methyl-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4-amino-5- methyl-1H-pyrazol-1-yl)methyl]benzonitrile
Figure imgf000327_0001
In analogy to intermediate 3C-2, 7.27 g (30.0 mmol) 4-[(3-methyl-4-nitro-1H-pyrazol- 1-yl)methyl]benzonitrile and 4-[(5-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate 17B-2 and 18B-2) were reacted to give after purification of the crude product via a Biotage chromatography system (100g snap KP-Sil column, hexane / 50 – 100% ethyl acetate, then ethyl acetate / 0– 40% methanol) 4.42 g (69% yield) of the desired title compounds as a mixture. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 1.98 (s, 3H), 3.66 (br. s., 2H), 5.15 / 5.25 (s, 2H), 6.97 / 7.06 (s, 1H), 7.15 / 7.26 (d, 2H), 7.77 (d, 2H).
Intermediate 19C-2
1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol- 4-amine
Figure imgf000327_0002
In analogy to intermediate 3C-2, 1.80 g (5.90 mmol) 3-ethyl-5-{[5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2,4-oxadiazole (intermediate 20B-2) were reacted to give 1.36 g (84% yield) of the desired title compound without purification. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 1.20 (t, 3H), 2.18 (s, 3H), 2.71 (q, 2H), 4.10 (br. s., 2H), 5.70 (s, 2H).
Intermediate 20C-2
5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-
Figure imgf000328_0001
In analogy to intermediate 3C-2, 4.55 g (15.7 mmol) 5-methyl-3-{[5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2-oxazole (intermediate 21B-2) were reacted to give 3.08 g (68% yield) of the desired title compound without purification. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.14 (s, 3H), 2.36 (s, 3H), 4.02 (br. s., 2H), 5.29 (s, 2H), 6.03 (s, 1H).
Intermediate 21C-2
1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol- 4-amine
Figure imgf000328_0002
In analogy to intermediate 3C-2, 1.94 g (6.04 mmol) 5-methyl-5-ethyl-3-{[5-methyl-4- nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2,4-oxadiazole (intermediate 22B- 2) were reacted to give 1.49 g (81% yield) of the desired title compound without purification. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 1.25 (t, 3H), 2.18 (s, 3H), 2.93 (q, 2H), 4.04 (br. s., 2H), 5.42 (s, 2H).
Intermediate 22C-2
3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-amine
Figure imgf000329_0001
In analogy to intermediate 3C-2, 200 mg (847 µmol) 3-[(3,5-dimethyl-4-nitro-1H- pyrazol-1-yl)methyl]-5-methyl-1,2-oxazole (intermediate 23B-2) were reacted to give 67 mg (31% yield) of the desired title compound without purification. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 1.98 (s, 3H), 2.06 (s, 3H), 2.33 (s, 3H), 3.97 (br. s., 2H), 5.07 (s, 2H), 5.90 (s, 1H).
Intermediate 23C-2
3,5-dimethyl-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1H-pyrazol-4-amine
Figure imgf000329_0002
In analogy to intermediate 3C-2, 1.72 g (7.25 mmol) 3-[(3,5-dimethyl-4-nitro-1H- pyrazol-1-yl)methyl]-4-methyl-1,2,5-oxadiazole (intermediate 24B-2) were reacted to give 1.35 g (90% yield) of the desired title compound without purification. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 1.97 (s, 3H), 2.10 (s, 3H), 2.19 (s, 3H), 3.72 (br. s., 2H), 5.33 (s, 2H).
Intermediate 24C-2
tert-butyl 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-
Figure imgf000330_0001
In analogy to intermediate 3C-2, 1.89 g (4.58 mmol) tert-butyl 4-{[5-methyl-4-nitro-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}piperidine-1-carboxylate (intermediate 19B- 2) were reacted to give 1.62 g (59% yield) of the desired title compound which was used without further purification. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.17 (dddd, 2H), 1.46 (s, 9H), 1.54 (m, 2H), 2.07 (m, 1H), 2.17 (s, 3H), 2.66 (m, 2H), 3.87 (d, 2H), 4.12 (m, 2H).
Intermediate 25C-2
5-methyl-1-(piperidin-4-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-amine
Figure imgf000331_0001
A solution of 800 mg (1.88 mmol) tert-butyl 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}piperidine-1-carboxylate (intermediate 24C- 2) in 11 mL dichloromethane was stirred with 1.45 mL (18.8 mmol) trifluoroacetic acid for 4 hours. The reaction mixture was filtered over NH2 derivatized silica gel, and the filtrate was evaporated yielding 1.0 g of the desired title compound as crude product which was used without further purification. 1H NMR (300 MHz, DMSO-d6): δ (ppm) = 1.33 (dddd, 2H), 1.62 (m, 2H), 2.08 (m, 1H), 2.18 (s, 3H), 2.83 (m, 2H), 3.25 (m, 2H), 3.94 (d, 2H).
Intermediate 26C-2
1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-5-methyl-3-(trifluoromethyl)-1H-
Figure imgf000331_0002
A solution of 500 mg (crude, ~800 µmol) 5-methyl-1-(piperidin-4-ylmethyl)-3- (trifluoromethyl)-1H-pyrazol-4-amine (intermediate 25C-2) in 3 mL DMF was stirred with 106 µL (1.12 mmol) ethanesulfonyl chloride and 670 µL (4.80 mmol) triethylamine for 30 minutes. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the reaction. The mixture was extracted with butanol, and the combined organic phase was washed with brine, dried, filtered, and evaporated. Purification by flash chromatography yielded 144 mg (48% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 1.19 (t, 3H), 1.21 (dddd, 2H), 1.53 (m, 2H), 1.91 (m, 1H), 2.14 (s, 3H), 2.75 (m, 2H), 3.00 (q, 2H), 3.58 (m, 2H), 3.90 (d, 2H), 3.94 (s, 2H). Intermediate 1D-2
2-(1H-tetrazol-5-yl)quinoline-4-carboxylic acid
Figure imgf000332_0001
Step 1: methyl 2-carbamoylquinoline-4-carboxylate
To a solution of 10 g (40.8 mmol) dimethyl quinoline-2,4-dicarboxylate (preparation described in J. Am. Chem. Soc., 1939, vol. 61, p. 3320) in 100 mL methanol was added 117 mL of a 7M solution of ammonia in methanol and stirred for 3 hours at 50°C. After cooling to 25°C the formed solid was isolated by filtration and dried. Using this methodology we obtained the desired methyl 6-bromo-2- carbamoylquinoline-4-carboxylate. Yield: 8.21 g (83%) 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 4.01 (s, 3H), 7.85 (ddd, 1H), 7.89 (br. s., 1H), 7.95 (ddd, 1H), 8.22 (d, 1H), 8.37 (br. s., 1H), 8.53 (s, 1H), 8.71 (d, 1H). Step 2: methyl 2-cyanoquinoline-4-carboxylate
3.17 mL (34.0 mmol) phosphorus oxychloride (POCl3) was added to 41 mL DMF at 0°C and then warmed to 25°C. To this mixture was added 1.50 g (6.51 mmol) methyl 2- carbamoylquinoline-4-carboxylate (step 1) intermediate 1D-2). After stirring for 20 hours at 25°C this mixture was diluted with 200 mL ethyl acetate. The resulting organic phase was washed with water, saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate and, after filtration, evaporated to dryness. The resulting residue was purified via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 10– 60% ethyl acetate) yielding 1.27 g (89% yield) of the desired methyl 2-cyanoquinoline-4-carboxylate. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 4.02 (s, 3H), 7.94 (ddd, 1H), 8.02 (ddd, 1H), 8.24 (d, 1H), 8.39 (s, 1H), 8.66 (d, 1H).
Step 3: methyl 2-(1H-tetrazol-5-yl)quinoline-4-carboxylate
To a solution of 100 mg (0.47 mmol) of the nitrile of step 2) intermediate 1D-2 in 1.0 mL DMF was added 113 mg (1.74 mmol) sodium azide and 113 mg (2.12 mmol) ammonium chloride. This mixture was stirred at 115°C for 1.5 hours. After cooling to room temperature 1M aq. hydrochloric acid was added and this mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration and evaporation to dryness the residue was purified via a Biotage chromatography system (10 g snap KP-Sil column, ethyl acetate / 0- 40% methanol). Using this methodology we obtained the desired methyl 2-(1H-tetrazol-5-yl)quinoline-4-carboxylate. Yield: 121 mg (100%). 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 4.04 (s, 3H), 7.85 (ddd, 1H), 7.96 (ddd, 1H), 8.25 (d, 1H), 8.67 (s, 1H), 8.71 (dd, 1H). Step 4: 2-(1H-tetrazol-5-yl)quinoline-4-carboxylic acid
To a solution of 121 mg (0.47 mmol) of the compound from step 3) intermediate 1D-2 in 2.18 mL methanol and 0.84 mL tetrahydrofuran was added a solution of 171 mg sodium hydroxide in 4.37 mL water. This mixture was stirred for 2 hours at 25°C and then concentrated in vacuum. The residue was diluted with water and 10% aq. sulfuric acid was added to adjust to pH 5. After stirring for additional 15 minutes the formed solid was isolated by filtration and dried in vacuum. Using this methodology we obtained the desired title compound. Yield: 110 mg (91%). 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 7.85 (dt, 1H), 7.97 (td, 1H), 8.26 (d, 1H), 8.67 (s, 1H), 8.82 (d, 1H). Intermediate 2D-2
2-(3,5-dimethyl-1,2-oxazol-4-yl)quinoline-4-carboxylic acid
Figure imgf000334_0001
539 mg (3.60 mmol) isatin (1H-indole-2,3-dione) was stirred with1 g (7.19 mmol) 1- (3,5-dimethyl-1,2-oxazol-4-yl)ethanone (CAS-No. 35166-20-2) and 30 mL of a 30% aqueous potassium hydroxide solution at 40°C for 16 hours. 10% aqueous sulfuric acid was added until pH 1 was reached. The precipitate was filtered, washed with water, and dried in vacuum. Then, the solid was heated with THF for 1 hour, and again filtered. The filtrate was evaporated and dried to yield 863 mg (90% yield) of the title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.49 (s, 3H), 2.69 (s, 3H), 7.72 (ddd, 1H), 7.86 (ddd, 1H), 8.05 (s, 1H), 8.12 (dd, 1H), 8.66 (dd, 1H). The following intermediates were prepared in analogy to intermediate 2D-2:
Figure imgf000334_0002
Figure imgf000335_0001
Example Compounds– Section 2
Example 1-2
6-bromo-2-(4-ethylphenyl)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
Figure imgf000336_0001
75 mg (0.34 mmol) 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (intermediate 1C-2) was dissolved in 20 mL tetrahydrofuran and 146 mg (0.41 mmol) 6-bromo-2-(4- ethylphenyl)quinoline-4-carboxylic acid ([CAS-No. 350998-45-7], commercially available at e.g. Fluorochem, Matrix, Zerenex), 89 µL (0.51 mmol) N,N- diisopropylethylamine and 165 mg (0.51 mmol) TBTU were added. The reaction mixture was stirred for 2 h at 25°C. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted two further times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated The residue was purified via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0– 100% ethyl acetate) yielding 149 mg (78% yield) of the desired title compound. 1H-NMR (300 MHz, CDCl3) δ (ppm) = 1.30 (t, 3H) 2.23 (s, 3H) 2.33 (s, 3H) 2.74 (q, 2H) 5.24 (s, 2H) 6.96 - 7.11 (m, 2H) 7.17 (dd, 2H) 7.36 (d, 3H) 7.83 (dd, 1H) 7.98 (s, 1H) 8.06 (d, 3H) 8.44 (d, 1H). Example 2-2
6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- methoxyphenyl)quinoline-4-carboxamide
Figure imgf000337_0001
In analogy to example 1-2, 75 mg (0.34 mmol) 1-(4-fluorobenzyl)-3,5-dimethyl-1H- pyrazol-4-amine (intermediate 1C-2) and 147 mg (0.41 mmol) 6-bromo-2-(4- methoxyphenyl)quinoline-4-carboxylic acid ([CAS-No. 109540-19-4], commercially available at e.g. Fluorochem, Matrix, Zerenex) were reacted to give after purification via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0– 100% ethyl acetate) 127 mg (66% yield) of the desired title compound. 1H NMR (300 MHz, DMSO d6): δ (ppm) = 2.16 (s, 3H) 2.20 (s, 3H) 3.86 (s, 3H) 5.26 (s, 2H) 7.07 - 7.33 (m, 6H) 7.89 - 8.01 (m, 1H) 8.06 (d, 1H) 8.28 - 8.45 (m, 4H) 10.06 (s, 1H). Example 3-2
6-bromo-2-(4-chlorophenyl)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
Figure imgf000338_0001
In analogy to example 1-2, 75 mg (0.34 mmol) 1-(4-fluorobenzyl)-3,5-dimethyl-1H- pyrazol-4-amine (intermediate 1C-2) and 149 mg (0.41 mmol) 6-bromo-2-(4- chlorophenyl)quinoline-4-carboxylic acid ([CAS-No. 351327-32-7], commercially available at e.g. Fluorochem, Wuhan Chemwish Technology) were reacted for 2 h, during which a solid precipitate was formedwhich was obtained via filtration after washing with dichloromethane and drying to yield 154 mg (80% yield) of the desired title compound. 1H NMR (400 MHz, DMF d7): δ (ppm) = 2.26 (s, 3H) 2.31 (s, 3H) 5.35 (s, 2H) 7.17 - 7.30 (m, 2H) 7.35 (dd, 2H) 7.71 (m, 2H) 8.05 (d, 1H) 8.17 (d, 1H) 8.48 (m, 2H) 8.56 - 8.65 (m, 2H) 10.11 (s, 1H). Example 4-2
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(thiophen-3-yl)quinoline-4- carboxamide
Figure imgf000339_0001
A mixture of 75 mg (0.16 mmol) 2-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H- pyrazol-4-yl]quinoline-4-carboxamide (intermediate 1A-2), 42 mg (0.33 mmol) 3- thienylboronic acid, 13.5 mg (0.017 mmol) [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II), 52.6 mg (0.59 mmol) sodium carbonate in 0.30 mL water and 2.5 mL dioxan was heated for 4 hours at 105°C in a microwave reactor. After cooling the mixture was added to a mixture of saturated aq. ammonium chloride solution and dichloromethane, followed by stirring for 15 minutes at 25°C. Then the layers were separated and the organic layer was extracted twice with brine, dried over sodium sulfate, filtered and evaporated The residue was purified via preparative HPLC (method 3) to give 42 mg (56% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.18 (s, 3H) 2.21 (s, 3H) 5.26 (s, 2H) 7.16 - 7.27 (m, 4H) 7.65 (ddd, 1H) 7.74 (dd, 1H) 7.82 (ddd, 1H) 8.01 (dd, 1H) 8.09 (d, 1H) 8.15 (d, 1H) 8.23 (s, 1H) 8.54 (dd, 1H) 9.96 (s, 1H).
Example 5-2
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-furyl)quinoline-4- carboxamide
Figure imgf000340_0001
In analogy to example 4-2, 75 mg (0.16 mmol) 2-bromo-N-[1-(4-fluorobenzyl)-3,5- dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide (intermediate 1A-2) and 37 mg (0.33 mmol) 2-furylboronic acid were reacted to give after purification via preparative HPLC (method 3) 45 mg (62% yield) of the desired title compound. 1H NMR (400 MHz, DMF d7): δ (ppm) = 2.16 (s, 3H) 2.20 (s, 3H) 5.25 (s, 2H) 6.77 (dd, 1H) 7.16 - 7.27 (m, 4H) 7.46 - 7.49 (m, 1H) 7.66 (ddd, 1H) 7.83 (ddd, 1H) 7.99 (dd, 1H) 8.06 - 8.10 (m, 2H) 8.12 - 8.17 (m, 1H) 9.99 (s, 1H).
Example 6-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- methoxyphenyl)quinoline-4-carboxamide
Figure imgf000340_0002
To a solution of 100 mg (0.44 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 2C-2) in 2.0 mL DMSO was added 185 mg (0.49 mmol) HATU, 154 µL N,N-diisopropylethylamine and 123 mg (0.44 mmol) 2-(4- methoxyphenyl)quinoline-4-carboxylic acid ([CAS-No. 4364-02-7], commercially available at e.g. ABCR, Fluorochem).The reaction mixture was stirred for 20 hours at 25°C. This mixture was directly purified via preparative HPLC (method 3) to obtain 128 mg (60% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.17 (s, 3H), 2.20 (s, 3H), 3.86 (s, 3H), 5.38 (s, 2H), 7.11 - 7.15 (m, 2H), 7.28 - 7.33 (m, 2H), 7.63 (ddd, 1H), 7.78 - 7.87 (m, 3H), 8.11 (d, 1H), 8.18 (dd, 1H), 8.26 (s, 1H), 8.30 - 8.35 (m, 2H), 9.98 (s, 1H). Example 7-2
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- methoxyphenyl)quinoline-4-carboxamide
Figure imgf000341_0001
In analogy to example 6-2, 100 mg (0.36 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5C-2) and 100 mg (0.36 mmol) 2-(4-methoxyphenyl)quinoline-4-carboxylic acid, were reacted to give after purification via preparative HPLC (method 3) 91 mg (44% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.32 (s, 3H), 3.87 (s, 3H), 5.63 (s, 2H), 7.16 (d, 2H), 7.39 (d, 2H), 7.66 (ddd, 1H), 7.84 (ddd, 1H), 7.91 (d, 2H), 8.10 - 8.17 (m, 2H), 8.23 (s, 1H), 8.29 - 8.33 (m, 2H), 10.35 (s, 1H). Example 8-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-hydroxy-2- phenylquinoline-4-carboxamide
Figure imgf000342_0001
In analogy to example 6-2, 100 mg (0.44 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]benzonitrile (intermediate 2C-2) and 117 mg (0.44 mmol) 6-hydroxy-2- phenylquinoline-4-carboxylic acid ([CAS-No. 964-30-7], commercially available at e.g. Amatek Chemical), were reacted to give after purification via preparative HPLC (method 3) 92 mg (42% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.19 (s, 3H), 2.21 (s, 3H), 5.40 (s, 2H), 7.32 (d, 2H), 7.39 (dd, 1H), 7.49 - 7.53 (m, 2H), 7.54 - 7.60 (m, 2H), 7.84 - 7.89 (m, 2H), 8.01 (d, 1H), 8.19 (s, 1H), 8.27 - 8.31 (m, 2H), 9.94 (s, 1H), 10.23 (s, 1H).
Example 9-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4-methylphenyl)quinoline- 4-carboxamide
Figure imgf000343_0001
In analogy to example 6-2, 100 mg (0.44 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]benzonitrile (intermediate 2C-2) and 116 mg (0.44 mmol) 2-(4- methylphenyl)quinoline-4-carboxylic acid ([CAS-No. 20389-05-3], commercially available at e.g. ABCR, Fluorochem), were reacted to give after purification via preparative HPLC (method 3) 137 mg (62% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.19 (s, 3H), 2.21 (s, 3H), 2.42 (s, 3H), 5.40 (s, 2H), 7.33 (d, 2H), 7.41 (d, 2H), 7.67 (ddd, 1H), 7.82 - 7.88 (m, 3H), 8.15 (d, 1H), 8.21 (dd, 1H), 8.26 - 8.31 (m, 3H), 10.02 (s, 1H). Example 10-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4-fluorophenyl)quinoline- 4-carboxamide
Figure imgf000343_0002
In analogy to example 6-2, 100 mg (0.44 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]benzonitrile (intermediate 2C-2) and 118 mg (0.44 mmol) 2-(4- fluorophenyl)quinoline-4-carboxylic acid ([CAS-No. 441-28-1], commercially available at e.g. Fluorochem, Matrix, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 9.7 mg (4.2% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.19 (s, 3H), 2.21 (s, 3H), 5.40 (s, 2H), 7.32 (d, 3H), 7.40 - 7.48 (m, 2H), 7.70 (ddd, 1H), 7.84 - 7.89 (m, 3H), 8.16 (d, 1H), 8.22 (d, 1H), 8.34 (s, 1H), 8.41 - 8.47 (m, 2H), 10.02 (s, 1H). Example 11-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-2-(pyridin-3- yl)quinoline-4-carboxamide
Figure imgf000344_0001
In analogy to example 6), 100 mg (0.44 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]benzonitrile (intermediate 2C-2) and 117 mg (0.44 mmol) 6-methyl-2- (pyridin-3-yl)quinoline-4-carboxylic acid ([CAS-No. 5110-02-1], commercially available at e.g. Fluorochem, ABCR, Zerenex), were reacted to give a precipitate which was isolated by filtration and then washed with ethyl acetate to give 96 mg (45% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.20 (s, 3H), 2.22 (s, 3H), 2.55 (s, 3H), 5.40 (s, 2H), 7.33 (d, 2H), 7.62 (ddd, 1H), 7.73 (dd, 1H), 7.84 - 7.89 (m, 2H), 8.01 (s, 1H), 8.10 (d, 1H), 8.38 (s, 1H), 8.69 (dt, 1H), 8.73 (dd, 1H), 9.52 (d, 1H), 10.01 (s, 1H). Example 12-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- methoxyphenyl)quinoline-4-carboxamide
Figure imgf000345_0001
In analogy to example 6-2, 100 mg (0.44 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]benzonitrile (intermediate 2C-2) and 123 mg (0.44 mmol) 2-(3- methoxyphenyl)quinoline-4-carboxylic acid ([CAS-No. 159782-19-1], commercially available at e.g. Fluorochem, Matrix, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 42 mg (19% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.19 (s, 3H), 2.21 (s, 3H), 3.90 (s, 3H), 5.40 (s, 2H), 7.13 (ddd, 1H), 7.33 (d, 2H), 7.52 (t, 1H), 7.70 (ddd, 1H), 7.83 - 7.89 (m, 3H), 7.90 - 7.96 (m, 2H), 8.17 (d, 1H), 8.23 (dd, 1H), 8.33 (s, 1H), 10.02 (s, 1H). Example 13-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(pyridin-3-yl)quinoline-4- carboxamide
Figure imgf000346_0001
In analogy to example 6-2, 100 mg (0.44 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]benzonitrile (intermediate 2C) and 111 mg (0.44 mmol) 2-(pyridin-3- yl)quinoline-4-carboxylic acid ([CAS-No. 7482-91-9], commercially available at e.g. Fluorochem, ABCR, Enamine, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 39 mg (18% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.19 (s, 3H), 2.22 (s, 3H), 5.40 (s, 2H), 7.33 (d, 2H), 7.65 (ddd, 1H), 7.74 (ddd, 1H), 7.84 - 7.92 (m, 3H), 8.21 (d, 1H), 8.25 (dd, 1H), 8.44 (s, 1H), 8.71 - 8.77 (m, 2H), 9.55 (d, 1H), 10.04 (s, 1H). Example 14-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4-ethylphenyl)quinoline-4- carboxamide
Figure imgf000346_0002
In analogy to example 6-2, 100 mg (0.44 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]benzonitrile (intermediate 2C-2) and 123 mg (0.44 mmol) 2-(4- ethylphenyl)quinoline-4-carboxylic acid ([CAS-No. 301320-96-7], commercially available at e.g. Fluorochem, Chemical Diversity Labs, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 136 mg (60% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 1.26 (t, 3H), 2.19 (s, 3H), 2.21 (s, 3H), 2.72 (q, 2H), 5.40 (s, 2H), 7.33 (d, 2H), 7.44 (d, 2H), 7.68 (ddd, 1H), 7.81 - 7.90 (m, 3H), 8.15 (d, 1H), 8.21 (dd, 1H), 8.26 - 8.32 (m, 3H), 10.02 (s, 1H). Example 15-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-2-phenylquinoline- 4-carboxamide
Figure imgf000347_0001
In analogy to example 6-2, 100 mg (0.44 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]benzonitrile (intermediate 2C-2) and 116 mg (0.44 mmol) 6-methyl-2- phenylquinoline-4-carboxylic acid ([CAS-No. 60538-98-9], commercially available at e.g. Enamine, Chemical Diversity Labs, Matrix, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 123 mg (56% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.19 (s, 3H), 2.21 (s, 3H), 2.54 (s, 3H), 5.40 (s, 2H), 7.34 (d, 2H), 7.51 - 7.63 (m, 3H), 7.70 (dd, 1H), 7.84 - 7.89 (m, 2H), 8.00 (s, 1H), 8.07 (d, 1H), 8.28 (s, 1H), 8.32 - 8.37 (m, 2H), 10.00 (s, 1H). Example 16-2
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methyl-2- phenylquinoline-4-carboxamide
Figure imgf000348_0001
In analogy to example 6-2, 100 mg (0.36 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5C-2) and 94 mg (0.36 mmol) 6-methyl-2-phenylquinoline-4-carboxylic acid ([CAS-No. 60538-98-9], commercially available at e.g. Enamine, Chemical Diversity Labs, Matrix, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 93 mg (48% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.30 (s, 3H), 2.51 (s, 3H), 5.62 (s, 2H), 7.38 (d, 2H), 7.49 - 7.63 (m, 3H), 7.70 (dd, 1H), 7.87 - 7.95 (m, 3H), 8.06 (d, 1H), 8.23 (s, 1H), 8.27 - 8.33 (m, 2H), 10.33 (s, 1H). Example 17-2
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(pyridin-3- yl)quinoline-4-carboxamide
Figure imgf000349_0001
In analogy to example 6-2, 100 mg (0.36 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5C-2) and 89 mg (0.36 mmol) 2-(pyridin-3-yl)quinoline-4-carboxylic acid ([CAS-No. 7482-91-9], commercially available at e.g. Fluorochem, ABCR, Enamine, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 44 mg (23% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.31 (s, 3H), 5.62 (s, 2H), 7.37 (d, 2H), 7.64 (dd, 1H), 7.73 (ddd, 1H), 7.86 - 7.92 (m, 3H), 8.20 (d, 1H), 8.17 (d, 1H), 8.38 (s, 1H), 8.69 (dt, 1H), 8.74 (dd, 1H), 9.51 (d, 1H), 10.37 (s, 1H). Example 18-2
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(3- methoxyphenyl)quinoline-4-carboxamide
Figure imgf000350_0001
In analogy to example 6-2, 100 mg (0.36 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5C-2) and 100 mg (0.36 mmol) 2-(3-methoxyphenyl)quinoline-4-carboxylic acid ([CAS-No. 159782-19-1], commercially available at e.g. Fluorochem, Matrix, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 99 mg (49% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.30 (s, 3H), 3.88 (s, 3H), 5.62 (s, 2H), 7.13 (ddd, 1H), 7.37 (d, 2H), 7.51 (t, 1H), 7.69 (ddd, 1H), 7.83 - 7.92 (m, 5H), 8.15 (d, 1H), 8.17 (d, 1H), 8.26 (s, 1H), 10.36 (s, 1H). Example 19-2
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methyl-2- (pyridin-3-yl)quinoline-4-carboxamide
Figure imgf000351_0001
In analogy to example 6-2, 100 mg (0.36 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5C-2) and 100 mg (0.36 mmol) 6-methyl-2-(pyridin-3-yl)quinoline-4-carboxylic acid ([CAS-No. 5110-02- 1], commercially available at e.g. Fluorochem, ABCR, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 85 mg (41% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.31 (s, 3H), 2.52 (s, 3H), 5.62 (s, 2H), 7.38 (d, 2H), 7.61 (dd, 1H), 7.73 (dd, 1H), 7.87 - 7.96 (m, 3H), 8.09 (d, 1H), 8.33 (s, 1H), 8.65 (dt, 1H), 8.72 (dd, 1H), 9.48 (d, 1H), 10.33 (s, 1H). Example 20-2
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- ethylphenyl)quinoline-4-carboxamide
Figure imgf000352_0001
In analogy to example 6-2, 100 mg (0.36 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5C-2) and 99 mg (0.36 mmol) 2-(4-ethylphenyl)quinoline-4-carboxylic acid ([CAS-No. 301320-96-7], commercially available at e.g. Fluorochem, Chemical Diversity Labs, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 98 mg (50% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 1.24 (t, 3H), 2.30 (s, 3H), 2.70 (q, 2H), 5.62 (s, 2H), 7.37 (d, 2H), 7.43 (d, 2H), 7.67 (ddd, 1H), 7.84 (ddd, 1H), 7.90 (d, 2H), 8.14 (d, 2H), 8.22 - 8.26 (m, 3H), 10.35 (s, 1H). Example 21-2
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- fluorophenyl)quinoline-4-carboxamide
Figure imgf000353_0001
In analogy to example 6-2, 100 mg (0.36 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5C-2) and 95 mg (0.36 mmol) 2-(4-fluorophenyl)quinoline-4-carboxylic acid ([CAS-No. 441-28-1], commercially available at e.g. Fluorochem, Matrix, Zerenex), were reacted to give after purification via preparative HPLC (method 3) 98 mg (43% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.30 (s, 3H), 5.62 (s, 2H), 7.35 - 7.47 (m, 4H), 7.69 (ddd, 1H), 7.82 - 7.94 (m, 3H), 8.15 (d, 2H), 8.27 (s, 1H), 8.36 - 8.44 (m, 2H), 10.36 (s, 1H). Example 22-2
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- methylphenyl)quinoline-4-carboxamide
Figure imgf000354_0001
In analogy to example 6-2, 100 mg (0.36 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5C-2) and 95 mg (0.36 mmol) 2-(4-methylphenyl)quinoline-4-carboxylic acid ([CAS-No. 20389-05-3], commercially available at e.g. ABCR, Fluorochem), were reacted to give after purification via preparative HPLC (method 3) 89 mg (46% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.30 (s, 3H), 2.40 (s, 3H), 5.62 (s, 2H), 7.35 - 7.43 (m, 4H), 7.66 (ddd, 1H), 7.84 (ddd, 1H), 7.88 - 7.92 (m, 2H), 8.14 (d, 2H), 8.21 - 8.26 (m, 3H), 10.35 (s, 1H). Example 23-2
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-hydroxy-2- phenylquinoline-4-carboxamide
Figure imgf000355_0001
In analogy to example 6-2, 100 mg (0.36 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5C-2) and 95 mg (0.36 mmol) 6-hydroxy-2-phenylquinoline-4-carboxylic acid ([CAS-No. 964-30-7], commercially available at e.g. Amatek Chemical), were reacted to give after two subsequent preparative HPLC purifications (method 3) 28 mg (14% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.28 (s, 3H), 5.62 (s, 2H), 7.34 - 7.41 (m, 3H), 7.46 - 7.52 (m, 2H), 7.53 - 7.59 (m, 2H), 7.87 - 7.92 (m, 2H), 8.00 (d, 1H), 8.12 (s, 1H), 8.19 - 8.27 (m, 2H), 10.22 (s, 1H), 10.25 (s, 1H). Example 24-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- hydroxyphenyl)quinoline-4-carboxamide
Figure imgf000356_0001
In analogy to example 6-2, 256 mg (1.13 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]benzonitrile (intermediate 2C-2) and 300 mg (1.13 mmol) 2-(4- hydroxyphenyl)quinoline-4-carboxylic acid ([CAS-No. 6952-34-7], commercially available at e.g. ABCR, Enamine, Fluorochem), were reacted to give after purification give after purification using a Biotage chromatography system (10 g snap KP-Sil column, dichloromethane / 0– 10% methanol) 440 mg (78% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.17 (s, 3H), 2.19 (s, 3H), 5.38 (s, 2H), 6.94 (d, 2H), 7.31 (d, 2H), 7.61 (ddd, 1H), 7.75 - 7.88 (m, 3H), 8.08 (d, 1H), 8.15 (d, 1H), 8.19 - 8.26 (m, 3H), 9.92 (s, 1H), 9.99 (s, 1H). Example 25-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4-ethoxyphenyl)quinoline- 4-carboxamide
Figure imgf000357_0001
To a suspension of 100 mg (0.21 mmol) N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H- pyrazol-4-yl]-2-(4-hydroxyphenyl)quinoline-4-carboxamide (example 24-2) in 1.6 mL acetone was added 103 mg (0.32 mmol) cesium carbonate and 25 µL (0.32 mmol) ethyl iodide. After stirring this mixture for 18 hours at 25°C the formed solid was isolated via filtration and dried to give 84 mg (79% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 1.39 (t, 3H), 2.18 (s, 3H), 2.20 (s, 3H), 4.14 (q, 2H), 5.39 (s, 2H), 7.12 (d, 2H), 7.32 (d, 2H), 7.63 (t, 1H), 7.78 - 7.89 (m, 3H), 8.11 (d, 1H), 8.26 (s, 1H), 8.32 (d, 2H). Example 26-2
N-[1-(4-cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
Figure imgf000358_0001
In analogy to example 6-2, 96 mg (0.39 mmol) 4-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]-3-fluorobenzonitrile (intermediate 12C-2) and 100 mg (0.39 mmol) 2-(2- thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 61 mg (30% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.17 (s, 3H), 2.26 (s, 3H), 5.41 (s, 2H), 7.14 (t, 1H), 7.28 (dd, 1H), 7.66 (ddd, 1H), 7.74 (dd, 1H), 7.78 - 7.85 (m, 2H), 7.93 (dd, 1H), 8.05 (d, 1H), 8.13 (dd, 1H), 8.16 (dd, 1H), 8.30 (s, 1H), 10.04 (s, 1H). Example 27-2
N-{1-[(6-methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(2- thienyl)quinoline-4-carboxamide
Figure imgf000358_0002
In analogy to example 6-2, 91 mg (0.39 mmol) 1-[(6-methoxypyridin-3-yl)methyl]-3,5- dimethyl-1H-pyrazol-4-amine (intermediate 14C-2) and 100 mg (0.39 mmol) 2-(2- thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 59 mg (29% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.17 (s, 3H), 2.26 (s, 3H), 3.84 (s, 3H), 5.22 (s, 2H), 6.81 - 6.86 (m, 1H), 7.27 (dd, 1H), 7.57 (dd, 1H), 7.65 (ddd, 1H), 7.78 - 7.85 (m, 2H), 8.05 (d, 1H), 8.09 (d, 1H), 8.12 (dd, 1H), 8.15 (dd, 1H), 8.28 (s, 1H), 9.98 (s, 1H). Example 28-2
N-[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
Figure imgf000359_0001
In analogy to example 6-2, 91 mg (0.39 mmol) 1-(4-methoxybenzyl)-3,5-dimethyl-1H- pyrazol-4-amine (intermediate 4C-2) and 100 mg (0.39 mmol) 2-(2-thienyl)quinoline- 4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 92 mg (46% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.17 (s, 3H), 2.21 (s, 3H), 3.74 (s, 3H), 5.19 (s, 2H), 6.90 - 6.97 (m, 2H), 7.14 - 7.19 (m, 2H), 7.27 (dd, 1H), 7.65 (ddd, 1H), 7.77 - 7.85 (m, 2H), 8.05 (d, 1H), 8.12 (dd, 1H), 8.15 (dd, 1H), 8.28 (s, 1H), 9.97 (s, 1H). Example 29-2
N-{1-[(3-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(2- thienyl)quinoline-4-carboxamide
Figure imgf000360_0001
In analogy to example 6-2, 89 mg (0.39 mmol) 2-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]nicotinonitrile (intermediate 9C-2) and 100 mg (0.39 mmol) 2-(2- thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 102 mg (47% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.11 (s, 3H), 2.34 (s, 3H), 5.53 (s, 2H), 7.26 (dd, 1H), 7.57 (dd, 1H), 7.64 (ddd, 1H), 7.75 - 7.84 (m, 2H), 8.04 (d, 1H), 8.12 (d, 1H), 8.16 (dd, 1H), 8.28 (s, 1H), 8.38 (dd, 1H), 8.79 (dd, 1H), 10.01 (s, 1H). Example 30-2
N-[1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
Figure imgf000361_0001
In analogy to example 6-2, 99 mg (0.39 mmol) 1-(3-chloro-4-fluorobenzyl)-3,5- dimethyl-1H-pyrazol-4-amine (intermediate 6C-2) and 100 mg (0.39 mmol) 2-(2- thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 92 mg (43% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.17 (s, 3H), 2.22 (s, 3H), 5.27 (s, 2H), 7.18 (ddd, 1H), 7.26 (dd, 1H), 7.37 - 7.46 (m, 2H), 7.64 (ddd, 1H), 7.76 - 7.84 (m, 2H), 8.03 (d, 1H), 8.09 - 8.16 (m, 2H), 8.28 (s, 1H), 10.00 (s, 1H). Example 31-2
N-[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
Figure imgf000361_0002
In analogy to example 6-2, 89 mg (0.39 mmol) 2-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]benzonitrile (intermediate 3C-2) and 100 mg (0.39 mmol) 2-(2- thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after stirring a formed solid, which was isolated via filtration and dried to give 116 mg (61% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.16 (s, 3H), 2.28 (s, 3H), 5.44 (s, 2H), 7.08 (d, 1H), 7.26 (dd, 1H), 7.52 (dt, 1H), 7.64 (ddd, 1H), 7.71 (dt, 1H), 7.76 - 7.84 (m, 2H), 7.90 (dd, 1H), 8.04 (d, 1H), 8.12 (d, 1H), 8.15 (dd, 1H), 8.29 (s, 1H), 10.05 (s, 1H). Example 32-2
N-{1-[(6-cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(2- thienyl)quinoline-4-carboxamide
Figure imgf000362_0001
In analogy to example 6-2, 89 mg (0.39 mmol) 5-[(4-amino-3,5-dimethyl-1H-pyrazol- 1-yl)methyl]pyridine-2-carbonitrile (intermediate 7C-2) and 100 mg (0.39 mmol) 2-(2- thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 50 mg (25% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.17 (s, 3H), 2.25 (s, 3H), 5.44 (s, 2H), 7.26 (dd, 1H), 7.64 (ddd, 1H), 7.71 - 7.84 (m, 3H), 8.01 - 8.08 (m, 2H), 8.11 (d, 1H), 8.14 (dd, 1H), 8.28 (s, 1H), 8.60 (d, 1H), 10.03 (s, 1H). Example 33-2
N-[1-(3-fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
Figure imgf000363_0001
In analogy to example 6-2, 89 mg (0.39 mmol) 1-(3-fluoro-4-methoxybenzyl)-3,5- dimethyl-1H-pyrazol-4-amine (intermediate 10C-2) and 100 mg (0.39 mmol) 2-(2- thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 109 mg (53% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.16 (s, 3H), 2.20 (s, 3H), 3.81 (s, 3H), 5.19 (s, 2H), 6.95 - 7.05 (m, 2H), 7.15 (t, 1H), 7.26 (dd, 1H), 7.63 (ddd, 1H), 7.76 - 7.84 (m, 2H), 8.03 (d, 1H), 8.11 (d, 1H), 8.14 (dd, 1H), 8.27 (s, 1H), 9.98 (s, 1H). Example 34-2
N-[1-(4-cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
Figure imgf000364_0001
In analogy to example 6-2, 116 mg (0.39 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3-fluorobenzonitrile (intermediate 16C-2) and 100 mg (0.39 mmol) 2-(2-thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47- 9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 82 mg (37% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.38 (s, 3H), 5.64 (s, 2H), 7.26 - 7.33 (m, 2H), 7.66 (ddd, 1H), 7.77 - 7.86 (m, 3H), 7.97 (dd, 1H), 8.04 - 8.10 (m, 2H), 8.12 (dd, 1H), 8.25 (s, 1H), 10.38 (s, 1H). Example 35-2
N-{1-[(6-methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}-2-(2-thienyl)quinoline-4-carboxamide
Figure imgf000365_0001
In analogy to example 6-2, 112 mg (0.39 mmol) 1-[(6-methoxypyridin-3-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (intermediate 11C-2) and 100 mg (0.39 mmol) 2-(2-thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 99 mg (47% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.36 (s, 3H), 3.84 (s, 3H), 5.43 (s, 2H), 6.86 (d, 1H), 7.26 (dd, 1H), 7.60 - 7.68 (m, 2H), 7.77 - 7.85 (m, 2H), 8.03 (d, 1H), 8.06 (d, 1H), 8.10 (dd, 1H), 8.17 (d, 1H), 8.22 (s, 1H), 10.32 (s, 1H). Example 36-2
N-[1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
Figure imgf000365_0002
In analogy to example 6-2, 112 mg (0.39 mmol) 1-(4-methoxybenzyl)-5-methyl-3- (trifluoromethyl)-1H-pyrazol-4-amine (intermediate 13C-2) and 100 mg (0.39 mmol) 2-(2-thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 103 mg (49% yield) of the desired title compound. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.31 (s, 3H), 3.74 (s, 3H), 5.39 (s, 2H), 6.93 - 6.99 (m, 2H), 7.19 - 7.28 (m, 3H), 7.64 (ddd, 1H), 7.77 - 7.84 (m, 2H), 8.04 (d, 1H), 8.06 (d, 1H), 8.09 (dd, 1H), 8.21 (s, 1H), 10.31 (s, 1H). Example 37-2
N-{1-[(6-cyanopyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}-2-(2-thienyl)quinoline-4-carboxamide
Figure imgf000366_0001
In analogy to example 6-2, 110 mg (0.39 mmol) 5-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyridine-2-carbonitrile (intermediate 15C-2) and 100 mg (0.39 mmol) 2-(2-thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47- 9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification via preparative HPLC (method 3) 95 mg (45% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.32 (s, 3H), 5.63 (s, 2H), 7.28 (dd, 1H), 7.39 (d, 2H), 7.66 (ddd, 1H), 7.79 - 7.85 (m, 2H), 7.89 - 7.93 (m, 2H), 8.04 - 8.10 (m, 2H), 8.11 (dd, 1H), 8.24 (s, 1H), 10.37 (s, 1H). Example 38-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
Figure imgf000367_0001
A mixture of 100 mg (0.29 mmol) 2-bromo-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H- pyrazol-4-yl]quinoline-4-carboxamide (intermediate 2A-2), 56 mg (0.43 mmol) 2- thienylboronic acid, 159 mg (0.22 mmol) [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II), 69.1 mg (0.65 mmol) sodium carbonate in 0.29 mL water and 2.25 mL dioxan was heated for 90 minutes at 105°C in a microwave reactor. After cooling the mixture was purified via a Biotage chromatography system (10 g snap KP-Sil column, hexane / 20– 100% ethyl acetate, then ethyl acetate / 0– 100% methanol) and a subsequent preparative HPLC (method 3) yielding 66 mg (66% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.17 (s, 3H), 2.20 (s, 3H), 5.38 (s, 2H), 7.22 - 7.37 (m, 3H), 7.63 (t, 1H), 7.76 - 7.91 (m, 4H), 8.03 (d, 1H), 8.07 - 8.17 (m, 2H), 8.28 (s, 1H), 10.02 (s, 1H). Example 39-2
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3-thienyl)quinoline-4- carboxamide
Figure imgf000368_0001
A mixture of 100 mg (0.29 mmol) 2-bromo-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H- pyrazol-4-yl]quinoline-4-carboxamide (intermediate 2A-2), 56 mg (0.43 mmol) 3- thienylboronic acid, 159 mg (0.22 mmol) [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II), 69.1 mg (0.65 mmol) sodium carbonate in 0.29 mL water and 2.25 mL dioxan was heated for 90 minutes at 105°C in a microwave reactor. After cooling the mixture was purified via a Biotage chromatography system (10 g snap KP-Sil column, hexane / 30– 100% ethyl acetate, then ethyl acetate / 30% methanol) yielding 85 mg (80% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.17 (s, 3H), 2.20 (s, 3H), 5.38 (s, 2H), 7.31 (d, 3H), 7.64 (ddd, 2H), 7.73 (dd, 1H), 7.79 - 7.86 (m, 3H), 8.00 (dd, 1H), 8.09 (d, 1H), 8.14 (d, 1H), 8.23 (s, 1H), 8.53 (dd, 1H), 9.98 (s, 1H).
Example 40-2
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(1H- tetrazol-5-yl)quinoline-4-carboxamide
Figure imgf000369_0001
In analogy to example 6-2, 153 mg (0.55 mmol) 4-{[4-amino-5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (intermediate 5C-2) and 110 mg (0.47 mmol) 2-(1H-tetrazol-5-yl)quinoline-4-carboxylic acid (intermediate 1D-2), were reacted to give after purification via preparative HPLC (method 5) 66 mg (27% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.30 (s, 3H), 5.61 (s, 2H), 7.39 (d, 2H), 7.84 (ddd, 1H), 7.87 - 7.91 (m, 2H), 7.98 (ddd, 1H), 8.22 (d, 1H), 8.27 (d, 1H), 8.43 (s, 1H), 10.51 (s, 1H). Example 41-2 and 42-2
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-6-methyl-2-phenylquinoline-4- carboxamide and N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-6-methyl-2- phenylquinoline-4-carboxamide
Figure imgf000370_0001
In analogy to example 6-2, 98.2 mg (0.46 mmol) of a mixture of 4-[(4-amino-3- methyl-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4-amino-5-methyl-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 17C-2 and 18C-2) and 102 mg (0.39 mmol) 6- methyl-2-phenylquinoline-4-carboxylic acid ([CAS-No. 60538-98-9], commercially available at e.g. Enamine, Chemical Diversity Labs, Matrix, Zerenex), were reacted to give after purification using a Biotage chromatography system (25 g snap KP-Sil column, hexane / 50– 100% ethyl acetate, then ethyl acetate / 0– 100% methanol) followed by a separation and purification via preparative HPLC (method 6a) 121 mg (67% yield) of the desired example 41 and 16 mg (9.0% yield) of the desired example 42-2. N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-6-methyl-2-phenylquinoline-4- carboxamide, example 41-2:
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.21 (s, 3H), 2.52 (s, 3H), 5.41 (s, 2H), 7.44 (d, 2H), 7.49 - 7.61 (m, 3H), 7.68 (dd, 1H), 7.85 (d, 2H), 7.90 (s, 1H), 8.06 (d, 1H), 8.23 (s, 1H), 8.30 - 8.34 (m, 3H), 8.36 (s, 1H), 10.34 (s, 1H). N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-6-methyl-2-phenylquinoline-4- carboxamide, example 42-2:
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.24 (s, 3H), 2.53 (s, 3H), 5.47 (s, 2H), 7.32 (d, 2H), 7.50 - 7.62 (m, 3H), 7.69 (dd, 1H), 7.84 - 7.88 (m, 2H), 7.89 (s, 1H), 7.96 (s, 1H), 8.06 (d, 1H), 8.26 (s, 1H), 8.31 - 8.36 (m, 2H), 10.27 (s, 1H). Example 43-2 and 44-2
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(4-fluorophenyl)quinoline-4- carboxamide and N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(4- fluorophenyl)quinoline-4-carboxamide
Figure imgf000371_0001
In analogy to example 6-2, 104 mg (0.49 mmol) of a mixture of 4-[(4-amino-3-methyl- 1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4-amino-5-methyl-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 17C-2 and 18C-2) and 110 mg (0.41 mmol) 2-(4- fluorophenyl)quinoline-4-carboxylic acid ([CAS-No. 441-28-1], commercially available at e.g. Fluorochem, Matrix, Zerenex), were reacted to give after purification using a Biotage chromatography system (25 g snap KP-Sil column, hexane / 50– 100% ethyl acetate, then ethyl acetate / 0– 100% methanol) followed by a separation and purification via preparative HPLC (method 6b) 39 mg (19% yield) of the desired example 43 and 37 mg (19% yield) of the desired example 44-2. N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(4-fluorophenyl)quinoline-4- carboxamide, example 43-2:
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.20 (s, 3H), 5.40 (s, 2H), 7.37 - 7.44 (m, 4H), 7.65 (ddd, 1H), 7.80 - 7.87 (m, 3H), 8.09 - 8.16 (m, 2H), 8.29 (s, 1H), 8.34 (s, 1H), 8.38 - 8.45 (m, 2H), 10.36 (s, 1H). N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(4-fluorophenyl)quinoline-4- carboxamide, example 44-2:
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.23 (s, 3H), 5.45 (s, 2H), 7.29 (d, 2H), 7.37 - 7.44 (m, 2H), 7.66 (ddd, 1H), 7.81 - 7.87 (m, 4H), 8.18 (d, 1H), 8.14 (d, 1H), 8.18 (d, 1H), 8.31 (s, 1H), 8.39 - 8.44 (m, 2H), 10.26 (s, 1H). Example 45-2 and 46-2
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide and N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
Figure imgf000372_0001
In analogy to example 6-2, 235 mg (1.11 mmol) of a mixture of 4-[(4-amino-3-methyl- 1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4-amino-5-methyl-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 17C-2 and 18C-2) and 235 mg (0.92 mmol) 2-(2- thienyl)quinoline-4-carboxylic acid ([CAS-No. 31792-47-9], commercially available at e.g. Enamine, Matrix, Fluorochem, Enamine), were reacted to give after purification using a Biotage chromatography system (25 g snap KP-Sil column, hexane / 50– 100% ethyl acetate, then ethyl acetate / 0– 100% methanol) followed by a separation and purification via preparative HPLC (method 6c) 93 mg (22% yield) of the desired example 45 and 113 mg (26% yield) of the desired example 46-2. N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide, example 45-2: 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.21 (s, 3H), 5.41 (s, 2H), 7.25 (dd, 1H), 7.42 (d, 2H), 7.61 (ddd, 1H), 7.76 - 7.83 (m, 2H), 7.83 - 7.87 (m, 2H), 8.04 (d, 2H), 8.12 (dd, 1H), 8.26 (s, 1H), 8.31 (s, 1H), 8.35 (s, 1H), 10.39 (s, 1H). N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide, example 46-2:
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.24 (s, 3H), 5.47 (s, 2H), 7.26 (dd, 1H), 7.31 (d, 2H), 7.63 (ddd, 1H), 7.76 - 7.84 (m, 2H), 7.86 (d, 2H), 7.89 (s, 1H), 8.04 (d, 1H), 8.10 (d, 1H), 8.14 (dd, 1H), 8.30 (s, 1H), 10.31 (s, 1H). Example 47-2 and 48-2
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(pyridin-3-yl)quinoline-4- carboxamide and N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(pyridin-3- yl)quinoline-4-carboxamide
Figure imgf000373_0001
In analogy to example 6-2, 254 mg (1.20 mmol) of a mixture of 4-[(4-amino-3-methyl- 1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4-amino-5-methyl-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 17C-2 and 18C-2) and 250 mg (1.00 mmol) 2- (pyridin-3-yl)quinoline-4-carboxylic acid ([CAS-No. 7482-91-9], commercially available at e.g. Fluorochem, ABCR, Enamine, Zerenex), were reacted to give after purification using a Biotage chromatography system (25 g snap KP-Sil column, hexane / 50– 100% ethyl acetate, then ethyl acetate / 0– 100% methanol) followed by a separation and purification via preparative HPLC (method 6d) 132 mg (28% yield) of the desired example 47 and 46 mg (9.7% yield) of the desired example 48-2. N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(pyridin-3-yl)quinoline-4- carboxamide, example 47-2:
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.21 (s, 3H), 5.41 (s, 2H), 7.43 (d, 2H), 7.62 (dd, 1H), 7.70 (ddd, 1H), 7.82 - 7.91 (m, 3H), 8.15 (d, 1H), 8.19 (d, 1H), 8.36 (s, 1H), 8.40 (s, 1H), 8.70 (dt, 1H), 8.73 (dd, 1H), 9.52 (d, 1H), 10.38 (s, 1H). N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(pyridin-3-yl)quinoline-4- carboxamide, example 48-2:
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 2.23 (s, 3H), 5.46 (s, 2H), 7.29 (d, 2H), 7.61 (dd, 1H), 7.70 (t, 1H), 7.82 - 7.90 (m, 4H), 8.19 (t, 2H), 8.40 (s, 1H), 8.67 - 8.74 (m, 2H), 9.51 (d, 1H), 10.27 (s, 1H). The following examples were prepared in analogy to example 6 using the respective intermediates as specified in the table below:
Figure imgf000374_0001
Figure imgf000375_0001
Figure imgf000376_0001
Figure imgf000377_0001
Figure imgf000378_0001
Figure imgf000379_0001
Figure imgf000380_0001
Figure imgf000381_0001
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000390_0001
Figure imgf000391_0001
Figure imgf000392_0001
Figure imgf000393_0001
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Figure imgf000406_0001
Further, the compounds of formula (I-2) of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of formula (I-2) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
Biological in vitro assays The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
Biological Evaluation
In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety. Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent to inhibit glucose transporter GLUT1 and/or GLUT2 the following assays may be used.
Indirect measurement of GLUT activity by quantification of intracellular ATP levels It is well known that a combination of small-molecule inhibitors of mitochondrial electron transport chain and glucose catabolism synergistically suppress ATP production and impair cellular viability (Ulanovskaya et al., 2008,2011; Liu, et al. 2001). We therefore used DLD1 or CHO-K1 cells in combination with an oxidative phosphorylation inhibitor to identify GLUT inhibitors. Cell lines were maintained in DMEM medium supplemented with 10% FCS and 1% Penicillin-Streptomycin solution and 2% Glutamax. The cells were treated with trypsin and seeded into 384 plates at a density of 4000 cells/well. The cells were then cultured overnight in glucose free media containing 1% FCS to reduce intracellular ATP levels. After 24h the cells were incubated at 37°C containing the appropriate glucose or in case of GLUT2 fructose concentration (1 mM and 30 mM respectively, preferably 0,1 mM and 10 mM) with or without compounds and 1uM Rotenone for 15min. The CellTiter-Glo® Luminescent Cell Viability Assay from Promega was then used to measure ATP levels. Compounds able to reduce the ATP levels within 15 min of glucose application were considered to be glucose uptake inhibitors.
Table A: Measured IC50 values of compounds regarding glucose induced ATP increase (GLUT1 inhibition)
Figure imgf000408_0001
Figure imgf000409_0002
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0002
1 DLD1 cells used for ATP level measurements, all IC50 values were standardized to cytochalasin B IC50 values;
Table B: Measured IC50 values of compounds regarding fructose induced ATP increase (GLUT2 inhibition)
Figure imgf000412_0001
Biological Assay: Glucose uptake assay
Cells (e.g. H460 or CHO-K1) were cultured under standard conditions. 10000 cells per well were seeded in clear 96 well tissue culture isoplate plates and cultured overnight (PerkinElmer, 1450-516) under standard conditions. Culture medium was removed and cells were washed two times with 100 µL KRP buffer and then incubated for 45 minutes at 37°C (KRP buffer: 10 mM sodium hydrogen phosphate, 130 mM sodium chloride, 5 mM potassium chloride, 1.3 mM magnesium sulfate, 1.3 mM calcium chloride (pH 7.5), 50 mM HEPES (pH 7.5), 4.7 mM potassium chloride, 1.25 mM magnesium sulfate, 1.25 mM calcium chloride) each. KRP wash buffer was removed and compound 126 (diluted in KRP buffer) was added and incubated for 30 minutes at 37°C. 200 nM radioligand (radioligand 2[1,2] 3H-Deoxy D-Glucose in KRP buffer) were added and incubated for 5 minutes at room temperature. The supernatant was removed and cells were washed with 100 µL ice-cold KRP for two times each. 25 µL of lysis buffer (1 % Triton-X, 0,5N sodium hydroxide) were added and incubated at room temperature for 5 minutes. 75 µL scintillation solution (Microscint-20, PerkinElmer) were added and the plates were shaken for 1 minute. The plates were incubated for 3h at room temperature and the counts were determined by using a Wallace MicroBeta counter (60 seconds per well). Biological assay: Proliferation Assay
Cultivated tumor cells (MCF7, hormone dependent human mammary carcinoma cells, ATCC HTB22; NCI-H460, human non-small cell lung carcinoma cells, ATCC HTB-177; DU 145, hormone-independent human prostate carcinoma cells, ATCC HTB-81; HeLa-MaTu, human cervical carcinoma cells, EPO-GmbH, Berlin; HeLa- MaTu-ADR, multidrug-resistant human cervical carcinoma cells, EPO-GmbH, Berlin; HeLa human cervical tumor cells, ATCC CCL-2; B16F10 mouse melanoma cells, ATCC CRL-6475) were plated at a density of 5000 cells/well (MCF7, DU145, HeLa-MaTu-ADR), 3000 cells/well (NCI-H460, HeLa-MaTu, HeLa), or 1000 cells/well (B16F10) in a 96-well multititer plate in 200 μL of their respective growth medium supplemented 10% fetal calf serum. After 24 hours, the cells of one plate (zero-point plate) were stained with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 μL), to which the test substances were added in various concentrations (0 μM, as well as in the range of 0.01-30 μM; the final concentration of the solvent dimethyl sulfoxide was 0.5%). The cells were incubated for 4 days in the presence of test substances. Cell proliferation was determined by staining the cells with crystal violet: the cells were fixed by adding 20 μL/measuring point of an 11% glutaric aldehyde solution for 15 minutes at room temperature. After three washing cycles of the fixed cells with water, the plates were dried at room temperature. The cells were stained by adding 100 μL/measuring point of a 0.1% crystal violet solution (pH 3.0). After three washing cycles of the stained cells with water, the plates were dried at room temperature. The dye was dissolved by adding 100 μL/measuring point of a 10% acetic acid solution. The extinction was determined by photometry at a wavelength of 595 nm. The change of cell number, in percent, was calculated by normalization of the measured values to the extinction values of the zero-point plate (=0%) and the extinction of the untreated (0 μm) cells (=100%). The IC50 values were determined by means of a 4 parameter fit.
Determination of metabolic stability in vitro
(including calculation of hepatic in vivo blood clearance (CL) and of maximal oral bioavailability (Fmax)) The metabolic stability of test compounds in vitro was determined by incubating them at 1 µM with a suspension liver microsomes in 100 mM phosphate buffer, pH7.4 (NaH2PO4 x H2O + Na2HPO4 x 2H2O) at a protein concentration of 0.5 mg/mL and at 37° C. The reaction was activated by adding a co-factor mix containing 1.2 mg NADP, 3 IU glucose-6-phosphate dehydrogenase, 14.6 mg glucose-6-phosphate and 4.9 mg MgCl2 in phosphate buffer, pH 7.4. Organic solvent in the incubations was limited to <0.2 % dimethylsulfoxide (DMSO) and <1% methanol. During incubation, the microsomal suspensions were continuously shaken and aliquots were taken at 2, 8, 16, 30, 45 and 60 min, to which equal volumes of cold methanol were immediately added. Samples were frozen at -20° C over night, subsequently centrifuged for 15 minutes at 3000 rpm and the supernatant was analyzed with an Agilent 1200 HPLC-system with LCMS/MS detection. The half-life of a test compound was determined from the concentration-time plot. From the half-life the intrinsic clearances were calculated. Together with the additional parameters liver blood flow, specific liver weight and microsomal protein content the hepatic in vivo blood clearance (CL) and the maximal oral bioavailability (Fmax) were calculated for the different species. The following parameter values were used: Liver blood flow– 1.3 L/h/kg (human), 2.1 L/h/kg (dog), 4.2 L/h/kg (rat); specific liver weight– 21 g/kg (human), 39 g/kg (dog), 32 g/kg (rat); microsomal protein content– 40 mg/g. With the described assay only phase-I metabolism of microsomes is reflected, e.g. typically oxidoreductive reactions by cytochrome P450 enzymes and flavin mono-oxygenases (FMO) and hydrolytic reactions by esterases (esters and amides). Literature
Liu H, Hu YP, Savarai N, Priebe W, Lampadis T. Hypersensitization of tumor cells to glycolytic inhibitors. Biochemistry. 2001;40:5542–5547.
Ulanovskaya O, Janjic J, Matsumoto K, Schumacker PT, Kron SJ, Kozmin SA. Synthesis enables identification of the cellular target of leucascandrolide A and neopeltolide. Nat Chem Biol. 2008;4:418–424.
Ulanovskaya O, Jiayue Cui, Stephen J. Kron, and Sergey A. Kozmin. A pairwise chemical genetic screen identifies new inhibitors of glucose transport. Chem Biol. 2011 February 25; 18(2): 222–230.

Claims

CLAIMS 1. A compound of general formula (I) :
Figure imgf000416_0001
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R4a represents a group selected from: aryl-, heteroaryl-;
wherein said aryl- and heteroaryl - group is optionally substituted, one or more times, identically or differently, with R8d; R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; R5 represents a group selected from:
* *
Figure imgf000417_0001
,
* * * * *
Figure imgf000418_0001
,
*
* * ,
Figure imgf000418_0002
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule;
or
R5 represents
Figure imgf000418_0003
wherein * represents the point of attachment to the rest of the molecule; R5a,
Figure imgf000418_0004
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-,
halo-C 4
1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R14, -C(=O)N(H)R1 , -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c,
-N(R14a)C(=O)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14,
-S(=O)2N(R14a)R14b or -S(=O)(=NR14a)R14b ,
said phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a,
-C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a, -S(=O)(=NR15)-R14, phenyl-, 5- to 6-membered heteroaryl-; R7 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl- and benzyl-;
R8 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl-, benzyl-, -C(=O)R10, -C(=O)OR10, -C(=O)N(R10a)R10b, -S(=O)2R10; R8a represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-,
C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8b, R8c represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4-to 10-membered heterocycloalkyl-,
(4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group; said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R8d;
or
R8b and 8c, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl-group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d; R8d represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -NO2, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14, -S(=O)2N(R14a)R14b, -S(=O)(=NR14a)R14b or a tetrazolyl- group; or two R8d groups present ortho to each other on a phenyl- or heteroaryl- ring form a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R14a)(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- ring; R9 represents a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10,
Figure imgf000421_0001
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R10,
Figure imgf000421_0002
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-;
or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group; R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; R14, R14a, R14b, R14c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, said C1-C3-alkyl- group being optionally substituted once with -N(R16)R16a; or
R14a and R14b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R17; R15 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b or -C(=O)O-R14 group; R16, R16a
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group,
or,
R16, R16a,
together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group; R17 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R14 or -C(=O)O-R14 group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-,
-C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R14a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; L3 represents a -C1-C6-alkylene- group; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for use in the treatment and prophylaxis of a disease.
2. The compound for use according to claim 1, wherein R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ; wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
*-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R5 represents a group selected from:
* *
Figure imgf000424_0001
, * * * * *
Figure imgf000425_0001
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4- alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R10, - C(=O)-O-R10, -C(=O)N(R10a)R10b, -N(R10a)R10b, -S(=O)2R10, -S(=O)(=NR11)-R10, phenyl-, 5- to 6-membered heteroaryl-; R7 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl- and benzyl-;
R8 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl-, benzyl-, -C(=O)R10, -C(=O)OR10, -C(=O)N(R10a)R10b, -S(=O) 10
2R ; R9 represents a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b or -S(=O)(=NR11)-R10 ,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R10,
Figure imgf000426_0001
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-;
or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group; R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; p is an integer of 0 or 1; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
3. The compound for use according to claim 1 having a structural formula (I- 1) :
Figure imgf000427_0001
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group, with the proviso that at least one of R1 and R2 is different from hydrogen;
R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally form a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*,
*-CH2C(R14a)(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*,
*-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group;
R4a represents a group selected from: aryl-, heteroaryl-;
wherein said aryl- and heteroaryl - group is optionally substituted, one or more times, identically or differently, with R8d; R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; R5a,
Figure imgf000428_0001
independently from each other represent a hydrogen atom, a halogen atom or a group selected from: cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-,
halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14,
-N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c,
-N(R14a)C(=O)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14,
-S(=O)2N(R14a)R14b or -S(=O)(=NR14a)R14b ,
said phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a,
-C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a, -S(=O)(=NR15)-R14, phenyl-, 5- to 6-membered heteroaryl-; R8a represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8b, R8c
represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4-to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group; said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R8d;
or
R8b and R8c, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl-group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d; R8d represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -NO2, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14, -S(=O)2N(R14a)R14b, -S(=O)(=NR14a)R14b or a tetrazolyl- group; or
two R8d groups present ortho to each other on a phenyl- or heteroaryl- ring form a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R14a)(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- ring;
Figure imgf000431_0001
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, said C1-C3-alkyl- group being optionally substituted once with -N(R16)R16a; or
R14a and R14b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R17; R15 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b or -C(=O)O-R14 group; R16, R16a
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group,
or,
R16, R16a,
together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group; R17 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-,
trifluoromethyl-, -C(=O)R14 or -C(=O)O-R14 group; L1 represents a group selected from: -C1-C4-alkylene-,
Figure imgf000432_0001
-C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R14a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; L3 represents a -C1-C6-alkylene- group; p is an integer of 0 or 1; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
4. The compound for use according to any one of claims 1 to 3, wherein said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by GLUT1, more particularly in which the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
5. The compound for use according to claim 1, which is selected from the group consisting of:
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)-1,8- naphthyridine-4-carboxamide
6-bromo-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2- (trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2- (trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-[3,5-dimethyl-1-(1,3-oxazol-2-ylmethyl)-1H-pyrazol-4-yl]-2- (trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-(3,5-dimethyl-1-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}-1H- pyrazol-4-yl)-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4- yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4- yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{1-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{3,5-dimethyl-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1H- pyrazol-4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-(1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-3,5-dimethyl- 1H-pyrazol-4-yl)-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-(3,5-dimethyl-1-{[5-(methylcarbamoyl)-1,2,4-oxadiazol-3- yl]methyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)-1,8-naphthyridine-4- carboxamide 6-bromo-N-{1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-[1-(imidazo[1,2-a]pyridin-2-ylmethyl)-3,5-dimethyl-1H-pyrazol-4- yl]-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{3,5-dimethyl-1-[(1-methyl-1H-imidazol-2-yl)methyl]-1H-pyrazol-4- yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
N4-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,8-naphthyridine-2,4- dicarboxamide
N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,8- naphthyridine-2,4-dicarboxamide
N4-{3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-1,8- naphthyridine-2,4-dicarboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-5-carboxamide N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-5- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]isoquinoline-4-carboxamide N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl]isoquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]isoquinoline-5-carboxamide N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl]isoquinoline-5-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]isoquinoline-8-carboxamide N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl]isoquinoline-8-carboxamide
N4-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-oxo-1,2,5,6,7,8- hexahydroquinoline-3,4-dicarboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-oxo-1,2,5,6,7,8- hexahydroquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-oxo- 1,2,5,6,7,8-hexahydroquinoline-4-carboxamide N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[b]pyridine-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-oxo- 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxamide
N4-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7,7-dimethyl-5-oxo- 5,6,7,8-tetrahydroquinoline-2,4-dicarboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]cinnoline-4-carboxamide 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinazoline-4- carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,5-naphthyridine-4- carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methoxy-1,5- naphthyridine-4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridine-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridine-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,6- naphthyridine-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-5,6,7,8- tetrahydro-1,6-naphthyridine-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methyl- 5,6,7,8-tetrahydro-1,6-naphthyridine-4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)-1,6- naphthyridine-4-carboxamide
N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,6- naphthyridine-2,4-dicarboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,7-naphthyridine-4- carboxamide N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,7- naphthyridine-2,4-dicarboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,8-naphthyridine-4- carboxamide
ethyl 3-{[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]carbamoyl}-1H- indole-2-carboxylate
N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3- methyl[1,2]oxazolo[5,4-b]pyridine-4,6-dicarboxamide
N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1H- pyrazolo[3,4-b]pyridine-4,6-dicarboxamide
N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1-methyl- 1H-pyrazolo[3,4-b]pyridine-4,6-dicarboxamide
N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6,7- dihydro-5H-cyclopenta[b]pyridine-2,4-dicarboxamide
N4-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}-6,7-dihydro-5H-cyclopenta[b]pyridine-2,4-dicarboxamide
N4-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5,6,7,8- tetrahydroquinoline-2,4-dicarboxamide
N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5,6,7,8- tetrahydroquinoline-2,4-dicarboxamide
N4-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}-5,6,7,8-tetrahydroquinoline-2,4-dicarboxamide
N5-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,5- dicarboxamide
N5-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline- 2,5-dicarboxamide
N5-{1-[(5-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,5- dicarboxamide
N5-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}quinoline-2,5-dicarboxamide N1-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl]naphthalene-1,3-dicarboxamide
N1-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}naphthalene-1,3-dicarboxamide
N3-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1H-indole-1,3- dicarboxamide
N3-{1-[(5-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-1H-indole- 1,3-dicarboxamide
N5-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline- 5,7-dicarboxamide
N5-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}quinoline-5,7-dicarboxamide
N4-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-4,6-dicarboxamide
N4-{1-[(5-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-1,3- dimethyl-1H-pyrazolo[3,4-b]pyridine-4,6-dicarboxamide
N7-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl][1,3]thiazolo[5,4-b]pyridine-5,7-dicarboxamide
N7-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}[1,3]thiazolo[5,4-b]pyridine-5,7-dicarboxamide
N4-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}-3-methyl[1,2]thiazolo[5,4-b]pyridine-4,6-dicarboxamide
6-bromo-N-[3,5-dimethyl-1-(1H-tetrazol-5-ylmethyl)-1H-pyrazol-4-yl]-2- (trifluoromethyl)-1,8-naphthyridine-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-(3,5- dimethyl-1,2-oxazol-4-yl)-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide 6-bromo-2-(4-ethylphenyl)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- methoxyphenyl)quinoline-4-carboxamide 6-bromo-2-(4-chlorophenyl)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(thiophen-3-yl)quinoline- 4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-furyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- methoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- methoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-hydroxy-2- phenylquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- methylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- fluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-2-(pyridin-3- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- methoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(pyridin-3-yl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4-ethylphenyl)quinoline- 4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-2- phenylquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methyl- 2-phenylquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(pyridin- 3-yl)quinoline-4-carboxamide N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(3- methoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methyl- 2-(pyridin-3-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- ethylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- fluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- methylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-hydroxy- 2-phenylquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- hydroxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- ethoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
N-{1-[(6-methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(2- thienyl)quinoline-4-carboxamide
N-[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
N-{1-[(3-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(2- thienyl)quinoline-4-carboxamide
N-[1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
N-[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
N-{1-[(6-cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(2- thienyl)quinoline-4-carboxamide N-[1-(3-fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
N-[1-(4-cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2- (2-thienyl)quinoline-4-carboxamide
N-{1-[(6-methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl}-2-(2-thienyl)quinoline-4-carboxamide
N-[1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
N-{1-[(6-cyanopyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}-2-(2-thienyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3-thienyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(1H- tetrazol-5-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-6-methyl-2-phenylquinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-6-methyl-2-phenylquinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(4-fluorophenyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(4-fluorophenyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(pyridin-3-yl)quinoline-4- carboxamide N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(pyridin-3-yl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(1,3- thiazol-2-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(2,4- dimethyl-1,3-thiazol-5-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(3,5- dimethyl-1,2-oxazol-4-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(1,5- dimethyl-1H-pyrazol-4-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(1,3- dimethyl-1H-pyrazol-5-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(1- methyl-1H-1,2,4-triazol-5-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3,5-dimethyl-1,2- oxazol-4-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1,3-thiazol-2- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2,4-dimethyl-1,3- thiazol-5-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1-methyl-1H-1,2,4- triazol-5-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1,5-dimethyl-1H- pyrazol-4-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1,3-dimethyl-1H- pyrazol-5-yl)quinoline-4-carboxamide
2-(1,5-dimethyl-1H-pyrazol-4-yl)-N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
2-(1,3-dimethyl-1H-pyrazol-5-yl)-N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
2-(2,4-dimethyl-1,3-thiazol-5-yl)-N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1,3-thiazol-2-yl)quinoline-4-carboxamide
N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1-methyl-1H-1,2,4-triazol-5-yl)quinoline-4-carboxamide 2-(1,3-dimethyl-1H-pyrazol-5-yl)-N-{5-methyl-1-[(5-methyl-1,2-oxazol-3- yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide 2-(1,5-dimethyl-1H-pyrazol-4-yl)-N-{5-methyl-1-[(5-methyl-1,2-oxazol-3- yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N-{5-methyl-1-[(5-methyl-1,2-oxazol-3- yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide 2-(2,4-dimethyl-1,3-thiazol-5-yl)-N-{5-methyl-1-[(5-methyl-1,2-oxazol-3- yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide N-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1,3-thiazol-2-yl)quinoline-4-carboxamide
N-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1-methyl-1H-1,2,4-triazol-5-yl)quinoline-4-carboxamide 2-(2,4-dimethyl-1,3-thiazol-5-yl)-N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1,3-thiazol-2-yl)quinoline-4-carboxamide
2-(3,5-dimethyl-1,2-oxazol-4-yl)-N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
2-(1,5-dimethyl-1H-pyrazol-4-yl)-N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1-methyl-1H-1,2,4-triazol-5-yl)quinoline-4-carboxamide 2-(1,3-dimethyl-1H-pyrazol-5-yl)-N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(1,3- thiazol-2-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(2,4- dimethyl-1,3-thiazol-5-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(3,5- dimethyl-1,2-oxazol-4-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(3,5- dimethyl-1,2-oxazol-4-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(2,4- dimethyl-1,3-thiazol-5-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(1,3- thiazol-2-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1H-pyrazol-4-yl}-2- (1,3-thiazol-2-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1H-pyrazol-4-yl}-2- (2,4-dimethyl-1,3-thiazol-5-yl)quinoline-4-carboxamide
N-[1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-5-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl]-2-(1-methyl-1H-1,2,4-triazol-5-yl)quinoline-4-carboxamide 2-(1,5-dimethyl-1H-pyrazol-4-yl)-N-[1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}- 5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2,3-dihydro-1,4- benzodioxin-6-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[3- (hydroxymethyl)phenyl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- methylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(6-methoxypyridin-3- yl)quinoline-4-carboxamide N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(5-cyano-2- thienyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-{4- [(methylsulfonyl)amino]phenyl}quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-{3- [(methylsulfonyl)amino]phenyl}quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,3'-biquinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[3- (dimethylamino)phenyl]quinoline-4-carboxamide
2-(4-aminophenyl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,5'-biquinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1H-indol-6-yl)quinoline- 4-carboxamide
2-(4-carbamoylphenyl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
2-(3-carbamoylphenyl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[3- (methoxymethyl)phenyl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[4- (methoxymethyl)phenyl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1-methyl-1H-pyrazol-4- yl)quinoline-4-carboxamide
2-(3-acetamidophenyl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
2-(5-chloro-2-thienyl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- fluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- methoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- fluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[4- (hydroxymethyl)phenyl]quinoline-4-carboxamide
2-(1,3-benzodioxol-5-yl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2,4- difluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3,5- difluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1-methyl-1H-pyrazol-5- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3,4- difluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(pyridin-4-yl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- hydroxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- cyanophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3-furyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1H-indol-5-yl)quinoline- 4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(pyrimidin-5- yl)quinoline-4-carboxamide N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[2- (hydroxymethyl)phenyl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1H-pyrazol-3- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- sulfamoylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- sulfamoylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1H-pyrazol-4- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(5-cyanopyridin-3- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(pyrimidin-4- yl)quinoline-4-carboxamide
2-(3-carbamoylphenyl)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
2-(2,5-dimethyl-3-thienyl)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 6-methylquinoline-4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-furyl)-6,8- dimethylquinoline-4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methoxy-2-(5-methyl-2- furyl)quinoline-4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-furyl)quinoline-4- carboxamide
or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
6. A compound of general formula (I-2):
Figure imgf000447_0001
(I-2)
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R14 or -C(=O)N(R14a)R14b group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally form a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*,
*-CH a
2C(R14 )(R14b)O-*, *-C(=O)N(R14a)CH2-*, *-N(R14a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4a represents a group selected from:
phenyl- or naphthyl-, wherein said phenyl- or naphthyl- group is optionally substituted, one or more times, identically or differently, with R8d,
furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, and benzocondensed derivatives thereof,
wherein said furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, and benzocondensed derivatives thereof are optionally substituted, one or more times, identically or differently, with R8d,
thienyl- which is unsubstituted,
thienyl- which is substituted once with R18, and which is optionally substituted, one or more times, identically or differently, with R8d, and pyrazolyl- which is unsubstituted; R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; R5a, R5b, R5c
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-,
halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c,
-N(R14a)C(=O)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14,
-S(=O)2N(R14a)R14b or -S(=O)(=NR14a)R14b ,
said phenyl- or heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R5d represents a hydrogen atom or a fluorine atom; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R8a, -C(=O)-O-R8a,
-C(=O)N(R8b)R8c, -N(R14a)R14b, -S(=O)2R8a, -S(=O)(=NR15)-R14, phenyl-, 5- to 6-membered heteroaryl-; R8a represents a hydrogen atom or a C1-C6-alkyl-, cyano-
Figure imgf000449_0001
C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8b, R8c
represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4-to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group; said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R8d;
or
R8b and R8c, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl-group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R8d; R8d represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, -CN, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b, -C(=O)O-R14, -N(R14a)R14b, -NO2, -N(H)C(=O)R14, -N(R14a)C(=O)R14b, -N(H)C(=O)N(R14a)R14b, -N(R14a)C(=O)N(R14b)R14c, -N(H)C(=O)OR14, -N(R14a)C(=O)OR14b, -N(H)S(=O)2R14, -N(R14a)S(=O)2R14b, -OR14, -O(C=O)R14, -O(C=O)N(R14a)R14b, -O(C=O)OR14, -SR14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(H)R14, -S(=O)2N(R14a)R14b, -S(=O)(=NR14a)R14b or a tetrazolyl- group;
R14, R14a, R14b, R14c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, said C1-C3-alkyl- group being optionally substituted once with -N(R16)R16a; or
R14a and R14b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R17; R15 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R14, -C(=O)N(H)R14, -C(=O)N(R14a)R14b or -C(=O)O-R14 group; R16, R16a
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl- group,
or,
R16, R16a,
together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group; R17 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-,
trifluoromethyl-, -C(=O)R14 or -C(=O)O-R14 group; R18 represents a fluorine atom, a chlorine atom, a bromo atom, or a cyano or methyl- group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-,
-C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R14a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; L3 represents a -C1-C6-alkylene- group; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I-2) are not:
N-[1-[(4-Fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
N-[1-[(3,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- pyridinyl)-4-quinolinecarboxamide,
2-(3,4-Dimethoxyphenyl)-N-[1-[(4-fluorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide,
6-Bromo-N-[3,5-dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide hydrochloride (1:1) ,
2-(3-Chlorophenyl)-N-[1-[(2,4-dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl]-4-quinolinecarboxamide,
N-[1-[(2,4-Dichlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- pyridinyl)-4-quinolinecarboxamide,
N-[3,5-Dimethyl-1-(phenylmethyl)-1H-pyrazol-4-yl]-2-phenyl-4- quinolinecarboxamide.
7. The compound according to claim 6, wherein : R1 represents a methyl- or trifluoromethyl- group; R2 represents a methyl- group; R3 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ; wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6; R4a represents a group selected from:
phenyl-, wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R8d,
furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl-,
wherein said furanyl-, thiazolyl-, isoxazolyl-, triazolyl-, tetrazolyl-, pyridyl-, pyrimidyl-, indolyl- and quinolinyl- group is optionally substituted, one or two times, identically or differently, with R8d, thienyl- which is unsubstituted,
thienyl- which is substituted once with R18, and which is optionally substituted once with R8d, and
pyrazolyl- which is unsubstituted; R4b represents a hydrogen atom;
Figure imgf000453_0001
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-; R18 represents a fluorine atom, a chlorine atom, a bromo atom, or a cyano or methyl- group;
and
L1 represents a–CH2- group.
8. The compound according to claim 6, which is selected from the group consisting of: 6-bromo-2-(4-ethylphenyl)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- methoxyphenyl)quinoline-4-carboxamide
6-bromo-2-(4-chlorophenyl)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(thiophen-3-yl)quinoline- 4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-furyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- methoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- methoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-hydroxy-2- phenylquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- methylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- fluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-2-(pyridin-3- yl)quinoline-4-carboxamide N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- methoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(pyridin-3-yl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4-ethylphenyl)quinoline- 4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-2- phenylquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methyl- 2-phenylquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(pyridin- 3-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(3- methoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methyl- 2-(pyridin-3-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- ethylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- fluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(4- methylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-hydroxy- 2-phenylquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- hydroxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- ethoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide N-{1-[(6-methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(2- thienyl)quinoline-4-carboxamide
N-[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
N-{1-[(3-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(2- thienyl)quinoline-4-carboxamide
N-[1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
N-[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
N-{1-[(6-cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(2- thienyl)quinoline-4-carboxamide
N-[1-(3-fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
N-[1-(4-cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2- (2-thienyl)quinoline-4-carboxamide
N-{1-[(6-methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl}-2-(2-thienyl)quinoline-4-carboxamide
N-[1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(2- thienyl)quinoline-4-carboxamide
N-{1-[(6-cyanopyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}-2-(2-thienyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3-thienyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(1H- tetrazol-5-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-6-methyl-2-phenylquinoline-4- carboxamide N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-6-methyl-2-phenylquinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(4-fluorophenyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(4-fluorophenyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(2-thienyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(pyridin-3-yl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(pyridin-3-yl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(1,3- thiazol-2-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(2,4- dimethyl-1,3-thiazol-5-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(3,5- dimethyl-1,2-oxazol-4-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(1- methyl-1H-1,2,4-triazol-5-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3,5-dimethyl-1,2- oxazol-4-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1,3-thiazol-2- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2,4-dimethyl-1,3- thiazol-5-yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1-methyl-1H-1,2,4- triazol-5-yl)quinoline-4-carboxamide 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
2-(2,4-dimethyl-1,3-thiazol-5-yl)-N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1,3-thiazol-2-yl)quinoline-4-carboxamide
N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1-methyl-1H-1,2,4-triazol-5-yl)quinoline-4-carboxamide 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N-{5-methyl-1-[(5-methyl-1,2-oxazol-3- yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide 2-(2,4-dimethyl-1,3-thiazol-5-yl)-N-{5-methyl-1-[(5-methyl-1,2-oxazol-3- yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide N-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1,3-thiazol-2-yl)quinoline-4-carboxamide
N-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1-methyl-1H-1,2,4-triazol-5-yl)quinoline-4-carboxamide 2-(2,4-dimethyl-1,3-thiazol-5-yl)-N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1,3-thiazol-2-yl)quinoline-4-carboxamide
2-(3,5-dimethyl-1,2-oxazol-4-yl)-N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide
N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl}-2-(1-methyl-1H-1,2,4-triazol-5-yl)quinoline-4-carboxamide N-{3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(1,3- thiazol-2-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(2,4- dimethyl-1,3-thiazol-5-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(3,5- dimethyl-1,2-oxazol-4-yl)quinoline-4-carboxamide N-{3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(3,5- dimethyl-1,2-oxazol-4-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(2,4- dimethyl-1,3-thiazol-5-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(1,3- thiazol-2-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1H-pyrazol-4-yl}-2- (1,3-thiazol-2-yl)quinoline-4-carboxamide
N-{3,5-dimethyl-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1H-pyrazol-4-yl}-2- (2,4-dimethyl-1,3-thiazol-5-yl)quinoline-4-carboxamide
N-[1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-5-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl]-2-(1-methyl-1H-1,2,4-triazol-5-yl)quinoline-4-carboxamide N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[3- (hydroxymethyl)phenyl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- methylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(6-methoxypyridin-3- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(5-cyano-2- thienyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-{4- [(methylsulfonyl)amino]phenyl}quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-{3- [(methylsulfonyl)amino]phenyl}quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,3'-biquinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[3- (dimethylamino)phenyl]quinoline-4-carboxamide
2-(4-aminophenyl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,5'-biquinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1H-indol-6-yl)quinoline- 4-carboxamide
2-(4-carbamoylphenyl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
2-(3-carbamoylphenyl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[3- (methoxymethyl)phenyl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[4- (methoxymethyl)phenyl]quinoline-4-carboxamide
2-(3-acetamidophenyl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
2-(5-chloro-2-thienyl)-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- fluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- methoxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2- fluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[4- (hydroxymethyl)phenyl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2,4- difluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3,5- difluorophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3,4- difluorophenyl)quinoline-4-carboxamide N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(pyridin-4-yl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- hydroxyphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- cyanophenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3-furyl)quinoline-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1H-indol-5-yl)quinoline- 4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(pyrimidin-5- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-[2- (hydroxymethyl)phenyl]quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1H-pyrazol-3- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(4- sulfamoylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(3- sulfamoylphenyl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(1H-pyrazol-4- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(5-cyanopyridin-3- yl)quinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(pyrimidin-4- yl)quinoline-4-carboxamide
2-(3-carbamoylphenyl)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4- yl]quinoline-4-carboxamide
2-(2,5-dimethyl-3-thienyl)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 6-methylquinoline-4-carboxamide N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methoxy-2-(5-methyl-2- furyl)quinoline-4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(2-furyl)quinoline-4- carboxamide, or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
9. A compound of general formula (I):
Figure imgf000462_0001
in which :
R1 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group; R2 represents a hydrogen atom, or a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group,
with the proviso that at least one of R1 and R2 is different from hydrogen; R3 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed; wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
*-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R4 represents a hydrogen atom or group selected from: C1-C3-alkyl-, 1
2
Figure imgf000463_0001
wherein said group is optionally substituted, one or more times, identically or differently, with R9;
and wherein * represents the point of attachment to the rest of the molecule; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4- alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R10, - C(=O)-O-R10, -C(=O)N(R10a)R10b, -N(R10a)R10b, -S(=O)2R10, -S(=O)(=NR11)-R10, phenyl-, 5- to 6-membered heteroaryl-; R7 represents a hydrogen atom, or a group selected from: C1-C4-alkyl-, halo-C1-C4-alkyl-, C3-C7-cycloalkyl- and benzyl-; R9 represents a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)OR10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b or -S(=O)(=NR11)-R10 ,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-;
or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group; R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; with the proviso that compounds of the formula (I) are not:
4-Cinnolinecarboxamide, N-[1-[(3,5-dimethyl-4-isoxazolyl)methyl]-1H- pyrazol- 4-yl]-3-phenyl-4-cinnolinecarboxamide, CAS Registry-Nr.1024526-45-1;
Isoxazolo[5,4-b]pyridine-4-carboxamide, 3,6-dimethyl-N-[1-(phenylmethyl)-1H- pyrazol-4-yl]- CAS Registry-Nr.1626778-45-7; 1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-1H- pyrazol-4-yl]-3,6-dimethyl-1-phenyl-, hydrochloride (1:1); CAS Registry-Nr. 1432030-01-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1-(1-methylethyl)-N-[1- (phenylmethyl)-1H-pyrazol-4-yl]-6-(2-thienyl)-, CAS Registry-Nr.1302712-02-2; 1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1,3-dimethyl-6-(1-methylethyl)-N- [1-(3-pyridinylmethyl)-1H-pyrazol-4-yl]-, CAS Registry-Nr. 1295087-01-2;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 6-cyclopropyl-N-[1-[(2- fluorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl]- 1,3-dimethyl-, CAS Registry-Nr.1179485-80-3;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-3,5- dimethyl-1H-pyrazol-4-yl]-3,6-dimethyl-1- phenyl-, CAS Registry-Nr. 1179467-28-7;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[1-[(2-fluorophenyl)methyl]-3,5- dimethyl-1H-pyrazol-4-yl]-1,3,6- trimethyl-, CAS Registry-Nr.1179381-50-0; Isoxazolo[5,4-b]pyridine-4-carboxamide, N-[3,5-dimethyl-1-(phenylmethyl)-1H- pyrazol-4-yl]-3-(4-methoxyphenyl)-6- methyl-, CAS Registry-Nr. 1174881-46-9;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, N-[3,5-dimethyl-1-[(3- methylphenyl)methyl]-1H-pyrazol-4-yl]-1,6-dimethyl-, CAS Registry- Nr.1174856-57-5;
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 1-butyl-N-[3,5-dimethyl-1- (phenylmethyl)-1H-pyrazol-4-yl]-3,6-dimethyl-, CAS Registry-Nr.1005577-44-5; 1-Naphthalenecarboxamide, N-[1-[(2-chlorophenyl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl]-; CAS Registry-Nr. 1171567-34-2
1H-Pyrazolo[3,4-b]pyridine-4-carboxamide, 3,6-dicyclopropyl-N-[1-[(1,3- dimethyl-1H-pyrazol-4-yl)methyl]-1H-pyrazol-4- yl]-1-methyl-, CAS Registry- Nr.1005685-96-0.
10. The compound according to claim 9, wherein R3 represents a group selected from: phenyl-, heteroaryl-;
wherein said phenyl- and heteroaryl-group is optionally substituted, one or more times, identically or differently, with R6; R4 represents a hydrogen atom; R9 represents a halogen atom or a group selected from: C1-C3-alkyl-, trifluoromethyl-, C1-C3-alkoxy-, 5-membered heteroaryl-, -C(=O)N(H)R10, -C(=O)OR10,
said 5-membered heteroaryl- group being optionally substituted one or more times with a methyl- group; L1 represents a–CH2- group; R5 represents a group selected from
* * *
Figure imgf000467_0001
, *
Figure imgf000467_0002
,
wherein * represents the point of attachment to the rest of the molecule.
11. The compound according to claim 9, which is selected from the group consisting of:
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)-1,8- naphthyridine-4-carboxamide 6-bromo-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2- (trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2- (trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-[3,5-dimethyl-1-(1,3-oxazol-2-ylmethyl)-1H-pyrazol-4-yl]-2- (trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-(3,5-dimethyl-1-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}-1H- pyrazol-4-yl)-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4- yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4- yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{1-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{3,5-dimethyl-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1H- pyrazol-4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazol- 4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-(1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-3,5-dimethyl- 1H-pyrazol-4-yl)-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-(3,5-dimethyl-1-{[5-(methylcarbamoyl)-1,2,4-oxadiazol-3- yl]methyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)-1,8-naphthyridine-4- carboxamide
6-bromo-N-{1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]-3,5-dimethyl-1H- pyrazol-4-yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
6-bromo-N-[1-(imidazo[1,2-a]pyridin-2-ylmethyl)-3,5-dimethyl-1H-pyrazol-4- yl]-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide 6-bromo-N-{3,5-dimethyl-1-[(1-methyl-1H-imidazol-2-yl)methyl]-1H-pyrazol-4- yl}-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide
N4-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,8-naphthyridine-2,4- dicarboxamide
N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,8- naphthyridine-2,4-dicarboxamide
N4-{3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-1,8- naphthyridine-2,4-dicarboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-5-carboxamide N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-5- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]isoquinoline-4-carboxamide N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl]isoquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]isoquinoline-5-carboxamide N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl]isoquinoline-5-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]isoquinoline-8-carboxamide N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl]isoquinoline-8-carboxamide
N4-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-oxo-1,2,5,6,7,8- hexahydroquinoline-3,4-dicarboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-oxo-1,2,5,6,7,8- hexahydroquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-oxo- 1,2,5,6,7,8-hexahydroquinoline-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[b]pyridine-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-oxo- 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxamide N4-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7,7-dimethyl-5-oxo- 5,6,7,8-tetrahydroquinoline-2,4-dicarboxamide
6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinazoline-4- carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,5-naphthyridine-4- carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methoxy-1,5- naphthyridine-4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridine-4- carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridine-4- carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,6- naphthyridine-4-carboxamide
N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-5,6,7,8- tetrahydro-1,6-naphthyridine-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methyl- 5,6,7,8-tetrahydro-1,6-naphthyridine-4-carboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)-1,6- naphthyridine-4-carboxamide
N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,6- naphthyridine-2,4-dicarboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,7-naphthyridine-4- carboxamide
N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,7- naphthyridine-2,4-dicarboxamide
N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,8-naphthyridine-4- carboxamide
N4-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5,6,7,8- tetrahydroquinoline-2,4-dicarboxamide N4-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5,6,7,8- tetrahydroquinoline-2,4-dicarboxamide
N4-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}-5,6,7,8-tetrahydroquinoline-2,4-dicarboxamide
N5-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,5- dicarboxamide
N5-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline- 2,5-dicarboxamide
N5-{1-[(5-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,5- dicarboxamide
N5-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}quinoline-2,5-dicarboxamide
N3-{1-[(5-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-1H-indole- 1,3-dicarboxamide
N5-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline- 5,7-dicarboxamide
N5-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}quinoline-5,7-dicarboxamide
N7-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl][1,3]thiazolo[5,4-b]pyridine-5,7-dicarboxamide
N7-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}[1,3]thiazolo[5,4-b]pyridine-5,7-dicarboxamide
N4-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl}-3-methyl[1,2]thiazolo[5,4-b]pyridine-4,6-dicarboxamide
6-bromo-N-[3,5-dimethyl-1-(1H-tetrazol-5-ylmethyl)-1H-pyrazol-4-yl]-2- (trifluoromethyl)-1,8-naphthyridine-4-carboxamide
N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-(3,5- dimethyl-1,2-oxazol-4-yl)-2-(trifluoromethyl)-1,8-naphthyridine-4-carboxamide or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
12. A method of preparing a compound of formula (I), as defined in claim 9 in which method an intermediate compound of general formula (II) :
Figure imgf000472_0001
in which R1, R2, R3, R4 and L1 are as defined in claim 9; is allowed to react with a compound of general formula (III) :
Figure imgf000472_0002
(III) in which R5 is as defined in claim 9,
thus providing a compound of general formula (I) :
Figure imgf000472_0003
(I) in which which R1, R2, R3, R4, R5 and L1 are as defined in claim 9.
13. A method of preparing a compound of formula (I-2) as defined in claim 6, in which method an intermediate compound of general formula (II) :
Figure imgf000473_0001
(II)
in which R1, R2, R3, R4 and L1 are as defined in claim 6; is allowed to react with a compound of general formula (III-2) :
Figure imgf000473_0002
in which R4a, R4b, R5a, R5b, R5c, and R5d are as defined in claim 6 ;
thus providing a compound of general formula (I-2) :
Figure imgf000474_0001
(I-2) in which R1, R2, R3, R4a, R4b, R5a, R5b, R5b, R5d, R4 and L1 are as defined in claim 6.
14. A method of preparing a compound of formula (I-2) as defined in claim 6, in which method an intermediate compound of general formula (XI-2) :
Figure imgf000474_0002
- in which G represents a group selected from a chlorine atom, a bromine atom, a iodine atom or a [(trifluoromethyl)sulfonyl]oxy- group, and in which R4b, R5a, R5b, R5c and R5d are as defined in claim 6, but are different from G; is allowed to react with a compound of general formula (XII-2) :
Figure imgf000475_0001
in which R4a is as defined in claim 6, and in which the RB groups represent hydrogen atoms, C1-C3-alkyl- groups, or together represent a–C(CH3)2-C(CH3)2- group; thus providing a compound of general formula (I-2) :
Figure imgf000475_0002
(I-2) in which R1, R2, R3, R4a, R4b, R5a, R5b, R5b, R5d, R4 and L1 are as defined in claim 6.
15. Intermediate compound of general formula (III-2):
Figure imgf000476_0001
in which R4a, R4b, R5a, R5b, R5c, and R5d are as defined in claim 6.
16. Intermediate compound of general formula (XI-2):
Figure imgf000476_0002
- in which G represents a group selected from a chlorine atom, a bromine atom, a iodine atom or a [(trifluoromethyl)sulfonyl]oxy- group, and in which R4b, R5a, R5b, R5c and R5d are as defined in claim 6, but are different from G.
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