WO2020128036A1 - Modulateurs du récepteur a2a de l'adénosine - Google Patents

Modulateurs du récepteur a2a de l'adénosine Download PDF

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Publication number
WO2020128036A1
WO2020128036A1 PCT/EP2019/086786 EP2019086786W WO2020128036A1 WO 2020128036 A1 WO2020128036 A1 WO 2020128036A1 EP 2019086786 W EP2019086786 W EP 2019086786W WO 2020128036 A1 WO2020128036 A1 WO 2020128036A1
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Prior art keywords
amino
fluorophenyl
alkyl
pyrazine
imidazo
Prior art date
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PCT/EP2019/086786
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English (en)
Inventor
Aneta BOBOWSKA
Michal GALEZOWSKI
Joanna SZEREMETA-SPISAK
Marcin NOWOGRODZKI
Alicja OBARA
Iwona LOZINSKA-RAJ
Marcelina DUDEK
Anita JANIGA
Jacek REUS
Marek WRONOWSKI
Magdalena ZASTAWNA
Charles-Henry Fabritius
Anna RAJDA
Roderick Alan Porter
Przemyslaw Wyrebek
Mateusz SWIRSKI
Luigi Stasi
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Ryvu Therapeutics S.A.
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Publication of WO2020128036A1 publication Critical patent/WO2020128036A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to substituted imidazo[1 ,2- ⁇ s]pyrazine compounds and salts, ste reoisomers, tautomers, isotopologues, or N-oxides thereof.
  • the present invention is further con cerned with the use of substituted imidazo[1 ,2-a]pyrazine compounds or salts, stereoisomers, tautomers, isotopologues, or N-oxides thereof as medicament and a pharmaceutical composi tion comprising said compounds.
  • cancer cells produce large quantities of mutated proteins (called neoantigens), which - when presented to the immune system - might lead to natural eradication of the tumor.
  • neoantigens mutated proteins
  • cancer cells produce also specific immunosuppressive metabolites that change the microenvironment and impair the function of immune cells.
  • One of the key metabo lites, which works this way is adenosine. Its immunosuppressive function is mediated by adeno sine receptors, which are members of the G protein-coupled receptor (GPCR) family and pos sess seven transmembrane alpha helices.
  • GPCR G protein-coupled receptor
  • A2A, A2B can be coupled to adenylate cyclase either positively (A2A, A2B) or negatively (A1 , A3).
  • A1 and A2A are heavily distributed in immune cells and mainly responsible for immunosuppression mediated by adenosine.
  • CD8+ lymphocytes lower their secretion of I L-2, Th1 cytokines and IFN-g, while NK cells produce lower levels of GzmB, NKG2d, CD69 andCD27
  • Dendritic cells and macro phages are also affected by increased amounts of adenosine upon which they start to produce immunosuppressing agents such as IL-8, IL10 and TGFb, and stop production of immunostimu- latory cytokines such as IL12, TNFa, IFNg.
  • Adenosine also stimulates in macrophages the con version of M 1 to M2.
  • Antagonists of the A2A receptor have already been shown as promising therapeutic for other diseases.
  • the A2A receptor is abundant in the brain, where it plays a crucial role in the regula tion of dopamine and glutamate release.
  • the A2A receptor antagonists have been proposed useful in treatment of neurodegenerative disorders such as Parkinson's, Flun- tington's and Alzheimer's disease causing motor impairment, which can be improved by employ ment of A2A antagonists [Tuite P, et al., J. Expert Opin. Investig. Drugs. 2003; 12, 1335-52; Popoli P. et al. J Neurosci.
  • A2A antagonists may be used for the treatment of psychosis, stroke, extra pyramidal syndrome, e.g., dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia (see Jenner P. J Neurol. 2000; 247 Suppl2: 1 143-50) and attention related disorders such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADFID).
  • ADD attention deficit disorder
  • ADFID attention deficit hyperactivity disorder
  • A2A antagonists have been shown as useful agents for the treatment of amyotrophic lateral sclerosis (US 2007037033), cirrhosis, fibrosis and fatty liver (WO 01/058241 ) and the mitigation of addictive behavior (WO 06/009698).
  • Adenosine A2A antagonists may be useful for the treatment and prevention of dermal fibrosis in diseases such as scleroderma (Chan et al. Arthritis & Rheumatism, 2006, 54(8), 2632-2642).
  • Recently antagonists of A2A receptors were shown to possess the therapeutic potential as neuroprotectants (Stone TW. et al., Drag. Dev. Res. 2001 , 52, 323-330), in the treatment of migraine (Kurokowa et al., 2009. Program No.
  • WO 2017/098421 discloses inhibitors of CD73, wherein CD73 catalyzes the conversion of AM P to adenosine and is thought to be the major contributor to extracellular adenosine, in particular in the tumor micro environment. CD73 inhibition results in decreased extracellular adenosine such that the activity of the A2A receptor is decreased, resulting in less (or no) immunosuppression - exactly the ef fect achieved with A2A receptor antagonists. It can thus be assumed that the diseases dis closed in WO 2017/098421 may also be treated by A2A antagonists.
  • A2B receptor plays an important role in cancer prolifera tion, especially in immune suppression in tumor microenvironment, as well as tumor prolifera tion, angiogenesis, metastasis (Zhan-Guo Gao et al., Int J Mol Sci. 2019; 20(20): 5139). It was shown that A2BR expression is significantly upregulated under many pathological conditions such as hypoxia, inflammation and cancer (Borea PA et al., Trends Pharmacol Sci. 2016;
  • A2BR antagonists have already been suggested as promising therapeutic approach for other diseases such as idiopathic pulmonary fibrosis (J. Clin. Invest.116:2173-2182 (2006)), systemic sclerosis (H Karmouty-Quintana; Arthritis & Reumatology 2018; Vol. 70, No. 10, 1673- 1684) and broader - all the fibrotic diseases (Bruce N. Cronstein F1000 Biol Reports 201 1 ,
  • a disease selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome (in par ticular dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia
  • the inventors of the present invention inter alia found that the compounds of formula (I), as defined herein below (see first aspect), antagonize adenosine A2A receptor activity. Further more, the inventors of the present invention inter alia found that the compounds of formula (I), as defined herein below (see first aspect), antagonize adenosine A2B receptor activity. Further more, the inventors of the present invention inter alia found that the compounds of formula (I), as defined herein below (see first aspect), antagonize adenosine both A2A and A2B receptor activity.
  • the compounds of formula (I) or a pharmaceutical composition comprising a compound of formula (I), as defined herein below can be used for the treatment of diseases linked to the adenosine A2A receptor, in particular the diseases given herein and most preferably cancer.
  • the compounds of formula (I) or a pharmaceu tical composition comprising a compound of formula (I), as defined herein below can be used for the treatment of diseases linked to the adenosine A2B receptor, in par ticular the diseases given herein and most preferably cancer.
  • the compounds of formula (I) or a pharmaceutical composition comprising a compound of formula (I), as defined herein below can be used for the treatment of diseases linked to the aden osine A2A and A2B receptor, in particular the diseases given herein and most preferably can cer.
  • the present invention relates to a compound of formula (I)
  • G 1 is selected from the group consisting of phenyl and a 5- to 6-membered fully un saturated heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized, and wherein one or more of the substitutable carbon or heteroatoms in the aforementioned cyclic moieties is substituted with same or different substituents selected from the group consisting of CHs, F and CN.
  • G 2 is selected from the group consisting of
  • G 3 is selected from the group consisting of of
  • R 1a is selected from the group consisting of H and Cl;
  • R 1 b is selected from the group consisting of H and Cl;
  • R 1c is selected from the group consisting of H and Cl
  • R 2a is selected from the group consisting of Cl and Ci-C3-alkyl, wherein each substi tutable carbon atom is unsubstituted or substituted with one or more F;
  • R 2b is selected from the group consisting of Cl and Ci-C3-alkyl, wherein each substi tutable carbon atom is unsubstituted or substituted with one or more F;
  • R 2c is CrC3-alkyl, wherein each substitutable carbon atom is unsubstituted or substi tuted with one or more F;
  • R 3 is selected from the group consisting of
  • halogen CN, NO2, CrC 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 4 ;
  • R 4 is selected from the group consisting of (i) halogen, CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 9 ;
  • R 5 , R 6 , R 6a , R 6b are independently selected from the group consisting of H, Ci-C 6 -alkyl,
  • R 7 , R 8 , R 8a , R 8b are independently selected from the group consisting of H, Ci-C 6 -alkyl,
  • R 10 , R 11 , R 11a , R 11b are independently selected from the group consisting of H, C1-C6- alkyl, C -C 6 -alkenyl, C -C 6 -alkynyl, a 3- to 9-membered saturated, partially un saturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 17 ;
  • R 12 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 18 ;
  • R 13 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 21 ;
  • R 14 , R 15 , R 15a , R 15b are independently selected from the group consisting of
  • R 16 is selected from the group consisting of
  • R 17 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C 4 -alkyi), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl);
  • R 18 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 24 ;
  • R 19 , R 20 , R 20a , R 20b are independently selected from the group consisting of H, C1-C6- alkyl, C -C 6 -alkenyl, C -C 6 -alkynyl, a 3- to 9-membered saturated, partially un saturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 27 ; R 21 is selected from the group consisting of halogen, CN, NO 2 , Ci-C
  • R 22 , R 23 , R 23a , R 23b are independently selected from the group consisting of H, C 1 -C 6 - alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, a 3- to 9-membered saturated, partially un saturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 28 ;
  • R 24 is selected from the group consisting of halogen, CN, NO 2 , Ci-C 6 -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 29 ;
  • R 25 , R 26 , R 26a , R 26b are independently selected from the group consisting of H, C 1 -C 4 - alkyl, Ci-C 4 -haloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, and C 2 - C 4 -haloalkynyl;
  • R 27 is selected from the group consisting of halogen, CN, NO 2 , OH, 0(Ci-C 4 -alkyl),
  • R 28 is selected from the group consisting of halogen, CN, NO 2 , OH, 0(Ci-C 4 -alkyl),
  • R 29 , R 30 , R 31 are independently selected from the group consisting of halogen, CN,
  • R 33 , R 33a , R 33b , R 34 are independently selected from the group consisting of H, C1-C4- alkyl, CrC -haloalkyl, C2-C 4 -alkenyl, C2-C -haloalkenyl, C2-C -alkynyl, and C2- C4-haloalkynyl;
  • n 0, 1 or 2;
  • n 1 or 2.
  • the present invention relates to a compound of formula (I) as defined above in the first aspect A1 , wherein the compound is not:
  • the present invention relates to a compound of formula (I) as defined above in the first aspect A1 , wherein the compound is not:
  • the present invention relates to a compound of formula (I) as defined above in the first aspect A1 , wherein the compound is not:
  • the present invention relates to a compound of formula (I) as defined above in the first aspect A1 , wherein the compound is not:
  • the present invention relates to a compound of formula (I) as defined above in the first aspect A1 , wherein the compound is not:
  • G 1 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, furan-2-yl, furan-3-yl, pyra- zol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl, wherein one or more of the substitutable carbon or heteroatoms in the aforementioned cyclic moieties is substituted with same or differ- ent substituents selected from the group consisting of Chh, F and CN, and wherein all other substituents have the meaning as defined above in the first aspects A1 , A1 a, A1 b, A1 c, A1 d or A1e.
  • G 1 is selected from the group consisting of phenyl, pyridin-2-yl, pyri- din-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl, and pyrazol-3-yl, wherein one or two of the sub- stitutable carbon or heteroatoms in the aforementioned cyclic moieties is substituted with same or different substituents selected from the group consisting of CH 3 , F and CN, and wherein all other substituents have the meaning as defined above in the first aspects A1 , A1a, A1b, A1c, Aid or A1e.
  • R 1a is selected from the group consisting of H and Cl;
  • R 1b is selected from the group consisting of H and Cl;
  • R 1c is selected from the group consisting of H and Cl;
  • R 2a is Ch ;
  • R 2b is Ch ;
  • R 2c is Ch ; and wherein all other substituents have the meaning as defined above in the first aspects A1 , A1 a, A1 b, A1 c, A1 d or A1 e.
  • G 3 is selected from the group consisting of
  • Ci-C 6 -alkyl a 3- to 6-membered saturated, partially unsaturated or fully un saturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or heteroatom in the afore mentioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R 3 ;
  • R 3 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 4 ;
  • R 4 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 9 ;
  • R 5 , R 6 , R 6a , R 6b are independently selected from the group consisting of H, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially un saturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 12 ;
  • R 7 , R 8 , R 8a , R 8b are independently selected from the group consisting of H, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially un saturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 13 ;
  • R 9 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C1-C6- haloalkyl, OH, 0(Ci-C 4 -alkyi), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 - alkyl);
  • R 10 , R 11 , R 11a , R 11b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 17 ;
  • R 12 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 18 ;
  • R 13 is selected from the group consisting of
  • R 17 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C 4 -alkyl), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl); wherein R 18 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 24 ;
  • R 19 , R 20 , R 20a , R 20b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie
  • R 21 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C1-C6- haloalkyl, C -C 6 -alkenyl, C -C 6 -haloalkenyl, C -C 6 -alkynyl, C -C 6 -haloalkynyl, OH, 0(CrC 4 -alkyl), NH 2 , NH(CrC 4 -alkyl), and N(Ci-C 4 -alkyl)(CrC 4 -alkyl); wherein R 22 , R 23 , R 23a , R 23b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-
  • R 24 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C2-C6- alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 29 ;
  • R 25 , R 26 , R 26a , R 26b are independently selected from the group consisting of H, Ci- C4-alkyl, Ci-C4-haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, and C2-C4-haloalkynyl;
  • R 27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C 4 -al- kyl), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl), CrCe-alkyl, C 2 -C 6 - alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable carbon or hetero-atom
  • R 28 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C 4 -al- kyl), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl), CrCe-alkyl, C 2 -C 6 - alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable carbon or hetero-atom
  • R 29 , R 30 , R 31 are independently selected from the group consisting of halogen,
  • Ci-C 6 -alkyl Ci-C 6 -haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6- alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C 4 -alkyl), NH2, NH(Ci-C4-alkyl), and N(Cr C4-alkyl)(Ci-C4-alkyl), and
  • R 12 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 18 ;
  • R 18 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 24 ;
  • R 19 , R 20 , R 20a , R 20b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie
  • R 24 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C2-C6- alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 29 ;
  • R 25 , R 26 , R 26a , R 26b are independently selected from the group consisting of H, Ci- C4-alkyl, Ci-C4-haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, and C2-C4-haloalkynyl;
  • R 27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C 4 -al- kyl), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl), CrCe-alkyl, C 2 -C 6 - alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable carbon or hetero-atom
  • R 29 , R 30 are independently selected from the group consisting of halogen, CN,
  • said compound is selected from the group consisting of 8-amino-6-(4- fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxylic acid; 8-amino-N- ethyl-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 2- ⁇ 2,6- diazaspiro[3.4]octane-2-carbonyl ⁇ -6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]py- razin-8-amine; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(pyridin-2-yl)methyl]imid- azo[1 ,2-a]pyr
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to formula (I) as defined above in the first aspects A1 , A1 a, A1 b, A1 c, A1 d, and A1 e, and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention relates to the compound according to formula (I) as defined above in the first aspects A1 , A1 a, A1 b, A1 c, Ai d, and A1 e , or a pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to formula (I) as defined above in the first aspects A1 , A1 a, A1 b, A1 c, Ai d, and A1 e, for use in medicine.
  • the present invention relates to a compound according to formula (I) as defined above in the first aspects A1 , A1 a, A1 b, A1 c, A1 d, and A1 e, or a pharmaceutical com position comprising a pharmaceutically effective amount of the compound according to formula (I) as defined above in the first aspects A1 , A1 a, A1 b, A1 c, Ai d, and A1 e , for use in the treat ment of a disease selected from the group consisting of cancer, Parkinson's disease, Hunting ton's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome (in particular dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADH D), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis (in particular dermal fibrosis (in particular dermal
  • the present invention is concerned with a method for antagonizing the adenosine A2A receptor, wherein said receptor is exposed to at least one compound according to formula (I) as defined above in the first aspects A1 , A1 a, A1 b, A1 c, Ai d, and A1 e, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to the use of a compound according to for mula (I) as defined above in the first aspects A1 , A1 a, A1 b, A1 c, A1 d, and A1 e as adenosine A2A receptor antagonist.
  • the following embodiments relate to G 1 as defined above in the first aspects A1 , A1 a, A1 b, A1 c, Ai d, and A1 e.
  • G 1 is selected from the group consisting of phenyl and a 5- to 6-mem- bered fully unsaturated heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are in dependently oxidized or non-oxidized, and wherein one or more of the substitutable carbon or heteroatoms in the aforementioned cyclic moieties is substituted with same or different substitu ents selected from the group consisting of CH 3 , F and CN.
  • G 1 is selected from the group consisting of phenyl, pyridin-2- yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, furan-2-yl, furan-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl, wherein one or more of the substituta ble carbon or heteroatoms in the aforementioned cyclic moieties is substituted with same or dif ferent substituents selected from the group consisting of CH 3 , F and CN.
  • G 1 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl, and pyrazol-3-yl, wherein one or two of the substitutable carbon or heteroatoms in the aforementioned cyclic moieties is substituted with same or different substituents selected from the group consisting of CH 3 , F and CN.
  • G 1 is phenyl, wherein one or two of the substitutable carbon at oms in the aforementioned phenyl is substituted with same or different substituents selected from the group consisting of CH 3 , F and CN.
  • the following embodiments relate to G 2 as defined above in the first aspects A1 , A1a, A1 b, A1c, Aid, and A1e.
  • G 2 is selected from the group consisting of
  • R 1a is selected from the group consisting of H and Cl;
  • R 1 b is selected from the group consisting of H and Cl;
  • R 1c is selected from the group consisting of H and Cl
  • R 2a is selected from the group consisting of Cl and Ci-C3-alkyl, wherein each substi tutable carbon atom is unsubstituted or substituted with one or more F;
  • R 2b is selected from the group consisting of Cl and Ci-C 3 -alkyl, wherein each substi tutable carbon atom is unsubstituted or substituted with one or more F;
  • R 2c is CrC 3 -alkyl, wherein each substitutable carbon atom is unsubstituted or substi tuted with one or more F;
  • G 2 is selected from the group consisting of
  • R 1a is selected from the group consisting of H and Cl
  • R 1 b is selected from the group consisting of H and Cl
  • R 1c is selected from the group consisting of H and Cl
  • R 2a is CH 3 ;
  • R 2b is CH 3 ;
  • R 2c is CH 3 ;
  • G 3 is selected from the group consisting of
  • R 3 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 4 ;
  • R 4 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 9 ;
  • R 5 , R 6 , R 6a , R 6b are independently selected from the group consisting of H, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially un saturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one
  • R 7 , R 8 , R 8a , R 8b are independently selected from the group consisting of H, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially un saturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 13 ;
  • R 10 , R 11 , R 11a , R 11b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 17 ;
  • R 12 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 18 ;
  • R 13 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 21 ;
  • R 14 , R 15 , R 15a , R 15b are independently selected from the group consisting of
  • R 16 is selected from the group consisting of
  • R 17 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C 4 -alkyi), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl); wherein R 18 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 24 ;
  • R 19 , R 20 , R 20a , R 20b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 27 ;
  • R 21 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C -alkyi), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl); wherein R 22 , R 23 , R 23a , R 23b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-
  • R 27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C 4 -al- kyl), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl), Ci-C 6 -alkyl, C 2 -C 6 - alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable carbon or hetero
  • Ci-C 6 -alkyl Ci-C 6 -haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6- alkynyl, C 2 -C 6 -haloalkynyl, OH, 0(Ci-C 4 -alkyi), NH , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl);
  • n 0, 1 or 2;
  • n 1 or 2.
  • G 3 is selected from the group consisting of
  • Ci-C 6 -alkyl a 3- to 6-membered saturated, partially unsaturated or fully un saturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or heteroatom in the afore mentioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R 3 ;
  • R 3 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 4 ;
  • R 4 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 9 ;
  • R 5 , R 6 , R 6a , R 6b are independently selected from the group consisting of H, C1-C6- alkyl, C -C 6 -alkenyl, C -C 6 -alkynyl, a 3- to 9-membered saturated, partially un saturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 12 ;
  • R 7 , R 8 , R 8a , R 8b are independently selected from the group consisting of H, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially un saturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 13 ;
  • R 9 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C1-C6- haloalkyl, OH, 0(Ci-C 4 -alkyi), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 - alkyl);
  • R 10 , R 11 , R 11a , R 11b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 17 ;
  • R 12 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 18 ;
  • R 13 is selected from the group consisting of (i) halogen, CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 21 ;
  • R 17 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C 4 -alkyi), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl); wherein R 18 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 24 ;
  • R 19 , R 20 , R 20a , R 20b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie
  • R 21 is selected from the group consisting of halogen, CN, NO2, Ci-C 6 -alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C 4 -alkyi), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl); wherein R 22 , R 23 , R 23a , R 23b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14
  • R 24 is selected from the group consisting of halogen, CN, NO 2 , Ci-C 6 -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 29 ; wherein R 25 , R 26 , R 26a , R 26b are independently selected from the group
  • R 27 is selected from the group consisting of halogen, CN, NO 2 , OH, 0(Ci-C 4 -al- kyl), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl), CrCe-alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable
  • Ci-C 6 -alkyl Ci-C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 - alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl);
  • R 5 , R 6 , R 6a , R 6b are independently selected from the group consisting of H, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially un saturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 12
  • R 12 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 18 ;
  • R 18 is selected from the group consisting of
  • halogen CN, NO2, Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-mem- bered saturated, partially unsaturated or fully unsaturated carbocyclic or het erocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocy disrupt or heterobicyclic ring comprises one or more, same or different heteroa toms selected from O, N or S, wherein said N- and/or S-atoms are inde pendently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 24 ;
  • R 19 , R 20 , R 20a , R 20b are independently selected from the group consisting of H , Ci- C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14- membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie
  • R 24 is selected from the group consisting of halogen, CN, NO 2 , Ci-C 6 -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 29 ;
  • R 25 , R 26 , R 26a , R 26b are independently selected from the group consisting of H, Ci- C 4 -alkyl, Ci-C 4 -haloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, and C 2 -C 4 -haloalkynyl;
  • R 27 is selected from the group consisting of halogen, CN, NO 2 , OH, 0(Ci-C 4 -al- kyl), NH 2 , NH(Ci-C 4 -alkyl), and N(Ci-C 4 -alkyl)(Ci-C 4 -alkyl), CrCe-alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered sat urated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi tutable
  • R 29 , R 30 are independently selected from the group consisting of halogen, CN,
  • R 5 is selected from the group consisting of a 5- to 6-membered saturated or par tially unsaturated heterocyclic ring and a 7- to 10-membered saturated or partially unsaturated heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O or N, wherein said N-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is un substituted or substituted with one or more, same or different substituents se lected from the group consisting halogen, CN, NO 2 , Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, OH, (C C 4 -alkyl)OH, 0(C C 4 -alkyl), (C 1 -C 4 -alkyl)0(C 1 -C 4 -alkyl), NH 2 , (C C 4 -al- ky
  • R 6a is selected from the group consisting of H and Ci-C3-alkyl
  • R 6b is selected from the group consisting of H, Ci-C 6 -alkyl, C2-C6-alkynyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbocy-hack or heterocyclic ring, wherein said heterocyclic or heterobicyclic ring com prises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 12 ;
  • R 12 is selected from the group consisting of
  • halogen CN, NO2, Ci-C4-alkyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or dif ferent heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 18 ;
  • R 18 is selected from the group consisting of
  • halogen CN, NO2, Ci-C4-alkyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or dif ferent heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 24 ;
  • R 20 , R 20a , R 20b are independently selected from the group consisting of H, C1-C4- alkyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsatu rated carbocyclic or heterocyclic ring, wherein said heterocyclic or heterobicy disrupt ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non- oxidized, and wherein each substitutable carbon or hetero-atom in the afore mentioned moieties is unsubstituted or substituted with one or more, same or different substituents R 27 ;
  • R 24 is selected from the group consisting of halogen, CN, NO2, Ci-C4-alkyl, and a
  • heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or hetero-atom in the aforemen tioned moieties is unsubstituted or substituted with one or more, same or dif ferent substituents R 29 ;
  • R 26 , R 26a , R 26b are independently selected from the group consisting of H, C1-C4- alkyl, and Ci-C4-haloalkyl;
  • R 27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C 4 -al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C4-alkyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbo- cyclic or heterocyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or hetero-atom in the aforemen tioned moieties is unsubstituted or substituted with one or more, same or dif ferent substituents R 30 ;
  • R 29 , R 30 are independently selected from the group consisting of halogen, CN,
  • R 6b is selected from the group consisting of Ci-C 6 -alkyl, C2-C6-alkynyl, and a 3- to
  • heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moie ties is unsubstituted or substituted with one or more, same or different substit uents R 12 ;
  • R 12 is selected from the group consisting of
  • halogen CN, NO2, Ci-C4-alkyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or dif ferent heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 18 ;
  • R 18 is selected from the group consisting of
  • halogen CN, NO2, Ci-C4-alkyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or dif ferent heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 24 ;
  • R 20 , R 20a , R 20b are independently selected from the group consisting of H, C1-C4- alkyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsatu rated carbocyclic or heterocyclic ring, wherein said heterocyclic or heterobicy- disrupt ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non- oxidized, and wherein each substitutable carbon or hetero-atom in the afore mentioned moieties is unsubstituted or substituted with one or more, same or different substituents R 27 ;
  • R 24 is selected from the group consisting of halogen, CN, NO2, Ci-C4-alkyl, and a
  • heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or hetero-atom in the aforemen tioned moieties is unsubstituted or substituted with one or more, same or dif ferent substituents R 29 ;
  • R 26 , R 26a , R 26b are independently selected from the group consisting of H, C1-C4- alkyl, and Ci-C4-haloalkyl;
  • R 27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C 4 -al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C4-alkyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbo cyclic or heterocyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or hetero-atom in the aforemen tioned moieties is unsubstituted or substituted with one or more, same or dif ferent substituents R 30 ;
  • R 29 , R 30 are independently selected from the group consisting of halogen, CN,
  • R 6a is selected from the group consisting of H and Ci-C3-alkyl
  • R 6b is selected from the group consisting of Ci-C 6 -alkyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, wherein each substitutable carbon atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 12 ; with the pro viso that if R 6b is CrC 6 -alkyl, said CrC 6 -alkyl is substituted with one or more, same or different substituents R 12 ;
  • R 12 is selected from the group consisting of halogen, CN, NO2, Ci-C3-alkyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, wherein each substitutable carbon atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 18 ; and
  • R 18 is selected from the group consisting of halogen, CN, NO2, and Ci-C3-alkyl.
  • R 6a is selected from the group consisting of H and Ci-C3-alkyl
  • R 6b is selected from the group consisting of H and Ci-C 6 -alkyl, wherein each sub stitutable carbon in the aforementioned Ci-C 6 -alkyl is unsubstituted or substi- tuted with one or more, same or different substituents R 12 ;
  • R 12 is selected from the group consisting of halogen and OR 20 ;
  • R 20 is selected from the group consisting of H and Ci-C4-alkyl.
  • the present invention relates to a compound of formula (I), in partic ular to a compound according to embodiment 36 of Table 1 , wherein
  • G 1 is phenyl, wherein one or two of the substitutable carbon atoms in the aforementioned phe- nyl is substituted with same or different substituents selected from the group consisting of
  • G 2 is selected from the group consisting of
  • R 1 b is selected from the group consisting of H and Cl;
  • R 2b is CH 3 ;
  • R 6a is selected from the group consisting of H
  • R 6b is selected from the group consisting of Ci-C3-alkyl, wherein each substituta ble carbon atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 12 ; wherein R 12 is a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, wherein each substitutable carbon atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different sub stituents R 18 ; and
  • R 18 is selected from the group consisting of halogen, CN, NO2, and Ci-C3-alkyl.
  • the present invention relates to a compound of formula (I), in particular to a compound according to embodiment 36 of Table 1 , wherein
  • G 1 is phenyl, wherein one or two of the substitutable carbon atoms in the aforementioned phe nyl is substituted with same or different substituents selected from the group consisting of CH 3 , F and CN;
  • G 2 is selected from the group consisting of
  • R 1 b is selected from the group consisting of H and Cl;
  • R 2b is CH 3 ;
  • R 6a is selected from the group consisting of H
  • R 6b is Ci-alkyl, wherein the carbon atom is substituted with one or more, same or different substituents R 12 ;
  • R 12 is a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, wherein each substitutable carbon atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different sub stituents R 18 ;
  • R 18 is selected from the group consisting of halogen, CN, NO2, and Ci-C 3 -alkyl. Definitions relating to aspects A1a, A1b, A1c, Aid, A1e, A2, A3, A4, and A5
  • the compounds according to the invention may be amorphous or may exist in one or more dif ferent crystalline states (polymorphs) which may have different macroscopic properties such as stability or show different biological properties such as activities.
  • the present invention relates to amorphous and crystalline compounds of formula (I), mixtures of different crystalline states of the respective compound of the invention, as well as amorphous or crystalline salts thereof.
  • Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the US FDA Or ange Book database. They can be formed in a customary manner, e.g., by reacting the com pound with an acid of the anion in question if the compounds according to the invention have a basic functionality or by reacting acidic compounds according to the invention with a suitable base.
  • Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals, preferably manganese, copper, silver, zinc and iron, and also am monium (NH 4 + ) and substituted ammonium in which one to four of the hydrogen atoms are re placed by Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkyl, hydroxy-Ci- C4-alkoxy-Ci-C4-alkyl, phenyl or benzyl.
  • substituted ammonium ions comprise me- thylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trime- thylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxy- ethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltri- methylammonium and benzyltriethylammonium, furthermore the cations of 1 ,4-piperazine, me glumine, benzathine and lysine.
  • Suitable acidic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihy- drogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluoro- silicate, hexafluorophosphate, benzoate, and the anions of Ci-C4-alkanoic acids, preferably for mate, acetate, propionate and butyrate, furthermore lactate, gluconate, and poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, furthermore sulfonate anions such as besylate (benzenesulfonate), tosylate (p-toluenesulfonate), napsylate (naphthalene-2- sulfonate), mesylate (methanesulfonate), esylate (ethanesulfonate), and ethan
  • They can be formed by reacting compounds according to the invention that have a basic func tionality with an acid of the corresponding anion.
  • the compounds according to the invention may have one or more centres of chirality, including axial chirality.
  • the invention provides both pure enan tiomers or pure diastereomers of the compounds according to the invention, and their mixtures, including racemic mixtures.
  • Suitable compounds according to the invention also include all pos sible geometrical stereoisomers (cis/trans isomers or E/Z isomers) and mixtures thereof.
  • Cis/trans isomers may be present with respect to, e.g., an alkene, carbon-nitrogen double-bond or amide group.
  • Tautomers may be formed, if a substituent is present at the compound of formula (I), which al lows for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, am- ide-imidic acid tautomers or the like.
  • An isotopologue is an isotopically enriched compound.
  • isotopically enriched com pound refers to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • the isotopologue is a deuter- ium(i.e. D or 2 H)-enriched compound.
  • N-oxide includes any compound of the present invention which has at least one ter tiary nitrogen atom that is oxidized to a N-oxide moiety.
  • substituted means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected.
  • substituted when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent.
  • substituents e.g. 1 to 10 substituents, preferably 1 , 2, 3, 4, or 5 substituents, more preferably 1 , 2, or 3 substituents, most prefer ably 1 , or 2 substituents.
  • the organic moieties mentioned in the above definitions of the variables are - like the term hal ogen - collective terms for individual listings of the individual group members.
  • the prefix C n -C m indicates in each case the possible number of carbon atoms in the group.
  • halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular flu orine or chlorine.
  • alkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably 1 to 5 or 1 to 4 carbon atoms, more prefera bly 1 to 3 or 1 to 2 or 1 carbon atoms.
  • Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1 -methyl butyl, 2-methyl butyl, 3-methyl- butyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1 ,1 -dim ethyl propyl, 1 ,2-dimethylpropyl, 1- methylpentyl, 2-methyl pentyl, 3-methylpentyl, 4-methylpentyl, 1 , 1 -dimethylbutyl, 1 ,2-dimethyl- butyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2- ethylbutyl
  • haloalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally re placed with halogen atoms.
  • Preferred haloalkyl moieties are selected from Ci-C4-haloalkyl, more preferably from Ci-C3-haloalkyl or Ci-C2-haloalkyl, in particular from Ci-C2-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
  • alkenyl denotes in each case an unsaturated hydrocarbon group having usually 2 to 6, preferably 2 to 4 carbon atoms comprising at least one carbon-carbon double bond in any position, e.g. vinyl (ethenyl), allyl (2-propen-1-yl), 1 -propen- 1-yl, 2-propen-2- yl, methallyl (2-methylprop-2-en-1-yl), 2-buten-1-yl, 3-buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4- penten-1-yl, 1-methylbut-2-en-1-yl, 2-ethyl prop-2-en- 1-yl and the like.
  • the present invention relates to both, the E- and Z-iso- mers.
  • Preferred alkenyl groups according to the invention are terminal alkenyl groups.
  • the bonding of vinyl is exemplified below.
  • haloalkenyl refers to an alkenyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms.
  • alkynyl denotes in each case an unsaturated hydrocarbon group having usually 2 to 6, preferably 2 to 5 or 2 to 4 carbon atoms, more preferably 2 to 3 carbon at oms, comprising at least one carbon-carbon triple bond in any position, e.g.
  • ethynyl propargyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylprop-2-yn-1-yl), 2-butyn-1-yl, 3-butyn-1-yl, 1-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1-methylbut-2-yn-1-yl, 1-ethylprop-2-yn-1-yl and the like.
  • haloalkynyl refers to an alkynyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms.
  • alkoxy denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 6 carbon atoms, prefera bly 1 to 2 carbon atoms, more preferably 1 carbon atom. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the like.
  • haloalkoxy denotes in each case a straight-chain or branched alkoxy group having from 1 to 6 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms.
  • Preferred haloalkoxy moieties include Ci-haloal- koxy, in particular Ci-fluoroalkoxy, such as trifluoromethoxy and the like.
  • carbocyclic includes, unless otherwise indicated, in general a 3- to 9-membered, preferably a 4- to 8-membered or a 5- to 7-membered, more preferably a 5- or 6-membered monocyclic ring comprising 3 to 9, preferably 4 to 8 or 5 to 7, more preferably 5 or 6 carbon at oms.
  • the carbocycle may be saturated, partially unsaturated, or fully unsaturated.
  • the term“carbocycle” covers cycloalkyl and cycloalkenyl groups as defined above, for example cyclopropane, cyclobutane, cyclopentane and cyclohexane rings.
  • a fully unsaturated carbocycle is an aromatic carbocycle as defined below, preferably a 6-membered aromatic carbocycle.
  • Phenyl is a preferred fully unsaturated carbocy cle.
  • carrier includes in general bicyclic 6 to 14-membered, preferably 7- to 12- membered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings comprising 6 to 14, preferably 7 to 12 or 8 to 10, more preferably 9 or 10 carbon atoms.
  • the carbobicycle may be saturated, partially unsaturated, or fully unsaturated.
  • the term“carbobicycle” covers bicycloalkyl, bicycloalkenyl and bicyclic aromatic groups, for example bicyclohexane, bi cycloheptane (such as norbornane), bicyclooctane (such as bicyclo[2.2.2]octane, bicy- clo[3.2.1]octane or bicyclo[4.2.0]octane), bicyclononane (such as bicyclo[3.3.1]nonane or bicy- clo[4.3.0]nonane ), bicyclodecane (such as bicyclo[4.4.0]decane), bicycloundecane (such as bi- cyclo[3.3.3]undecane), norbornene, naphthalene and the like.
  • the carbobicycle is a fused carbobicycle, for example naphthalene and the like.
  • heterocyclic includes, unless otherwise indicated, in general a 3- to 9-membered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered, in par ticular 6-membered monocyclic ring.
  • the heterocycle may be saturated, partially unsaturated, or fully unsaturated.
  • the term“fully unsaturated” also includes“aromatic”.
  • a fully unsaturated heterocycle is thus an aromatic heterocycle, preferably a 5- or 6-membered aromatic heterocycle comprising one or more, e.g. 1 , 2, 3, or 4, preferably 1 , 2, or 3 heteroatoms selected from N , O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2.
  • aromatic heterocycles are pro vided below in connection with the definition of“hetaryl”.“Hetaryls” or“heteroaryls” are covered by the term“heterocycles”.
  • the saturated or partially unsaturated heterocycles usually comprise 1 , 2, 3, 4 or 5, preferably 1 , 2 or 3 heteroatoms selected from N , O and S as ring members, where S-atoms as ring members may be present as S, SO or S0 .
  • the S atom will not be present in oxidized form in fully unsaturated compounds.
  • the following sce narios are covered: o ° °
  • Saturated heterocycles include, unless otherwise indicated, in general 3- to 9-membered, pref erably 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered monocyclic rings comprising 3 to 9, preferably 4 to 8 or 5 to 7, more preferably 5 or 6 atoms comprising at least one heteroatom, such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tet- rahydropyran, dioxane, morpholine or piperazine.
  • heteroatoms such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tet- rahydropyran, dioxane, morpholine or piperazine.
  • heteroaryl or“heteroaryl” or“aromatic heterocycle” or“aromatic heterocyclic ring” in cludes monocyclic 5- or 6-membered aromatic heterocycles comprising as ring members 1 , 2, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO2
  • S-atoms as ring members may be present as S, SO or SO2
  • the S atom will not be present in oxidized form in fully unsaturated compounds.
  • the following scenarios are covered:
  • 5- or 6-membered aromatic heterocycles include pyridyl, i.e. 2-, 3-, or 4-pyridyl, py- rimidinyl, i.e. 2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e. 3- or 4-pyridazinyl, thienyl, i.e. 2- or 3-thienyl, furyl, i.e. 2-or 3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e.
  • heterocyclic includes in general bicyclic 6 to 14-membered, preferably 7- to 12- membered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings comprising as ring members 1 , 2, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO2.
  • the heterobicycle may be saturated, partially un saturated, or fully unsaturated.
  • heterobicycles include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzox- azinyl, quinolinyl, isoquinolinyl, purinyl, 1 ,8-naphthyridyl, pteridyl, pyrido[3,2-d]pyrimidyl, pyri- doimidazolyl, triethylenediamine or quinuclidine and the like.
  • the heterobicycle is a fused heterobicycle, for example quinolinyl and the like.
  • the term“comprising” is not limiting.
  • the term“consisting of is considered to be a preferred embodiment of the term“comprising of. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group which preferably consists of these em bodiments only.
  • pharmaceutically acceptable excipient refers to compounds com monly comprised in pharmaceutical compositions, which are known to the skilled person. Exam ples of suitable excipients are exemplary listed below. Typically, a pharmaceutically acceptable excipient can be defined as being pharmaceutically inactive.
  • treatment is to be understood as also including the option of“prophylaxis”.
  • treatment and/or prophylaxis or“treating and/or preventing”.
  • a pharmaceutical composition according to the present invention may be formulated for oral, buccal, nasal, rectal, topical, transdermal or parenteral application. Oral application may be pre ferred. Parenteral application can also be preferred and includes intravenous, intraarterial, intra- tumoral, intrathecal, intravesical, intramuscular or subcutaneous administration.
  • the compound according to formula (I) should be applied in pharmaceutically effective amounts, for example in the amounts as set out herein below.
  • a pharmaceutical composition of the present invention may also be designated as formulation or dosage form.
  • a compound of formula (I) may also be designated in the following as (pharma ceutically) active agent or active compound.
  • compositions may be solid or liquid dosage forms or may have an intermedi ate, e.g. gel-like character depending inter alia on the route of administration.
  • inventive dosage forms can comprise various pharmaceutically acceptable ex cipients, which will be selected depending on which functionality is to be achieved for the dos age form.
  • A“pharmaceutically acceptable excipient” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, release-modifying materials, car rier materials, diluents, binding agents and other adjuvants.
  • Typical pharmaceutically accepta ble excipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents.
  • carrier denotes pharmaceutically acceptable organic or inorganic carrier sub stances with which the active ingredient is combined to facilitate the application.
  • Suitable phar maceutically acceptable carriers include, for instance, water, aqueous salt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbitans, polyethylene-poly- propylene block co-polymers such as poloxamer 188 or poloxamer 407, polyethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and triglycerides, pol- yoxyethylated medium or long chain fatty acids such as ricinoleic acid, and polyoxyethylated fatty acid mono-, di, and triglycerides such as capric or caprilic acids, petroethral fatty acid e
  • compositions can be sterile and, if desired, mixed with auxiliary agents, like lubricants, preserv atives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.
  • auxiliary agents like lubricants, preserv atives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.
  • liquid dosage forms can include pharmaceuti cally acceptable emulsions, solutions, suspensions and syrups containing inert diluents com monly used in the art such as water.
  • These dosage forms may contain e.g. microcrystalline cel lulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners/flavouring agents.
  • suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants.
  • Pharmaceutical formula tions for parenteral administration are particularly preferred and include aqueous solutions of the compounds of formula (I) in water-soluble form.
  • suspensions of the compounds of formula (I) may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic sol vents or vehicles include fatty oils such as sesame oil, soybean oil, or tocopherols, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspen sions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • sterile injectable aqueous or oleaginous suspensions can for example be formulated ac cording to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
  • a sterile injectable preparation can also be a sterile injectable solution or suspension or an emulsion in a non-toxic parenterally acceptable diluant or solvent.
  • acceptable ve hicles and solvents that can be used are water and isotonic sodium chloride solution. Sterile oils are also conventionally used as solvent or suspending medium.
  • Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g. mixing the compound with a suitable non-irritating excipient such as cocoa butter, synthetic tri glycerides and polyethylene glycols which are solid at room temperature but liquid at rectal tem perature such that they will melt in the rectum and release the compound according to formula (I) from said suppositories.
  • a suitable non-irritating excipient such as cocoa butter, synthetic tri glycerides and polyethylene glycols which are solid at room temperature but liquid at rectal tem perature such that they will melt in the rectum and release the compound according to formula (I) from said suppositories.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, di- chlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, di- chlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Cap sules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated contain ing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, pow ders, effervescent formulations, dragees and granules.
  • Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methyl cellu lose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrat ing agents may be added, such as the cross-linked polyvinyl pyrrolidone (crosspovidone), agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral dosage forms may be formu lated to ensure an immediate release of the compound of formula (I) or a sustained release of the compound of formula (I).
  • a solid dosage form may comprise a film coating.
  • the inventive dosage form may be in the form of a so-called film tablet.
  • a capsule of the invention may be a two-piece hard gel atin capsule, a two-piece hydroxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose or a two-piece capsule made of polysaccharide.
  • the dosage form according to the invention may be formulated for topical application.
  • Suitable pharmaceutical application forms for such an application may be a topical nasal spray, sublin gual administration forms and controlled and/or sustained release skin patches.
  • the compositions may take the form of tablets or lozenges formulated in conven tional manner.
  • compositions may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy.
  • the methods can include the step of bringing the compounds into association with a carrier which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • Liquid dose units are vials or ampoules.
  • Solid dose units are tablets, capsules and suppositories.
  • the compound of formula (I) may be administered to a patient in an amount of about 0.001 mg to about 5000 mg per day, preferably of about 0.01 mg to about 100 mg per day, more preferably of about 0.1 mg to about 50 mg per day, which is the effective amount.
  • the phrase“effective amount” means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to treat or prevent a particular disease or condition.
  • the pharmaceutical composition may also contain the compound of formula (I) as a prodrug such as an ester or amide thereof.
  • a prodrug is any compound which is converted un der physiological conditions or by solvolysis to any of the compounds of the invention.
  • a pro drug may be inactive prior to administration but may be converted to an active compound of the invention in vivo.
  • the compounds according to the present invention are preferably used for the treatment of a disease selected from the group consisting of cancer, Parkinson's disease, Huntington's dis ease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome (in particular dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia), attention deficit disorder (ADD), atten tion deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis (in particular dermal fibrosis in scleroderma), sleep dis orders, AIDS, autoimmune diseases, infections, atherosclerosis and ischemia-reperfusion in- jury.
  • the compounds according to the present invention are used for idiopathic pul monary fibrosis, systemic sclerosis, irritable bowel disease and as analgesic.
  • the use for the treatment of cancer is particularly preferred.
  • the compounds according to the present invention can be used for the treat ment of a disease selected from the group consisting of neurodegenerative, proliferative, inflam matory and infectious diseases, sickle cell disease, diabetic nephropathy, cognition and CNS disorders.
  • a disease selected from the group consisting of neurodegenerative, proliferative, inflam matory and infectious diseases, sickle cell disease, diabetic nephropathy, cognition and CNS disorders.
  • the proliferative diseases include cancer.
  • said cancer is selected from the group consisting of breast cancer, inflammatory breast cancer, ductal carcinoma, lobular carcinoma, colon cancer, pancreatic cancer, insulino mas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carci noma, glucagonoma, skin cancer, melanoma, metastatic melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan- Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver
  • said cancer cancer is selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, aci nar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer.
  • the compounds of the invention may be used to treat inflammation associated with autoimmune diseases or diseases resulting from inflammation including systemic lupus ery- thematosis, Addison's disease, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), glomerulonephritis, rheumatoid arthritis scleroderma, chronic thyroidi tis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, glomerulo nephritis, rheumatoid arthritis autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ul cerative colitis, Crohn's disease, psoriasis, graft vs. host disease, asthma, bronchitis, acute pan creatitis, chronic pancreatitis and allergies of various types.
  • the compounds of the present invention may also be used to treat a neurodegenerative dis eases including Alzheimer's disease (including early onset Alzheimer ' s disease), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, senile chorea, Sydenham ' s cho rea, frontotemporal lobar dementia, spinocerebellar ataxia, dementia with Lewy bodies, cerebral ischemia or neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hy poxia, peripheral neuropathy, including mononeuropathy, multiple mononeuropathy or polyneu ropathy.
  • Alzheimer's disease including early onset Alzheimer ' s disease
  • Parkinson's disease amyotrophic lateral sclerosis
  • Huntington's disease Huntington's disease
  • senile chorea Huntington's disease
  • Sydenham ' s cho rea frontotemporal lobar dementia
  • spinocerebellar ataxia dementia with Lewy bodies, cerebral ischemia or neurode
  • peripheral neuropathy may be found in diabetes mellitus, Lyme disease or uremia, peripheral neuropathy caused by a toxic agent, demyelinating disease such as acute or chronic inflammatory polyneuropathy, leukodystrophies, or Guillain-Barre syndrome, multiple mononeuropathy secondary to a collagen vascular disorder (e.g. polyarteritis nodosa, SLE, Sjogren's syndrome), multiple mononeuropathy secondary to sarcoidosis, multiple mononeurop athy secondary to a metabolic disease (e.g. diabetes or amyloidosis), or multiple mononeuropa thy secondary to an infectious disease (e.g Lyme disease or HIV infection).
  • demyelinating disease such as acute or chronic inflammatory polyneuropathy, leukodystrophies, or Guillain-Barre syndrome
  • multiple mononeuropathy secondary to a collagen vascular disorder e.g. polyarteritis nodosa, SLE, Sjogren's syndrome
  • Said pharmaceutical composition may comprise said compound as the only pharmaceutically active agent. It is to be understood that in connection with the medical uses of the invention, it can be preferred that the compounds according to the present invention are administered in combination with antibodies, radiotherapy, surgical therapy, immunotherapy, chemotherapy, toxin therapy, gene therapy, or any other therapy known to those of ordinary skill in the art for treatment of a particular disease. This is particularly relevant in connection with the treatment of cancer.
  • the compounds of the present invention may be coadministered with an anti-neo- plastic agent and/or an anti-neoplastic agent may be comprised in the pharmaceutical composi tion according to the present invention.
  • an anti-neo-plastic agent may be comprised in the pharmaceutical composi tion according to the present invention.
  • the cancer treated by the combination of (i) a com pound according to the present invention and (ii) an anti-neoplastic agent may be selected from one of the cancers listed above.
  • said cancer is selected from the group consisting of colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer in cluding squamous non-small cell lung cancer (NSCLC) and non-squamous NSCLC, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, colo rectal cancer, gastric cancer, melanoma, hepatocellular carcinoma, pancreatic carcinoma and a hematological malignancy.
  • NSCLC non-small cell lung cancer
  • An anti-neoplastic agent has activity versus a tumor and examples can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Heilman (editors), 6th edition (Febru ary 15, 2001 ), Lippincott Williams & Wilkins Publishers.
  • Typical anti-neoplastic agents useful in the present invention include chemotherapeutic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, tyrosine kinase inhibitors, angio genesis inhibitors, proapoptotic agents, cell cycle signaling inhibitors, proteasome inhibitors, in hibitors of cancer metabolism, and immunotherapeutic agents (such as STING pathway modu lating compounds, TLR agonists and checkpoint inhibitors).
  • chemotherapeutic agents such as STING pathway modu lating compounds, TLR agonists and checkpoint inhibitors.
  • chemotherapeutic agents are anti-microtubule or anti-mitotic agents (such as paclitaxel), platinum coordination complexes (such as cisplatin), alkylating agents (such as cy clophosphamide) and antibiotic anti-neoplastics (such as doxorubicin).
  • anti-microtubule or anti-mitotic agents such as paclitaxel
  • platinum coordination complexes such as cisplatin
  • alkylating agents such as cy clophosphamide
  • antibiotic anti-neoplastics such as doxorubicin
  • the corresponding receptors targeted by such agents are PD-1 , PD-L1 , CTLA-4, IDO, KIR, TIM-3, LAG-3, CD39, CD73, ICOS, 0X40, Tim-3, Vista, BTLA, TDO, and TIGIT and such agents are typically antibodies (including variants, such as e.g. fusion proteins or the like, thereof) but may also be macrocyclic inhibitors or the like.
  • a checkpoint inhibitor as described herein can in particular be an antibody, a small molecule inhibitor or an antisense oligonucleotide selected from the group consisting of an anti-PD-1 , anti-PD-L1 , anti-CTLA-4, anti-IDO, anti-KIR, anti-TIM-3, anti-LAG-3, anti-CD39, anti-CD73, anti- ICOS, anti-OX40, anti-Tim-3, anti-Vista, anti-BTLA, anti-TDO, and anti-TIGIT-agent.
  • BMS-936559, MPDL3280A and M EDI4736 anti-PD-L1 antibodies
  • MK-3475 and pembrolizumab anti-PD-1 antibodies
  • ipilimumab anti-CTLA-4 antibodies
  • the compounds of the present invention are administered in combination with anti bodies.
  • Preferred antibodies include anti-PD-1 , anti-PD-L1 , anti-CTLA-4, anti-IDO, anti-KI R, anti-TIM-3, anti-Vista, anti-TIGIT, anti-BTLA and anti-LAG3 antibody.
  • Non-limiting examples are BMS-936559, M PDL3280A and M EDI4736 or avelumab (anti-PD-L1 antibodies), M K-3475, pembrolizumab or pidilizumab (anti-PD-1 antibodies) as well as ipilimumab (anti-CTLA-4 anti bodies).
  • the compounds of the present invention are administered in a pharmaceuti cal composition
  • a pharmaceuti cal composition comprising one or more of adjuvants, inactivated or attenuated bacteria (e.g., inactivated or attenuated Listeria monocytogenes), modulators of innate immune activation, preferably agonists of Toll-like Receptors (TLRs, preferably TLR7 or TLR9 agonists, e.g.
  • adjuvants e.g., inactivated or attenuated bacteria
  • modulators of innate immune activation preferably agonists of Toll-like Receptors (TLRs, preferably TLR7 or TLR9 agonists, e.g.
  • TLRs Toll-like Receptors
  • the medical use may further compromise administering at least one H BV vaccine, a nucleoside HBV inhibitor or any combination thereof (e.g. RECOM BIVAX HB, ENGERIX-B, GENEVAC-B).
  • Combination therapy may be achieved by use of a single pharmaceutical composition that in cludes both agents, or by administering two distinct compositions at the same time, wherein one composition includes a compound of the present invention, and the other includes the second agent(s).
  • the two therapies may be given in either order and may precede or follow the other treatment by intervals ranging from minutes to weeks.
  • the other agents are applied separately, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the agents would still be able to exert an advantageously combined effect on the patient.
  • the compound of the pre sent invention is administered prior to administration of the distinct cancer treatment.
  • the distinct cancer treatment is administered prior to administration of the com pound of the present invention.
  • the present invention is further illustrated by the following examples.
  • Microwave heating was done using a Biotage Emrys Initiator microwave or Microwave Reactor Anton Paar Monowave 450. Column chromatography was carried out using an Isco Rf200d or an Interchim Puriflash 450. Solvent removal was carried out using either a Buchi, Heidolph or VWR rotary evaporator or a Genevac centrifugal evaporator. Preparative LC/MS was conducted using either a preparative HPLC instrument Waters (chromatography conditions 1) or prepara tive HPLC Instrument Shimadzu (chromatography conditions 2). NMR spectra were recorded using a Bruker 300 MHz or 400MHz spectrometer.
  • inerted e.g., a reaction vessel, flask, glass reac tor, and the like
  • a reactor e.g., a reaction vessel, flask, glass reac tor, and the like
  • inert gas such as nitrogen, argon, and the like
  • UV detector Waters 2489 dual wavelength UV detector
  • UV detector Waters 2998 photodiode array detector, 254 nm
  • Aqueous cAMP Cyclic adenosine monophosphate
  • DIBAL Diisobutylaluminium hydride
  • DIPEA N-Ethyldiisopropylamine
  • FIATU 1-[Bis(dimethylamino)methylene]-1 FI-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro- phosphate
  • FIBTU N,N,N',N'-Tetramethyl-0-(1 FI-benzotriazol-1-yl)uronium hexafluorophosphate
  • FITRF Flomogeneous Time Resolved Fluorescence
  • NBS N-bromosuccinimide
  • NECA 5'-(N-Ethylcarboxamido)adenosine
  • Pd(amphos)CI2 Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ll)
  • Pd(dppf)CI2 [1 ,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll)
  • THF Tetrahydrofuran Materials
  • the following compounds are commercially available and/or can be prepared in a number of ways well known to one skilled in the art of organic synthesis. More specifically, dis closed compounds can be prepared using the reactions and techniques described herein. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, du ration of the experiment, and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction condi tions will be apparent to one skilled in the art, and alternate methods are therefore indicated.
  • the starting materials for the examples are either commercially available or are readily pre pared by standard methods from known materials.
  • N-bromosuccinimide (12.6 g, 70.6 mmol) was added in 3 portions to the solution of 6-chloro-5-(4-fluorophenyl)pyrazin-2-amine (15 g, 64.2 mmol) in CH 3 CN (100 ml).
  • the reaction mixture was allowed to warm to room temperature then was heated at 70 °C for 1 h. After that time precipitate occurred, after cooling down the reaction mixture precipitate was filtered off to afford the title product (12.6 g, 65%) as a light yellow solid.
  • ESI-MS 303.70
  • Microwave tube was charged with 6-bromo-4-(difluoromethyl)quinoline (0.100 g, 0.39 mmol), bis(pinacolate)diboron (167 mg, 0.66mmol), potassium acetate (0.076 g, 0.77 mmol) and diox- ane (2 ml) and sparged with argon for 15 min.
  • Pd(dppf)Cl2*DCM 0.085 g, 0.12 mmol
  • Microwave tube was charged with 8-amino-5-chloro-6-(4-fluorophenyl)-N-methylimidazo[1 ,2- a]pyrazine-2-carboxamide (40 mg, 0.125 mmol), 4-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)quinoline (Procedure E, 40 mg, 0.15mmol) potassium carbonate (43 mg, 0.31 mmol) and dioxane/water 2: 1 (1 ml) and sparged with argon for 15 min.
  • a pressure tube was charged with 5-bromo-3-chloro-N-methyl-2-nitroaniline (966 mg, 3.64 mmol), EtOH (30 ml), water (5 ml), 4N HCI in dioxane (4.55ml, 18.2mmol) and then tin(ll) chlo ride was added and the mixture was stirred at 80°C for 3 h. After that time, the mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was cau tiously treated with an excess of 12.5M NaOH. The mixture was diluted with EtOAc and washed with water. Organic phase was dried over MgS04 , filtered, and concentrated.
  • 6-bromo-4-chloro-1-methyl-1 H-1 ,3-benzodiazole 200 mg, 0.85 mmol
  • bis(pinacolato)diboron 280 mg, 1.10mmol
  • KOAc 104 mg, 1.06 mmol
  • Pd(dppf)CI 2 ⁇ DCM 34.7 mg, 0.04 mmol
  • the pressure tube was capped and the reaction mixture was stirred at 100°C for 16 h.
  • Example 34 1-[8-amino-6-(4-fluorophenyl)-5-( 1 -methyl ⁇ 1H- 1, 3-benzodiazol-6-yl)imidazo[ 1 ,2-a]pyrazine-2- carbonyl]pyrrolidin-3-amine
  • a pressure tube was charged with 8-amino-5-chloro-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine- 2-carboxamid (110 mg, 0.36 mmol), (8-chloroquinolin-6-yl)boronic acid (95 mg, 0.54 mmol), so dium carbonate (1 14 mg, 0.0.54 mmol) and dioxane/water 2/1 (1 ml) and sparged with argon for 15 min. Pd(amphos)Cl 2 (25 mg, 0.04 mmol) was added in one portion and argon was bubbled through the suspension for another 5 minutes.

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Abstract

La présente invention concerne les composés de formule (I) et des sels, stéréoisomères, tautomères, isotopologues ou N-oxydes de ceux-ci. La présente invention concerne en outre l'utilisation de tels composés ou sels, stéréo-isomères, tautomères, isotopologues ou N-oxydes de ceux-ci en tant que modulateurs du récepteur A2A de l'adénosine dans le traitement du cancer et une composition pharmaceutique comprenant lesdits composés.
PCT/EP2019/086786 2018-12-21 2019-12-20 Modulateurs du récepteur a2a de l'adénosine WO2020128036A1 (fr)

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