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WO2020128036A1 - Modulators of the adenosine a2a receptor - Google Patents

Modulators of the adenosine a2a receptor 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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WO
WIPO (PCT)
Prior art keywords
amino
fluorophenyl
alkyl
pyrazine
imidazo
Prior art date
Application number
PCT/EP2019/086786
Other languages
French (fr)
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
Original Assignee
Ryvu Therapeutics S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ryvu Therapeutics S.A. filed Critical Ryvu Therapeutics S.A.
Publication of WO2020128036A1 publication Critical patent/WO2020128036A1/en

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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

The present invention relates to the compounds of formula (I) and salts, stereoisomers, tautomers, isotopologues, or N-oxides thereof. The present invention is further concerned with the use of such a compounds or salt, stereoisomer, tautomer, isotopologues, or N- oxide thereof as modulators of the adenosine A2A receptor in the treatment of cancer and a pharmaceutical composition comprising said compounds.

Description

Modulators of the adenosine A2A receptor
Field of the Invention
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.
Background of the Invention
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. However, to counteract this process, 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. There are 4 subtypes of adenosine receptors de scribed so far: A1 , A2A, A2B, A3. They can be coupled to adenylate cyclase either positively (A2A, A2B) or negatively (A1 , A3). Only forms A1 and A2A are heavily distributed in immune cells and mainly responsible for immunosuppression mediated by adenosine.
Stressed or injured tissues (i.e. tumor tissue) release endogenous ATP, which works as a pro- inflammatory agent. Hydrolysis of ATP by endonucleases (such as CD39 and CD73) leads to adenosine formation. Its binding to A2A and A2B receptors leads to cAMP elevation in immune cells and results in the activation of the CREB/ATF pathway (cAMP-responsive element (CRE)- binding protein/activating transcription factor), the cell’s main immunosuppressive mechanism [Grenz et al Antioxid Redox Signal 201 1 ;15:2221-34,23. Fredholm et al Prog Neurobiol 2007;83:263-76. , 24. Sitkovsky Trends Immunol 2009;30:102-8] Its activation has been shown to either induce anergy of CD4+ T cells or their conversion into Tregs. This subpopulation of T cells is further activated by adenosine and produces immunosuppressive cytokines such as TGF-b and IL-10. Another group of immunosuppressing cells which respond to higher concen tration of adenosine are MDSC, which undergo differentiation upon activation by this metabolite (Morrello et al Oncoimmunology. 2016 Mar; 5(3): e1 108515). On the other hand, stimulation of adenosine might also lead to decreased cytotoxic activity, e.g. 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 [Sitkovsky Trends Immunol 2009;30:102-8] 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. [Allard et al Curr Opin Pharmacol. 2016 Aug;29:7-16; Allard et al. Immunol Cell Biol 2017 Apr; 95(4) :333-339.]
The above clearly shows that antagonizing adenosine receptors and thus reactivating the anti tumor immune response may be an effective way of fighting all types of cancer. [Allard et al Curr Opin Pharmacol. 2016 Aug;29:7-16] It was shown in an allograft model that the use of A2A antagonists not only slows down the tumor growth but also blocks metastasis (in this par ticular case to lungs). Moreover, a strong synergistic correlation with checkpoint inhibitor anti bodies has been demonstrated, likely improving the treatment [lannone Am J Cancer Res. 2014 Mar 1 ;4(2): 172-81 , Cancer Immunol Res. 2015 May;3(5):506-17; Allard et al. Immunol Cell Biol 2017 Apr; 95(4) :333-339.].
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. Not surprisingly, 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. 2002; 22, 1967-75; and Dall'lgna, et al., Experimental Neurology, 2007, 241 -245] Additionally, 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). Fur thermore, 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.
714.4/B101. 2009 Neuroscience Meeting Planner. Chicago, I L: Society for Neuroscience) and sleep disorders (Dunwiddie TV et al., Ann. Rev. Neurosci. 2001 , 24, 31- 55). 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.
There is growing evidence that also the A2B receptor plays an important role in cancer progres sion, 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;
37(6) :419-434, Borea PA et al., Physiol Rev. 2018; 98(3) : 1591 - 1625 , Cekic C and Linden J Nat Rev Immunol. 2016; 16(3):177-92.). Particularly bladder urothelial carcinoma expresses high levels of A2BAR and it is suggested to be associated with a poor patient prognosis (Zhou Y et al.; Oncotarget. 2017; 8(30):48755-48768). Moreover, it was postulated that A2BR controls cel lular proliferation via HIF-1 a activation, which may indicate that A2BR may be a key regulator of oral squamous cell carcinoma progression (Kasama H et al. BMC Cancer. 2015; 15:563). Addi tionally, 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 ,
3:21 ). Yet another indication where A2BR might play significant role is Irritable Bowel Disease (Teita Asano and Mitsuko Takenaga J Clin Med. 2017 6(1 1 ): 104). Moreover, it was shown that analgesic effects might be achieved by antagonization of A2BR (J Pharmacol Exp Ther. 2004; 308(1 ):358-66.).
In view of the above, there is the need for further compounds, which antagonize the A2A re ceptor in order to be capable of treating the afore-mentioned diseases. Furthermore, there is also the need for further compounds, which antagonize the A2B receptor.
Objects and Summary of the Invention
It is therefore an object of the present invention to provide compounds, which antagonize the adenosine A2A receptor.
It is another object of the present invention to provide compounds, which are capable of treat ing diseases, which are linked to the adenosine A2A receptor.
It is another object of the present invention to provide compounds, which antagonize the aden osine A2B receptor.
It is another object of the present invention to provide compounds, which are capable of treat ing diseases, which are linked to the adenosine A2B receptor.
It is another object of the present invention to provide compounds, which antagonize the aden osine A2A and A2B receptor.
It is another object of the present invention to provide compounds, which are capable of treat ing diseases, which are linked to the adenosine A2A and A2B receptor.
It is still another object of the present invention to provide compounds, which are suitable for the treatment of 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), attention deficit disor der (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrho sis, fibrosis, fatty liver, addictive behavior, dermal fibrosis (in particular dermal fibrosis in sclero derma), sleep disorders, AIDS, autoimmune diseases, infections, atherosclerosis and ischemia- reperfusion injury. In particular, it is an object of the present invention to provide compounds, which are suitable for the treatment of cancer, wherein this relates to the treatment of the tumor and the block of metastases.
The above objects can be achieved by the compounds of formula (I) as defined herein, and uses thereof.
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. Accordingly, the compounds of formula (I) or a pharmaceutical composition comprising a compound of formula (I), as defined herein below (see second aspect), can be used for the treatment of diseases linked to the adenosine A2A receptor, in particular the diseases given herein and most preferably cancer. Furthermore, the compounds of formula (I) or a pharmaceu tical composition comprising a compound of formula (I), as defined herein below (see second aspect), 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. Furthermore, the compounds of formula (I) or a pharmaceutical composition comprising a compound of formula (I), as defined herein below (see second aspect), 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.
Therefore, in the first aspect A1 , the present invention relates to a compound of formula (I)
Figure imgf000005_0001
or a salt, stereoisomer, tautomer, isotopologue, or N-oxide thereof,
wherein
G1 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.
G2 is selected from the group consisting of
Figure imgf000006_0001
G3 is selected from the group consisting of of
(i) Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, par tially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated car- bobicyclic 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 heteroatom in the afore mentioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R3;
(ii) C(=0)R5, C(=0)0R6, C(=0)SR6, C(=0)N(R6a)(R6b), OR6, S(=0)nR6,
S(=0)nN(R6a)(R6b), S(=0)m0R6, N(R6a)(R6b), N(R6)C(=0)R5, N(R6)C(=0)0R6, N(R6)C(=0)N(R6a)(R6b), N(R6)S(=0)n(R6), N(R6)S(=0)mN(R6a)(R6b), and N(R6)S(=0)m0R6;
R1a is selected from the group consisting of H and Cl;
R1 b is selected from the group consisting of H and Cl;
R1c is selected from the group consisting of H and Cl;
R2a 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;
R2b 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;
R2c is CrC3-alkyl, wherein each substitutable carbon atom is unsubstituted or substi tuted with one or more F;
R3 is selected from the group consisting of
(i) halogen, CN, NO2, CrC6-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 clic 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 R4;
(ii) C(=0)R7, C(=0)0R8, C(=0)SR8, C(=0)N(R8a)(R8b), OR8, S(=0)nR8,
S(=0)nN(R8a)(R8b), S(=0)m0R8, N(R8a)(R8b), N(R8)C(=0)R7, N(R8)C(=0)0R8, N(R8)C(=0)N(R8a)(R8b), N(R8)S(=0)n(R8), N(R8)S(=0)mN(R8a)(R8b), and N(R8)S(=0)m0R8;
R4 is selected from the group consisting of (i) halogen, CN, NO2, Ci-C6-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 clic 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 R9;
(ii) C(=0)R1°, C(=0)OR11, C(=0)SR11, C(=0)N(R11a)(R11b), OR11, S(=0)nR11, S(=0)nN(R11a)(R11b), S(=0)mOR11, N(R11a)(R11b), N(R11)C(=0)R1°, N(R11)C(=0)OR11, N(R11)C(=0)N(R11a)(R11b), N(R11)S(=0)n(R11), N(R11)S(=0)mN(R11a)(R11b), and N(R11)S(=0)mOR11;
R5, R6, R6a, R6b are independently selected from the group consisting of H, Ci-C6-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsatu rated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-mem- bered saturated, partially unsaturated or fully unsaturated carbobicyclic or het erobicyclic 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 moieties is unsubstituted or substituted with one or more, same or different substituents R12;
R7, R8, R8a, R8b are independently selected from the group consisting of H, Ci-C6-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsatu rated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-mem- bered saturated, partially unsaturated or fully unsaturated carbobicyclic or het erobicyclic 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 moieties is unsubstituted or substituted with one or more, same or different substituents R13;
R9 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C -C6-alkenyl, C -C6-haloalkenyl, C -C6-alkynyl, C -C6-haloalkynyl, C(=0)R14, C(=0)OR15, C(=0)SR15, C(=0)N(R15a)(R15b), OR15, S(=0)nR15, S(=0)nN(R15a)(R15b), S(=0)mOR15, N(R15a)(R15b), N(R15)C(=0)R14, N(R15)C(=0)0R15, N(R15)C(=0)N(R15a)(R15b), N(R15)S(=0)n(R15),
N(R15)S(=0)mN(R15a)(R15b), and N(R15)S(=0)m0R15;
R10, R11, R11a, R11b are independently selected from the group consisting of H, C1-C6- alkyl, C -C6-alkenyl, C -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 R17;
R12 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)0R2°, C(=0)SR2°, C(=O)N(R20a)(R20b), OR20, S(=0)nR2°, S(=O)nN(R20a)(R20b), S(=0)mOR2°, N(R20a)(R20b), N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b), N(R20)S(=O)n(R20),
N (R20)S(=O)mN (R20a)(R20b), and N(R20)S(=O)mOR20;
and/or two R12 present on one carbon atom together form =0;
R13 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R21;
(ii) C(=0)R22, C(=0)0R23, C(=0)SR23, C(=0)N(R23a)(R23b), OR23, S(=0)nR23, S(=0)nN(R23a)(R23b), S(=0)m0R23, N(R23a)(R23b), N(R23)C(=0)R22, N(R23)C(=0)0R23, N(R23)C(=0)N(R23a)(R23b), N(R23)S(=0)n(R23),
N (R23)S(=0)mN (R23a)(R23b), and N(R23)S(=0)m0R23;
R14, R15, R15a, R15b are independently selected from the group consisting of
(i) H, Ci-C6-alkyl, C2-C6-alkenyl, and C2-C6-alkynyl, wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R16;
(ii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated car bocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially un saturated or fully unsaturated carbobicyclic or heterobicyclic 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 heteroatom in the aforementioned cyclic or bicyclic moieties is in dependently unsubstituted or substituted with one or more, same or different substituents R32;
R16 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloal- kenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, N(R33a)(R33b), C(=0)NR33aR33b, S(=0)nNR33aR33b, OR33 and S(=0)nR33;
(ii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated car- bocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially un saturated or fully unsaturated carbobicyclic or heterobicyclic 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 heteroatom in the aforementioned cyclic or bicyclic moieties is in dependently unsubstituted or substituted with one or more, same or different substituents R32;
R17 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl);
R18 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)SR26, C(=0)N(R26a)(R26b), OR26, S(=0)nR26, S(=0)nN(R26a)(R26b), S(=0)m0R26, N(R26a)(R26b), N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b), N(R26)S(=0)n(R26),
N (R26)S(=0)mN (R26a)(R26b), and N(R26)S(=0)m0R26;
R19, R20, R20a, R20b are independently selected from the group consisting of H, C1-C6- alkyl, C -C6-alkenyl, C -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 R27; R21 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl);
R22, R23, R23a, R23b 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 R28;
R24 is selected from the group consisting of halogen, CN, NO2, Ci-C6-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 R29;
R25, R26, R26a, R26b are independently selected from the group consisting of H, C1-C4- alkyl, Ci-C4-haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, and C2- C4-haloalkynyl;
R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-alkyl),
NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R30;
R28 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-alkyl),
NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R31 ;
R29, R30, R31 are independently selected from the group consisting of halogen, CN,
NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-al- kynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci- C4-alkyl)(Ci-C4-alkyl);
R32 is selected from the group consisting of halogen, CN, NO2, Ci-C4-alkyl, C1-C4- haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, C(=0)R34, C(=0)0R33, C(=0)SR33, C(=0)N(R33a)(R33b), OR33, S(=0)nR33, S(=0)nN(R33a)(R33b), S(=0)m0R33, N(R33a)(R33b), N(R33)C(=0)R34,
N(R33)C(=0)0R33, N(R33)C(=0)N(R33a)(R33b), N(R33)S(=0)n(R33),
N(R33)S(=0)mN(R33a)(R33b), and N(R33)S(=0)m0R33;
R33, R33a, R33b, R34 are independently selected from the group consisting of H, C1-C4- alkyl, CrC -haloalkyl, C2-C4-alkenyl, C2-C -haloalkenyl, C2-C -alkynyl, and C2- C4-haloalkynyl;
and wherein
n is 0, 1 or 2; and
m is 1 or 2.
In the first aspect A1 a, the present invention relates to a compound of formula (I) as defined above in the first aspect A1 , wherein the compound is not:
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
In the first aspect A1 b, the present invention relates to a compound of formula (I) as defined above in the first aspect A1 , wherein the compound is not:
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
tassium salt thereof.
In the first aspect A1 c, the present invention relates to a compound of formula (I) as defined above in the first aspect A1 , wherein the compound is not:
Figure imgf000018_0002
Figure imgf000019_0001
Figure imgf000020_0001
In the first aspect Aid, the present invention relates to a compound of formula (I) as defined above in the first aspect A1 , wherein the compound is not:
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
mer, tautomer, isotopologue, or N-oxide thereof. In the first aspect A1e, the present invention relates to a compound of formula (I) as defined above in the first aspect A1 , wherein the compound is not:
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000025_0001
In a preferred embodiment, G1 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.
In another embodiment, G1 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 CH3, 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. In another embodiment, R1a is selected from the group consisting of H and Cl; R1b is selected from the group consisting of H and Cl; R1c is selected from the group consisting of H and Cl; R2a is Ch ; R2b is Ch ; R2c 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.
In another preferred embodiment, G3 is selected from the group consisting of
(i) Ci-C6-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 R3;
(ii) C(=0)R5, C(=0)OR6, and C(=0)N(R6a)(R6b);
wherein R3 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R4;
(ii) C(=0)R7, C(=0)OR8, C(=0)N(R8a)(R8b), OR8, N(R8a)(R8b), N(R8)C(=0)R7, N(R8)C(=0)0R8, and N(R8)C(=0)N(R8a)(R8b);
wherein R4 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R9;
(ii) C(=0)R1°, C(=0)OR11, C(=0)N(R11a)(R11b), OR11, N(R11a)(R11b), N(R11)C(=0)R1°, N(R11)C(=0)OR11, N(R11)C(=0)N(R11a)(R11b);
wherein R5, R6, R6a, R6b 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 R12;
wherein R7, R8, R8a, R8b 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 R13;
wherein R9 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4- alkyl);
wherein R10, R11, R11a, R11b are independently selected from the group consisting of H , Ci- C6-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 R17;
wherein R12 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)OR2°, C(=O)N(R20a)(R20b), OR20, N(R20a)(R20b),
N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b); and/or two R12 present on one carbon atom together form =0;
wherein R13 is selected from the group consisting of
(i) halogen, CN, N0 , CrC6-alkyl, C -C6-alkenyl, C -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 clic 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 R21;
(ii) C(=0)R22, C(=0)0R23, C(=0)N(R23a)(R23b), OR23, N(R23a)(R23b),
N(R23)C(=0)R22, N(R23)C(=0)0R23, N(R23)C(=0)N(R23a)(R23b); wherein R17 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl); wherein R18 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)N(R26a)(R26b), OR26, N(R26a)(R26b),
N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b); wherein R19, R20, R20a, R20b are independently selected from the group consisting of H , Ci- C6-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 R27;
wherein R21 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C -C6-alkenyl, C -C6-haloalkenyl, C -C6-alkynyl, C -C6-haloalkynyl, OH, 0(CrC4-alkyl), NH2, NH(CrC4-alkyl), and N(Ci-C4-alkyl)(CrC4-alkyl); wherein R22, R23, R23a, R23b are independently selected from the group consisting of H , Ci- C6-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 R28;
wherein R24 is selected from the group consisting of halogen, CN, NO2, Ci-C6-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 R29;
wherein R25, R26, R26a, R26b 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;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), CrCe-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 R30;
wherein R28 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), CrCe-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 R31;
wherein R29, R30, R31 are independently selected from the group consisting of halogen,
CN, NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6- alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Cr C4-alkyl)(Ci-C4-alkyl), and
wherein all other substituents have the meaning as defined above in the first aspects A1 , A1a, A1 b, A1 c, Aid or A1e.
In another embodiment, G3 is selected from the group consisting of C(=0)R5, C(=0)OR6, and C(=0)N(R6a)(R6b); wherein R5, R6, R6a, R6b 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 R12;
wherein R12 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)OR2°, C(=O)N(R20a)(R20b), OR20, N(R20a)(R20b),
N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b); and/or two R12 present on one carbon atom together form =0;
wherein R18 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)N(R26a)(R26b), OR26, N(R26a)(R26b),
N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b); wherein R19, R20, R20a, R20b are independently selected from the group consisting of H , Ci- C6-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 R27;
wherein R24 is selected from the group consisting of halogen, CN, NO2, Ci-C6-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 R29;
wherein R25, R26, R26a, R26b 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;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), CrCe-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 R30;
wherein R29, R30 are independently selected from the group consisting of halogen, CN,
NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-al- kynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci- C4-alkyl)(Ci-C4-alkyl); and
wherein all other substituents have the meaning as defined above in the first aspects A1 , A1a, A1 b, A1 c, Aid or A1e.
In another embodiment, 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]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N- (oxan-4-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(4-fluoropyrroli- din-3-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-[3-(difluoro- methoxy)propyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-N-tert-butyl-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine- 2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(2,2,2-trifluoroethyl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N- [(morpholin-2-yl)methyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[2- (methylamino)ethyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6- (4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(pyrrolidin-3-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide 8-amino-N-(1 , 1-dioxo-1A6-thiolan-3-yl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(2- oxopyrrolidin-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1-hy- droxypropan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 2-(4,4-difluor- opiperidine-1-carbonyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8- amine; 8-amino-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)im- idazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-5-(8-chloro-4-methylquinolin-6-yl)-6-(4-fluoro- phenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-[4-(difluoromethyl)quinolin- 6-yl]-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)-N-(propan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-N-(2H3)methyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-N-(3-ethylpyrrolidin-3-yl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 2-(2,6-dimethylmorpholine-4-carbonyl)-6-(4-fluorophenyl)-5- (4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-5-(4-chloro-1 -methyl-1 H-1 ,3-ben- zodiazol-6-yl)-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4- fluorophenyl)-N-methyl-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 , 3-benzodiazol-6-yl)-N-(oxolan-3-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 2-(2,6-dimethylmorpholine-4-carbonyl)-6-(4-fluorophenyl)-5- (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-N-(4-aminobutyl)-6- (4-fluorophenyl)-5-(1-methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-N-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 , 3- benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 2-[4-(2,4-difluorophenyl)piperazine-1- carbonyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 6-(4-fluoro- phenyl)-2-[4-(2-methoxyethyl)piperazine-1-carbonyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]py- razin-8-amine; 8-amino-6-(4-fluorophenyl)-N-methyl-5-(4-methylquinolin-6-yl)-N-(propan-2-yl)im- idazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(2-methoxyethyl)-N-methyl- 5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 1-[8-amino-6-(4-fluorophenyl)- 5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carbonyl]pyrrolidin-3-amine; 8- amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-N-(oxan-4-yl)imidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(piperidin-4-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-2- (piperazine-1 -carbonyl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-N,N-diethyl-6-(4-fluorophenyl)- 5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluor- ophenyl)-N-(2-methoxyethyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-N-[(1-methylpyrrolidin-3-yl)methyl]-5-(4-methylquinolin-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-[3-(dimethylamino)butyl]-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide 8-amino-N-(4,4-difluoro- cyclohexyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-(2-methoxy- ethyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-[2-(dimethylamino)propyl]-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)-N-(prop-2-yn-1-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1-methylpiperidin-4-yl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)-N-[(oxetan-2-yl)methyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6- (4-fluorophenyl)-N-{[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl}-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(1-methyl-1 H-1 ,3-benzodiazol- 6-yl)-N-(2,2,2-trifluoroethyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-
5-(4-methylquinolin-6-yl)-N-(3,3,3-trifluoropropyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-N-methyl-5-[4-(2H3)methylquinolin-6-yl]imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino- 5-(4-ethylquinolin-6-yl)-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine- 2-carboxamide; 8-amino-N-[2-(dimethylamino)ethyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1-methoxy-2- methylpropan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6- (4-fluorophenyl)-N-(3-hydroxybutan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-6-(4-fluorophenyl)-N-[(4-methylmorpholin-2-yl)methyl]-5-(4-methylquinolin-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)- N-[(oxetan-3-yl)methyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)-N-(oxolan-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-N-[1-(methoxymethyl)cyclopropyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2- carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1-methyl-2-oxopyrrolidin-3-yl)-5-(4-methylquinolin-
6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6- yl)-N-{2-[(oxolan-2-yl)methoxy]ethyl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-N-(2-methoxy-2-methylpropyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(1 ,1 ,1-trifluoro-3-hydroxypro- pan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin- 6-yl)-N-(oxetan-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 1-[8-amino-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbonyl]-3-methylpyrrolidin-3-ol; 8-amino- 5-(8- chloro-4-methylquinolin-6-yl)-6-(4-fluorophenyl)-N-(2-methoxyethyl)imidazo[1 ,2-a]pyrazine-2- carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1-methylcyclobutyl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(2-fluoroethyl)-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 1-[8-amino-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbonyl]pyrrolidin-3-amine; 8-amino-6-(4-fluoro- phenyl)-N-(1-methylpyrrolidin-3-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-N-[(1-hydroxycyclopentyl)methyl]-5-(4-methylquinolin-6-yl)im- idazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(2,2-dimethylpropyl)-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1- methoxypropan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(4-chloro-1 -methyl-1 H-1 , 3-benzodiazol-6-yl)-N-(2-fluoroethyl)-6-(4-fluorophenyl)imidazo[1 , 2- a]pyrazine-2-carboxamide; 8-amino-5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-6-(4-fluoro- phenyl)-N-[(1-hydroxycyclopropyl)methyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(4- chloro-1-methyl-1 H-1 ,3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[1 -(1-hydroxycyclopro- pyl)ethyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-{3- chloroimidazo[1 ,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-5-[4-(2H3)methylquinolin-6-yl]imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino- 5-{8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-me- thylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(1-methyl-1 H-1 ,3-ben- zodiazol-6-yl)-N-(propan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-N-(3-hydroxypropyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-N-(2-fluoroethyl)-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-5-{8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}-6-(4-fluoro- phenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(4-chloro-1 -methyl-1 H-1 ,3-benzodia- zol-6-yl)-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- N-ethyl-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino- 5-{8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-(pro- pan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-5-{8-chloro-3-methylimidazo[1 ,2-a]pyr- idin-6-yl}-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-N-[1 -(dimethylamino)-2-methylpropan-2-yl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[(1-methylazetidin-3- yl)methyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-({1 -[(2,4- difluorophenyl)methyl]piperidin-4-yl}methyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[2-methyl-1-(propan-2- yloxy)propan-2-yl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6- (4-fluorophenyl)-N-methyl-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-N-(pyrrolidin-3-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[(5-methyl-1 ,3,4-oxadiazol-2-yl)me- thyl]-5-(1-methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N- tert-butyl-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-6-(3-cyano-2-methylphenyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-5-[1-(2,2-difluoroethyl)-1 H-1 ,3-benzodiazol-6-yl]-6-(4-fluoro- phenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 6-(4-fluorophenyl)-2-[(methyla- mino)methyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)-N-[2-(pyrrolidin-1-yl)ethyl]imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-N-(cyclopropylmethyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-6-(4-fluoro- phenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)- 5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5- (4-methylquinolin-6-yl)-N-(oxetan-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-5-{8- chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-(1-methylcyclobutyl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1 -methylcyclobutyl)-5-{3-methylimid- azo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-{3- methylimidazo[1 ,2-a]pyridin-6-yl}-N-(propan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-N-methyl-5-[1 -(propan-2-yl)-1 H-1 ,3-benzodiazol-6-yl]imidazo[1 ,2-a]py- razine-2-carboxamide; 8-amino-6-(3-cyanophenyl)-N-methyl-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-{3-methylimidazo[1 ,2-a]pyri- din-6-yl}imidazo[1 ,2-a]pyrazine-2-carboxylic acid; 8-amino-6-(3-cyanophenyl)-N-(2,2-difluoro- ethyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6- (2-fluorophenyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(3-cyanophenyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}-N-(propan-2-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-N-(cyclopropylmethyl)-6-(4-fluorophenyl)-5-(1 -methyl-1 H- 1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(3-cyano-4-fluoro- phenyl)-N-(2,2-difluoroethyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-car- boxamide; 1-[8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-2- yl]ethan-1-one; 8-amino-6-(4-fluorophenyl)-N-(1 -methoxy-2-methylpropan-2-yl)-5-(1 -methyl-1 H- 1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(1- methyl-1 H-1 ,3-benzodiazol-6-yl)-N-[1 -(trifluoromethyl)cyclopropyl]imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-6-(3-cyano-4-fluorophenyl)-N-(2,2-difluoroethyl)-5-(1 -methyl-1 H-1 ,3-benzo- diazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-{3-methylimid- azo[1 ,2-a]pyridin-6-yl}-N-[1 -(trifluoromethyl)cyclopropyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(cyclopropylmethyl)-6-(4-fluorophenyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}imid- azo[1 ,2-a]pyrazine-2-carboxamide; 2-(4,5-dihydro-1 H-imidazol-2-yl)-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-N-(4,4-difluorocyclohexyl)-6-(4- fluorophenyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-N-(1 -cyanocyclopropyl)-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 , 3-benzodiazol-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)-5-{3-me- thylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(4,4-difluorocy- clohexyl)-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 , 3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-N-(1 ,1 -difluoropropan-2-yl)-6-(4-fluorophenyl)-5-(1-methyl-1 H-1 ,3-benzodia- zol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(3-cyano-4-fluorophenyl)-N-methyl-5- (4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(2-cyanoethyl)-6-(4- fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4- fluorophenyl)-5-(1-methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxylic acid; and 8-amino-N-tert-butyl-6-(4-fluorophenyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]py- razi ne-2-carboxam ide .
In a second aspect A2, the present invention relates to a pharmaceutical composition compris ing 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. Put in different words, 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.
In a third aspect A3, 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 sclero derma), sleep disorders, AIDS, autoimmune diseases, infections, atherosclerosis, ischemia- reperfusion injury, idiopathic pulmonary fibrosis, systemic sclerosis, irritable bowel disease and as analgesic. Further indications are described below in the detailed description, together with preferred combinations, namely the compounds of the present invention together with check point inhibitors, wherein such combinations are used for the treatment of cancer.
In a fourth aspect A4, 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.
In a fifth aspect A5, 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.
Detailed description relating to aspects A1 , A1a, A1 b, A1c, Ai d, A1e, A2, A3, A4, and A5
In the following, preferred embodiments of the substituents in the above formula (I) are de scribed in further detail.
The following embodiments relate to G1 as defined above in the first aspects A1 , A1 a, A1 b, A1 c, Ai d, and A1 e.
In embodiment 1 (A), G1 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 CH3, F and CN.
In a preferred embodiment 1 (B), G1 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 CH3, F and CN.
In another embodiment 1 (C), G1 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 CH3, F and CN.
In another embodiment 1(D), G1 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 CH3, F and CN.
The following embodiments relate to G2 as defined above in the first aspects A1 , A1a, A1 b, A1c, Aid, and A1e.
In embodiment 2(A), G2 is selected from the group consisting of
Figure imgf000037_0001
wherein
R1a is selected from the group consisting of H and Cl;
R1 b is selected from the group consisting of H and Cl;
R1c is selected from the group consisting of H and Cl;
R2a 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;
R2b 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; and
R2c is CrC3-alkyl, wherein each substitutable carbon atom is unsubstituted or substi tuted with one or more F;
In another embodiment 2(B), G2 is selected from the group consisting of
Figure imgf000037_0002
wherein
R1a is selected from the group consisting of H and Cl
R1 b is selected from the group consisting of H and Cl
R1c is selected from the group consisting of H and Cl
R2a is CH3;
R2b is CH3;
R2c is CH3;
The following embodiments relate to G3 as defined above in the first aspects A1 , A1a, A1 b, A1c, Aid, and A1e. In embodiment 3(A), G3 is selected from the group consisting of
(i) Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, par tially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated car- bobicyclic 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 heteroatom in the afore mentioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R3;
(ii) C(=0)R5, C(=0)OR6, C(=0)SR6, C(=0)N(R6a)(R6b), OR6, S(=0)nR6, S(=0)nN(R6a)(R6b), S(=0)mOR6, N(R6a)(R6b), N(R6)C(=0)R5, N(R6)C(=0)0R6, N(R6)C(=0)N(R6a)(R6b), N(R6)S(=0)n(R6), N(R6)S(=0)mN(R6a)(R6b), and N(R6)S(=0)m0R6;
wherein R3 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R4;
(ii) C(=0)R7, C(=0)OR8, C(=0)SR8, C(=0)N(R8a)(R8b), OR8, S(=0)nR8, S(=0)nN(R8a)(R8b), S(=0)mOR8, N(R8a)(R8b), N(R8)C(=0)R7, N(R8)C(=0)0R8, N(R8)C(=0)N(R8a)(R8b), N(R8)S(=0)n(R8), N(R8)S(=0)mN(R8a)(R8b), and N(R8)S(=0)m0R8;
wherein R4 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R9;
(ii) C(=0)R1°, C(=0)OR11, C(=0)SR11, C(=0)N(R11a)(R11b), OR11, S(=0)nR11, S(=0)nN(R11a)(R11b), S(=0)mOR11, N(R11a)(R11b), N(R11)C(=0)R1°,
N(R11)C(=0)OR11, N(R11)C(=0)N(R11a)(R11b), N(R11)S(=0)n(R11),
N(R11)S(=0)mN(R11a)(R11b), and N(R11)S(=0)mOR11; wherein R5, R6, R6a, R6b 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 R12;
wherein R7, R8, R8a, R8b 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 R13;
wherein R9 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C(=0)R14, C(=0)OR15, C(=0)SR15, C(=0)N(R15a)(R15b), OR15, S(=0)nR15, S(=0)nN(R15a)(R15b), S(=0)mOR15, N(R15a)(R15b), N(R15)C(=0)R14, N(R15)C(=0)0R15, N(R15)C(=0)N(R15a)(R15b), N(R15)S(=0)n(R15), N(R15)S(=0)mN(R15a)(R15b), and N(R15)S(=0)m0R15;
wherein R10, R11, R11a, R11b are independently selected from the group consisting of H , Ci- C6-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 R17;
wherein R12 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)0R2°, C(=0)SR2°, C(=O)N(R20a)(R20b), OR20, S(=0)nR2°, S(=O)nN(R20a)(R20b), S(=0)m0R20, N(R20a)(R20b), N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b), N(R20)S(=O)n(R20), N(R20)S(=O)mN(R20a)(R20b), and N(R20)S(=O)mOR20;
and/or two R12 present on one carbon atom together form =0;
wherein R13 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R21;
(ii) C(=0)R22, C(=0)0R23, C(=0)SR23, C(=0)N(R23a)(R23b), OR23, S(=0)nR23, S(=0)nN(R23a)(R23b), S(=0)m0R23, N(R23a)(R23b), N(R23)C(=0)R22, N(R23)C(=0)0R23, N(R23)C(=0)N(R23a)(R23b), N(R23)S(=0)n(R23),
N (R23)S(=0)mN (R23a)(R23b), and N(R23)S(=0)m0R23;
wherein R14, R15, R15a, R15b are independently selected from the group consisting of
(i) H, Ci-C6-alkyl, C2-C6-alkenyl, and C2-C6-alkynyl, wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R16;
(ii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated car bocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially un saturated or fully unsaturated carbobicyclic or heterobicyclic 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 heteroatom in the aforementioned cyclic or bicyclic moieties is in dependently unsubstituted or substituted with one or more, same or different substituents R32;
wherein R16 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloal- kenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, N(R33a)(R33b), C(=0)NR33aR33b, S(=0)nNR33aR33b, OR33 and S(=0)nR33;
(ii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated car bocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially un saturated or fully unsaturated carbobicyclic or heterobicyclic 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 heteroatom in the aforementioned cyclic or bicyclic moieties is in dependently unsubstituted or substituted with one or more, same or different substituents R32;
wherein R17 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl); wherein R18 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)SR26, C(=0)N(R26a)(R26b), OR26, S(=0)nR26, S(=0)nN(R26a)(R26b), S(=0)m0R26, N(R26a)(R26b), N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b), N(R26)S(=0)n(R26),
N (R26)S(=0)mN (R26a)(R26b), and N(R26)S(=0)m0R26;
wherein R19, R20, R20a, R20b are independently selected from the group consisting of H , Ci- C6-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 R27;
wherein R21 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C -alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl); wherein R22, R23, R23a, R23b are independently selected from the group consisting of H , Ci- C6-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 R28; wherein R24 is selected from the group consisting of halogen, CN, NO2, Ci-C6-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 R29; wherein R25, R26, R26a, R26b 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;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R30; wherein R28 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R31; wherein R29, R30, R31 are independently selected from the group consisting of halogen,
CN, NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6- alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyi), NH , NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl);
wherein R32 is selected from the group consisting of halogen, CN, NO2, Ci-C4-alkyl, C1-C4- haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, C(=0)R34, C(=0)0R33, C(=0)SR33, C(=0)N(R33a)(R33b), OR33, S(=0)nR33, S(=0)nN(R33a)(R33b), S(=0)m0R33, N(R33a)(R33b), N(R33)C(=0)R34, N(R33)C(=0)0R33, N(R33)C(=0)N(R33a)(R33b), N(R33)S(=0)n(R33), N(R33)S(=0)mN(R33a)(R33b), and N(R33)S(=0)m0R33; wherein R33, R33a, R33b, R34 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;
and wherein
n is 0, 1 or 2; and
m is 1 or 2.
In a preferred embodiment 3(B), G3 is selected from the group consisting of
(i) Ci-C6-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 R3;
(ii) C(=0)R5, C(=0)OR6, and C(=0)N(R6a)(R6b);
wherein R3 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R4;
(ii) C(=0)R7, C(=0)OR8, C(=0)N(R8a)(R8b), OR8, N(R8a)(R8b), N(R8)C(=0)R7, N(R8)C(=0)0R8, and N(R8)C(=0)N(R8a)(R8b);
wherein R4 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R9;
(ii) C(=0)R1°, C(=0)OR11, C(=0)N(R11a)(R11b), OR11, N(R11a)(R11b), N(R11)C(=0)R1°, N(R11)C(=0)OR11, N(R11)C(=0)N(R11a)(R11b);
wherein R5, R6, R6a, R6b are independently selected from the group consisting of H, C1-C6- alkyl, C -C6-alkenyl, C -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 R12;
wherein R7, R8, R8a, R8b 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 R13;
wherein R9 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4- alkyl);
wherein R10, R11, R11a, R11b are independently selected from the group consisting of H , Ci- C6-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 R17;
wherein R12 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)OR2°, C(=O)N(R20a)(R20b), OR20, N(R20a)(R20b),
N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b); and/or two R12 present on one carbon atom together form =0;
wherein R13 is selected from the group consisting of (i) halogen, CN, NO2, Ci-C6-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 clic 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 R21;
(ii) C(=0)R22, C(=0)0R23, C(=0)N(R23a)(R23b), OR23, N(R23a)(R23b),
N(R23)C(=0)R22, N(R23)C(=0)0R23, N(R23)C(=0)N(R23a)(R23b); wherein R17 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl); wherein R18 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)N(R26a)(R26b), OR26, N(R26a)(R26b),
N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b); wherein R19, R20, R20a, R20b are independently selected from the group consisting of H , Ci- C6-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 R27;
wherein R21 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl); wherein R22, R23, R23a, R23b are independently selected from the group consisting of H , Ci- C6-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 R28;
wherein R24 is selected from the group consisting of halogen, CN, NO2, Ci-C6-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 R29; wherein R25, R26, R26a, R26b 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;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), CrCe-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 R30; wherein R28 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), CrCe-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 R31; wherein R29, R30, R31 are independently selected from the group consisting of halogen,
CN, NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6- alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(C1-C4-alkyl)(C1-C4-alkyl);
In another embodiment 3(C), G3 is selected from the group consisting of C(=0)R5,
C(=0)OR6, and C(=0)N(R6a)(R6b); wherein R5, R6, R6a, R6b 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 R12;
wherein R12 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)OR2°, C(=O)N(R20a)(R20b), OR20, N(R20a)(R20b),
N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b); and/or two R12 present on one carbon atom together form =0;
wherein R18 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)N(R26a)(R26b), OR26, N(R26a)(R26b),
N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b); wherein R19, R20, R20a, R20b are independently selected from the group consisting of H , Ci- C6-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 R27;
wherein R24 is selected from the group consisting of halogen, CN, NO2, Ci-C6-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 R29;
wherein R25, R26, R26a, R26b 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;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), CrCe-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 R30;
wherein R29, R30 are independently selected from the group consisting of halogen, CN,
NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-al- kynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci- C4-alkyl)(Ci-C4-alkyl);
In another embodiment 3(D), G3 is selected from the group consisting of C(=0)R5, C(=0)OR6, and C(=0)N(R6a)(R6b);
wherein R5 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, NO2, Ci-C4-alkyl, Ci-C4-haloalkyl, OH, (C C4-alkyl)OH, 0(C C4-alkyl), (C1-C4-alkyl)0(C1-C4-alkyl), NH2, (C C4-al- kyl)NH2, NH(C C4-alkyl), (C1-C4-alkyl)NH(C1-C4-alkyl), N(C1-C4-alkyl)(C1-C4-al- kyl), and (Ci-C4-alkyl)N(Ci-C4-alkyl)(Ci-C4-alkyl) with the proviso that the point of attachment on said heterocyclic or heterobicyclic ring is N; wherein R6 is selected from the group consisting of H and Ci-C3-alkyl;
wherein R6a is selected from the group consisting of H and Ci-C3-alkyl,
wherein R6b is selected from the group consisting of H, Ci-C6-alkyl, C2-C6-alkynyl, and a 3- to 6-membered saturated, partially unsaturated or fully unsaturated carbocy- clic 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 R12;
wherein R12 is selected from the group consisting of
(i) 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 R18;
(ii) OR20, N(R20a)(R20b);
and/or two R12 present on one carbon atom together form =0;
wherein R18 is selected from the group consisting of
(i) 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 R24;
(ii) OR26, N(R26a)(R26b);
wherein R20, R20a, R20b 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 clic 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 R27;
wherein R24 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 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 R29;
wherein R26, R26a, R26b are independently selected from the group consisting of H, C1-C4- alkyl, and Ci-C4-haloalkyl;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-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 R30;
wherein R29, R30 are independently selected from the group consisting of halogen, CN,
NO2, Ci-C4-alkyl, Ci-C4-haloalkyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl);
In another embodiment 3(D2), G3 is selected from the group consisting of C(=0)N(R6a)(R6b); wherein R6a is H,
wherein R6b is selected from the group consisting of Ci-C6-alkyl, C2-C6-alkynyl, 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 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 R12;
wherein R12 is selected from the group consisting of
(i) 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 R18;
(ii) OR20, N(R20a)(R20b);
and/or two R12 present on one carbon atom together form =0;
wherein R18 is selected from the group consisting of
(i) 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 R24;
(ii) OR26, N(R26a)(R26b);
wherein R20, R20a, R20b 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- clic 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 R27;
wherein R24 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 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 R29;
wherein R26, R26a, R26b are independently selected from the group consisting of H, C1-C4- alkyl, and Ci-C4-haloalkyl;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-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 R30;
wherein R29, R30 are independently selected from the group consisting of halogen, CN,
NO2, Ci-C4-alkyl, Ci-C4-haloalkyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl);
In another embodiment 3(E), G3 is C(=0)N(R6a)(R6b);
wherein R6a is selected from the group consisting of H and Ci-C3-alkyl;
wherein R6b is selected from the group consisting of Ci-C6-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 R12; with the pro viso that if R6b is CrC6-alkyl, said CrC6-alkyl is substituted with one or more, same or different substituents R12;
wherein R12 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 R18; and
wherein R18 is selected from the group consisting of halogen, CN, NO2, and Ci-C3-alkyl.
In another embodiment 3(F), G3 is C(=0)N(R6a)(R6b);
wherein R6a is selected from the group consisting of H and Ci-C3-alkyl,
wherein R6b is selected from the group consisting of H and Ci-C6-alkyl, wherein each sub stitutable carbon in the aforementioned Ci-C6-alkyl is unsubstituted or substi- tuted with one or more, same or different substituents R12;
wherein R12 is selected from the group consisting of halogen and OR20; and
wherein R20 is selected from the group consisting of H and Ci-C4-alkyl.
The following combinations of embodiments of the first aspects A1 , A1 a, A1 b, A1 c, A1 d, and A1 e , which are summarized in Table 1 are disclosed in combination with each other:
Table 1 :
Figure imgf000052_0001
Figure imgf000053_0002
In a preferred embodiment, the present invention relates to a compound of formula (I), in partic ular to a compound according to embodiment 36 of Table 1 , wherein
G1 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
CH3, F and CN;
G2 is selected from the group consisting of
Figure imgf000053_0001
wherein
R1 b is selected from the group consisting of H and Cl;
R2b is CH3; and
G3 is C(=0)N(R6a)(R6b);
wherein R6a is selected from the group consisting of H;
wherein R6b 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 R12; wherein R12 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 R18; and
wherein R18 is selected from the group consisting of halogen, CN, NO2, and Ci-C3-alkyl.
In a more preferred embodiment, the present invention relates to a compound of formula (I), in particular to a compound according to embodiment 36 of Table 1 , wherein
G1 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 CH3, F and CN;
G2 is selected from the group consisting of
Figure imgf000054_0001
wherein
R1 b is selected from the group consisting of H and Cl;
R2b is CH3; and
G3 is C(=0)N(R6a)(R6b);
wherein R6a is selected from the group consisting of H;
wherein R6b is Ci-alkyl, wherein the carbon atom is substituted with one or more, same or different substituents R12;
wherein R12 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 R18; and
wherein R18 is selected from the group consisting of halogen, CN, NO2, and Ci-C3-alkyl. Definitions relating to aspects A1a, A1b, A1c, Aid, A1e, A2, A3, A4, and A5
The term "compound(s) of the present invention" is to be understood as equivalent to the term "compound(s) according to the invention", therefore also comprising a salt, stereoisomer, tauto mer, isotopologue, or N-oxide thereof.
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 (NH4 +) 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. Examples of 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 ethanedisulfonate.
They can be formed by reacting compounds according to the invention that have a basic func tionality with an acid of the corresponding anion.
Depending on the substitution pattern, 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. The term "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. Preferably, the isotopologue is a deuter- ium(i.e. D or 2H)-enriched compound.
The term "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.
The term "substituted", as used herein, 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.
The term "substitutable", 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. When it is referred to certain atoms or moieties being substituted with“one or more” substitu ents, the term“one or more” is intended to cover at least one substituent, e.g. 1 to 10 substitu ents, preferably 1 , 2, 3, 4, or 5 substituents, more preferably 1 , 2, or 3 substituents, most prefer ably 1 , or 2 substituents. When neither the term“unsubstituted” nor“substituted” is explicitly mentioned concerning a moiety, said moiety is to be considered as unsubstituted.
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 Cn-Cm indicates in each case the possible number of carbon atoms in the group.
The term“halogen” denotes in each case fluorine, bromine, chlorine or iodine, in particular flu orine or chlorine.
The term "alkyl" as used herein 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, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl-1 -methylpropyl, and 1 -ethyl-2- methylpropyl.
The term "haloalkyl" as used herein 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.
The term "alkenyl" as used herein 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. If geometric isomers are possible with regard to the double bond, 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.
Figure imgf000056_0001
The term "haloalkenyl" as used herein refers to an alkenyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms.
The term "alkynyl" as used herein 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.
The term "haloalkynyl" as used herein refers to an alkynyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms. The term "alkoxy" as used herein 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.
The term "haloalkoxy" as used herein 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.
The term“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. Preferably, the term“carbocycle” covers cycloalkyl and cycloalkenyl groups as defined above, for example cyclopropane, cyclobutane, cyclopentane and cyclohexane rings. When it is referred to“fully un saturated” carbocycles, this term also includes“aromatic” carbocycles or aryls. In certain pre ferred embodiments, 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.
The term "carbobicyclic" 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. Preferably, 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. Preferably, the carbobicycle is a fused carbobicycle, for example naphthalene and the like.
The term“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. As used in this context, the term“fully unsaturated” also includes“aromatic”.
In a preferred embodiment, 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. Examples of 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 . Preferably, the S atom will not be present in oxidized form in fully unsaturated compounds. In particular, the following sce narios are covered: o ° °
A skilled person is aware that resonance structures of the oxidized forms may be possible.
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.
The term "hetaryl" 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 Preferably, the S atom will not be present in oxidized form in fully unsaturated compounds. In particular, the following scenarios are covered:
AS„ AS
Figure imgf000058_0001
o ° o
A skilled person is aware that resonance structures of the oxidized forms may be possible. Ex amples of 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. 2-, 3- or 5-oxazolyl, isoxazolyl, i.e. 3-, 4- or 5-isoxazolyl, thiazolyl, i.e. 2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl, pyrazolyl, i.e. 1-, 3-, 4- or 5-pyrazolyl, i.e. 1-, 2-, 4- or 5-imidazolyl, oxadiazolyl, e.g. 2- or 5-[1 ,3,4]oxadiazolyl, 4- or 5-(1 ,2,3-oxadiazol)yl, 3- or 5-(1 ,2,4-oxadiazol)yl, 2- or 5-(1 ,3,4-thiadiazol)yl, thiadiazolyl, e.g. 2- or 5-(1 ,3,4-thiadiazol)yl, 4- or 5-(1 ,2,3-thiadiazol)yl, 3- or 5-(1 ,2,4-thiadiazol)yl, triazolyl, e.g. 1 H-, 2H- or 3H-1 ,2 , 3-tri azo l-4-yl , 2H-triazol-3-yl, 1 H-, 2H-, or 4H-1 ,2,4-triazolyl and tetrazolyl, i.e. 1 H- or 2H-tetrazolyl.
The term "heterobicyclic" 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. Examples of 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. Preferably, the heterobicycle is a fused heterobicycle, for example quinolinyl and the like.
As used in the specification and the claims, the singular forms of“a” and“an” also include the corresponding plurals unless the context clearly dictates otherwise. The same applies for plural forms used herein, which also include the singular forms unless the context clearly dictates oth erwise.
The terms“about” and“approximately” in the context of the present invention denotes an inter val of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10% and preferably ±5%.
It needs to be understood that the term“comprising” is not limiting. For the purposes of the present invention, 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.
The term“pharmaceutically acceptable excipient” as used herein 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.
The term“treatment” is to be understood as also including the option of“prophylaxis”. Thus, whenever reference is made herein to a“treatment” or“treating”, this is to be understood as “treatment and/or prophylaxis” or“treating and/or preventing”.
Description of pharmaceutical compositions according to the present invention
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.
Pharmaceutical 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.
In general, the 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.
The term“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 es ters, hydroxymethyl celluloses such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy- propyl acetate succinate, polyvinylpyrrolidone, crosspovidone and the like. The pharmaceutical 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.
If liquid dosage forms are considered for the present invention, these 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.
For parenteral application, particularly 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. Additionally, 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.
Particularly preferred dosage forms are injectable preparations of a compound of formula (I). Thus, 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. Among the 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.
For administration by inhalation, 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. In the case of a pressurized aero sol 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). If desired, 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. For example, 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. For buccal ad ministration, the compositions may take the form of tablets or lozenges formulated in conven tional manner.
The 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. In general, 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.
As regards human patients, 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.
Furthermore, 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.
Indications, for which the compounds of the present invention may be used
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. Furthermore, 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.
More generally, 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. The proliferative diseases include cancer.
Preferably, 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, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, aci nar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tu mor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lympho blastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder can cer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, meso thelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, na- sopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tu mor), neuroendocrine cancers and testicular cancer.
More preferably, 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.
Additionally, 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. Examples of 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).
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.
Preferably, 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. 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. It can further be preferred that 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.
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).
Examples for 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).
It is widely known today that tumors can evade the immune system by suppressing the im mune response. As discussed above, a strategy for doing so resides in the change of the micro environment. Another (additional) strategy resides on the upregulation of receptors, which act (co-)inhibitory on the immune system (a negative“immune checkpoint” or“checkpoint”). Agents blocking or inhibiting these receptors (thus resulting in a block of the immunosuppressive sig nals of the tumor) are commonly referred to as“checkpoint inhibitors” and this reference is also used herein. 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. Specific ex amples are BMS-936559, MPDL3280A and M EDI4736 (anti-PD-L1 antibodies), MK-3475 and pembrolizumab (anti-PD-1 antibodies) as well as ipilimumab (anti-CTLA-4 antibodies).
Preferably, 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). Preferably, the compounds of the present invention are administered in 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.
SM360320, AZD8848), (NOD)-like receptors (NLRs, preferably NOD2 agonist), retinoic acid in ducible gene-based (RIG)-l-like receptors (RLRs), C-type lectin receptors (CLRs), or pathogen- associated molecular patterns (“PAMPs”), cytokines (not limiting examples e.g. IL-2, IL-12, IL- 6), interferons (including, but not limited to IFN alpha, IFN beta, I FN gamma, IFN lambda) or chemotherapeutic agents. 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. In embodiments where 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. In such instances, it is contemplated that one may administer both modalities within about 12-24 h of each other and, more preferably, within about 6-12 h of each other. In some situations, it may be desirable to extend the time period for treatment signif icantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1 , 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations. In some embodiments, the compound of the pre sent invention is administered prior to administration of the distinct cancer treatment. In other embodiments, 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.
Examples Part 1 : Synthesis
General
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. Chemical shifts (d) are reported in ppm rela tive to the residual solvent signal (measurement range - 6.4 kHz). 1 H NMR data are reported as follows: chemical shift (multiplicity, coupling constants and number of hydrogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).
When the term "inerted" is used to describe a reactor (e.g., a reaction vessel, flask, glass reac tor, and the like) it is meant that the air in the reactor has been replaced with an essentially moisture-free or dry, inert gas (such as nitrogen, argon, and the like).
Preparative HPLC Conditions for the Purification of Target Compounds
Chromatography Conditions 1:
Prep HPLC Instrument: Waters 2545 pump with 2767 fraction collector
ColummWaters Xbridge C18 100mmx19mm,5pm particle size
MS Detector: Waters 3100 mass detector
UV detector: Waters 2489 dual wavelength UV detector
Flow Rate : 30 ml/min
Example Gradient Time:
Time(min) B%
0 20
1.5 20
6.5 40 35 Representative Mobile Phase:
6.55 95 (1 )
8.5 95 Mobile Phase: A: 0.1 %formic acid in water
Mobile Phase: B: 0.1 % formic acid in ACN
(2)
Mobile Phase: A: 0.1%NH4OH in water
Mobile Phase: B: 0.1% NH40H in ACN
Chromatography conditions 2:
Prep HPLC Instrument: Shimadzu Column: Gemini-NX 5 pm C18 110A, 250*21.2mm
Detector: SPD -20A/20AV UV-VIS
Flow Rate : 30 ml/min
Representative Mobile Phase:
(1 )
Mobile Phase: A: 0.01 %formic acid in water or TFA
Mobile Phase: B: 0.01 % formic acid in ACN or TFA
(2)
Mobile Phase: A: 0.01 %NFI4OFI in water
Mobile Phase: B: 0.01 % NH40H in ACN
Preparative SFC Conditions for the Purification of Target Compounds
Chromatography Conditions:
SFC Instrument: Thar SFC Prep Investigator (Waters)
Column: Chiral Technologies chiralpak IA 250mm x10mm,5pm particle size
ELS Detector: Waters 2424 detector
UV detector: Waters 2998 photodiode array detector, 254 nm
Flow Rate : 10 ml/min
Isocratic run: 40% isopropanol as a cosolvent
UPLC, HPLC and MS data provided in the examples described below were registered on:
LC-MS analyses on Bruker Amazon SL
Method name: lc-ms1-2-ba
Equipment:
MS Bruker Amazon SL
LC Dionex Ultimate 3000
HPLC with UV-Vis or DAD detector
column: Waters Acquity UPLC HSS C18, 50 mm x 2.1 mm x 1.8 pm
Eluents:
(A) 0.1 % formic acid in ACN
(B) 0.1 % formic acid in water
Analytical method:
- Autosampler: injection volume: 1 pL
Pump:
Flow % B
Time [min] [ml/min]
0.00 0.5 95
0.00 0.5 95
4.00 0.5 5
5.00 0.5 5
5.20 0.5 95
6.00 0.5 95 - Column compartment:
column temperature: 25°C
time of analysis: 6 min
- Detector:
wave length:254, 230, 270, 280 nm
LC-MS analyses Bruker Amazon SL
Method name: BCM-30
Equipment:
MS Bruker Amazon SL
LC Dionex Ultimate 3000
HPLC with UV-Vis or DAD detector
column: Waters Symmetry C18 3.9x150mm 5pm
Eluents:
(A) 0.1 % formic acid-water solution
(B) 0.1 % formic acid- ACN solution
Analytical method:
- Autosampler: injection volume: 3 pL
Pump:
flow: 1.2 ml/min
Time [min] [%] B
0.0 20
20.0 80
22.0 80
22.5 95
25.0 95
25.3 20
30.0 20
- Column compartment:
column temperature: 25°C
time of analysis: 30 min
- Detector:
wave length: 254 nm
LC-MS analyses on Shimadzu:
Method name: lc-ms1-2-ba
Equipment:
- Shimadzu LC-MS 2020
HPLC with UV-Vis or DAD detector
column: Waters Acquity UPLC HSS C18, 50 mm x 2.1 mm x 1.8 pm
Eluents:
(A) 0.1 % formic acid in ACN
(B) 0.1 % formic acid in water
Analytical method: - Autosampler: injection volume: 1mI_ Pump:
Time [min] Flow % B
[ml/min]
0.00 0.5 95
0.00 0.5 95
4.00 0.5 5
5.00 0.5 5
5.20 0.5 95
6.00 0.5 95
- Column compartment
column temperature: 25°C
time of analysis: 6 min
- Detector:
wave length:254, 230, 270, 280 nm
LC-MS analyses on Corona ultra:
Method name: BCM-30
Equipment:
Corona ultra
LC Dionex Ultimate 3000
column: Waters Symmetry C18 3.9x150mm 5pm Eluents:
(A) 0.1 % formic acid-water solution
(B) 0.1 % formic acid- ACN solution
Analytical method:
- Autosampler: injection volume: 3 pl_
- Pump:
flow: 1.2 ml/min
Time [min] [%] B
0.0 20
20.0 80
22.0 80
22.5 95
25.0 95
25.3 20
30.0 20
LC-MS analyses on Bruker Daltonik
Method name: Kinetex-Rot
Equipment:
- HPLC with UV-Vis or DAD detector
- column: Kinetex XB C18 4.6x50mm 2.6pm
- MS: HCT Ion Trap Bruker Daltonik Eluents:
- (A) 0.1 % formic acid-water solution
- (B) 0.1 % formic acid- ACN solution Analytical method:
Autosampler:
- injection volume: 1 pl_
Pump:
- flow: 0.45ml_/min
Time [min] [%] B
0.0 5
2.0 5
9.5 80
10.5 80
12.0 5
14.0 5
Column compartment:
- column temperature: 25°C
- time of analysis: 14min
Detector:
- DAD
LC-MS analyses on Bruker Daltonik Method name: Kinetex-BCM
Equipment:
- HPLC with UV-Vis or DAD detector
- column: Kinetex XB C18 4.6x50mm 2.6pm
- MS: HCT Ion Trap Bruker Daltonik
Eluents:
- (A) 0.1 % formic acid-water solution
- (B) 0.1 % formic acid- ACN solution Analytical method:
Autosampler:
- injection volume: 1 pl_
Pump:
- flow: 0.5ml_/min
Time [min] [%] B
0.0 20
6.7 80
7.5 80
7.8 95 9.5 95
10.0 20
12.0 20
Column compartment:
- column temperature: 25°C
- time of analysis: 12min
Detector:
- DAD
1. Mass spectrometer parameters
-Nebulizer: 40psi
-Dry gas flow: 9.0 l/min
-Temp: 365 C
-Ionization: positive and negative
-Scan range : 100- 1000 m/z
LC-MS analyses on Bruker Daltonik
Method name: Kinetex-BCM-NP
Equipment:
- HPLC with UV-Vis or DAD detector
- Column: Kinetex XB C18 (4.6 x 50mm, 2.6pm);
Eluents:
- (A) 0.1 % formic acid-water solution
- (B) 0.1 % formic acid- ACN solution
Analytical method:
Autosampler:
- injection volume: 1 pL
Pump:
- flow: 0.5ml_/min
Time [min] [%] B
0.0 20
5.0 80
5.7 80
5.9 95
8.5 95
8.7 20
11.0 20
Column compartment:
- column temperature: 25°C
- time of analysis: 1 1 min
Detector: - DAD
LC-MS analyses on Waters Acquity UPLC SQD2
Column: Acquity UPLC BEH C18 (2.1 mm x 100 mm, 1.7miti );
Detection: DAD at 254nm and 280 nm + ESI , ESCI (ESI i+APCI)- positive and negative detec tion
Method: Midpolar
Eluents:
- (A) 0.1 % formic acid-water solution
- (B) 0.1 % formic acid- ACN solution
- injection volume: 3mI
- flow= 0.5 ml/min
Time [min] [%] B
0.0 20
0.1 20
1.1 100
2.0 100
2.5 20
3.0 20
Analysis time: 3 min Method: Polar
Eluents:
- (A) 0.1 % formic acid-water solution
- (B) 0.1 % formic acid- ACN solution
- injection volume: 3mI
- flow= 0.5 ml/min
%B
Time [min] [%] B
0.0 1
0.1 1
1.1 100
2.0 100
2.5 1
3.0 1
Analysis time: 3 min The following abbreviations are used herein:
ACN: Acetonitrile
AcOK: Potassium acetate
AcOH: Acetic acid
aq: Aqueous cAMP: Cyclic adenosine monophosphate
cod: cyclooctadiene
Cone.: Concentrated
DAST: (Diethylamino)sulfur trifluoride
DBU: 1 ,8-Diazabicyclo[5.4.0]undec-7-ene
DBU: 1 ,8-Diazabicyclo[5.4.0]undec-7-ene
DCE: 1 ,2-Dichloroethane
DCM: Dichloromethane
DIBAL: Diisobutylaluminium hydride
DIPEA: N-Ethyldiisopropylamine
DME: 1 ,2-Dimethoxyethane
DMF: Dimethylformamide
DMF: N,N-Dimethylformamide
DMSO: Dimethylsulfoxide
DPPA: Diphenyl phosphoryl azide
DPPA: Diphenylphosphoryl azide
ESI-MS: Electrospray ionization - mass spectrometry
Et20: Diethyl ether
Et3N: Triethylamine
EtOAc: Ethyl acetate
EtOH: Ethanol
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
LCMS: Liquid chromatography - mass spectrometry
MCPBA: 3-Chloroperbenzoic acid
MeOH: Methanol
MW: Microwave
NBS: N-bromosuccinimide
NCS: N-chlorosuccinimide
NECA: 5'-(N-Ethylcarboxamido)adenosine
NMR: Nuclear magnetic resonance
on or o.n.: overnight
Pd(amphos)CI2: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ll) Pd(dppf)CI2: [1 ,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll)
prep-HPLC: Preparative high-performance liquid chromatography
r.t. or rt: Room temperature
Sphos Pd G3: (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1 ,T-bi- phenyl)]palladium(ll) methanesulfonate
TFA: Trifluoroacetic acid
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.
Procedure A:
Preparation of ethyl 8-amino-5-chloro-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxylate
Figure imgf000073_0001
a. 6-chloro-5-(4-fluorophenyl)pyrazin-2-amine
Figure imgf000073_0002
In a pressure tube were mixed 2-amino-5-bromo-6-chloropyrazine (20 g, 96.0 mmol), 4-fluoro- phenylboronic acid (14.8 g, 105.5 mmol), sodium carbonate (20.3 g, 191.9 mmol) in a 4:1 mix ture of 1 ,4-dioxane : water (250 ml). The reaction mixture was sparged with argon and
Pd(PPhi3)4 (2.2 g, 2.0 mmol) was then added. The mixture was sparged with argon shortly and the vessel was sealed. The reaction mixture was heated at 100 °C for 20 h. After that time, the reaction mixture was cooled down to r.t., filtered through Celite® pad, extracted with EtOAc/Na- HCO3 solution, organic layer was washed with brine and dried over Na2S04. Then the mixture was concentrated in vacuo to dryness. The obtained crude material was purified by flash chro matography on silica eluting with hexane : EtOAc (1 :0— 1 : 1 ) to lead to the title product as a light yellow solid (18.2 g, 85%). ESI-MS: 224.00 [M+H]+. b. 3-bromo-6-chloro-5-(4-fluorophenyl)pyrazin-2-amine
Figure imgf000074_0001
Into a pressure tube 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 CH3CN (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
[M+H]+. c. ethyl 8-bromo-5-chloro-6-(4-fluorophenyl)imidazo[ 1 ,2-a]pyrazine-2-carboxy!ate
Figure imgf000074_0002
To the 3-bromo-6-chloro-5-(4-fluorophenyl)pyrazin-2-amine (10 g; 33.06 mmol), dissolved in 130 ml of DME, 3-bromopyruvic acid ethyl ester (19.3 g; 99.17 mmol) was added. Reaction was stirred for 1 h at room temperatue (appearance of yellow solid was observed) and then heated to 85 °C for 16 h, under an argon atmosphere. After that time extraction was performed (DCM/NaHCOa aq). Combined organic layers were dried over MgS04. Product was purified by column chromatography, eluting with DCM/EtOH (0-5%) to afford the title product as a white solid (4.5 g, 31 %). ESI-MS: 400.05 [M+H]+. d. ethyl 8-amino-5-chloro-6-(4-fluorophenyl)imidazo[ 1 ,2-a]pyrazine-2-carboxy!ate
Figure imgf000074_0003
To the ethyl 8-bromo-5-chloro-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxylate (1 1 g; 31.06 mmol) ammonia in dioxane (140 ml) was added, reaction was heated for 20 h at 110 °C Product was purified by column chromatography, eluting with DCM/EtOH (0-5%) to afford the title product as a white solid (10.5 g, 31.06 mmol, quant). ESI-MS: 335.15 [M+H]+. 1 H NMR (400 MHz, DM SO -i/6) d 8.48 (s, 1 H), 7.77 - 7.70 (m, 2H), 7.60 (s, 2H), 7.35 - 7.28 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).
Procedure B
Example 1 : 8-amino-6-(4-fluorophenyl)-5-(4-methylquinoHn-6-yl)imidazo[1,2-a]pyrazine-2-car- boxy!ic acid
Figure imgf000075_0001
a. ethyl 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[ 1,2-a]pyrazine-2-car- boxy!ate
Figure imgf000075_0002
To the ethyl 8-amino-5-chloro-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxylate (Procedure A) (230 mg; 0.69 mmol) was added (4-methylquinolin-6-yl)boronic acid (380 mg, 2.06 mmol) and sodium carbonate (284 mg, 2.06 mmol) dissolved in 10ml of mixture dioxane/water 13: 1 and then Sphos Pd G3 (27 mg; 0.034 mmol) was added after argon purge (15 min). Reac tion mixture was heated at 130°C for 16 h. After that time the reaction mixture was cooled down to r.t., filtered and concentrated under reduced pressure. Product was purified by flash chroma tography (NH2 modified silica, DCM/EtOAc (0-50%)) to afford the title product (306 mg, 34%) as a white solid. ESI-MS: 442.40 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.04 (d, J = 5.0 Hz, 1 H), 8.39 (s, 1 H), 8.24 - 8.20 (m, 1 H), 7.96 - 7.90 (m, 2H), 7.74 (d, J = 4.7 Hz, 1 H), 7.39 - 7.32
(m, 2H), 7.09 - 7.01 (m, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.71 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). b . 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[ 1, 2-a]pyrazine-2-carboxylic acid
Figure imgf000076_0001
Pressure tube was charged with ethyl 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)im- idazo[1 ,2-a]pyrazine-2-carboxylate (240 mg, 0.54 mmol) and dissolved in ethanol (5 ml) then LiOH (34 mg, 0.82 mmol) in water (2 ml) was added and reaction mixture was stirred at 90°C for 2h. Then the mixture was concentrated in vacuo to dryness and transformed into hydrochloride salt to afford the title product (230 mg, quant) as a yellow solid. ESI-MS: 414.20 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.12 (d, J = 5.2 Hz, 1 H), 8.49 (d, J = 1.9 Hz, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 8.02 - 7.92 (m, 2H), 7.85 (d, J = 5.2 Hz, 1 H), 7.45 - 7.35 (m, 2H), 7.1 1 (dd, J = 10.0,
7.8 Hz, 2H), 2.78 (s, 3H).
Procedure C
Example 2: 8-amino-N-ethyl-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[ 1,2-a]pyra- zine-2-carboxamide
Figure imgf000076_0002
To a solution of 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2- carboxylic acid (Example 1 , 25 mg, 0.06 mmol) in DMF (3 ml) were added: HATU (28mg, 0.07mmol), DIPEA (0.021 ml, 0.12 mmol) and ethylamine 2M in THF (0.036 ml). The mixture was stirred at room temperature for 16 h. The mixture was evaporated. Extracted with
EtOAc/H20, organic layer was washed with brine and dried over Na2S0 . Then the mixture was concentrated in vacuo to dryness. The obtained crude material was purified by flash chromatog raphy (silica gel, DCM, MeOH 0-7%), then transformed into hydrochloride salt to give the title compound (18 mg, 68%) as white solid, hydrochloride salt. ESI-MS: 441.20 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.03 (d, J = 5.0 Hz, 1 H), 8.39 (s, 1 H), 8.23 - 8.14 (m, 2H), 7.89 (d, J = 7.6 Hz, 2H), 7.72 (s, 1 H), 7.38 (dd, J = 8.3, 5.7 Hz, 2H), 7.07 (t, J = 8.8 Hz, 2H), 3.33 - 3.25 (m, 2H), 2.71 (s, 3H), 1 .1 1 (t, J = 7.2 Hz, 3H). Exa m pi e 3 : 2-{2, 6-diazaspiro[3.4]octane-2-carbonyl}-6-(4-fluorophenyl)-5-(4-methylquinolin-6- y!)imidazo[ 1 ,2-a]pyrazin-8-amine
Figure imgf000077_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2,6-diaza-spiro[3.4]octane-6-carboxylic acid tert-butyl ester for ethylamine to lead to the title compound (2 mg, 69%) as white solid. ESI-MS: 508.40 [M+H]+. 1 H NMR (400 MHz, Deuterium Oxide) d 9.16 (d, J = 4.6 Hz, 1 H), 8.89 (s, 1 H), 8.47 (d, J = 8.5 Hz, 1 H), 8.43 (d, J = 1.9 Hz, 1 H), 8.27 (s, 1 H), 8.16 (dd, J = 8.7, 1.9 Hz, 1 H), 7.83 (d, J = 4.9 Hz, 1 H), 7.75 - 7.69 (m, 2H), 7.40 - 7.34 (m, 2H), 5.13 (s, 3H), 4.02 (d, J = 4.1 Hz, 2H), 3.88 - 3.82 (m, 2H), 2.92 (s, 3H), 2.83 - 2.77 (m, 2H), 2.64 (s, 1 H).
Example 4:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(pyridin-2-yl)methyl]imidazo[1,2-a]py- razine-2-carboxamide
Figure imgf000077_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing pyridin-2-ylmethanamine for ethylamine and substituting Et3N for DIPEA and substituting HBTU for HATU to lead to the title compound (36 mg, 17%) as yellow solid, hydrochloride salt. ESI-MS: 502.10 [M+H]+. 1 H NMR (400 MHz, Methanol- 4) d 9.1 1 (d, J = 5.5 Hz, 1 H), 8.77 (d, J = 5.7 Hz, 1 H), 8.67 (s, 1 H), 8.50 (td, J = 8.0, 1.5 Hz, 1 H), 8.28 (d, J = 8.8 Hz, 1 H), 8.19 (s, 1 H), 8.1 1 (dd, J = 8.8, 1.5 Hz, 1 H), 8.00 (dd, J = 15.4, 6.8 Hz, 2H), 7.96 - 7.87 (m, 1 H), 7.52 (dt, J = 14.3, 7.2 Hz, 2H), 7.10 (t, J = 8.7 Hz, 2H), 4.97 (s, 2H), 2.96 (s, 3H).
Example 5: 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(oxan-4-yl)imidazo[1,2-a]pyrazine-2- carboxamide
Figure imgf000078_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 4-aminotetrahydropyran for ethylamine and conducting this step for 3 h to lead to the title compound (18 mg, 87%) as yellow solid, hydrochloride salt. ESI-MS: 497.30 [M+H]+. 1 H NMR (400 MHz, DM SO -£#5) d 9.10 (d, J = 5.2 Hz, 1 H), 8.47 (d, J = 1.8 Hz, 1 H), 8.30 (d, J = 8.7 Hz,
1 H), 8.1 1 (d, J = 8.0 Hz, 1 H), 7.99 (s, 1 H), 7.95 (dd, J = 8.7, 1.8 Hz, 1 H), 7.83 (d, J = 5.1 Hz,
1 H), 7.44 - 7.35 (m, 2H), 7.15 - 7.04 (m, 2H), 4.05 - 3.92 (m, 1 H), 3.90 - 3.80 (m, 2H), 3.38 (m, J = 1 1.8, 2.1 Hz, 2H), 2.77 (s, 3H), 1.81 - 1.68 (m, 2H), 1 .63 - 1.49 (m, 2H).
Example 6:
8-amino-6-(4-fluorophenyl)-N-(4-fluoropyrrolidin-3-yl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000078_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate for ethylamine and substituting EtsN for DIPEA and substituting HBTU for HATU to lead to the title compound (27.5 mg, 52%) as yellow solid, hydrochloride salt. ESI-MS: 500.20 [M+H]+. 1 H NMR (300 MHz, DMSO -d6) d 9.71 (s,
2H), 9.12 (d, J = 5.2 Hz, 1 H), 9.03 (d, J = 7.3 Hz, 1 H), 8.53 (s, 1 H), 8.34 - 8.21 (m, 2H), 7.95 - 7.79 (m, 2H), 7.45 - 7.33 (m, 2H), 7.16 - 7.03 (m, 2H), 5.42 - 5.16 (m, 1 H), 4.76 - 4.62 (m, 1 H), 3.63 - 3.55 (m, 2H), 3.44 - 3.30 (m, 2H), 2.84 (s, 3H).
Example 7:
8-amino-N-[3-(difluoromethoxy)propyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000079_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3-(difluoromethoxy)propan-1 -amine for ethylamine and performing this step for 1.5 h to lead to the title compound (26 mg, 17%) as yellow solid, hydrochloride salt. ESI-MS: 521.30 [M+H]+.
1 H NMR (400 MHz, DMSO-r/6) d 9.08 (d, J = 5.1 Hz, 1 H), 8.45 (s, 1 H), 8.33 (t, J = 6.0 Hz, 1 H), 8.25 (d, J = 8.7 Hz, 1 H), 7.96 - 7.89 (m, 2H), 7.81 - 7.76 (m, 1 H), 7.42 - 7.36 (m, 2H), 7.12 - 7.05 (m, 2H), 6.66 (t, J = 76.2 Hz, 1 H), 3.86 (t, J = 6.4 Hz, 2H), 3.34 (q, J = 6.7 Hz, 2H), 2.75 (s, 3H), 1.87-1.80 (m, J = 6.6 Hz, 2H).
Example 8:
8-amino-N-tert-butyl-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazine-2-car- boxamide
Figure imgf000079_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut- ing tert-butylamine for ethylamine to lead to the title compound (19 mg, 28%) as yellow solid, hydrochloride salt. ESI-MS: 469.30 [M+H]+. 1 H NMR (400 MHz, DMSO-c 6) d 9.13 (d, J = 5.2 Hz, 1 H), 8.49 (s, 1 H), 8.32 (d, J = 8.7 Hz, 1 H), 7.95 (dd, J = 8.8, 1.8 Hz, 1 H), 7.91 - 7.82 (m, 2H), 7.48 (s, 1 H), 7.43 - 7.36 (m, 2H), 7.10 (t, J = 8.9 Hz, 2H), 2.79 (s, 3H), 1.39 (s, 9H).
Example 9:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000080_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2,2,2-trifluoroethylamine for ethylamine to lead to the title compound (23 mg, 99%) as yellow solid, hydrochloride salt. ESI-MS: 495.2 [M+H]+. 1 H NMR (400 MHz, DMSO-</6) d 9.04 (d, J = 5.0 Hz, 1 H), 8.75 (t, J = 6.6 Hz, 1 H), 8.42 (s, 1 H), 8.22 (d, J = 8.6 Hz, 1 H), 8.02 (s, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.74 (s, 1 H), 7.41 - 7.34 (m, 2H), 7.06 (t, J = 8.9 Hz, 2H), 4.09 (dd, J = 9.8, 6.8 Hz, 2H), 2.73 (d, J = 1 .7 Hz, 3H).
Example 10:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(morpholin-2-yl)methyl]imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000080_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 4-Boc-2-aminomethylmorpholine for ethylamine to lead to the title compound (19 mg, 34%) as yellow solid, hydrochloride salt. ESI-MS: 512.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.41 - 9.23 (m, 2H), 9.06 (d, J = 5.1 Hz, 1 H), 8.43 (s, 1 H), 8.33 (t, J = 6.2 Hz, 1 H), 8.26 (d, J = 8.7 Hz, 1 H), 7.97 (s, 1 H), 7.91 (d, J = 8.7 Hz, 1 H), 7.77 (s, 1 H), 7.42 - 7.35 (m, 2H), 7.08 (t, J = 8.9 Hz, 2H), 3.99 - 3.93 (m, 2H), 3.89 - 3.83 (m, 2H), 3.42 - 3.35 (m, 2H), 3.23 (d, J = 12.5 Hz,
1 H), 3.16 (d, J = 12.9 Hz, 1 H), 3.01 - 2.89 (m, 1 H), 2.74 (s, 3H).
Example 1 1 :
8-amino-6-(4-fluorophenyl)-N-[2-(methylamino)ethyl]-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000081_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing N-methylenediamine for ethylamine to lead to the title compound (14 mg, 19%) as yellow solid, hydrochloride salt. ESI-MS: 470.30 [M+H]+.1H NMR (400 MHz, DMSO -c/6) d 9.00 (d, J = 4.9 Hz, 1H), 8.67 (s, 2H), 8.58 (t, J = 6.0 Hz, 1H), 8.36 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.97 (s,
1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.68 (s, 2H), 7.41 - 7.35 (m, 2H), 7.09 - 7.02 (m, 2H), 3.58 - 3.52 (m, 2H), 3.10 - 3.02 (m, 2H), 2.70 (s, 3H), 2.56 (t, J = 5.4 Hz, 3H).
Example 12:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(pyrrolidin-3-yl)imidazo[1,2-a]pyrazine-
2-carboxamide
Figure imgf000081_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1-Boc-3-aminopyrrolidine for ethylamine to lead to the title compound (9 mg, 21%) as yellow solid, hydrochloride salt. ESI-MS: 482.30 [M+H]+.1H NMR (400 MHz, DMSO -d6) d 9.25 (s,
1 H), 9.15 (s, 1H), 9.07 (d, J = 5.1 Hz, 1H), 8.71 (d, J = 7.2 Hz, 1H), 8.45 (s, 1H), 8.26 (d, J = 8.8 Hz, 1 H), 8.10 (s, 1 H), 7.98 (s, 1H), 7.92-7.86 (m, 1H), 7.78 (s, 1H), 7.42-7.34 (m, 2H), 7.08 (t, J = 8.9 Hz, 2H), 4.57 (h, J = 6.4 Hz, 1H), 3.43-3.29 (m, 2H), 3.21 (q, J = 6.3 Hz, 1H), 3.14 (dq, J = 11.5, 5.7 Hz, 1H), 2.78 (s, 3H), 2.26-2.15 (m, 1H), 2.01 - 1.89 (m, 1H).
Example 13:
8-amino-N-(1,1-dioxo-1A6-thiolan-3-yl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a] pyrazi ne-2-carboxam id e
Figure imgf000082_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing tetrahydro-3-thiophenamine 1 ,1 -dioxide hydrochloride for ethylamine and substituting HBTU for HATU to lead to the title compound (65 mg, 19%) as yellow solid, hydrochloride salt. ESI- MS: 531.20 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.12 (d, J = 5.2 Hz, 1 H), 8.71 (d, J = 7.7 Hz, 1 H), 8.50 (d, J = 1 .9 Hz, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 8.06 (s, 1 H), 7.95 (dd, J = 8.7, 1.8 Hz, 1 H), 7.85 (d, J = 5.3 Hz, 1 H), 7.43 - 7.37 (m, 2H), 7.14 - 7.06 (m, 2H), 4.70 (h, J = 8.0 Hz,
1 H), 3.47 (dd, J = 13.2, 7.8 Hz, 1 H), 3.35 (ddd, J = 12.9, 8.2, 4.3 Hz, 1 H), 3.24 - 3.16 (m, 1 H), 3.16 - 3.08 (m, 1 H), 2.79 (s, 3H), 2.43 (dq, J = 13.1 , 7.1 , 6.7 Hz, 1 H), 2.27 - 2.17 (m, 1 H).
Example 14:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(2-oxopyrrolidin-3-yl)imidazo[1,2-a]py- razine-2-carboxamide
Figure imgf000082_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3-amino-2-pyrrolidinone for ethylamine 2M in THF and substituting HBTU for HATU to lead to the title compound (16 mg, 20%) as yellow solid, hydrochloride salt. ESI-MS: 496.30 [M+H]+.
1 H NMR (300 MHz, DMSO-dS) d 9.12 (d, J = 5.2 Hz, 1 H), 8.51 (s, 1 H), 8.36 (dd, J = 13.2, 5.2 Hz, 2H), 8.02 (s, 1 H), 7.95 (s, 1 H), 7.86 (d, J = 5.3 Hz, 1 H), 7.42 (dd, J = 8.6, 5.6 Hz, 2H), 7.1 1 (t, J = 8.8 Hz, 2H), 4.52 (q, J = 9.0 Hz, 1 H), 3.28 - 3.20 (m, 2H), 2.79 (s, 3H), 2.06-1.85 (m, 1 H), 2.06 - 1.85 (m, 1 H).
Example 15:
8-amino-6-(4-fluorophenyl)-N-(1-hydroxypropan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000083_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2-aminopropan-1-ol for ethylamine and substituting HBTU for HATU to lead to the title com- pound (12 mg, 13%) as yellow solid, hydrochloride salt. ESI-MS: 471.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.10 (d, J = 5.2 Hz, 1 H), 8.47 (d, J = 1.9 Hz, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 8.00 - 7.90 (m, 2H), 7.84 (dd, J = 10.7, 6.8 Hz, 2H), 7.44 - 7.36 (m, 2H), 7.10 (t, J = 8.9 Hz,
2H), 4.04-3.98 (m, 2H), 3.47-3.39 (m, 2H), 2.77 (s, 3H), 1.14 (d, J = 6.7 Hz, 3H). Example 16:
2-(4,4-difluoropiperidine-1-carbonyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazin-8-amine
Figure imgf000083_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 4,4-difluoropiperidine for ethylamine to lead to the title compound (43 mg, 48%) as yellow solid, hydrochloride salt. ESI-MS: 517.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.09 (d, J = 5.1 Hz, 1 H), 8.48 (s, 1 H), 8.27 (d, J = 8.8 Hz, 1 H), 8.10 (s, 2H), 7.92 (dd, J = 8.7, 1.8 Hz, 1 H), 7.88 (s, 1 H), 7.82 (d, J = 5.1 Hz, 1 H), 7.43 - 7.35 (m, 2H), 7.14 - 7.06 (m, 2H), 4.17 (s, 2H), 3.73 (s, 2H), 2.76 (s, 3H), 2.06 (s, 4H).
Example 17:
8-amino-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000084_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2,2-difluoroethylamine for ethylamine and substituting (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)bo- ronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(am- phos)C for Sphos Pd G3 in this step and performing this step for 2 h at 100°C to lead to the title compound (24.2 mg, 91 %) as beige solid, hydrochloride salt. ESI-MS: 466.20 [M+H]+. 1 H NMR (400 MHz, DMSO-i/6) d 9.61 (s, 1 H), 8.64 (t, J = 6.2 Hz, 1 H), 8.21 (d, J = 1.4 Hz, 1 H),
8.02 (s, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 7.51 - 7.36 (m, 3H), 7.13 (t, J = 8.9 Hz, 2H), 6.13 (tt, J = 55.9, 3.8 Hz, 1 H), 4.05 (s, 3H), 3.69 (tt, J = 15.7, 3.8 Hz, 2H).
Procedure D
Preparation of 8-chloro-4-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline
Figure imgf000084_0002
a. 6-bromo-8-chloro-4-methylquinoline
In a 3-neckled flask 4-bromo-2-chloroaniline (6.6 g, 32mmol) and 1 ,4-dioxane (450 ml) were stirred at 12°C, into it sulfuric acid (3.4 ml, 64 mmol) was added slowly and the mixture was heated to reflux. Into this refluxing mixture 3-buten-2-one (3.89 ml, 48 mmol) was added drop- wise. Reaction was heated for 6 h at reflux and then another portion of 3-buten-2-one (3.89 ml, 48 mmol) was added and reaction was carried for additional 4 h. The reaction mixture was cooled to r.t. and the solvent was evaporated, the residue was dissolved in DCM, 1 M solution of sodium carbonate (aq) was added until pH 8. Organic layer was washed with water, dried with Na2S0 , filtered and concentrated. Product was purified by flash chromatography (silica gel, hexane/DCM 50-100% of DCM) to afford a title product (3.82 g, 47%) as a yellow solid. ESI-MS: 257.80 [M+H]+.
b. 8-chloro-4-methyl-6-(4, 4, 5, 5-tetramethy 1- 1, 3,2-dioxaborolan-2-yl)quinoline
A pressure tube was charged with 6-bromo-8-chloro-4-methylquinoline (500 mg, 1.95 mmol), bis(pinacolato)diboron (643 mg, 2.53 mmol) and KOAc (574 mg, 5.85 mmol) and 75mL of di ethyl ether and sparged with argon for 10 min. Pd(dppf)Cl2 · DCM (71 mg, 0.1 mmol) was added in one portion and the reaction mixture was sparged with argon for additional 5 min. The pressure tube was capped and the reaction mixture was stirred at 80°C for 2 h. Then the reac tion mixture was cooled to r.t., filtered through Celite® and the filtrate was concentrated under reduced pressure. Product was purified by flash chromatography (silica gel, hexane/EtOAc) to afford the title compound (0.518g, 87.5%) as a yellowish solid. ESI-MS: 304.20 [M+H]+.
Example 18:
8-amino-5-(8-chloro-4-methylquinolin-6-yl)-6-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyrazine-
2-carboxamide
Figure imgf000085_0001
The title compound was synthesized following the approach outlined in Procedure F, substitut ing 8-chloro-4-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline (Procedure D) for 4-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline in Procedure F, step b substituting SPhos Pd G3 for Pd(amphos)Cl2 in step b and performing this step for 2 h at 120°C on oil bath to lead to the title compound (24.5 mg, 6.5%) as yellow solid, hydrochloride salt. ESI-MS: 461.20 [M+H]+. 1 H NMR (400 MHz, DMSO-i/6) d 8.94 (d, J = 4.4 Hz, 1 H), 8.23 - 8.17 (m, 2H), 8.04 (bs, 1 H), 7.97 (d, J = 1.8 Hz, 1 H), 7.56 (d, J = 4.3 Hz, 1 H), 7.45 - 7.39 (m, 2H), 7.17 - 7.10 (m, 2H), 2.78 (d, J = 4.7 Hz, 3H), 2.60 (s, 3H).
Procedure E:
Preparation of 4-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline
Figure imgf000085_0002
a. 6-bromo-4-(difluoromethyl)quinoline
Figure imgf000085_0003
Into the flask 6-bromoquinoline-4-carbaldehyde (500 mg, 2.21 mmol) was added and dis solved in DCM (5 ml) to this (diethylamino)sulfur trifluoride (DAST) (0.705ml, 4.24mmol) was added. The mixture was stirred for 3 h at room temperature. The mixture was carefully quenched with saturated sodium bicarbonate and extracted with DCM. Combined organic layers were dried with magnesium sulfate and evaporated to provide the product (446 mg, 82%) as a brown solid. ESI-MS: 257.90 [M+H]+. 1 H NMR (300 MHz, DMSO-i/6) d 9.10 (d, J = 4.3 Hz, 1 H), 8.38 (q, J = 1.6 Hz, 1 H), 8.11 (d, J = 8.9 Hz, 1 H), 8.02 (dd, J = 9.0, 2.1 Hz, 1 H), 7.82 (d, J = 4.4 Hz, 1 H), 7.74 (t, J = 53.6 Hz, 1 H). b. 4-(difIuoromethy!)-6-(4, 4, 5, 5-tetramethyl· 1, 3,2-dioxaborolan-2-yl)quinoline
Figure imgf000086_0001
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) was added and argon was bubbled through the suspension for another 5 minutes. Subsequently the tube was closed and the reaction mixture was heated at 100°C for 30 minutes under microwave irradiation. Then reaction mixture was cooled to r.t. then diluted with EtOAc, washed with brine. Organic layer was dried over magnesium sulfate, filtered and concentrated to give crude prod uct as a yellowish oil. The product containing a mixture of the acid and ester was used for the next step without further purification. ESI-MS: 223.0, 306.3 [M+H]+.
Example 19:
Procedure F
8-amino-5-[4-(difluoromethyl)quinolin-6-yl]-6-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyrazine-
2-carboxamide
Figure imgf000086_0002
Figure imgf000087_0001
Into the pressure tube ethyl 8-amino-5-chloro-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-car- boxylate (1 g, 2.64 mmol), absolute ethanol (4 ml) and methylamine 33%(w) in absolute ethanol (1.64 ml, 13.2 mmol) were added. Reaction was heated for 16 h at 100°C. The mixture was evaporated to lead to the title compound as yellowish solid (0.81 g, 96%). ESI-MS: 321.30
[M+H]+. b. 8-amino-5-[4-(difluoromethyl)quinolin-6-yl]-6-(4-fluorophenyl)-N-methylimidazo[ 1, 2-a]py- razine-2-carboxamide
Figure imgf000087_0002
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. Pd(amphos)Cl2 (4 mg, 0.05 eq) was added in one portion and argon was bubbled through the suspension for another 5 minutes. Subsequently the tube was closed and the reaction mixture was heated for 1 h at 100°C under microwave irradiation. After that time reaction mixture was diluted with EtOAc and water. Water phase was washed with EtOAc. The combined organic phases were dried over MgS04, filtered and evaporated. Product was purified by flash chromatography (diol-modified silica gel, EtOAc, Hexane 20-80%) to lead to the title compound (27 mg, 47%) as yellow solid, hydrochloride salt. ESI-MS: 463.25 [M+H]+. 1 H NMR (400 MHz, DMSO-i/6) d 9.13 (d, J = 4.4 Hz, 1 H), 8.55 (s, 2H), 8.28 - 8.17 (m, 3H), 7.97 (s, 1 H), 7.88 (dd, J = 8.7, 1.9 Hz, 1 H), 7.81 (d, J = 4.4 Hz, 1 H), 7.55 (t, J = 53.7 Hz, 1 H), 7.40 - 7.32 (m, 2H), 7.19 - 7.04 (m, 2H), 2.77 (d, J =
4.7 Hz, 3H)
Example 20:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(propan-2-yl)imidazo[1,2-a]pyrazine-2- carboxamide
Figure imgf000088_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing isopropylamine for ethylamine to lead to the title compound (30.5 mg, 30%) as yellow solid, hydrochloride salt. ESI-MS: 455.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.09 (d, J = 5.2 Hz, 1 H), 8.45 (s, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.97 - 7.92 (m, 2H), 7.90 (d, J = 8.1 Hz, 1 H),
7.82 (d, J = 5.0 Hz, 1 H), 7.43 - 7.36 (m, 2H), 7.09 (t, J = 8.9 Hz, 2H), 4.07 (dt, J = 7.9, 6.4 Hz,
1 H), 2.76 (s, 3H), 1 .16 (d, J = 6.6 Hz, 6H).
Example 21 :
8-amino-6-(4-fluorophenyl)-N-(2H3)methyl-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazine-2- carboxamide
Figure imgf000088_0002
In a pressure tube ethyl 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]py- razine-2-carboxylate (Procedure B, step a) (30 mg, 0.07 mmol) was suspended in a solution of NH2CD3 in NMP (5 ml, 0.07 mmol) and stirred for 72 h at 120°C. Then solvent was evaporated and product was purified by flash chromatography (DCM/MeOH 0-10%) to lead to the title com pound (22 mg, 75%) as yellow solid, hydrochloride salt. ESI-MS: 430.30 [M+H]+. 1 H NMR (300 MHz, DM SO -i/6) d 9.15 (d, J = 5.2 Hz, 1 H), 8.54 (d, J = 1.7 Hz, 1 H), 8.36 (d, J = 8.7 Hz, 1 H), 8.26 (s, 1 H), 8.06 (s, 1 H), 7.99 - 7.86 (m, 2H), 7.47 - 7.37 (m, 2H), 7.19 - 7.07 (m, 2H), 2.82 (s, 3H).
Example 22:
8-amino-N-(3-ethylpyrrolidin-3-yl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]py- razine-2-carboxamide
Figure imgf000089_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing tert-butyl 3-amino-3-ethylpyrrolidine-1 -carboxylate for ethylamine and substituting EtaN for DIPEA and substituting HBTU for HATU to lead to the title compound (22 mg, 50%) as yellow solid, hydrochloride salt. ESI-MS: 510.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.31 (s,
2H), 9.06 (d, J = 4.9 Hz, 1 H), 8.43 (s, 1 H), 8.26 (d, J = 8.7 Hz, 1 H), 8.14 (s, 1 H), 8.07 (s, 1 H), 7.90 (d, J = 8.2 Hz, 1 H), 7.77 (s, 1 H), 7.38 (dd, J = 8.7, 5.6 Hz, 2H), 7.08 (t, J = 8.9 Hz, 2H),
3.76 (s, 1 H), 3.28 (s, 2H), 3.17 - 3.08 (m, 1 H), 2.76 (s, 3H), 2.47 - 2.36 (m, 1 H), 2.17 - 2.03 (m,
1 H), 2.00 - 1.87 (m, 1 H), 1.83 - 1.69 (m, 1 H), 0.83 (t, J = 7.4 Hz, 3H).
Procedure G
Example 23:
2-(2,6-dimethylmorpholine-4-carbonyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazin-8-amine
Figure imgf000089_0002
In the microware reactor ethyl 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2- a]pyrazine-2-carboxylate (Procedure B, step a, 40 mg, 0.091 mmol) and 2,6-dimethylmorpholine (0.1 1 ml, 0.91 mmol) were dissolved in THF (2.3 ml). Then 2M AIMb3 in toluene (0.18 ml, 0.36mmol) was added slowly under argon atmosphere. The resulted mixture was heated to 130°C under microwave irradiation for 20 min. Then reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Product was purified by HPLC (with TFA addition) to lead to the title compound (10 mg, 19%) as yellow solid, hydrochlo ride salt. ESI-MS: 51 1.30 [M+H]+. 1 H NMR (300 MHz, DMSO-tf6) d 9.07 (d, J = 5.1 Hz, 1 H), 8.50 - 8.42 (m, 1 H), 8.23 (d, J = 8.7 Hz, 1 H), 7.97 - 7.71 (m, 3H), 7.45 - 7.34 (m, 2H), 7.19 - 6.98 (m, 2H), 5.05 - 4.89 (m, 1 H), 4.41 - 4.30 (m, 1 H), 3.22 - 3.07 (m, 2H), 2.96 - 2.79 (m, 2H), 2.75 (s, 3H), 1.13 (d, J = 5.8 Hz, 6H). Procedure H
Preparation of (4-chloro-1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid
Figure imgf000090_0002
In a pressure tube 4-bromo-2-chloro-6-fluoroaniline (1 g, 4.45 mmol) was dissolved in 1 ,2-di- chloroethane (20 ml) into it 3-chloroperbenzoic acid (3.12 ml, 17.15 mmol) was added. Reaction was heated for 12 h at 70°C. Resulting mixture was diluted with DCM and washed with water followed by saturated solution of NaHCOa. Organic phase was dried over MgS04, filtrated and concentrated. Crude reaction mixture was used to the next step without further purification. b. 5-bromo-3-chloro-N-methyl-2-nitroaniline
Figure imgf000090_0001
Round bottom flask was charged with 5-bromo-1 -chloro-3-fluoro-2-nitrobenzene (100 mg, 0.4 mmol), K2C03 (81.5 mg, 0.59 mmol) and DMF (2 ml), the mixture was cooled to 0°C and methyl- amine 2M in THF (0.3 ml, 0.59 mmol) was added. Reaction was left at r.t. for 6 h. Then the sol- vent was evaporated and product was purified by flash chromatography (silica gel, hexane/chlo roform 0-20%) to afford the title product as orange solid (26 mg, 25%). c. 5-bromo-3-chioro-N 1-methyibenzene- 1, 2-diamine Br SnCI Br
Figure imgf000091_0001
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. Resulting brown oil was used for the next step without further purification (0,82 g, 96%). ESI-MS: 236,00[M+H]+. d. 6-bromo-4-chloro- 1 -methyl· 1H- 1, 3-benzodiazote
Figure imgf000091_0002
Into a pressure tube suspension of 5-bromo-3-chloro-N 1 -methylbenzene-1 , 2-diamine (822 mg, 3.5 mmol) in water was (5 ml) added followed by formic acid (1.32 ml, 35 mmol). Reaction was heated for 3 h at 100°C. After that time reaction mixture was cooled, flask was put into an ice bath and 0.5M NaOH solution was added until pH 9-10. White precipitate was filtered off and a filtrate was washed with EtOAc and DCM. Organic phase was dried over MgS04 and evapo rated. Product was purified by flash chromatography (silica gel, DCM/MeOH 95:5) to afford the title product as a brown solid (0.622 g, 73%). ESI-MS: 246.95 [M+H]+. e. (4-ch!oro- 1 -methyl· 1H- 1, 3-benzodiazol-6-yl)boronic acid
Figure imgf000091_0003
In a pressure tube, 6-bromo-4-chloro-1-methyl-1 H-1 ,3-benzodiazole (200 mg, 0.85 mmol), bis(pinacolato)diboron (280 mg, 1.10mmol) and KOAc (104 mg, 1.06 mmol) were dissolved in 15ml_ of dry 1 ,4-dioxane and sparged with argon for 10 min. Pd(dppf)CI2 · DCM (34.7 mg, 0.04 mmol) was added in one portion and the reaction mixture was sparged with argon for additional 5 min. The pressure tube was capped and the reaction mixture was stirred at 100°C for 16 h. Then the reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and precipitated with hexane to afford the title product as a mixture of acid and ester, a beige solid (0.480 g, 0.2 mmol, 79%). ESI-MS: 293.10; 211 05[M+H]+.
Example 24:
8-amino-5-(4-chloro- 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-6-(4-fIuorophenyl)-N-methylimid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000092_0001
The title compound was synthesized following the approach outlined in Procedure F, substitut ing (4-chloro-1-methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid (Procedure H) for 4-(difluorome- thyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline in step b to lead to the title com pound (25 mg, 34%) as off-white solid, hydrochloride salt. ESI-MS: 450.20 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 8.49 (s, 1 H), 8.20 (d, J = 4.9 Hz, 1 H), 7.85 (s, 1 H), 7.79 (d, J = 1.4 Hz,
1 H), 7.46 - 7.36 (m, 2H), 7.33 (d, J = 1.4 Hz, 1 H), 7.13 (t, J = 8.9 Hz, 2H), 3.85 (s, 3H), 2.78 (d,
J = 4.6 Hz, 3H).
Example 25:
8-amino-6-(4-fluorophenyl)-N-methyl-5-{3-methylimidazo[1,2-a]pyridin-6-yl}imidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000092_0002
The title compound was synthesized following the approach outlined in Procedure F, substitut ing {3-methylimidazo[1 ,2-a]pyridin-6-yl}boronic acid for 4-(difluoromethyl)-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)quinoline in step b and substituting Pd(PPh3)4 for Pd(amphos)Cl2 and performing this step at 130°C for 16 h to lead to the title compound (25.6 mg, 20%) as yellow solid, hydrochloride salt. ESI-MS: 416.20 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.14 (s,
1 H), 8.22 (s, 1 H), 8.13 (q, J = 4.2, 3.7 Hz, 1 H), 8.07 (d, J = 1.3 Hz, 1 H), 7.98 (dd, J = 9.3, 0.9 Hz, 1 H), 7.73 (dd, J = 9.2, 1.5 Hz, 1 H), 7.49 - 7.43 (m, 2H), 7.15 - 7.07 (m, 2H), 2.80 (d, J = 4.8 Hz, 3H), 2.54 (d, J = 1 .1 Hz, 3H). Example 26:
8-amino-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-N-(oxolan-3-yl)imidazo[ 1,2- a]pyrazine-2-carboxamide
Figure imgf000093_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2 h at 100°C and then following Procedure C, substituting 3-amino- tetrahydrofuran for ethylamine to lead to the title compound (19 mg, 17%) as off-white solid, hy drochloride salt. ESI-MS: 472.30 [M+H]+. 1 H NMR (400 MHz, DMSO-c/6) d 9.23 (s, 1 H), 8.19 (d, J = 7.2 Hz, 1 H), 8.10 (s, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.76 (s, 1 H), 7.42 (dd, J = 8.4, 1.5 Hz, 1 H), 7.40 - 7.34 (m, 2H), 7.1 1 - 7.01 (m, 2H), 4.51 - 4.44 (m, 1 H), 3.98 (s, 3H), 3.88 - 3.83 (m,
1 H), 3.82 - 3.78 (m, 1 H), 3.74 - 3.68 (m, 1 H), 3.62 - 3.57 (m, 1 H), 2.23 - 2.12 (m, 1 H), 1 .94 - 1.82 (m, 1 H).
Example 27:
2-(2, 6-dimethylmorpholine-4-carbonyl)-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6- y!)imidazo[ 1 ,2-a]pyrazin-8-amine
Figure imgf000093_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2h at 100°C and then following Procedure G, substituting (1-methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid to lead to the title compound (28 mg, 43%) as yellow solid, hydrochloride salt. ESI-MS: 500.30 [M+H]+. 1 H NMR (400 MHz, DMSO-c/6) d 9.34 (s,
1 H), 8.13 (s, 1 H), 7.87 (d, J = 8.5 Hz, 1 H), 7.66 (s, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.40 - 7.32 (m, 2H), 7.08 (t, J = 8.9 Hz, 2H), 5.08 (s, 1 H), 4.36 (d, J = 13.2 Hz, 1 H), 3.99 (s, 3H), 2.85 (s, 1 H), 2.47 - 2.41 (m, 3H), 1.14 (d, J = 6.2 Hz, 6H). Example 28:
8-amino-N-(4-aminobutyl)-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)imidazo[ 1,2- a]pyrazine-2-carboxamide
Figure imgf000094_0001
In a pressure tube ethyl 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 , 3-benzodiazol-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxylate (described in Procedure B, step a substituting (1 -methyl-1 H- 1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid and substituting Pd(amphos)Cl2 for Sphos Pd G3 in this step and performing this step for 2 h at 100°C) (20 mg, 0.05 mmol) was suspended in THF (2.5 ml) and 1 ,4-diaminobutane (0.14ml, 1.4mmol) was added into it, reaction was stirred for 4 h at 140°C. To the resulting mixture water was added and EtOAc. Organic layer was washed with brine, dried over Na2S04, filtered and concentrated to lead to the title compound (10 mg, 19%) as beige solid, hydrochloride salt. ESI-MS: 473.50 [M+H]+. 1 H NMR (300 MHz, Deuterium Oxide) d 9.02 (s, 1 H), 7.84 (s, 1 H), 7.84 - 7.75 (m, 2H), 7.51 (dd, J = 8.6, 1.4 Hz, 1 H), 7.31 - 7.20 (m, 2H), 6.99 - 6.86 (m, 2H), 3.90 (s, 3H), 3.40 - 3.32
(m, 2H), 3.00 - 2.87 (m, 2H), 1.72 - 1.53 (m, 4H).
Example 29:
8-amino-N-{2-[4-(2,4-difluorophenyl)piperazin- 1-yl]ethyl}-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazo!-6- y!)imidazo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000094_0002
Figure imgf000095_0001
A pressure tube was charged with 1-(2,4-difluorophenyl)piperazine (250 mg, 1.3 mmol), 2-(2- bromoethyl)-1 H-lsoindole-1 ,3(2H)-dione (384 mg, 1.5 mmol), K2CO3 (349 mg, 2.5 mmol) and DMF (4ml). Reaction was heated for 16 h at 70°C. The reaction mixture was diluted with water, extracted with EtOAc. Combined organic layers were washed with brine dried over Na2SC>4, filtered and concentrated. Product was isolated by flash chromatography (silica gel, Hex- ane/EtOAc 0% to 50%) to afford the title product as light beige solid (300 mg, 64%). ESI-MS: 372.7 [M+H]+. b. 2-[4-(2, 4-difluorophenyl)piperazin- 1-y!]ethan- 1 -amine
Figure imgf000095_0002
In a pressure tube were placed 2-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}-2,3-dihydro- 1 H-isoindole-1 ,3-dione (300 mg, 0.8 mmol) and hydrazinium hydroxide (N2H2 64-65%) (0.40 ml, 0.8 mmol) in EtOH (3 ml). The vessel was sealed and the mixture was stirred at 70°C for 16 h. Volatiles were distilled off in vacuo to afford the title product as a white solid (0.185 g, quant). ESI-MS: 242.10 [M+H]+. c. 8-amino-N-{2-[4-(2, 4-difluorophenyl)piperazin- 1-yl]ethyl}-6-(4-fluorophenyl)-5-( 1-methyt- 1H- 1, 3-benzodiazol-6-yl)imidazo[ 1 ,2-a]pyrazine-2-carboxamide
The title compound was synthesized following the approach outlined in Procedure B, substituting (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in step a and performing this step for 2 h at 100°C and the following Procedure G, substituting 2-[4-(2,4-difluorophenyl)pi- perazin-1-yl]ethan-1 -amine for 2,6-dimethylmorpholine to lead to the title compound (10 mg, 13%) as yellow solid, hydrochloride salt. ESI-MS: 626.25 [M+H]+. 1 H NMR (300 MHz, Deuter ium Oxide) d 9.03 (s, 1 H), 7.90 (s, 1 H), 7.85 (s, 1 H), 7.79 (d, J = 8.6 Hz, 1 H), 7.52 (dd, J = 8.5, 1.4 Hz, 1 H), 7.31 - 7.23 (m, 2H), 7.13 - 7.03 (m, 2H), 7.00 - 6.86 (m, 4H), 3.91 (s, 3H), 3.81 (t, J= 5.9 Hz, 2H), 3.79 - 3.60 (m, 2H), 3.63 - 3.47 (m, 2H), 3.45 (t, J= 6.0 Hz, 2H), 3.40 - 3.19 (m, 2H), 3.20 - 3.00 (m, 2H).
Example 30:
2-[4-(2, 4-difluorophenyl)piperazine- 1-carbonyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6- y!)im- idazo[ 1 ,2-a]pyrazin-8-amine
Figure imgf000096_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1 -(2,4-difluorophenyl)piperazine for ethylamine to lead to the title compound (19 mg, 40%) as yellow solid, hydrochloride salt. ESI-MS: 594.35 [M+H]+. 1 H NMR (400 MHz, DMSO-c/6) d 9.1 1 (d, J = 5.1 Hz, 1 H), 8.49 (d, J = 1.8 Hz, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.94 (dd, J = 8.8, 1.8
Hz, 1 H), 7.90 (s, 1 H), 7.84 (d, J = 5.2 Hz, 1 H), 7.45 - 7.36 (m, 2H), 7.24 (ddd, J = 12.2, 9.0, 2.9 Hz, 1 H), 7.16 - 7.07 (m, 3H), 7.02 (td, J = 8.4, 2.8 Hz, 1 H), 4.32 - 4.23 (m, 2H), 3.81 - 3.77 (m, 2H), 3.02 (t, J = 4.8 Hz, 4H), 2.78 (s, 3H). Example 31 :
6-(4-fluorophenyl)-2-[4-(2-methoxyethyl)piperazine- 1-carbonyl]-5-(4-methylquinolin-6-yl)imid- azo[ 1 ,2-a]pyrazin-8-amine
Figure imgf000096_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing N-(2-methoxyethyl)piperazine for ethylamine and performing this step at room temperature for 2 h to lead to the title compound (24 mg, 9%) as yellow solid, hydrochloride salt. ESI-MS: 540.00 [M+H]+. 1 H NMR (400 MHz, DMSO-i/6) d 1 1.27 (s, 1 H), 9.14 (d, J = 5.3 Hz, 1 H), 8.52 (s, 2H), 8.37 (d, J = 8.8 Hz, 1 H), 8.03 - 7.83 (m, 3H), 7.40 (dd, J = 8.7, 5.5 Hz, 2H), 7.10 (t, J = 8.9 Hz, 2H), 5.43 (s, 1 H), 4.59 - 4.49 (m, 1 H), 3.82 - 3.71 (m, 2H), 3.61 - 3.52 (m, 2H), 3.41 - 3.27 (m, 5H), 3.26 - 3.03 (m, 4H), 2.80 (s, 3H).
Example 32:
8-amino-6-(4-fluorophenyl)-N-methyl-5-(4-methylqulnolin-6-yl)-N-(propan-2-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000097_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing N-isopropylmethylamine for ethylamine to lead to the title compound (18 mg, 13%) as yellow solid, hydrochloride salt. ESI-MS: 469.00 [M+H]+. 1 H NMR (300 MHz, DMSO-c/6) d 9.15 (d, J = 5.3 Hz, 1 H), 8.94 (s, 1 H), 8.55 (s, 1 H), 8.38 (d, J = 8.7 Hz, 1 H), 8.01 - 7.87 (m, 3H), 7.48 - 7.38 (m, 2H), 7.21 - 7.08 (m, 2H), 4.78 - 4.63 (m, 1 H), 3.09 (s, 3H), 2.81 (s, 3H), 1.22 - 1.06 (m, 6H).
Example 33:
8-amino-6-(4-fluorophenyl)-N-(2-methoxyethyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000097_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing (2-methoxyethyl)methylamine for ethylamine to lead to the title compound (1 1 mg, 8%) as yellow solid, hydrochloride salt. ESI-MS: 485.00 [M+H]+. 1 H NMR (300 MHz, Deuterium Oxide) d 8.90 (d, J = 5.7 Hz, 1 H), 8.43 (s, 1 H), 8.15 (dd, J = 8.8, 1.7 Hz, 1 H), 8.02 - 7.82 (m, 3H), 7.37
- 7.26 (m, 2H), 7.02 - 6.90 (m, 2H), 3.94 (t, J = 5.2 Hz, 1 H), 3.67 (s, 2H), 3.59 (t, J = 5.2 Hz, 1 H), 3.32 - 3.22 (m, 3H), 3.10 - 2.98 (m, 3H), 2.78 (s, 3H).
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
Figure imgf000098_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2 h at 100°C and then following Procedure G, substituting 3-(Boc- amino)pyrrolidine for 2,6-dimethylmorpholine to lead to the title compound (26 mg, 75%) as beige solid, hydrochloride salt. ESI-MS: 471.20 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.43 (s, 1 H), 9.35 (s, 1 H), 9.27 (s, 1 H), 8.80 (d, J = 7.2 Hz, 1 H), 8.18 (s, 1 H), 8.06 (s, 1 H), 7.86 (d, J = 8.5 Hz, 1 H), 7.43 - 7.35 (m, 2H), 7.09 (t, J = 8.9 Hz, 2H), 4.57 (q, J = 6.2 Hz, 1 H), 4.06 (s,
3H), 3.39 - 3.31 (m, 2H), 3.26 - 3.15 (m, 2H), 2.19 (dq, J = 14.5, 7.3, 6.6 Hz, 1 H), 1.97 (s, 1 H).
Example 35:
8-amino-6-(4-fluorophenyl)-5-( 1 -methyl· 1H- 1, 3-benzodiazol-6-yl)-N-(oxan-4-yl)imidazo[ 1,2- a]pyrazine-2-carboxamide
Figure imgf000098_0002
The title compound was synthesized following the approach outlined in Procedure B substitut- ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in step a and performing this step for 2h at 100°C and then following Procedure G, substituting 4-aminotetrahydropyran for 2,6-dimethylmorpholine to lead to the title compound (19 mg, 25%) as yellow solid, hydro chloride salt. ESI-MS: 486.60 [M+H]+. 1 H NMR (400 MHz, DMSO-i/6) d 9.41 (s, 1 H), 8.16 (s,
1 H), 8.10 (d, J = 4.9 Hz, 1 H), 7.89 (d, J = 8.4 Hz, 1 H), 7.79 (s, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.42 - 7.35 (m, 2H), 7.08 (t, J = 8.6 Hz, 2H), 4.01 (s, 3H), 4.00 - 3.94 (m, 1 H), 3.90 - 3.83 (m, 2H), 3.43 - 3.33 (m, 2H), 1.80 - 1.70 (m, 2H), 1.66 - 1.50 (m, 2H).
Procedure I Example 36:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(piperidin-4-yl)imidazo[1,2-a]pyrazine-
2-carboxamide
Figure imgf000099_0001
a. lithium 8-amino-5-chioro-6-(4-fiuorophenyi)imidazo[ 1 ,2-a]pyrazine-2-carboxyiate
Figure imgf000099_0002
In a pressure tube was placed ethyl 8-amino-5-chloro-6-(4-fluorophenyl)imidazo[1 ,2-a]pyra- zine-2-carboxylate (Procedure A, 200 mg, 0.6 mmol) and dissolved in ethanol (10 ml), then
LiOH (75 mg, 1.8 mmol) in water (4 ml) was added and reaction mixture was stirred at 90°C for 2h. Product precipitated form the mixture after cooling down. Product was filtered off to afford the title product (187 mg, quant yield) as a yellow solid. ESI-MS: 308.90 [M+H]+. 1 H NMR (300 MHz, DM SO -c/6) d 7.95 (d, J = 9.4 Hz, 1 H), 7.69 - 7.73 (m, 2H), 7.38 - 7.24 (m, 2H). b. tert-butyl 4-[8-amino-5-chloro-6-(4-fluorophenyl)imidazo[ 1,2-a]pyrazine-2-amido]piperidine- 1-carboxyiate
Figure imgf000099_0003
Into a flask lithium 8-amino-5-chloro-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxylate (35 mg, 0.1 1 mmol) was dissolved in DMF (3 ml) and then HATU (51 g, 0.13 mmol), DIPEA (0.06mL, 0.37mmol) and 1-Boc-4-aminopiperidine (47.8 mg, 0.12 mmol) and reaction was stirred at room temperature for 1 h. Then reaction mixture was extracted with EtOAc/hhO, or ganic layer was washed with brine and dried over Na2SC>4, filtered and concentrated in vacuo to dryness. Resulting solid was used for the next step without further purification (55mg, quant) ESI-MS: 487.3 [M-H]+. c. 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(piperidin-4-yl)imidazo[ 1, 2-a]pyra- zine-2-carboxamide
Figure imgf000100_0001
In a pressure tube was placed tert-butyl 4-[8-amino-5-chloro-6-(4-fluorophenyl)imidazo[1 ,2- a]pyrazine-2-amido]piperidine-1 -carboxylate (55 mg, 0.1 1 mmol), (4-methylquinolin-6-yl)boronic acid (42 mg, 0.22 mmol) and potassium carbonate (46.5 mg, 0.34 mmol) dissolved in 3.5 ml of mixture dioxane/water 6:1 ; then Sphos Pd G3 (4.4 mg; 0.006 mmol) was added after argon purge (15 min). Product was purified by flash chromatography (silica gel, DCM/EtOAc 1 :1 , then DCM/MeOH (0-5%)) and transformed into hydrochloride salt to afford the title product (10 mg, 15%) as yellow solid. ESI-MS: 496.30 [M+H]+. 1 H NMR (400 MHz, DMSO-c/6) d 9.07 (d, J = 5.0 Hz, 1 H), 8.87 (d, J = 37.9 Hz, 3H), 8.43 (s, 1 H), 8.26 (dd, J = 12.8, 8.3 Hz, 2H), 8.01 (s, 1 H), 7.96 - 7.91 (m, 1 H), 7.79 (s, 1 H), 7.42 - 7.35 (m, 2H), 7.08 (t, J = 8.9 Hz, 2H), 4.07 - 4.04 (m,
1 H), 3.28 (d, J = 12.6 Hz, 2H), 3.00 (t, J = 1 1.8 Hz, 2H), 2.75 (s, 3H), 1.95 (d, J = 13.0 Hz, 2H), 1.76 (d, J = 13.2 Hz, 2H).
Example 37:
6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-2-(piperazine- 1-carbony/)imidazo[ 1,2- a]pyrazin-8-amine
Figure imgf000100_0002
The title compound was synthesized following the approach outlined in Procedure B substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2 h at 100°C and then following Procedure G, substituting tert- bu- tylpiperazine-1-carboxylate for 2,6-dimethylmorpholine to lead to the title compound (26 mg, 33%) as white solid, hydrochloride salt. ESI-MS: 471 .30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.40 (s, 1 H), 9.34 (s, 3H), 8.13 (s, 1 H), 7.88 (d, J = 8.5 Hz, 1 H), 7.69 (s, 1 H), 7.43 (dd, J = 8.5, 1.5 Hz, 1 H), 7.40 - 7.34 (m, 2H), 7.07 (t, J = 8.9 Hz, 2H), 4.51 (d, J = 20.3 Hz, 4H), 3.99 (s, 3H), 3.83 (s, 2H), 3.32 (s, 1 H), 3.17 (s, 1 H).
Example 38:
8-amino-N,N-diethyl-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1 ,3-benzodiazol-6-yl)imidazo[ 1,2-a]py- razine-2-carboxamide
Figure imgf000101_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2 h at 100°C and then following Procedure C, substituting N,N-di- ethylamine for ethylamine to lead to the title compound (6.2 mg, 21 %) as off-white solid, hydro chloride salt. ESI-MS: 458.20 [M+H]+. 1 H NMR (300 MHz, Deuterium Oxide) d 9.23 (s, 1 H), 8.00 (d, J = 1.3 Hz, 1 H), 7.96 - 7.89 (m, 1 H), 7.83 (s, 1 H), 7.67 (dd, J = 8.5, 1.5 Hz, 1 H), 7.49 - 7.33 (m, 2H), 7.14 - 7.00 (m, 2H), 4.03 (s, 3H), 3.68 (q, J = 7.1 Hz, 2H), 3.55 (q, J = 7.2 Hz,
2H), 1.30 - 1.10 (m, 6H).
Example 39:
8-amino-6-(4-fluorophenyl)-N-(2-methoxyethyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000101_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2-methoxyethylamine for ethylamine to lead to the title compound (36 mg, 55%) as yellow solid, hydrochloride salt. ESI-MS: 471.20 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.08 (d, J = 5.1 Hz, 1 H), 8.50 - 8.42 (m, 1 H), 8.26 (d, J = 8.7 Hz, 1 H), 8.12 (s, 1 H), 7.98 - 7.88 (m, 2H), 7.80 (d, J = 5.1 Hz, 1 H), 7.44 - 7.33 (m, 2H), 7.09 (t, J = 8.9 Hz, 2H), 3.47 - 3.43 (m, 4H), 3.26 (s, 3H), 2.76 (s, 3H).
Procedure J
Example 40:
8-amino-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)imidazo[ 1 ,2-a]pyrazine-2-car- boxamide
The title compound was synthesized following the approach outlined in Procedure A, subse quently Procedure B, step a, substituting (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4- methylquinolin-6-yl)boronic acid in this step and substituting Pd(amphos)Cl2 for Sphos Pd G3 and performing this step for 2 h at 100°C to yield the (ethyl 8-amino-6-(4-fluorophenyl)-5-(1 -me- thyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxylate).
Figure imgf000102_0001
Into the pressure tube ethyl 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxylate (25 mg, 0.06 mmol) and NH3 in methanol (7N, 5 ml) were added. Reaction was heated for 16 h at 100°C. Solvent was evaporated. Product was pu rified by flash chromatography (NH2 modified silica gel, eluted with DCM/hexane from 10% hex ane to 0% hexane then DCM/MeOH from 0% MeOH to 4% MeOH) to lead to the title compound (15 mg, 54%) as white solid, hydrochloride salt. ESI-MS: 402.40 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.44 (s, 1 H), 8.16 (s, 1 H), 7.89 (d, J = 8.4 Hz, 1 H), 7.83 (s, 1 H), 7.58 (s, 2H), 7.45 (dd, J = 8.5, 1.5 Hz, 1 H), 7.41 - 7.36 (m, 2H), 7.10 (t, J = 8.8 Hz, 2H).
Procedure K
Example 41 (not according to the invention):
8-amino-5-(8-chloroquinolin-6-yl)-6-(4-fluorophenyl)imidazo[1,2-a]pyrazine-2-carboxamide a. 8-amino-5-chloro-6-(4-fluorophenyl)imidazo[1,2-a]pyrazine-2-carboxamid
Figure imgf000103_0001
To the ethyl 8-amino-5-chloro-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxylate (0.84 g; 2.51 mmol) 7N ammonia in methanol (100 ml) was added, reaction was heated for 2 h in 100°C. Product was purified by column chromatography, eluting with DCM/MeOH (0-10%) to afford the title product as a pale yellow solid (0.78 g, 2.51 mmol, quant). ESI-MS: 305.85; [M+H]+.
b. 8-amino-5-(8-chloroquinolin-6-yl)-6-(4-fluorophenyl)imidazo[l,2-a]pyrazine-2-carbox- amide
Figure imgf000103_0002
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)Cl2 (25 mg, 0.04 mmol) was added in one portion and argon was bubbled through the suspension for another 5 minutes. Subsequently the tube was closed and the reac tion mixture was heated for 5 h at 130°C. After cooling reaction mixture was diluted with EtOAc and water. Water phase was washed with EtOAc. The combined organic phases were dried over MgS04, filtered and concentrated. Product was purified by flash chromatography (NH2 modified silica gel, Hexane/EtOAc/EtOH form 1/1/0 to 0/95/5) to lead to the title compound (11 mg, 7%) as yellowish solid. ESI-MS: 433.20 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.09 (dd, J = 4.2, 1.7 Hz, 1 H), 8.45 (dd, J = 8.4, 1.7 Hz, 1 H), 8.11 (d, J = 1.8 Hz, 1 H), 7.99 (d, J = 1.9 Hz,
1 H), 7.86 (s, 1 H), 7.70 (dd, J = 8.3, 4.2 Hz, 1 H), 7.49 (d, J = 25.5 Hz, 2H), 7.43 - 7.27 (m, 4H), 7.13 - 6.98 (m, 2H).
Example 42:
8-amino-6-(4-fluorophenyl)-N-[(1-methylpyrrolidin-3-yl)methyl]-5-(4-methylquinolin-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000104_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing (1 -methylpyrrolidyin-3-yl)-methanamine hydrochloride for ethylamine to lead to the title com pound (25 mg, 49%) as yellow solid, hydrochloride salt. ESI-MS: 510.30 [M+H]+. 1 H NMR (400 MHz, DM SO -c/6) d 10.33 (s, 1 H), 9.00 (d, J = 4.8 Hz, 1 H), 8.56 - 8.47 (m, 1 H), 8.34 (d, J = 8.6 Hz, 1 H), 8.20 (d, J = 8.4 Hz, 1 H), 7.89 (dd, J = 14.1 , 7.6 Hz, 2H), 7.67 (s, 2H), 7.41 - 7.34 (m, 2H), 7.06 (dd, J = 10.0, 7.8 Hz, 2H), 3.37 - 3.31 (m, 2H), 3.16 - 2.92 (m, 3H), 2.84 - 2.76 (m, 4H), 2.69 (s, 4H), 2.20 - 1.93 (m, 1 H), 1.90 - 1.59 (m, 1 H).
Example 43:
8-amino-N-[3-(dimethylamino)butyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000104_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing (4-aminobutan-2yl)dimethylamine for ethylamine to lead to the title compound (27 mg, 35%) as yellow solid, hydrochloride salt. ESI-MS: 512.30 [M+H]+. 1 H NMR (400 MHz, DMSO-c 6) d 9.96 (s, 1 H), 9.01 (d, J = 4.8 Hz, 1 H), 8.45 (t, J = 5.8 Hz, 1 H), 8.37 (d, J = 1.7 Hz, 1 H), 8.20 (d, J = 8.7 Hz, 1 H), 7.91 (s, 1 H), 7.87 (dd, J = 8.7, 1.8 Hz, 1 H), 7.69 (d, J = 4.8 Hz, 2H), 7.41 - 7.35 (m, 2H), 7.06 (t, J = 8.9 Hz, 2H), 3.39 - 3.31 (m, 2H), 2.70 (d, J = 1.8 Hz, 3H), 2.68 (d, J = 5.0 Hz, 4H), 2.63 (d, J = 5.0 Hz, 3H), 2.08 - 1.97 (m, 1 H), 1.72 - 1.60 (m, 1 H), 1.26 (d, J = 6.6 Hz, 3H).
Example 44:
8-amino-N-(4,4-difluorocyclohexyl)-6-(4-fluorophenyl)-5-(4-methylquinoHn-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000105_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 4,4-difluorocyclohexan-1-amine for ethylamine to lead to the title compound (26 mg, 42%) as yellow solid, hydrochloride salt. ESI-MS: 531.50 [M+H]+. 1 H NMR (300 MHz, DMSO-^6) d 9.08 (d, J = 5.1 Hz, 1 H), 8.44 (d, J = 1.8 Hz, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 8.13 (d, J = 8.1 Hz,
1 H), 8.01 - 7.88 (m, 2H), 7.80 (d, J = 5.2 Hz, 1 H), 7.44 - 7.32 (m, 2H), 7.09 (t, J = 8.9 Hz, 2H), 3.95 (m, 1 H), 2.75 (s, 3H), 2.12 - 1.76 (m, 6H), 1 .65 (d, J = 16.5 Hz, 2H)
Example 45:
8-amino-5-(4-chloro- 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-(2-methoxy- ethy!)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000105_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (4-chloro-1-methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid (Procedure H) for (4-methylquino- lin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in step a and performing this step at 100°C for 1 h and performing step b in Procedure B at 80°C for 1 h and then following Procedure C, substituting 2-methoxyethyl-1 -amine for ethylamine to lead to the title compound (19 mg, 33%) as yellow solid, hydrochloride salt. ESI-MS: 494.20 [M+H]+. 1 H NMR (400 MHz, Chloroform -d) d 8.1 1 (s, 1 H), 7.96 (s, 1 H), 7.45 (dd, J = 8.8, 5.0 Hz, 2H), 7.33 (d, J = 1 .4 Hz, 1 H), 7.25 (d, J = 1.5 Hz, 1 H), 7.08 - 7.00 (m, 2H), 3.85 (s, 3H),
3.74 - 3.65 (m, 2H), 3.61 (t, J = 4.9 Hz, 2H), 3.46 (s, 3H).
Example 46:
8-amino-N-[2-(dimethylamino)propyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000106_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing (1 -aminopropan-2-yl)dimethylamine for ethylamine and substituting EtsN for DIPEA and sub stituting HBTU for HATU in this step to lead to the title compound (5 mg, 32%) as white solid. ESI-MS: 498.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 8.81 (d, J = 4.4 Hz, 1 H), 8.17 (d, J = 1.6 Hz, 1 H), 8.07 (d, J = 8.6 Hz, 1 H), 7.93 (s, 1 H), 7.79 - 7.68 (m, 2H), 7.42 (d, J = 4.3 Hz, 1 H), 7.35 (dd, J = 8.8, 5.6 Hz, 4H), 7.01 (t, J = 8.9 Hz, 2H), 3.26 - 3.15 (m, 2H), 2.77 (s, 1 H), 2.55 (s, 3H), 2.20 (s, 6H), 0.90 (d, J = 6.4 Hz, 3H).
Example 47:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(prop-2-yn- 1-yl)imidazo[ 1, 2-a]pyrazine- 2-carboxamide
Figure imgf000106_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3-amino-1-propyne for ethylamine to lead to the title compound (12 mg, 17%) as yellow solid, hydrochloride salt. ESI-MS: 451.30 [M+H]+. H NMR (400 MHz, DMSO-r/6) d 9.04 (d, J = 4.8 Hz, 1 H), 8.56 (t, J = 5.8 Hz, 1 H), 8.43 - 8.39 (m, 1 H), 8.21 (d, J = 8.7 Hz, 1 H), 7.99 (s, 1 H), 7.89 (d, J = 8.7 Hz, 1 H), 7.73 (s, 1 H), 7.41 - 7.35 (m, 2H), 7.08 (t, J = 8.8 Hz, 2H), 4.06 (dd, J = 5.8, 2.5 Hz, 2H), 3.15 (t, J = 2.5 Hz, 1 H), 2.73 (s, 3H).
Example 48:
8-amino-6-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-5-(4-methylquinoHn-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000107_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1 -amino-2-methyl-2-propanol for ethylamine to lead to the title compound (37.5 mg, 37%) as yellow solid, hydrochloride salt. ESI-MS: 485.20 [M+H]+. 1 H NMR (400 MHz, DMSO-i/6) d 9.13 (d, J = 5.2 Hz, 1 H), 8.50 (s, 1 H), 8.32 (d, J = 8.8 Hz, 1 H), 8.00 - 7.93 (m, 2H), 7.92 - 7.83 (m, 2H), 7.44 - 7.37 (m, 2H), 7.15 - 7.07 (m, 2H), 3.27 (d, J = 6.1 Hz, 2H), 2.79 (s, 3H), 1.1 1 (s,
6H).
Example 49:
8-amino-6-(4-fluorophenyl)-N-(1-methylpiperidin-4-yl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000107_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1 -methylpiperidin-4-amine for ethylamine to lead to the title compound (17 mg, 38%) as yel low solid, hydrochloride salt. ESI-MS: 510.30 [M+H]+. 1 H NMR (400 MHz, DMSO-c/6) d 10.51 (s, 1 H), 9.05 (d, J = 5.0 Hz, 1 H), 8.42 (d, J = 1 1.6 Hz, 1 H), 8.26 (d, J = 8.7 Hz, 2H), 8.20 (d, J = 7.9 Hz, 1 H), 7.98 (s, 1 H), 7.91 (d, J = 8.5 Hz, 1 H), 7.76 (s, 1 H), 7.41 - 7.34 (m, 2H), 7.07 (t, J = 8.8 Hz, 2H), 4.03 - 3.98 (m, 1 H), 3.39 (s, 1 H), 3.28 (d, J = 5.9 Hz, 1 H), 3.06 (d, J = 12.0 Hz,
2H), 2.74 (d, J = 13.2 Hz, 3H), 2.71 - 2.67 (m, 3H), 1 .99 (d, J = 13.9 Hz, 2H), 1.90 (t, J = 12.6 Hz, 2H).
Example 50:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(oxetan-2-yl)methyl]imidazo[1,2-a]py- razine-2-carboxamide
Figure imgf000108_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing oxetan-2-ylmethanamine for ethylamine and substituting Et3N for DIPEA and substituting HBTU for HATU in this step to lead to the title compound (14 mg, 30%) as white solid. ESI-MS: 483.20 [M+H]+. 1 H NMR (400 MHz, DMSO-t/6) d 8.81 (d, J = 4.4 Hz, 1 H), 8.26 - 8.15 (m, 2H), 8.07 (d, J = 8.6 Hz, 1 H), 7.83 (s, 1 H), 7.74 (dd, J = 8.7, 1.9 Hz, 1 H), 7.41 (t, J = 7.4 Hz, 1 H),
7.41 - 7.30 (m, 4H), 7.02 (t, J = 8.9 Hz, 2H), 4.81 (dt, J = 12.3, 6.2 Hz, 1 H), 4.51 (dd, J = 13.7, 7.9 Hz, 1 H), 4.42 (dt, J = 9.0, 5.9 Hz, 1 H), 3.62 - 3.53 (m, 1 H), 3.53 - 3.45 (m, 1 H), 2.61 (dd, J = 11.6, 5.5 Hz, 1 H), 2.56 (s, 3H), 2.39 (dd, J = 16.8, 8.1 Hz, 1 H).
Example 51 :
8-amino-6-(4-fluorophenyl)-N-{[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl}-5-(4-methylquino- lin-6-yl)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000108_0002
a. 2-[6-(azidomethyl)pyridin-2-yl]propan-2-ol
In a flask was placed solution of 2-[6-(hydroxymethyl)pyridin-2-yl]propan-2-ol (371 mg, 2.2 mmol) in toluene (5 mL) and mixture was cooled to 0°C and then diphenylphosphoryl azide (0.6 ml, 2.66 mmol) was added followed by 1 ,8-diazabicyclo[5.4.0]undec-7-ene (0.4 ml, 2.66 mmol). Resulting mixture was allowed to warm to room temperature and stirred for 16 h. Crude mixture was diluted with EtOAc and washed with water. Organic layer was dried over MgS04, filtered and concentrated. The residue was dissolved in 1 M HCI (2 eq) and extracted with a mixture of methyl tert- butyl ether/hexane (3:7). Organic layer was washed with water and combined aque ous phase was neutralized with 2M NaOH aq and extracted with ethyl acetate. Organic phase was dried over MgS04, filtered and concentrated to afford yellow oil (210 mg, 49%) that was used for the next step without further purification. ESI-MS: 193.1 [M+H]+. b. 2-[6-(aminomethyl)pyridin-2-yl]propan-2-ol
In a flask 2-[6-(azidomethyl)pyridin-2-yl]propan-2-ol (70 mg, 0.36 mmol) in THF (5 ml) and wa ter (0.5 ml) and PPh3 in 10% aqueous THF (190 mg, 0.73 mmol) were stirred for 16 h at room temperature. Resulting mixture was evaporated into dynes and used for the next step without further purification. ESI-MS: 167.2 [M+H]+.
Figure imgf000109_0001
c. 8-amino-6-(4-fluorophenyl)-N-{[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl}-5-(4- methylquinolin-6-yl)imidazo[ 1, 2-a]pyrazine-2-carboxamide
The title compound was synthesized following the approach outlined in Procedure I, substitut ing 2-[6-(aminomethyl)pyridin-2-yl]propan-2-ol [prepared following the approach outlined in step A and B] for 1 -Boc-4-aminopiperidine in Procedure I, step b to lead to the title compound (7 mg, 7%) as yellow solid, hydrochloride salt. ESI-MS: 562.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.09 (d, J = 5.1 Hz, 1 H), 8.94 (s, 1 H), 8.48 (s, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 8.05 (s, 1 H), 7.93 (dd, J = 8.7, 1.8 Hz, 2H), 7.82 (t, J = 6.8 Hz, 1 H), 7.67 (d, J = 7.8 Hz, 1 H), 7.45 - 7.36 (m, 2H), 7.32 (s, 1 H), 7.09 (t, J = 8.8 Hz, 2H), 4.67 (d, J = 5.9 Hz, 2H), 2.77 (s, 3H), 1.47 (s, 6H).
Example 52:
8-amino-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-N-(2,2,2-trifluoroethyl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000109_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2 h at 100°C and then following Procedure C, substituting 2,2,2-tri- fluoroethylamine for ethylamine to lead
to the title compound (10 mg, 15%) as white solid, hydrochloride salt. ESI-MS: 484.20 [M+H]+. 1 H NMR (400 MHz, DMSO-i/5) d 9.39 (s, 1 H), 8.76 (t, J = 6.6 Hz, 1 H), 8.15 (d, J = 7.6 Hz, 1 H), 7.92 - 7.83 (m, 2H), 7.46 (dd, J = 8.4, 1.5 Hz, 1 H), 7.42 - 7.33 (m, 2H), 7.07 (t, J = 8.9 Hz, 2H), 4.13 - 4.06 (m, 2H), 4.01 (s, 3H).
Example 53: 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(3,3,3-trifluoropropyl)imidazo[1,2-a]py- razine-2-carboxamide
Figure imgf000110_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3,3,3-trifluoropropylamine for ethylamine to lead to the title compound (26 mg, 17%) as yel low solid, hydrochloride salt. ESI-MS: 509.20 [M+H]+. 1 H NMR (400 MHz, DMSO-i/5) d 9.06 (s, 1 H), 8.44 (s, 2H), 8.22 (d, J = 9.2 Hz, 1 H), 7.91 (d, J = 7.1 Hz, 2H), 7.77 (s, 1 H), 7.38 (dd, J = 8.6, 5.7 Hz, 2H), 7.08 (t, J = 8.7 Hz, 2H), 3.52 (q, J = 6.7 Hz, 2H), 2.59 - 2.54 (m, 2H), 2.74 (s, 3H).
Procedure L
Example 54:
8-amino-6-(4-fluorophenyl)-N-methyl-5-[4-(2H3)methylquinolin-6-yl]imidazo[1,2-a]pyrazine-2- carboxamide
Figure imgf000110_0002
The title compound was synthesized following the approach outlined in Procedure F, substitut ing (4-methylquinolin-6-yl)boronic acid for 4-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-diox- aborolan-2-yl)quinoline in step b, and performing additional step - Procedure L:
Into a pressure tube 8-amino-6-(4-fluorophenyl)-N-methyl-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide hydrochloride (25 mg, 0.05 mmol), benzoic acid (66 mg, 0.5 mmol) and 1 ml of D2O were added. The reaction was stirred for 48 h at 100°C. Then the sol vent was evaporated and product was purified by flash chromatography (NH2 modified silica gel, hexane/DCM 0-100%) to lead to the title compound (25 mg, quant) as yellow solid, hydro chloride salt. ESI-MS: 430.30 [M+H]+. 1 H NMR (400 MHz, DMSO-c 6) d 9.07 (d, J = 5.0 Hz,
1 H), 8.44 (d, J = 2.0 Hz, 1 H), 8.25 - 8.18 (m, 2H), 7.96 - 7.87 (m, 2H), 7.78 (d, J = 5.0 Hz, 1 H), 7.44 - 7.34 (m, 2H), 7.14 - 7.03 (m, 2H), 2.78 (d, J = 4.7 Hz, 3H).
Procedure M Preparation of (4-ethylquinolin-6-yl)boronic acid
Figure imgf000111_0001
A microwave reaction tube was charged with 6-bromo-4-ethylquinoline (41 1 mg, 1.74 mmol), bis(pinacolato)diboron (663 mg, 2.61 mmol) and KOAc (342 mg, 3.48mmol) and 5ml_ of 1 ,4-di- oxane. This suspension was then sparged with argon for 10 min. Pd(dppf)C · DCM (28 mg, 0.03 mmol) was added in one portion and the reaction mixture was sparged with argon for addi tional 5 min. The pressure tube was capped and the reaction mixture was stirred at 80°C for 1 h under microwave irradiation. Then the reaction mixture was filtered through Celite® and the fil trate was concentrated under reduced pressure. Resulting mixture was used for the next step without further purification to lead to the title compound (0.200 g, 57%). ESI-MS: 201.90
[M+H]+.
Example 55:
8-amino-5-(4-ethylquinolin-6-yl)-6-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyrazine-2-carbox- amide
Figure imgf000111_0002
The title compound was synthesized following the approach outlined in Procedure F, substitut ing (4-ethylquinolin-6-yl)boronic acid (Procedure M) for 4-(difluoromethyl)-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)quinoline in step b and substituting Pd Sphos G3 for Pd(amphos)Cl2 and performing this step at 130°C on oil bath for 3 h to lead to the title compound (87 mg, 52%) as yellow solid, hydrochloride salt. ESI-MS: 441.20 [M+H]+. 1 H NMR (400 MHz, DMSO-c/6) d 9.14 (d, J = 5.2 Hz, 1 H), 8.45 (d, J = 1.8 Hz, 1 H), 8.35 (d, J = 8.7 Hz, 1 H), 8.22 (d, J = 4.8 Hz,
1 H), 8.03 (dd, J = 8.7, 1.7 Hz, 1 H), 7.98 (s, 1 H), 7.82 (d, J = 5.2 Hz, 1 H), 7.43 - 7.35 (m, 2H), 7.16 - 7.06 (m, 2H), 3.23 - 3.07 (m, 2H), 2.79 (d, J = 4.7 Hz, 3H), 1.16 (t, J = 7.5 Hz, 3H).
Example 56:
8-amino-N-[2-(dimethylamino)ethyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imid- azo[l,2-a]pyrazine-2-carboxamide
Figure imgf000112_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing N,N-dimethylenediamine for ethylamine to lead to the title compound 32 mg, 24%) as yellow solid, hydrochloride salt. ESI-MS: 484.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.90 (s,
1 H), 9.04 (d, J = 4.8 Hz, 1 H), 8.66 - 8.59 (m, 1 H), 8.41 (s, 1 H), 8.23 (d, J = 8.6 Hz, 1 H), 8.04 - 8.00 (m, 1 H), 7.87 (d, J = 8.9 Hz, 1 H), 7.75 (s, 2H), 7.41 - 7.35 (m, 2H), 7.1 1 - 7.04 (m, 2H), 3.63 (q, J = 6.1 Hz, 2H), 3.23 (q, J = 6.0 Hz, 2H), 2.81 (s, 3H), 2.80 (s, 3H), 2.74 (s, 3H). Example 57:
8-amino-6-(4-fluorophenyl)-N-(1-methoxy-2-methylpropan-2-yl)-5-(4-methylquinolin-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000112_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1 -methoxy-2-methylpropan-2-amine for ethylamine to lead to the title compound (27 mg, 30%) as yellow solid, hydrochloride salt. ESI-MS: 499.30 [M+H]+. 1 H NMR (400 MHz, DMSO- d6) d 9.12 (d, J = 5.1 Hz, 1 H), 8.48 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 7.95 (dd, J = 8.9, 1.8 Hz,
1 H), 7.84 (s, 2H), 7.45 (s, 1 H), 7.42 - 7.35 (m, 2H), 7.13 - 7.05 (m, 2H), 3.47 (s, 2H), 3.31 (s, 3H), 2.78 (s, 3H), 1 .36 (s, 6H).
Example 58:
8-amino-6-(4-fluorophenyl)-N-(3-hydroxybutan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]py- razine-2-carboxamide
Figure imgf000113_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3-aminobutan-2-ol for ethylamine to lead to the title compound (10 mg, 9%) as yellow solid, hydrochloride salt. ESI-MS: 485.30 [M+H]+.1 H NMR (400 MHz, DMSO -d6) d 9.07 (d, J = 4.9 Hz, 1 H), 8.44 (s, 1 H), 8.28-8.21 (m, 1 H), 7.96 - 7.76 (m, 4H), 7.43 - 7.35 (m, 2H), 7.12-7.04 (m, 2H), 3.95-3.85 (m, 1H), 3.73-3.66 (m, 1H), 2.75 (s, 3H), 1.16-1.01 (m, 6H).
Example 59:
8-amino-6-(4-fluorophenyl)-N-[(4-methylmorpholin-2-yl)methyl]-5-(4-methylquinolin-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000113_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut- ing (4-methylmorpholin-2-yl)methanamine for ethylamine to lead to the title compound (22 mg, 32%) as yellow solid, hydrochloride salt. ESI-MS: 526.20 [M+H]+.1H NMR (400 MHz, Metha- nol -d4) d 9.14 (d, J = 5.7 Hz, 1H), 8.75 (t, J = 6.3 Hz, 1H), 8.68 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.16 - 8.10 (m, 2H), 8.02 (d, J = 5.6 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.11 (t, J = 8.6 Hz, 2H), 4.18 (dd, J = 13.3, 3.7 Hz, 1H), 4.02-3.95 (m, 1H), 3.89-3.79 (m, 1H), 3.71 -3.63 (m, 1H), 3.63- 3.54 (m,2H), 3.52 -3.42 (m, 1H), 3.20 - 3.11 (m, 1 H), 2.97 (s, 4H), 2.94 (s, 3H).
Example 60:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(oxetan-3-yl)methyl]imidazo[1,2-a]py- razine-2-carboxamide
Figure imgf000114_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3-oxetanemethanamine for ethylamine to lead to the title compound (11 mg, 19%) as white solid. ESI-MS: 483.20 [M+H]+. 1 H NMR (400 MHz, Methanol-c/4) d 8.77 (d, J = 4.5 Hz, 1 H),
8.17 (d, J = 1.9 Hz, 1 H), 8.10 (d, J = 8.7 Hz, 1 H), 7.97 (s, 1 H), 7.77 (dd, J = 8.7, 1.9 Hz, 1 H), 7.45 (d, J = 4.6 Hz, 1 H), 7.38 (dd, J = 8.7, 5.5 Hz, 2H), 6.93 (t, J = 8.8 Hz, 2H), 4.83 (dd, J =
7.8, 6.2 Hz, 2H), 4.62 (s, 1 H), 4.54 (t, J = 6.1 Hz, 2H), 3.71 (d, J = 6.8 Hz, 2H), 2.63 (s, 3H).
Example 61 :
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(oxolan-3-yl)imidazo[1,2-a]pyrazine-2- carboxamide
Figure imgf000114_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing tetrahydrofuran-3-amine for ethylamine to lead to the title compound (37 mg, 46%) as yellow solid, hydrochloride salt. ESI-MS: 483.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.10 (d, J = 5.0 Hz, 1 H), 8.47 (s, 1 H), 8.27 (dd, J = 16.5, 8.0 Hz, 2H), 8.03 (s, 1 H), 7.94 (d, J = 8.6 Hz, 1 H), 7.83 (s, 1 H), 7.39 (dd, J = 8.7, 5.6 Hz, 2H), 7.10 (t, J = 8.7 Hz, 2H), 3.84 (dd, J = 15.2, 7.9 Hz, 2H), 3.80 - 3.76 (m, 1 H), 3.69 (td, J = 8.3, 5.8 Hz, 1 H), 3.58 (dd, J = 9.0, 3.8 Hz, 1 H), 2.77 (s, 3H), 2.22 - 2.12 (m, 1 H), 1.91 - 1.83 (m, 1 H).
Example 62:
8-amino-6-(4-fluorophenyl)-N-[1-(methoxymethyl)cyclopropyl]-5-(4-methylquinolin-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000115_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1 -methoxymethyl-cyclopropylamine for ethylamine to lead to the title compound (14 mg, 14%) as yellow solid, hydrochloride salt. ESI-MS: 495.20 [M+H]+. 1 H NMR (400 MHz, DMSO- d6) d 9.06 (d, J = 5.0 Hz, 1 H), 8.41 (s, 1 H), 8.32 (s, 1 H), 8.24 (d, J = 8.7 Hz, 1 H), 7.97 (s, 1 H), 7.91 (d, J = 8.7 Hz, 1 H), 7.77 (s, 1 H), 7.43 - 7.34 (m, 2H), 7.13 - 7.04 (m, 2H), 3.42 (s, 2H),
3.24 (s, 4H), 2.74 (s, 3H), 0.77 (s, 3H).
Example 63:
8-amino-6-(4-fluorophenyl)-N-(1-methyl-2-oxopyrrolidin-3-yl)-5-(4-methylquinolin-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000115_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3-amino-N-methyl-2-pyrrolidinone for ethylamine to lead to the title compound (21 mg, 33%) as yellow solid, hydrochloride salt. ESI-MS: 510.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.1 1 (d, J = 5.1 Hz, 1 H), 8.49 (d, J = 1.8 Hz, 1 H), 8.42 (d, J = 8.2 Hz, 1 H), 8.30 (d, J = 8.7 Hz,
1 H), 8.00 (s, 1 H), 7.96 (dd, J = 8.8, 1.8 Hz, 1 H), 7.84 (d, J = 5.2 Hz, 1 H), 7.45 - 7.36 (m, 2H), 7.10 (t, J = 8.9 Hz, 2H), 4.59 (q, J = 9.0 Hz, 1 H), 3.35 - 3.26 (m, 2H), 2.78 (s, 3H), 2.76 (s, 3H), 2.37 (td, J = 6.9, 5.7, 3.9 Hz, 1 H), 1.90 (dq, J = 12.1 , 9.3 Hz, 1 H)
Example 64:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-{2-[(oxolan-2-yl)methoxy]ethyl}imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000116_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2-[(oxolan-2-yl)methoxy]ethan-1-amine for ethylamine to lead to the title compound (21 mg, 29%) as yellow solid, hydrochloride salt. ESI-MS: 541.30 [M+H]+. 1 H NMR (400 MHz, DMSO- d6) d 9.07 (d, J = 5.0 Hz, 1 H), 8.45 (s, 1 H), 8.24 (d, J = 8.8 Hz, 1 H), 8.14 (t, J = 5.9 Hz, 1 H),
7.92 (d, J = 13.2 Hz, 2H), 7.79 (s, 1 H), 7.42 - 7.35 (m, 2H), 7.09 (t, J = 8.8 Hz, 2H), 3.93 - 3.89 (m, 1 H), 3.73 - 3.68 (m, 1 H), 3.63 - 3.57 (m, 1 H), 3.54 (dd, J = 6.0, 4.5 Hz, 2H), 3.46 - 3.41 (m, 2H), 3.40 - 3.34 (m, 2H), 2.75 (s, 3H), 1.91 - 1.81 (m, 1 H), 1.81 - 1.70 (m, 2H), 1.54 - 1.44 (m,
1 H).
Example 65:
8-amino-6-(4-fIuorophenyl)-N-(2-methoxy-2-methylpropyl)-5-(4-methyIquinolin-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000116_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2-methoxy-2-methyl-1 -propanamine for ethylamine to lead to the title compound (40 mg, 32%) as yellow solid, hydrochloride salt. ESI-MS: 499.70 [M+H]+. 1 H NMR (400 MHz, DMSO- d6) d 9.10 (d, J = 5.2 Hz, 1 H), 8.47 (s, 1 H), 8.28 (d, J = 8.8 Hz, 1 H), 7.95 (d, J = 8.9 Hz, 2H), 7.83 (s, 1 H), 7.77 (t, J = 6.2 Hz, 1 H), 7.45 - 7.36 (m, 2H), 7.09 (t, J = 8.8 Hz, 2H), 3.36 (d, J = 6.2 Hz, 2H), 3.16 (s, 3H), 2.77 (s, 3H), 1.12 (s, 6H).
Example 66:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-( 1, 1, 1-trifluoro-3-hydroxypropan-2- y!)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000117_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2-amino-3,3,3-trifluoropropan-1-ol hydrochloride for ethylamine to lead to the title compound (9 mg, 1 %) as yellow solid, hydrochloride salt. ESI-MS: 525.20 [M+H]+. 1 H NMR (400 MHz,
DMSO -c/6) d 9.05 (d, J = 5.0 Hz, 1 H), 8.43 (s, 1 H), 8.37 (d, J = 9.5 Hz, 1 H), 8.23 (d, J = 8.7 Hz,
1 H), 8.01 (s, 1 H), 7.95 - 7.90 (m, 1 H), 7.76 (s, 1 H), 7.41 - 7.35 (m, 2H), 7.07 (t, J = 8.9 Hz, 2H), 4.79 (s, 2H), 2.74 (s, 3H), 2.53 (s, 1 H). Example 67:
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(oxetan-3-yl)imidazo[1,2-a]pyrazine-2- carboxamide
Figure imgf000117_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3-oxetaneamine for ethylamine to lead to the title compound (3.5 mg, 1 1 %) as white solid. ESI-MS: 469.20 [M+H]+. 1 H NMR (300 MHz, DMSO-i/6) d 8.91 (d, J = 6.9 Hz, 1 H), 8.82 (d, J = 4.3 Hz, 1 H), 8.18 (d, J = 1.5 Hz, 1 H), 8.08 (d, J = 8.6 Hz, 1 H), 7.89 (s, 1 H), 7.75 (dd, J = 8.6, 1 .8 Hz, 1 H), 7.48 - 7.22 (m, 5H), 7.02 (t, J = 8.9 Hz, 2H), 5.08 - 4.95 (m, 1 H), 4.75 (t, J = 6.9 Hz, 2H), 4.58 (t, J = 6.4 Hz, 2H), 2.56 (s, 3H).
Example 68:
1-[8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazine-2-carbonyl]-3- meth ylpyrrolidin-3-ol
Figure imgf000118_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3-hydroxy-3-methylpyrrolidine for ethylamine to lead to the title compound (19 mg, 28%) as yellow solid, hydrochloride salt. ESI-MS: 497.30 [M+H]+. 1 H NMR (400 MHz, DMSO -dff) d 9.09 (d, J = 5.0 Hz, 1 H), 8.46 (s, 1 H), 8.26 (d, J = 8.7 Hz, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.83 (s, 2H), 7.45 - 7.36 (m, 2H), 7.10 (t, J = 8.7 Hz, 2H), 4.21 (s, 1 H), 3.81 (d, J= 12.1 Hz, 1 H), 3.60 - 3.54 (m, 1 H), 3.54 - 3.49 (m, 1 H), 2.76 (s, 3H), 1.97 - 1 .74 (m, 2H), 1.34 (d, J= 1.6 Hz, 3H).
Example 69:
8-amino-5-(8-chloro-4-methylquinolin-6-yl)-6-(4-fIuorophenyl)-N-(2-methoxyethyl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000118_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing 8-chloro-4-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline (Procedure D) for (4-methylquinolin-6-yl)boronic acid and substituting Pd(PPhi3)4 for Sphos Pd G3 in Procedure B, step b and performing this step for 1 .5 h at 90°C and then following Procedure C, substituting 2- methoxyethylamine for ethylamine to lead to the title compound (16 mg, 23%) as yellow solid, hydrochloride salt. ESI-MS: 505.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 8.93 (d, J = 4.3 Hz, 1 H), 8.19 (d, J = 1 .8 Hz, 1 H), 8.14 (s, 1 H), 8.04 (s, 1 H), 7.97 (d, J = 1.8 Hz, 1 H), 7.55 (dd, J = 4.3, 1.1 Hz, 1 H), 7.44 - 7.39 (m, 2H), 7.12 (t, J = 8.8 Hz, 2H), 3.44 (d, J = 2.6 Hz, 4H), 3.25 (s, 3H), 2.59 (d, J = 0.9 Hz, 3H).
Example 70:
8-amino-6-(4-fluorophenyl)-N-(1-methylcyclobutyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000119_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1 -methylcyclobutan-1 -amine for ethylamine to lead to the title compound (7 mg, 15%) as yellow solid, hydrochloride salt. ESI-MS: 481.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.07 (d, J = 5.1 Hz, 1 H), 8.44 - 8.41 (m, 1 H), 8.24 (d, J = 8.7 Hz, 1 H), 8.01 (s, 1 H), 7.94 - 7.88 (m, 2H), 7.78 (d, J = 5.1 Hz, 1 H), 7.41 - 7.36 (m, 2H), 7.08 (t, J = 8.9 Hz, 2H), 2.74 (s, 3H), 2.30 (s, 2H), 2.02 - 1.95 (m, 2H), 1.81 (td, J = 10.1 , 9.1 , 5.1 Hz, 2H), 1.46 (s, 3H).
Example 71 :
8-amino-N-(2-fluoroethyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazine-2- carboxamide
Figure imgf000119_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2-fluoroethylamine hydrochloride for ethylamine to lead to the title compound (66 mg, 59%) as yellow solid, hydrochloride salt. ESI-MS: 459.20 [M+H]+. 1 H NMR (Deuterium Oxide): 9.00 (d, J = 5.8 Hz, 1 H), 8.53 (d, J = 1.7 Hz, 1 H), 8.24 (d, J = 8.9 Hz, 1 H), 8.12 (s, 1 H), 8.06 (dd, J = 8.9, 1 .8 Hz, 1 H), 7.96 (dd, J = 5.8 Hz, 1.0 Hz, 1 H), 7.46-7.38 (m, 2H), 7.10-7.02 (m, 2H), 4.65 (dt, J = 47.0, 4.9 Hz, 1 H), 3.75 (dt, J = 28.3, 4.9 Hz, 1 H), 3.79 - 3.77 (m, 1 H), 3.72 - 3.70 (m,
1 H), 2.88 (s, 3H).
Example 72:
1-[8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazine-2-carbonyl]pyr- roHdin-3-amine
Figure imgf000120_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3-(Boc-amino)pyrrolidine for ethylamine to lead to the title compound (18 mg, 47%) as yel low solid, hydrochloride salt. ESI-MS: 482.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.1 1 (d, J = 5.2 Hz, 1 H), 8.52 - 8.46 (m, 1 H), 8.41 (s, 2H), 8.31 (d, J = 8.7 Hz, 1 H), 7.93 (dd, J = 8.6, 1.9 Hz, 1 H), 7.86 (dd, J = 14.5, 4.4 Hz, 2H), 7.44 - 7.35 (m, 2H), 7.10 (td, J = 8.9, 1 .7 Hz, 2H), 4.25 (d, J = 7.3 Hz, 3H), 3.08 - 3.05 (m, 1 H), 2.77 (s, 3H), 2.31 - 1.98 (m, 3H).
Example 73:
8-amino-6-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000120_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1 -methylpyrrolidin-3-amine for ethylamine and substituting EtaN for DIPEA and substituting HBTU for HATU in this step to lead to the title compound (13 mg, 21 %) as yellow solid, hydro chloride salt. ESI-MS: 496.20 [M+H]+. 1 H NMR (400 MHz, DMSO-r 6) d 1 1.05 (s, 1 H), 8.89 (dd, J = 1 1.4, 5.9 Hz, 1 H), 8.70 (d, J = 7.3 Hz, 1 H), 8.28 (s, 1 H), 8.14 (dd, J = 8.6, 3.6 Hz, 1 H), 7.99 (d, J = 13.8 Hz, 1 H), 7.86 - 7.71 (m, 1 H), 7.55 (d, J = 4.6 Hz, 2H), 7.41 - 7.27 (m, 2H), 7.03 (t, J = 8.9 Hz, 2H), 4.80 - 4.50 (m, 1 H), 3.81 (dt, J = 12.1 , 7.2 Hz, 1 H), 3.04 (dq, J = 18.6, 9.8, 9.1 Hz, 2H), 2.82 (dd, J = 13.8, 4.8 Hz, 3H), 2.65 (d, J = 5.8 Hz, 3H), 2.26 (dt, J = 16.7, 8.5 Hz, 1 H), 1.98 (s, 2H).
Example 74:
8-amino-6-(4-fluorophenyl)-N-[(1-hydroxycyclopentyl)methyl]-5-(4-methylquinolin-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000121_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1 -(aminomethyl)cyclopentanol hydrochloride for ethylamine to lead to the title compound (10 mg, 15%) as yellow solid, hydrochloride salt. ESI-MS: 51 1 .30 [M+H]+. 1 H NMR (400 MHz,
DMSO-c/6) d 9.07 (d, J = 5.7 Hz, 1 H), 8.44 (s, 1 H), 8.24 (d, J = 9.1 Hz, 1 H), 7.97 - 7.86 (m, 3H), 7.79 (d, J = 4.2 Hz, 1 H), 7.38 (dd, J = 8.6, 5.4 Hz, 2H), 7.08 (t, J = 8.1 Hz, 2H), 3.37 (d, J = 6.0 Hz, 3H), 2.75 (s, 3H), 1.69 (s, 2H), 1.52 (s, 6H). Example 75:
8-amino-N-(2,2-dimethylpropyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000121_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2, 2-dimethyl-1 -propanamine for ethylamine to lead to the title compound (10 mg, 10%) as yellow solid, hydrochloride salt. ESI-MS: 483.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.03 (d, J = 4.5 Hz, 1 H), 8.40 (s, 1 H), 8.20 (d, J = 8.6 Hz, 1 H), 7.99 - 7.93 (m, 1 H), 7.91 (d, J = 5.2 Hz, 2H), 7.73 (s, 1 H), 7.42 - 7.33 (m, 2H), 7.07 (t, J = 8.8 Hz, 2H), 3.13 (d, J = 5.3 Hz, 2H), 2.72 (s, 3H), 0.90 (s, 9H).
Example 76:
8-amino-6-(4-fluorophenyl)-N-(1-methoxypropan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000122_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1 -methoxy-2-propylamine for ethylamine to lead to the title compound (28 mg, 42%) as yel low solid, hydrochloride salt. ESI-MS: 485.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.10 (d, J = 5.1 Hz, 1 H), 8.47 (s, 1 H), 8.28 (d, J = 8.8 Hz, 1 H), 7.98 - 7.92 (m, 2H), 7.90 (d, J = 8.5 Hz,
1 H), 7.83 (d, J = 5.2 Hz, 1 H), 7.44 - 7.34 (m, 2H), 7.13 - 7.04 (m, 2H), 4.22 - 4.16 (m, 1 H), 3.40 (dd, J = 9.6, 5.8 Hz, 1 H), 3.33 (dd, J = 9.6, 5.2 Hz, 1 H), 3.27 (s, 3H), 2.77 (s, 3H), 1 .15 (d, J =
6.7 Hz, 3H).
Example 77:
8-amino-5-(4-chloro- 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-N-(2-fluoroethyl)-6-(4-fluorophenyl)im- idazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000122_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (4-chloro-1-methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid (Procedure H) for (4-methylquino- lin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a performing this step at 100°C for 1 h and then following Procedure C, sub stituting 2-fluoroethylamine hydrochloride for ethylamine to the title compound (31 mg, 58%) as yellow solid, hydrochloride salt. ESI-MS: 482.20 [M+H]+. 1 H NMR (400 MHz, Methanol-c/4) d 9.45 (s, 1 H), 8.10 (s, 1 H), 8.04 (s, 1 H), 7.73 (d, J = 1.0 Hz, 1 H), 7.57 - 7.47 (m, 2H), 7.16 (t, J = 8.6 Hz, 2H), 4.65 (t, J = 4.9 Hz, 1 H), 4.53 (t, J = 4.9 Hz, 1 H), 4.1 1 (s, 3H), 3.77 (t, J = 5.0 Hz,
1 H), 3.71 (t, J = 5.0 Hz, 1 H).
Example 78:
8-amino-5-(4-chloro- 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-[( 1-hydroxycydo- propyl)methyl]imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000123_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (4-chloro-1-methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid (Procedure H) for (4-methylquino- lin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step at 100°C for 1 h and performing Procedure B, step b at 80°C for 1 h and then following Procedure C, substituting 1-(aminoethyl)-cyclopropanol for ethylamine to lead to the title compound (16 mg, 31 %) as off-white solid. ESI-MS: 506.20
[M+H]+. 1 H NMR (300 MHz, Methanol -d4) d 8.31 (s, 1 H), 7.89 (s, 1 H), 7.64 (d, J = 1.4 Hz, 1 H), 7.46 - 7.31 (m, 3H), 6.96 (t, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.57 (s, 2H), 0.81 - 0.65 (m, 4H).
Example 79:
8-amino-5-(4-chloro- 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-(2-hydroxy-2- methylpropyl)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000123_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (4-chloro-1-methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid (Procedure H) for (4-methylquino- lin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)C for Sphos Pd G3 in Procedure B, step a and performing this step at 100°C for 1 h and performing Procedure B, step b at 80°C for 1 h and then following Procedure C, substituting 1-amino-2-methylpropan-2-ol for ethylamine to lead to the title compound (5 mg, 38%) as yellow solid, hydrochloride salt. ESI- MS: 594.35 [M+H]+. 1 H NMR (300 MHz, Methanol-</4) d 8.31 (s, 1 H), 7.88 (s, 1 H), 7.64 (d, J =
1.4 Hz, 1 H), 7.44 - 7.37 (m, 2H), 7.35 (d, J = 1.4 Hz, 1 H), 6.96 (t, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.43 (s, 2H), 1.26 (s, 6H).
Example 80:
8-amino-6-(4-fluorophenyl)-N-[1-(1-hydroxycyclopropyl)ethyl]-5-(4-methylquinolin-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000124_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1 -(1 -aminoethyl)cyclopropanol for ethylamine to lead to the title compound (41 mg, 66%) as yellow solid. ESI-MS: 497.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 8.98 (d, J = 4.8 Hz, 1 H), 8.34 (d, J = 1.8 Hz, 1 H), 8.15 (d, J = 8.7 Hz, 1 H), 7.92 - 7.82 (m, 2H), 7.79 (s, 1 H), 7.65 (d, J = 4.8 Hz, 1 H), 7.41 - 7.33 (m, 2H), 7.09 - 7.00 (m, 2H), 3.64 - 3.54 (m, 1 H), 2.68 (s, 3H), 1.25 (d, J = 6.7 Hz, 3H), 0.65 - 0.46 (m, 4H).
Example 81 :
8-amino-5-{3-chloroimidazo[1,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000124_0002
The title compound was synthesized following the approach outlined in Procedure F substitut ing {3-chloroimidazo[1 ,2-a]pyridin-6-yl}boronic acid [the approach outlined in Procedure M, sub stituting 6-bromo-3-chloroimidazo[1 ,2-a]pyridine for 6-bromo-4-ethylquinoline] for 4-(difluorome- thyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline to lead to the title compound (18 mg, 29%) as yellow solid, hydrochloride salt. ESI-MS: 437.1 [M+H]+. d 1 H NMR (400 MHz, DMSO-d6) d 8.81 (s, 1 H), 8.18 (s, 1 H), 8.14 (q, J = 4.7 Hz, 2H), 8.10 (s, 1 H), 7.86 (d, J = 9.3 Hz, 1 H), 7.52 - 7.42 (m, 2H), 7.15 (t, J = 8.8 Hz, 2H), 2.80 (d, J = 4.8 Hz, 3H).
Example 82:
8-amino-6-(4-fluorophenyl)-5-[4-(2H3)methylquinolin-6-yl]imidazo[1,2-a]pyrazine-2-carbox- amide
Figure imgf000125_0001
The title compound was synthesized following the approach outlined in Procedure K, substitut ing (4-methylquinolin-6-yl)boronic acid for (8-chloroquinolin-6-yl)boronic acid in Procedure K, step b and then following Procedure L, substituting 8-amino-6-(4-fluorophenyl)-5-(4-methylquin- olin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide hydrochloride for 8-amino-6-(4-fluorophenyl)-N- methyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide hydrochloride in this step to lead to the title compound (25 mg, 10%) as yellow solid, hydrochloride salt. ESI-MS: 416.30 [M+H]+. 1 H NMR (400 MHz, DMSO-c/6) d 9.10 (d, J = 5.1 Hz, 1 H), 8.48 (d, J = 1.8 Hz, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 8.02 (s, 1 H), 7.92 (dd, J = 8.7, 1.8 Hz, 1 H), 7.83 (d, J = 5.1 Hz, 1 H), 7.66 - 7.54 (m, 2H), 7.46 - 7.35 (m, 2H), 7.17 - 7.05 (m, 2H).
Example 83:
8-amino-5-{8-chloro-3-methylimidazo[1,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-methylimid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000125_0002
The title compound was synthesized following the approach outlined in Procedure F, substitut ing {8-chloro- {8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}boronic acid [the approach outlined in Procedure M substituting 6-bromo-8-chloro-3-methylimidazo[1 ,2-a]pyridine for 6-bromo-4- ethylquinoline and performing this step at 100°C for 4 h on oil bath] for 4-(difluoromethyl)-6- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline in Procedure F, step b and performing this step at 100°C for 1.5 h on oil bath to lead to the title compound (15 mg, 67%) as yellowish solid, hydrochloride salt. ESI-MS: 450.30 [M+H]+. 1 H NMR (400 MHz, DMSO-</6) d 8.94 (s,
1 H), 8.13 (d, J = 12.5 Hz, 2H), 7.95 (d, J = 12.5 Hz, 2H), 7.81 (s, 2H), 7.51 - 7.44 (m, 2H), 7.18 - 7.09 (m, 2H), 2.81 (s, 3H), 2.80 (s, 3H).
Example 84:
8-amino-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-N-(propan-2-yl)imidazo[ 1,2- a]pyrazine-2-carboxamide
Figure imgf000126_0001
The title compound was synthesized following the approach outlined in Procedure B substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2 h at 100°C and then following Procedure C, substituting isopropyl amine for ethylamine to lead to the title compound (46 mg, 30%) as white solid, hydrochloride salt. ESI-MS: 444.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r 5) d 9.45 (bs, 1 H), 8.17 (s, 1 H), 7.95 - 7.87 (m, 2H), 7.79 (s, 1 H), 7.46 (dd, J = 8.5, 1.5 Hz, 1 H), 7.42 - 7.34 (m, 2H), 7.13 - 7.04 (m, 2H), 4.14 - 4.05 (m, 1 H), 4.02 (s, 3H), 1.17 (d, J = 6.6 Hz, 6H).
Example 85:
8-amino-6-(4-fluorophenyl)-N-(3-hydroxypropyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000126_0002
The title compound was synthesized from the Example 7, by performing additional step. In a pressure tube 8-amino-N-[3-(difluoromethoxy)propyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide (Example 7, 32mg, 0.06mmol) in 2 ml of 2M HCI aq were stirred for 16 h at 60°C. Product was purified by flash reversed-phase chromatography to lead to the title compound (3 mg, 10%) as yellow solid, hydrochloride salt. ESI-MS: 471.30 [M+H]+. 1 H NMR (400 MHz, DMSO-</6) d 9.10 (d, J = 5.2 Hz, 1 H), 8.47 (s, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 8.22 (t, J = 5.9 Hz, 1 H), 7.99 - 7.91 (m, 2H), 7.85 - 7.80 (m, 1 H), 7.44 - 7.35 (m, 2H), 7.14 - 7.05 (m, 2H), 3.45 (t, J = 6.2 Hz, 2H), 3.33 (q, J = 6.6 Hz, 2H), 2.77 (s, 3H), 1.67 - 1.63 (m, 2H).
Example 86:
8-amino-N-(2-fluoroethyl)-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)imidazo[ 1,2- a]pyrazine-2-carboxamide
Figure imgf000127_0001
The title compound was synthesized following the approach outlined in Procedure B substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2 h at 100°C to lead and then following Procedure C, substituting 2- fluoroethylamine hydrochloride for ethylamine to the title compound (13 mg, 10%) as white solid, hydrochloride salt. ESI-MS: 448.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.34 (s,
1 H), 8.35 (t, J = 5.8 Hz, 1 H), 8.14 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.78 (s, 1 H), 7.44 (dd, J = 8.4, 1 .5 Hz, 1 H), 7.41 - 7.33 (m, 2H), 7.07 (t, J = 8.9 Hz, 2H), 4.59 (t, J = 5.0 Hz, 1 H), 4.47 (t, J = 5.0 Hz, 1 H), 3.69 - 3.61 (m, 1 H), 3.57 - 3.54 (m, 1 H), 3.99 (s, 3H).
Example 87:
8-amino-5-{8-chloro-3-methylimidazo[1,2-a]pyridin-6-yl}-6-(4-fluorophenyl)imidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000127_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing {8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}boronic acid [the approach outlined in Proce dure M substituting 6-bromo-8-chloro-3-methylimidazo[1 ,2-a]pyridine for 6-bromo-4-ethylquino- line and performing this step at 100°C for 4 h, without microwave irradiation] for (4-methylquino- lin-6-yl)boronic acid in Procedure B, step a and instead of step b performing step according to Procedure J to lead to the title compound (43 mg, quant) as yellow solid, hydrochloride salt. ESI-MS: 436.20 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 8.89 (s, 1 H), 8.14 (s, 1 H), 7.90 (d, J = 12.3 Hz, 2H), 7.55 (s, 1 H), 7.51 - 7.41 (m, 3H), 7.17 - 7.08 (m, 2H), 2.48 - 2.46 (m, 3H).
Example 88:
8-amino-5-(4-chloro- 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-N-(2,2-difluoroethyl)-6-(4-fluoro- pheny!)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000128_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (4-chloro-1-methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid (Procedure H) for (4-methylquino- lin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step at 100°C for 1 h and performing step b at 80°C for 1 h and then following Procedure C, substituting 2,2-difluoroethylamine for ethylamine to lead to the title compound (13 mg, 39%) as white solid, hydrochloride salt. ESI-MS: 500.20 [M+H]+. 1 H NMR (300 MHz, DMSO-</6) d 8.54 (t, J = 6.5 Hz, 2H), 7.96 (s, 1 H), 7.80 (d, J = 1.4 Hz, 1 H),
7.50 - 7.29 (m, 3H), 7.14 (dd, J = 10.1 , 7.7 Hz, 2H), 6.12 (tt, J = 55.9, 3.8 Hz, 1 H), 3.71 - 3.68 (m, 2H), 3.85 (s, 3H).
Example 89:
8-amino-N-ethyl-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1,3-benzodiazol-6-yl)imidazo[ 1,2-a]pyra- zine-2-carboxamide
Figure imgf000128_0002
The title compound was synthesized following the approach outlined in Procedure B substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2 h at 100°C and then following Procedure C to lead to the title compound (9 mg, 10%) as white solid, hydrochloride salt. ESI-MS: 430.20 [M+H]+. 1 H NMR (400 MHz, DMSO-c 6) d 9.41 (s, 1 H), 8.24 - 8.14 (m, 2H), 7.89 (d, J = 8.5 Hz, 1 H), 7.77 (s, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.42 - 7.34 (m, 2H), 7.13 - 7.05 (m, 2H), 4.01 (s, 3H), 3.34 - 3.26 (m, 2H), 1.1 1 (t, J = 7.2 Hz, 3H).
Example 90:
8-amino-5-{8-chloro-3-methylimidazo[1,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-(propan-2-yl)im- idazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000129_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing {8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}boronic acid [the approach outlined in Proce dure M substituting 6-bromo-8-chloro-3-methylimidazo[1 ,2-a]pyridine for 6-bromo-4-ethylquino- line and performing this step at 100°C for 4 h on oil bath] for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl for Sphos Pd G3 in Procedure B, step a and performing this step at 100°C for 1.5 h and performing step b at 50°C for 16 h and then fol lowing Procedure C, substituting isopropylamine for ethylamine to lead to the title compound (31 mg, 83%) as yellowish solid, hydrochloride salt. ESI-MS: 478.20 [M+H]+. 1 H NMR (400 MHz, DMSO-o¾5) d 8.91 (s, 1 H), 8.13 (s, 1 H), 7.94 (d, J = 12.1 Hz, 2H), 7.81 (d, J = 8.2 Hz, 1 H), 7.50 - 7.42 (m, 2H), 7.18 - 7.07 (m, 2H), 4.13 - 4.00 (m, 1 H), 2.48 - 2.46 (m, 3H), 1.18 (d, J = 6.6
Hz, 6H).
Example 91 :
8-amino-5-{8-chloro-3-methylimidazo[1,2-a]pyridin-6-yl}-N-(2,2-difluoroethyl)-6-(4-fIuoro- pheny!)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000129_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing {8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}boronic acid [the approach outlined in Procedure M substituting 6-bromo-8-chloro-3-methylimidazo[1 ,2-a]pyridine for 6-bromo-4-ethylquino- line and performing this step at 100°C for 4 h, without microwave irradiation] for (4-methylquino- lin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl for Sphos Pd G3 in Procedure B, step a and performing this step at 100°C for 1.5 h and performing step b at 50°C for 16 h and then following Procedure C, substituting 2,2-difluoroethylamine for ethylamine and substituting EtaN for DIPEA in this procedure to lead to the title compound (20 mg, 30%) as yel lowish solid, hydrochloride salt. ESI-MS: 500.20 [M+H]+. 1 H NMR (300 MHz, Deuterium Oxide) d 8.74 (d, J = 1.3 Hz, 1 H), 8.15 - 7.95 (m, 2H), 7.83 (s, 1 H), 7.56 - 7.36 (m, 2H), 7.24 - 7.02 (m, 2H), 6.30 - 5.86 (m, 1 H), 3.85 (td, J = 16.0, 3.4 Hz, 2H), 2.49 (s, 3H).
Example 92 8-amino-N-[1-(dimethylamino)-2-methylpropan-2-yl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6- y!)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000130_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1-dimethylamino-2-methyl-2-aminopropane for ethylamine to lead to the title compound (21 mg, 29%) as yellow solid, hydrochloride salt. ESI-MS: 512.30 [M+H]+.1 H NMR (400 MHz, DMSO-o¾) d 9.58 (s, 1H), 9.00 (d, J = 4.9 Hz, 1H), 8.34 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.93 (s, 1 H), 7.88-7.83 (m, 1H), 7.79 (s, 1H), 7.68 (d, J = 4.7 Hz, 1H), 7.37 (dd, J = 8.5, 5.5 Hz, 2H), 7.06 (t, J = 8.7 Hz, 2H), 3.63 (d, J = 4.0 Hz, 2H), 2.79 (d, J = 4.7 Hz, 6H), 2.69 (s, 3H), 1.48 (s, 6H).
Example 93
8-amino-6-(4-fluorophenyl)-N-[(1-methylazetidin-3-yl)methyl]-5-(4-methylquinolin-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000130_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 1-methyl-3-azetidinemethanamine for ethylamine to lead to the title compound (5 mg, 5%) as yellow solid. ESI-MS: 496.30 [M+H]+.1 H NMR (400 MHz, DMSO-tf6) d 9.65 (s, 1 H), 8.90 (d, J = 4.6 Hz, 1 H), 8.59-8.52 (m, 1H), 8.25 (dd, J = 3.7, 1.8 Hz, 1H), 8.14-8.09 (m, 1H), 7.82 (d, J = 2.4 Hz, 1 H), 7.79 (dd, J = 8.7, 1.9 Hz, 1 H), 7.54 (d, J = 4.6 Hz, 1 H), 7.47 - 7.33 (m, 3H),
7.04 (t, J = 8.9 Hz, 2H), 4.17-4.16 (m, 1H), 4.04-4.02 (m, 1H), 3.94-3.92 (m, 1H), 3.79- 3.74 (m, 1H), 3.56-3.50 (m, 1H), 3.49-3.45 (m, 1H), 3.03-2.92 (m, 1H), 2.79 (dd, J = 18.9, 5.2 Hz, 3H), 2.61 (s, 3H).
Example 94
8-amino-N-({1-[(2,4-difluorophenyl)methyl]piperidin-4-yl}methyl)-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000131_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing {1 -[(2,4-difluorophenyl)methyl]piperidin-4-yl}methanamine for ethylamine to lead to the title compound (22 mg, 26%) as yellow solid, hydrochloride salt. ESI-MS: 636.30 [M+H]+. 1 H NMR (400 MHz, DMSO-i/6) d 10.87 (s, 1 H), 9.12 (d, J = 5.2 Hz, 1 H), 8.50 (d, J = 1.8 Hz, 1 H), 8.46 (t, J = 6.1 Hz, 1 H), 8.37 (d, J = 8.7 Hz, 1 H), 8.08 (s, 1 H), 8.01 - 7.81 (m, 3H), 7.40 (td, J = 10.3,
9.4, 6.4 Hz, 3H), 7.22 (td, J = 8.4, 2.5 Hz, 1 H), 7.17 - 7.04 (m, 2H), 4.26 (d, J = 4.8 Hz, 2H), 3.38 - 3.29 (m, 2H), 3.17 (t, J = 6.2 Hz, 2H), 2.93 (q, J = 1 1.3 Hz, 2H), 2.80 (s, 3H), 1.99 - 1 .91 (m, 1 H), 1.79 (d, J = 12.8 Hz, 2H), 1.57 (q, J = 13.5 Hz, 2H).
Example 95
8-amino-6-(4-fluorophenyl)-N-[2-methyl-1-(propan-2-yloxy)propan-2-yl]-5-(4-methylquinolin-6- y!)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000131_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2-methyl- 1-(propan-2-yloxy)propan-2-amine for ethylamine to lead to the title compound (40 mg, 42%) as yellow solid, hydrochloride salt. ESI-MS: 527.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.08 (d, J = 5.1 Hz, 1 H), 8.24 (d, J = 8.7 Hz, 1 H), 7.92 (dd, J = 8.8, 1 .8 Hz, 1 H), 7.79 (d, J = 5.6 Hz, 2H), 7.41 (s, 1 H), 7.38 (dd, J = 8.7, 5.6 Hz, 2H), 7.1 1 - 7.03 (m, 2H), 3.59 - 3.53 (m, 1 H), 3.52 (s, 2H), 2.74 (s, 3H), 1.34 (s, 6H), 1.09 (d, J = 6.1 Hz, 6H).
Example 96
8-amino-6-(4-fluorophenyl)-N-methyl-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-N-(pyrrolidin-3- y!)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000132_0001
The title compound was synthesized following the approach outlined in Procedure B substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2 h at 100°C and then following Procedure C, substituting 1-Boc-2- methylaminopyrrolidine for ethylamine to lead to the title compound (18 mg, 31 %) as beige solid, hydrochloride salt. ESI-MS: 485.30 [M+H]+. 1 H NMR (400 MHz, Methanol-*#) d 9.20 (s,
1 H), 8.06 (s, 1 H), 7.90 (d, J = 7.0 Hz, 2H), 7.59 (d, J = 8.1 Hz, 1 H), 7.49 - 7.40 (m, 2H), 7.09 - 6.99 (m, 2H), 4.81 - 4.62 (m, 1 H), 4.08 (s, 3H), 3.75 - 3.64 (m, 1 H), 3.58 (s, 3H), 3.47 - 3.35 (m, 2H), 3.13 - 2.99 (m, 1 H), 2.54 - 2.39 (m, 1 H), 2.37 - 2.24 (m, 1 H).
Example 97
8-amino-6-(4-fluorophenyl)-N-[(5-methyl- 1, 3, 4-oxadiazol-2-yl)methyl]-5-( 1 -methyl- 1H- 1, 3-ben- zodiazol-6-yl)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000132_0002
The title compound was synthesized following the approach outlined in Procedure B substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 in Procedure B, step a and performing this step for 2 h at 100°C and then following Procedure C, substituting (5-me- thyl-1 ,3,4-oxadiazol-2-yl)methylamine for ethylamine to lead to the title compound (2.2 mg, 4%) as beige solid. ESI-MS: 498.20 [M+H]+. 1 H NMR (300 MHz, Methanol-*#) d 8.24 (s, 1 H), 7.88 (s, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 1.2 Hz, 1 H), 7.39 (dd, J = 8.7, 5.5 Hz, 2H), 7.30 (dd, J = 8.4, 1.6 Hz, 1 H), 6.92 (t, J = 8.8 Hz, 2H), 4.81 (s, 2H), 3.87 (s, 3H), 2.53 (s, 3H).
Example 98
8-amino-N-tert-butyl-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)imidazo[ 1,2-a]py- razine-2-carboxamide
Figure imgf000133_0001
The title compound was synthesized following the approach outlined in Procedure B substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 Procedure B, step a and performing this step for 2 h at 100°C and then following Procedure C, substituting tert-butyla- mine for ethylamine to lead to the title compound (51 mg, 38%) as off-white solid, hydrochloride salt. ESI-MS: 458.30 [M+H]+. 1 H NMR (400 MHz, DMSO-tf5) d 9.49 (s, 1 H), 8.24 - 8.10 (m,
1 H), 7.89 (d, J = 8.5 Hz, 1 H), 7.71 (s, 1 H), 7.48 (s, 1 H), 7.48 - 7.33 (m, 3H), 7.17 - 6.99 (m, 2H), 4.02 (s, 3H), 1 .39 (s, 9H).
Example 99
8-amino-6-(3-cyano-2-methylphenyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000133_0002
The title compound was synthesized following the approach outlined in Procedure A, step a substituting 3-cyano-2-methylphenylboronic acid for 4-fluorophenylboronic acid and then follow ing Procedure F, substituting (4-methylquinolin-6-yl)boronic acid for 4-(difluoromethyl)-6- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline in Procedure F, step b and performing this step at 130°C for 1 h to lead to the title compound (20 mg, 17%) as yellow solid, hydrochlo ride salt. ESI-MS: 448.30 [M+H]+. 1 H NMR (400 MHz, DMSO-o^ d 9.06 (d, J = 5.1 Hz, 1 H), 8.33 (s, 1 H), 8.25 - 8.17 (m, 2H), 8.00 (s, 1 H), 7.78 (d, J = 5.1 Hz, 1 H), 7.70 (dd, J = 7.7, 1.3 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1 H), 7.27 (t, J = 7.7 Hz, 1 H), 2.82 - 2.78 (m, 3H), 2.72 (s, 3H), 2.41 (s, 3H).
Procedure N
Preparation of [1-(2,2-difluoroethyl)-1 H-1 ,3-benzodiazol-6-yl]boronic acid:
Figure imgf000134_0001
Into a stirred solution of 4-bromo-2-fluoro-1 -nitrobenzene (2.20 g, 10 mmol), 2,2-di- flouroethane-1 -amine (0.81 1 g, 10 mmol) in DMF (10 ml), DIPEA (3.48 ml, 20 mmol) was added and stirred at room temperature for 16 h under argon atmosphere. After that time, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic ex tracts were washed with brine, dried over anhydrous MgSC and concentrated under reduced pressure. Product was purified by flash chromatography (silica gel, hexane/EtOAc 0-10%) to af- ford the title compound of the yellow solid (2.44 g, 87%). ESI-MS: 448.30 [M+H]+. b. 5-bromo-N 1-(2, 2-difiuoroethyi)benzene- 1, 2-diamine
Figure imgf000134_0002
In a pressure tube a mixture of 5-bromo-N-(2,2-difluoroethyl)-2-nitroaniline (2.44 g, 8.68 mmol), iron powder (1.45 g, 26.04 mmol) and NH CI (2.32 g, 43.41 mmol) in 50% aqueous eth anol (60 ml) was stirred at 80°C for 1 h. The resulting suspension was filtered through a Celite® pad, washed with DCM and water and the filtrate was extracted with DCM. The combined or ganic layers were washed with brine and dried over MgSC . The solvent was evaporated and crude mixture was used for the next step without further purification. ESI-MS: 251.00 [M+H]+. c. 6-bromo- 1-(2,2-difiuoroethyi)- 1H- 1, 3-benzodiazoie
Figure imgf000135_0001
In a pressure tube to the solution of 5-bromo-N1-(2,2-difluoroethyl)benzene-1 , 2-diamine (1.98 g, 7.89 mmol) in triethyl orthoformate (5.56 ml, 39.43 mmol) was added p-toluenesulfonic acid monohydrate (136 mg, 0.789 mmol) and the reaction mixture was stirred at 60°C for 1.5 h. After cooling down, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over MgSCU. The product was puri fied by flash chromatography (silica gel, hexane/EtOAc 0-10% EtOAc) to afford the title product as brown solid (1.71 g, 83%). ESI-MS: 263.10 [M+H]+. d. [ 1-(2,2-difluoroethyl)- 1H- 1, 3-benzodiazol-6-yl]boronic acid
Figure imgf000135_0002
The pressure tube was charged with 6-bromo-1 -(2,2-difluoroethyl)-1 H-1 ,3-benzodiazole (1.71 g, 6.51 mmol), bis(pinacolato)diboron (2.15 g, 8.47 mmol) and potassium acetate (1.28 g, 13.02 mmol). To this mixture 1 ,4-dioxane (30 ml) was added. The resulting reaction mixture was purged with argon for 15 minutes. After that time, Pd(dppf)Cl2 DCM (106 mg, 0.13 mmol) was added and resulting mixture was heated in pre-heated oil bath at 100°C for 2 h. The mixture was filtered through Celite® pad and washed with ethyl acetate. The solvent was evaporated and the product was isolated by flash chromatography (silica gel, hexane/EtOAc) to afford the title compound (1.95 g, 97%) as brown oil. ESI-MS: 227.10 [M+H]+.
Example 100:
8-amino-5-[ 1-(2,2-difluoroethyl)- 1H- 1, 3-benzodiazol-6-yl]-6-(4-fluorophenyl)-N-methylimid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000135_0003
The title compound was synthesized following the approach outlined in Procedure F, substitut ing 1 -(2,2-difluoroethyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-1 ,3-benzodiazole (Procedure N) for 4-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline to lead to the title compound (10 mg, 27%) as white solid, hydrochloride salt. ESI-MS: 466.20
[M+H]+. 1 H NMR (400 MHz, DMSO-c/6) d 8.99 (s, 1 H), 8.30 (q, J = 4.8 Hz, 1 H), 8.01 - 7.81 (m, 3H), 7.38 (dd, J = 8.5, 6.0 Hz, 3H), 7.13 (t, J = 8.7 Hz, 2H), 6.47 (t, J = 54.3 Hz, 1 H), 4.94 (t, J = 16.4 Hz, 2H), 2.77 (d, J = 4.6 Hz, 3H).
Procedure O
Example 101
6-(4-fluorophenyl)-2-[(methylamino)methyl]-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazin-8- amine
Figure imgf000136_0001
Into the pressure tube 8-amino-6-(4-fluorophenyl)-N-methyl-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide hydrochloride (synthesized following the approach outlined in Procedure F, substituting (4-methylquinolin-6-yl)boronic acid for 4-(difluoromethyl)-6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline in step b) (212 mg, 0.5 mmol) and 3 ml of THF were added, into it diisobutylaluminium hydride (1 M solution in THF, 3 ml) was added dropwise at room temperature, under argon atmosphere. The resulting reaction mixture was then heated to 60°C and stirred for 16 h. After that time reaction mixture was cooled down and carefully quenched by water and extracted with EtOAc/NaHCCh organic layer was washed with brine and dried over MgS04, filtered and concentrated. Product was purified by preparative HPLC and transformed into hydrochloride salt to afford the title product (17 mg, 7%) as yellow solid. ESI- MS: 413.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.06 (s, 2H), 8.96 (s, 1 H), 8.32 (s, 1 H), 8.15 (d, J = 8.7 Hz, 1 H), 7.84 - 7.73 (m, 2H), 7.63 (s, 1 H), 7.39 (dd, J = 8.7, 5.5 Hz, 1 H), 7.08 (t, J = 8.7 Hz, 1 H), 4.22 (t, J = 5.6 Hz, 3H), 2.69 (s, 2H), 2.60 (t, J = 5.4 Hz, 3H).
Example 102
8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[2-(pyrrolidin- 1-yl)ethyl]imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000137_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2-pyrrolidinoethylamine for ethylamine to lead to the title compound (20 mg, 100%) as yel low solid, hydrochloride salt. ESI-MS: 510.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r76) d 10.68 (s, 1 H), 9.14 (d, J = 5.2 Hz, 1 H), 8.76 (t, J = 5.9 Hz, 1 H), 8.54 (s, 1 H), 8.34 (d, J = 8.8 Hz, 1 H), 8.29 (s, 1 H), 7.95 - 7.86 (m, 2H), 7.41 (dd, J = 8.7, 5.5 Hz, 2H), 7.12 (t, J = 8.8 Hz, 2H), 3.67 - 3.60 (m, 2H), 3.59 - 3.52 (m, 2H), 3.32 - 3.26 (m, 2H), 3.04 - 2.94 (m, 2H), 2.85 (s, 3H), 2.04 - 1.92 (m, 2H), 1.90 - 1.79 (m, 2H).
Example 103
8-amino-N-(cyclopropylmethyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000137_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing (aminomethyl)cyclopropane for ethylamine to lead to the title compound (12 mg, 32%) as yellow solid, hydrochloride salt. ESI-MS: 467.40 [M+H]+. 1 H NMR (D20) d 8.98 (d, J = 5.8 Hz,
1 H), 8.48 (d, J = 1.7 Hz, 1 H), 8.21 (d, J = 8.8 Hz, 1 H), 8.06 (s, 1 H), 8.03 (dd, J = 8.8; 1.7 Hz,
1 H), 7.93 (dd, J = 5.8; 0.9 Hz, 1 H), 7.42 - 7.34 (m, 2H), 7.10 - 6.96 (m, 2H), 1.81 (d, J = 7.0 Hz, 2H), 2.85 (s, 3H), 1 .20 - 1.10 (m, 1 H), 0.60 - 0.46 (m, 2H), 0.36 - 0.20 (m, 2H).
Example 104
8-amino-5-(4-chloro- 1 -methyl· 1H- 1, 3-benzodiazol-6-yl)-6-(4-fluorophenyl)imidazo[ 1,2-a]pyra- zine-2-carboxamide
Figure imgf000138_0001
The title compound was synthesized following the approach outlined in Procedure K, substitut ing (4-chloro-1-methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid (Procedure H) for (8-chloroquinolin- 6-yl)boronic acid to lead to the title compound (32 mg, 34%) as white solid, hydrochloride salt. ESI-MS: 436.20 [M+H]+. 1 H NMR (300 MHz, DMSO-r/6) d 8.55 (s, 1 H), 7.97 (s, 1 H), 7.81 (d, J = 1.2 Hz, 1 H), 7.62 (d, J = 18.3 Hz, 2H), 7.48 - 7.38 (m, 2H), 7.34 (d, J = 1.2 Hz, 1 H), 7.22 - 7.12 (m, 2H), 3.86 (s, 3H).
Example 105
8-amino-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyra- zine-2-carboxamide
Figure imgf000138_0002
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 2,2-difluoroethylamine for ethylamine to lead to the title compound (15 mg, 68%) as yellow solid, hydrochloride salt. ESI-MS: 477.20 [M+H]+. 1 H NMR (400 MHz, DMSO-</6) d 9.14 (d, J = 5.0 Hz, 1 H), 8.59 - 8.50 (m, 2H), 8.35 (d, J = 8.8 Hz, 1 H), 8.09 (s, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.89 (d, J = 5.1 Hz, 1 H), 7.41 (dd, J = 8.3, 5.6 Hz, 2H), 7.1 1 (t, J = 8.8 Hz, 2H), 6.13 (tt, J =
56.2, 3.6 Hz, 1 H), 3.72 - 3.70 (m, 2H), 2.81 (s, 3H).
Example 107
8-amino-5-{8-chloro-3-methylimidazo[1,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-(1-methylcyclo- buty!)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000138_0003
The title compound was synthesized following the approach outlined in Procedure B, substitut ing {8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}boronic acid [the approach outlined in Procedure M substituting 6-bromo-8-chloro-3-methylimidazo[1 ,2-a]pyridine for 6-bromo-4-ethylquino- line and performing this step at 100°C for 4 h, without microwave irradiation] for (4-methylquino- lin-6-yl)boronic acid in Procedure B, step a and substituting Pd(amphos)Cl for Sphos Pd G3 in Procedure B, step a and performing this step at 100°C for 1.5 h and performing step b at 50°C for 16 h and then following Procedure C, substituting 1-methyl-cyclobutylamine for ethylamine and substituting EtsN for DIPEA in this procedure to lead to the title compound (37 mg, 45%) as off-white solid, hydrochloride salt. ESI-MS: 504.40 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) d 8.89 (s, 1 H), 8.09 (s, 1 H), 7.98 - 7.86 (m, 3H), 7.52 - 7.43 (m, 2H), 7.13 (dd, J = 8.9 Hz, 2H), 2.48 (s, 3H), 2.41 - 2.33 (m, 2H), 2.06 - 1.96 (m, 2H), 1.88 - 1.77 (m, 2H), 1 .49 (s, 3H).
Example 108
8-amino-6-(4-fluorophenyl)-N-(1-methylcyclobutyl)-5-{3-methylimidazo[1,2-a]pyridin-6-yl}imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000139_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyridine for (4- methylquinolin-6-yl)boronic acid in Procedure B, step a and substituting Pd(PPh ) for Sphos Pd G3 in Procedure B, step a and then following Procedure C substituting 1-methyl-cyclobutyla- mine for ethylamine and substituting EtsN for DIPEA in this procedure to lead to the title com pound (20 mg, 22%) as yellowish solid, hydrochloride salt. ESI-MS: 470.30 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.13 (s, 1 H), 8.16 (s, 1 H), 8.07 (d, J = 1.3 Hz, 1 H), 7.98 (dd, J = 9.2, 1.0 Hz, 1 H), 7.93 (s, 1 H), 7.74 (dd, J = 9.2, 1.5 Hz, 1 H), 7.48 - 7.42 (m, 2H), 7.10 (t, J = 8.9 Hz,
2H), 2.54 (d, J = 1.1 Hz, 3H), 2.41 - 2.34 (m, 2H), 2.05 - 1.96 (m, 2H), 1.88 - 1.78 (m, 2H), 1.49 (s, 3H).
Example 109
8-amino-6-(4-fluorophenyl)-5-{3-methylimidazo[1,2-a]pyridin-6-yl}-N-(propan-2-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000140_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyridine for (4- methylquinolin-6-yl)boronic acid in Procedure B, step a and performing this step at 1 10° C for 3 h and then following Procedure C substituting isopropylamine for ethylamine in this procedure to lead to the title compound (42 mg, 43%) as beige solid, hydrochloride salt. ESI-MS: 444.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r 6) d 9.14 (t, J = 1 .2 Hz, 1 H), 8.31 (s, 1 H), 8.08 (d, J = 1.3 Hz, 1 H), 7.99 (dd, J = 9.3, 0.9 Hz, 1 H), 7.89 (d, J = 8.2 Hz, 1 H), 7.71 (dd, J = 9.3, 1.3 Hz, 1 H), 7.52 - 7.37 (m, 2H), 7.20 - 7.02 (m, 2H), 4.20 - 3.97 (m, 1 H), 2.55 (s, 3H), 1.18 (d, J = 6.5 Hz, 6H).
Example 1 10
8-amino-6-(4-fluorophenyl)-N-methyl-5-[ 1-(propan-2-y/)- 1H- 1, 3-benzodiazol-6-yl]imidazo[ 1,2- a]pyrazine-2-carboxamide
Figure imgf000140_0002
The title compound was synthesized following the approach outlined in Procedure B substituting 1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-1 ,3-benzodiazole [the ap proach outlined in Procedure M, substituting 6-bromo-1-(propan-2-yl)-1 H-1 ,3-benzodiazole for 6-bromo-4-ethylquinoline and Pd2(dba)3 with tricyclohexylphosphine for Pd(dppf)Cl2*DCM and performing this step at 85° C for 3 h, without MW irradiation] for (4-methylquinolin-6- yl)boronic acid in Procedure B, step a and performing this step at 1 10° C for 3 h to lead to the title compound (57 mg, 43%) as white solid, hydrochloride salt. ESI-MS: 444.20 [M+H]+. 1 H NMR (300 MHz, DMSO-r/6) d 9.65 (s, 1 H), 8.25 (d, J = 4.9 Hz, 1 H), 8.16 (d, J = 1.4 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.89 (s, 1 H), 7.60 (dd, J = 8.5, 1.4 Hz, 1 H), 7.43 - 7.33 (m, 2H), 7.12 (t, J = 8.9 Hz, 2H), 4.92 (p, J = 6.7 Hz, 1 H), 2.78 (d, J = 4.7 Hz, 3H), 1.52 (dd, J = 24.1 , 6.7 Hz,
6H)
Example 1 11
8-amino-6-(3-cyanophenyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazine-2-carbox- amide
Figure imgf000141_0001
The title compound was synthesized following the approach outlined in Procedure A, in step a substituting 3-cyanophenylboronic acid for 4-fluorophenylboronic acid and then following Proce dure F, substituting (4-methylquinolin-6-yl)boronic acid for 4-(difluoromethyl)-6-(4,4,5,5-tetrame- thyl-1 ,3,2-dioxaborolan-2-yl)quinoline in Procedure F, step b and performing this step at 130° C for 1 h to lead to the title compound (6 mg, 21 %) as yellow solid, hydrochloride salt. ESI-MS: 434.2 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.04 (d, J = 4.9 Hz, 1 H), 8.42 (s, 1 H), 8.22 (d, J = 8.7 Hz, 1 H), 8.17 (d, J = 4.9 Hz, 1 H), 7.96 - 7.90 (m, 1 H), 7.89 - 7.84 (m, 2H), 7.73 (d, J = 4.4 Hz, 1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.55 (d, J = 8.1 Hz, 1 H), 7.37 (t, J = 7.8 Hz, 1 H), 2.79 (d, J = 4.7 Hz, 3H), 2.72 (s, 3H).
Example 1 12
8-amino-6-(4-fluorophenyl)-5-{3-methylimidazo[1,2-a]pyridin-6-yl}imidazo[1,2-a]pyrazine-2-car- boxy!ic acid
Figure imgf000141_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyridine for (4- methylquinolin-6-yl)boronic acid in Procedure B, step a and performing this step at 1 10° C for 3 h to lead to the title compound (8 mg, 65%) as off-white solid, hydrochloride salt. ESI-MS:
403.20 [M+H]+. 1 H NMR (400 MHz, D20) d 8.83 - 8.71 (m, 1 H), 8.12 (s, 1 H), 7.96 (dd, J = 9.4, 1.0 Hz, 1 H), 7.89 (dd, J = 9.4, 1.5 Hz, 1 H), 7.79 - 7.71 (m, 1 H), 7.52 - 7.38 (m, 2H), 7.20 - 7.07 (m, 2H), 2.48 (d, J = 1.1 Hz, 3H).
Example 1 13
8-amino-6-(3-cyanophenyl)-N-(2,2-difluoroethyl)-5-{3-methylimidazo[1,2-a]pyridin-6-yl}imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000142_0001
The title compound was synthesized following the approach outlined in Procedure A, in step a substituting 3-cyanophenylboronic acid for 4-fluorophenylboronic acid and then following Proce dure B, substituting 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyri- dine for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and performing this step at 1 10° C for 3 h and then following Procedure C substituting 2,2-difluoroethan-1-amine for ethyla- mine in this procedure to lead to the title compound (20 mg, 14%) as yellowish solid, hydrochlo ride salt. ESI-MS: 473.20 [M+H]+. 1 H NMR (400 MHz, DMSO-r/5) d 9.15 (t, J = 1.2 Hz, 1 H), 8.40 (t, J = 6.3 Hz, 1 H), 8.27 (s, 1 H), 8.08 (d, J = 1.3 Hz, 1 H), 8.00 (dd, J = 9.2, 0.9 Hz, 1 H), 7.94 (t, J = 1.8 Hz, 1 H), 7.80 (dd, J = 9.2, 1.5 Hz, 1 H), 7.74 (dt, J = 7.8, 1.4 Hz, 1 H), 7.63 (dt, J = 8.0, 1.4 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 1 H), 6.15 (t, J = 3.8 Hz, 1 H), 3.74 (t, J = 16.5 Hz, 2H), 2.54 (d, J = 1.1 Hz, 3H).
Example 1 14
8-amino-6-(2-fluorophenyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazine-2-car- boxamide
Figure imgf000142_0002
The title compound was synthesized following the approach outlined in Procedure A, in step a substituting 2-fluorophenylboronic acid for 4-fluorophenylboronic acid and then following Procedure F, substituting (4-methylquinolin-6-yl)boronic acid for 4-(difluoromethyl)-6-(4,4,5,5-tetrame- thyl-1 ,3,2-dioxaborolan-2-yl)quinoline in Procedure F, step b and performing this step at 130° C for 1 h to lead to the title compound (6 mg, 21 %) as yellow solid, hydrochloride salt. ESI-MS: 427.20 [M+H]+. 1 H NMR (300 MHz, DMSO-c/6) d 9.1 1 (d, J = 5.2 Hz, 1 H), 8.36 (d, J = 1.7 Hz,
1 H), 8.30 (d, J = 8.8 Hz, 1 H), 8.27 - 8.19 (m, 1 H), 8.06 - 8.00 (m, 2H), 7.84 (d, J = 5.3 Hz, 1 H), 7.48 (td, J = 7.5, 1.8 Hz, 1 H), 7.34 (tdd, J = 7.4, 5.3, 1.8 Hz, 1 H), 7.19 - 7.03 (m, 2H), 2.79 (d, J = 4.6 Hz, 3H), 2.72 (s, 3H).
Example 1 15
8-amino-6-(3-cyanophenyl)-5-{3-methylimidazo[1,2-a]pyridin-6-yl}-N-(propan-2-yl)imidazo[1,2- a]pyrazine-2-carboxamide
Figure imgf000143_0001
The title compound was synthesized following the approach outlined in Procedure A, in step a substituting 3-cyanophenylboronic acid for 4-fluorophenylboronic acid and then following Proce dure B, substituting 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyri- dine for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and performing this step at 1 10° C for 3 h and then following Procedure C substituting isopropylamine for ethylamine in this procedure to lead to the title compound (40 mg, 43%) as yellowish solid, hydrochloride salt. ESI-MS: 451.30 [M+H]+. 1 H NMR (400 MHz, DMSO-r/6) d 9.13 (t, J = 1.3 Hz, 1 H), 8.18 (s, 1 H), 8.07 (d, J = 1.2 Hz, 1 H), 8.00 (dd, J = 9.3, 0.9 Hz, 1 H), 7.94 (t, J = 1.7 Hz, 1 H), 7.83 - 7.78 (m, 2H), 7.74 (dt, J = 7.7, 1.4 Hz, 1 H), 7.62 (dt, J = 8.0, 1.4 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 1 H), 4.09
(ddd, J = 12.9, 8.1 , 6.4 Hz, 1 H), 2.54 (d, J = 1.1 Hz, 3H), 1 .19 (d, J = 6.6 Hz, 6H).
Example 1 16
8-amino-N-(cyclopropylmethyl)-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1,3-benzodiazol-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000144_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 and performing this step for 3 h at 130 °C and then following Procedure C, substituting cyclopropanemethylamine for ethylamine to lead to the title compound (68 mg, 46%) as white solid, hydrochloride salt. ESI-MS: 456.30
[M+H]+. 1 H NMR (400 MHz, DMSO-d6) d 9.55 (s, 1 H), 8.29 (t, J = 5.9 Hz, 1 H), 8.22 - 8.18 (m,
1 H), 7.94 - 7.86 (m, 2H), 7.47 (dd, J = 8.5, 1.5 Hz, 1 H), 7.45 - 7.38 (m, 2H), 7.16 - 7.09 (m,
2H), 4.05 (s, 3H), 3.18 - 3.12 (m, 2H), 1.07 - 0.96 (m, 1 H), 0.47 - 0.41 (m, 2H), 0.26 - 0.20 (m, 2H).
Example 117
8-amino-6-(3-cyano-4-fluorophenyl)-N-(2,2-difluoroethyl)-5-{3-methylimidazo[1,2-a]pyridin-6- y!}imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000144_0002
The title compound was synthesized following the approach outlined in Procedure A, in step a substituting 3-cyano-4-fluorophenylboronic acid for 4-fluorophenylboronic acid and performing this step at 80 °C for 16 h, in step c substituting ACN for DME and performing this step with ad dition of Sc(OTf)3 (0.1 eq) at 100 °C for 24 h then following Procedure B, substituting 3-methyl- 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyridine for (4-methylquinolin-6- yl)boronic acid in step a and substituting Pd(PPh3) for Sphos Pd G3 and substituting cesium carbonate for sodium carbonate and performing this step at 120 °C for 1 h under microwave ir radiation, and then following Procedure C, substituting 2,2-difluoroethylamine for ethylamine and triethylamine for DIPEA to lead to the title compound (6 mg, 5%) as white solid, hydrochlo ride salt. ESI-MS: 491.30 [M+H]+. 1 H NMR (400 MHz, D20) d 8.80 (s, 1 H), 8.09 (s, 1 H), 7.98 (d, J = 9.3, 1.0 Hz, 1 H), 7.92 - 7.84 (m, 2H), 7.78 - 7.69 (m, 2H), 7.31 (t, J = 8.9 Hz, 1 H), 6.09 (tt, J = 55.3, 3.4 Hz, 1 H), 3.86 (td, J = 16.0, 3.4 Hz, 2H), 2.50 (s, 3H).
Procedure P Example 118
1-[8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazin-2-yl]ethan- 1-one a. 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[ 1, 2-a]pyrazine-2-carbonitri!e
Figure imgf000145_0001
8-Amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide was synthesized following the approach outlined in Procedure A, subsequently Procedure B, and then followed by Procedure J, substituting ethyl 8-amino-6-(4-fluorophenyl)-5-(4- ethylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxylate for ethyl 8-amino-6-(4-fluorophenyl)-5- (1-methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxylate. Obtained 8-amino-6- (4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide (300 mg, 0.73 mmol) was suspended in POCI3 (1 ml) and it was heated for 2 h at 100 °C. Then reaction mix ture was cooled down in an ice bath and quenched by the dropwise addition of water followed by saturated aqueous solution of sodium bicarbonate. Product was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSCU, filtered off and the solvent was evaporated. The product was purified by flash chromatography (silica gel, eluted with DCM/MeOH from 0% MeOH to 5% MeOH) to lead to the 8-amino-6-(4-fluorophenyl)- 5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbonitrile (247 mg, 86%) as brown solid. b. 1-[8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[ 1 ,2-a]pyrazin-2-yl]ethan- 1- one
Figure imgf000145_0002
To the 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboni- trile (125 mg, 0.32 mmol), dissolved in 3 ml of THF, methylmagnesium bromide solution in di ethyl eter (3N, 0.32 ml) and CuBr (9.1 mg, 0.06 mmol) were added. Reaction mixture was stirred for 2 days at 70 °C. Then reaction was quenched by water followed by saturated aque ous solution of sodium bicarbonate. Product was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgS0 , filtered off and the solvent was evaporated in vacuo. The obtained crude material was purified by flash chromatography, then transformed into hydrochloride salt to give the title compound (3 mg, 2%) as yellow solid, hydro chloride salt. ESI-MS: 412.30 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) d 9.01 - 8.97 (m, 1 H), 8.38 - 8.33 (m, 1 H), 8.16 (d, J = 8.7 Hz, 1 H), 8.01 (s, 1 H), 7.87 - 7.82 (m, 1 H), 7.69 - 7.64 (m, 1 H), 7.39 - 7.33 (m, 2H), 7.08 - 7.01 (m, 2H), 2.69 (s, 3H), 2.58 (s, 3H).
Example 119
8-amino-6-(4-fluorophenyl)-N-( 1-methoxy-2-methylpropan-2-yl)-5-( 1 -methyl- 1H- 1 ,3-benzodia- zol-6-yl)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000146_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 and performing this step for 2 h at 100 °C and then following Procedure C, substituting 1-methoxy-2-methylpropan-2-amine for ethyla- mine and triethylamine for DIPEA to lead to the title compound (35 mg, 22%) as white solid, hy drochloride salt. ESI-MS: 488.30 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) d 9.47 (s, 1 H), 8.17 (t, J = 1.0 Hz, 1 H), 7.93 - 7.86 (m, 1 H), 7.67 (s, 1 H), 7.48 - 7.35 (m, 4H), 7.13 - 7.04 (m, 2H), 4.02 (s, 3H), 3.46 (s, 2H), 3.30 (s, 3H), 1.35 (s, 6H).
Example 120
8-amino-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)-N-[ 1-(trifluoromethyl)cyclo- propy!]imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000146_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 , 3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 and performing this step for 2 h at 100 °C and then following Procedure C, substituting 1-(trifluoromethyl)cyclopropanamine for ethyla- mine and triethylamine for DIPEA and performing this step for 5 days at room temperature to lead to the title compound (45 mg, 30%) as white solid, hydrochloride salt. ESI-MS: 510.30 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) d 9.50 (s, 1 H), 9.02 (s, 1 H), 8.17 (s, 1 H), 7.98 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.47 (dd, J = 8.5, 1.5 Hz, 1 H), 7.42 - 7.37 (m, 2H), 7.14 - 7.07 (m, 2H), 4.04 (s, 3H), 1.34 - 1.29 (m, 2H), 1.19 - 1.13 (m, 2H).
Example 121
8-amino-6-(3-cyano-4-†luorophenyl)-N-(2,2-difluoroethyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazo/-6- y!)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000147_0001
The title compound was synthesized following the approach outlined in Procedure A, in step a substituting 3-cyano-4-fluorophenylboronic acid for 4-fluorophenylboronic acid and performing this step at 80 °C for 16 h, in step c substituting ACN for DME and performing this step with ad dition of Sc(OTf)3 (0.1 eq) at 100 °C for 24 h then following Procedure B, substituting (1-methyl- 1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in step a and sub stituting Pd(PPh3) for Sphos Pd G3 and substituting cesium carbonate for sodium carbonate and performing this step at 130 °C for 1 h under microwave irradiation, and then following Procedure C, substituting 2,2-difluoroethylamine for ethylamine and triethylamine for DIPEA to lead to the title compound (6 mg, 9%) as white solid, hydrochloride salt. ESI-MS: 491.20 [M+H]+. 1 H NMR (400 MHz, D20) d 9.24 (s, 1 H), 8.03 - 7.97 (m, 2H), 7.89 (dd, J = 8.6, 0.8 Hz, 1 H), 7.76 (dd, J = 6.0, 2.3 Hz, 1 H), 7.65 (ddd, J = 8.8, 5.1 , 2.4 Hz, 1 H), 7.59 (dd, J = 8.6, 1.5 Hz, 1 H), 7.22 (d, J = 8.9 Hz, 1 H), 6.24 - 5.93 (m, 1 H), 4.06 - 4.01 (m, 3H), 3.85 (td, J = 16.0, 3.4 Hz, 2H).
Example 122
8-amino-6-(4-fluorophenyl)-5-{3-meth ylimidazof 1 ,2-a]pyridin-6- yl}-N-[ 1-(trifluoromethyl)cyclo- propy!]imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000147_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyridine for (4- methylquinolin-6-yl)boronic acid in step a and substituting Pd(PPh3)2Cl2 for Sphos Pd G3 and substituting cesium carbonate for sodium carbonate and performing this step at 85 °C for 5 h, and then following Procedure C, substituting 1-trifluoromethyl-1 -cyclopropylamine for ethyla- mine and triethylamine for DIPEA to lead to the title compound (82 mg, 27%) as off-white solid, hydrochloride salt. ESI-MS: 510.20 [M+H]+. 1 H NMR (400 MHz, D20) d 8.76 (t, J = 1.3 Hz, 1 H), 8.1 1 (s, 1 H), 7.97 (dd, J = 9.4, 1.0 Hz, 1 H), 7.89 (dd, J = 9.4, 1.5 Hz, 1 H), 7.75 (d, J = 1.1 Hz,
1 H), 7.50 - 7.39 (m, 2H), 7.20 - 7.01 (m, 2H), 2.48 (d, J = 1.1 Hz, 3H), 1.51 - 1.41 (m, 2H), 1.27 (d, J = 7.0 Hz, 2H).
Example 123
8-amino-N-(cyclopropylmethyl)-6-(4-fluorophenyl)-5-{3-methylimidazo[1,2-a]pyridin-6-yl}imid- azo[ 1,2-a]pyrazine-2-carboxamide
Figure imgf000148_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyridine for (4- methylquinolin-6-yl)boronic acid in step a and substituting Pd(PPh3)2Cl2 for Sphos Pd G3 and substituting cesium carbonate for sodium carbonate and performing this step at 85 °C for 5 h, and then following Procedure C, substituting 1-cyclopropylmethanamine for ethylamine and tri- ethylamine for DIPEA and performing this step at room temperature for 4 h to lead to the title compound (72 mg, 43%) as off-white solid, hydrochloride salt. ESI-MS: 456.30 [M+H]+. 1 H NMR (400 MHz, D20) d 8.79 (t, J = 1.3 Hz, 1 H), 8.08 (s, 1 H), 7.98 (dd, J = 9.4, 1.0 Hz, 1 H), 7.90 (dd, J = 9.4, 1.6 Hz, 1 H), 7.76 (q, J = 1.0 Hz, 1 H), 7.54 - 7.41 (m, 2H), 7.20 - 7.05 (m, 2H), 3.28 (d, J = 7.0 Hz, 2H), 2.49 (d, J = 1.1 Hz, 3H), 1.23 - 0.97 (m, 1 H), 0.68 - 0.45 (m, 2H), 0.27 (dt, J = 6.0, 4.4 Hz, 2H).
Example 124
2-(4, 5-dihydro- 1H-imidazol-2-yl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[ 1,2-a]pyra- zin-8-amine
Figure imgf000148_0002
To the ethylene diamine (0.14 ml, 2.03 mmol) in dry toluene (3 ml), triethyl aluminium solution in heptane (2N, 0.63 ml) was added followed by the solution of 8-amino-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbonitrile (Procedure P, step a, 100 mg, 0.25 mmol) in toluene (3 ml). Reaction mixture was heated for 16 h at 80 °C. Then triethyl aluminium solution in heptane (2N, 0.30 ml) was added and reaction mixture was stirred for 1 h in 100 °C. Then the solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. Organic phase was dried over MgS04, filtrated and concentrated. Crude product was pu rified by preparative HPLC and transformed into hydrochloride salt to afford the title product (53 mg, 48%) as yellow solid. ESI-MS: 438.30 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) d 10.65 (s, 2H), 9.08 (d, J = 5.0 Hz, 1 H), 8.79 (s, 1 H), 8.55 (s, 1 H), 8.25 (d, J = 8.8 Hz, 1 H), 7.86 - 7.78 (m, 2H), 7.41 - 7.34 (m, 2H), 7.10 - 7.03 (m, 2H), 3.97 (s, 3H), 2.83 (s, 2H).
Example 125
8-amino-N-(4,4-difluorocyclohexyl)-6-(4-fluorophenyl)-5-{3-methylimidazo[1,2-a]pyridin-6-yl}im- idazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000149_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyridine for (4- methylquinolin-6-yl)boronic acid in step a and substituting Pd(PPh3)2Cl2 for Sphos Pd G3 and substituting cesium carbonate for sodium carbonate and performing this step at 85 °C for 5 h, and then following Procedure C, substituting 4,4-difluorocyclohexan-1 -amine for ethylamine and triethylamine for DIPEA and performing this step at room temperature for 4 h to lead to the title compound (135 mg, 71 %) as beige solid, hydrochloride salt. ESI-MS: 520.30 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) d 9.14 (t, J = 1.3 Hz, 1 H), 8.40 (s, 1 H), 8.18 (d, J = 8.2 Hz, 1 H), 8.07 (d, J = 1.3 Hz, 1 H), 7.99 (dd, J = 9.3, 0.9 Hz, 1 H), 7.70 (dd, J = 9.3, 1.5 Hz, 1 H), 7.55 - 7.38 (m, 2H), 7.20 - 7.05 (m, 2H), 4.07 - 3.87 (m, 1 H), 2.55 (d, J = 1 .1 Hz, 3H), 2.13 - 1 .78 (m, 6H), 1.77 - 1.56 (m, 2H).
Example 126
8-amino-N-( 1-cyanocyclopropyl)-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000149_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 and performing this step for 2 h at 100 °C and then following Procedure C, substituting 1 -amino-1 -cyclopropanecarbonitrile hydrochlo ride for ethylamine and triethylamine for DIPEA and performing this step at room temperature for 7 h to lead to the title compound (24 mg, 14%) as white solid, hydrochloride salt. ESI-MS: 467.30 [M+H]+. 1 H NM R (400 MHz, DMSO-d6) d 9.44 (s, 1 H), 9.29 (s, 1 H), 8.17 (s, 1 H), 7.92 - 7.87 (m, 2H), 7.46 (dd, J = 8.5, 1.5 Hz, 1 H), 7.41 - 7.35 (m, 2H), 7.1 1 - 7.05 (m, 2H), 4.03 (s, 3H), 1 .58 - 1.52 (m, 2H), 1.30 - 1.23 (m, 2H).
Example 127
8-amino-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)-5-{3-methylimidazo[1,2-a]pyridin-6-yl}imid- azo[ 1 ,2-a]pyrazine-2-carboxamide
Figure imgf000150_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyridine for (4- methylquinolin-6-yl)boronic acid in step a and substituting Pd(PPh3)2Cl2 for Sphos Pd G3 and substituting cesium carbonate for sodium carbonate and performing this step at 85 °C for 5 h, and then following Procedure C, substituting 2,2-difluoroethylamine for ethylamine and triethyla- mine for DIPEA to lead to the title compound (238 mg, 73%) as off-white solid, hydrochloride salt. ESI-MS: 466.20 [M+H]+. 1 H NMR (400 M Hz, DMSO-d6) d 9.14 (t, J = 1 .2 Hz, 1 H), 8.46 (t,
J = 6.3 Hz, 1 H), 8.40 (s, 1 H), 8.08 (d, J = 1 .3 Hz, 1 H), 8.00 (dd, J = 9.2, 0.9 Hz, 1 H), 7.71 (dd, J = 9.2, 1 .5 Hz, 1 H), 7.56 - 7.41 (m, 2H), 7.23 - 7.06 (m, 2H), 6.15 (tt, J = 55.8, 3.8 Hz, 1 H), 3.97 - 3.49 (m, 2H), 2.55 (d, J = 1.1 Hz, 3H).
Example 128
8-amino-N-(4,4-difIuorocyclohexyl)-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6-yl)im- idazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000150_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 and performing this step for 2 h at 100 °C and then following Procedure C, substituting 4,4-difluorocyclohexan-1-amine for ethylamine and triethylamine for DIPEA to lead to the title compound (23 mg, 13%) as white solid, hydro chloride salt. ESI-MS: 520.30 [M+H]+. 1 H NM R (400 MHz, DMSO-d6) d 9.42 (s, 1 H), 8.20 - 8.14 (m, 2H), 7.90 (d, J = 8.5 Hz, 1 H), 7.85 (s, 1 H), 7.45 (dd, J = 8.5, 1.5 Hz, 1 H), 7.42 - 7.36 (m, 2H), 7.12 - 7.06 (m, 2H), 4.02 (s, 3H), 4.00 - 3.93 (m, 1 H), 2.07 - 1.83 (m, 6H), 1.70 - 1 .57 (m, 2H).
Example 129
8-amino-N-( 1, 1-di†luoropropan-2-yl)-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazol-6- y!)imidazo[1,2-a]pyrazine-2-carboxamide
Figure imgf000151_0001
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in step a and substituting Pd(amphos)Cl2 for Sphos Pd G3 and performing this step for 2 h at 100 °C and then following Procedure C, substituting 1 ,1 -difluoropropan-2-amine hydrochloride for ethylamine and triethylamine for DIPEA to lead to the title compound (55 mg, 29%) as white solid, hydrochloride salt. ESI-MS: 480.20 [M+H]+. 1 H NMR (400 MHz, D20) d 9.20 (s, 1 H), 7.97 (s, 1 H), 7.95 - 7.94 (m, 1 H), 7.84 (dd, J = 8.6, 0.7 Hz, 1 H), 7.58 (dd, J = 8.6, 1.5 Hz, 1 H), 7.35 - 7.30 (m, 2H), 7.03 - 6.96 (m, 2H), 5.91 (td, J = 55.5, 3.0 Hz, 2H), 4.49 - 4.37 (m, 1 H), 3.97 (s, 3H), 1.28 (d, J = 7.1 Hz, 3H).
Example 130
8-amino-6-(3-cyano-4-fluorophenyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazine-
2-carboxamide
Figure imgf000151_0002
The title compound was synthesized following the approach outlined in Procedure A, in step a substituting 3-cyano-4-fluorophenylboronic acid for 4-fluorophenylboronic acid and performing this step at 80 °C for 16 h, in step c substituting ACN for DME and performing this step with ad dition of Sc(OTf)3 (0.1 eq) at 100 °C for 24 h then following Procedure F, performing step a at 1 10 °C for 8 h and in step b substituting (4-methylquinolin-6-yl)boronic acid for 4-(difluorome- thyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline and substituting Sphos Pd G3 for Pd(amphos)Cl2 and performing this step at 130 °C for 1 h under microwave irradiation to lead to the title compound (36 mg, 40%) as yellow solid, hydrochloride salt. ESI-MS: 452.20 [M+H]+.
1 H NMR (400 MHz, DMSO-d6) d 9.09 (d, J = 5.1 Hz, 1 H), 8.48 (d, J = 1.8 Hz, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 8.15 (q, J = 4.6 Hz, 1 H), 7.95 (ddd, J = 8.8, 7.5, 2.0 Hz, 2H), 7.86 (s, 1 H), 7.81 (d, J = 5.1 Hz, 1 H), 7.69 - 7.48 (m, 3H), 7.34 (t, J = 9.1 Hz, 1 H), 2.80 - 2.75 (m, 6H).
Example 131
8-amino-N-(2-cyanoethyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1,2-a]pyrazine-
2-carboxamide
Figure imgf000152_0001
The title compound was synthesized following the approach outlined in Procedure C, substitut ing 3-aminopropionitrile for ethylamine and substituting HBTU for HATU to lead to the title com pound (100 mg, 34%) as off-white solid, hydrochloride salt. ESI-MS: 466.2 [M+H]+. 1 H NMR (400 MHz, DMSO -d6) d 9.14 (d, J = 5.2 Hz, 1 H), 8.62 (t, J = 6.0 Hz, 1 H), 8.53 (bs, 1 H), 8.33 (d, J = 8.8 Hz, 1 H), 8.05 (s, 1 H), 7.97 (dd, J = 8.7, 1.8 Hz, 1 H), 7.88 (d, J = 5.2 Hz, 1 H), 7.44 - 7.38 (m, 2H), 7.15 - 7.07 (m, 2H), 3.52 (q, J = 6.3 Hz, 2H), 2.84 - 2.74 (m, 5H).
Example 132
8-amino-6-(4-fluorophenyl)-5-( 1 -methyl- 1H- 1, 3-benzodiazoi-6-yi)imidazo[ 1 ,2-a]pyrazine-2-car- boxy!ic acid
Figure imgf000152_0002
The title compound was synthesized following the approach outlined in Procedure B, substitut ing (1 -methyl-1 H-1 ,3-benzodiazol-6-yl)boronic acid for (4-methylquinolin-6-yl)boronic acid in Procedure B, step a and performing this step using Pd(PPh3)2Cl2 instead Sphos Pd G3 and sub stituting CS2CO3 for Na2C03 at 100 °C for 3 h to lead to the title compound (196 mg, 75%) as off-white solid, hydrochloride salt. ESI-MS: 403.2 [M+H]+. 1 H NMR (400 MHz, D20) d 9.28 (d, J = 0.7 Hz, 1 H), 8.08 (s, 1 H), 8.02 (dd, J = 1.5, 0.8 Hz, 1 H), 7.91 (dd, J = 8.6, 0.8 Hz, 1 H), 7.65 (dd, J = 8.6, 1.5 Hz, 1 H), 7.48 - 7.31 (m, 2H), 7.06 (t, J = 8.8 Hz, 2H), 4.04 (s, 3H).
Example 133
8-amino-N-tert-butyl-6-(4-fluorophenyl)-5-{3-methylimidazo[1,2-a]pyridin-6-yl}imidazo[1,2-a]py- razine-2-carboxamide
Figure imgf000153_0001
The title compound was synthesized following the approach outlined in Procedure B, substituting 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)imidazo[1 ,2-a]pyridine for (4- methylquinolin-6-yl)boronic acid in Procedure B, step a and performing this step using
Pd(PPfi3)2Cl2 instead Sphos Pd G3 and substituting CS2CO3 for Na2CC>3 at 85 °C for 5 h in Procedure B, step a and then following Procedure C substituting 2-methylpropan-2-amine for ethyl- amine and substituting EtsN for DIPEA in this procedure to lead to the title compound (171 mg, 36%) as white solid, hydrochloride salt. ESI-MS: 458.3 [M+H]+. 1 H NMR (400 MHz, DMSO-i/6) d 9.13 (s, 1 H), 8.24 (s, 1 H), 8.08 (d, J = 1.5 Hz, 1 H), 7.99 (d, J = 9.2 Hz, 1 H), 7.70 (dd, J = 9.2, 1.5 Hz, 1 H), 7.53 - 7.40 (m, 3H), 7.13 (t, J = 8.9 Hz, 2H), 2.54 (s, 3H), 1.40 (s, 9H).
Part 2: Activity
A2A activity low adenosine
Examples 1 to 133 (see synthesis part above for the structures and names of these 133 compounds) were tested for their antagonistic activity at the rat A2A receptor (endogenously expressed in PC12 cells, which were used in the assay). The antagonistic activity was determined by measuring the effect of each compound on agonist-induced cAMP production using the as say based on time-resolved fluorescence resonance energy transfer (TR-FRET).
General reference as regards the cells and background can be made to Gao et al.,“Novel short-acting A2A adenosine receptor agonists for coronary vasodilation: inverse relationship be tween affinity and duration of action ofA21A agonistd , J. Pharmacol. Exp. Ther., 298, 209.
More specifically, the assay to test each of examples 1 to 133 was performed as follows: The cells were suspended in HBSS buffer (Invitrogen) complemented with 20 mM HEPES (pH 7.4), with 0.1 % BSA and 100 mM Rolipram (a phosphodiesterase-4 inhibitor to block the degradation of cAMP), then distributed in microplates at a density of 2.103 cells/well (in a 384 well plate) in the presence of either (i) HBSS (basal control) with 0.2% DMSO, (ii) the test compound, i.e. each of examples 1 to 133, or (iii) the reference antagonist ZM 241385.
Thereafter, the reference adenosine receptor agonist NECA (e.g. CAS 35920-39-9, Calbio- chem) was added at a final concentration of 43 nM (concentration corresponding to ECso). For basal control measurements, separate assay wells did not contain NECA.
Following 30 min incubation at room temperature, the cells were lysed and the detection mix was added (standard reagents used according to a standard protocol; LANCE™ cAMP 384 Kit, PerkinElmer).
After 60 min at room temperature, the fluorescence transfer was measured at Aex=340 nm and Aem= 665 nm using a microplate reader according to a standard protocol (Envison, Perkin Elmer or Tecan Spark 20 M). For test compounds % of normalized vehicle control was calculated for each data point and plotted against test compound concentration:
Sample— Low control
y = 100 - 100
Vehicle control — Low control
Sample - mean fluorescence intensity of tested compound
Low control - mean fluorescence intensity of NECA 0.043 pM
Vehicle control - mean fluorescence intensity of DMSO 0.2%
EC50, Hill slope and efficacy parameters were determined by fitting a variable-slope sigmoidal function.
For each of example 1 to 133, the apparent dissociation constant (KB) was calculated using the modified Cheng Prusoff equation:
Figure imgf000154_0001
where A = concentration of reference agonist in the assay, and EC50A= EC50 value of the ref erence agonist.
The standard reference antagonist used was ZM 241385, which was tested in each experi ment at several concentrations to generate a concentration-response curve from which its EC50 value was calculated.
Each of examples 1 to 133 exhibited A2A receptor antagonist activity (KB < 1 mM). Thus, ex amples 1 to 133 as described herein are potent A2A receptor antagonists.
A2A activity high adenosine
Examples 1 to 133 (see synthesis part above for the structures and names of these 133 com pounds) were tested for their antagonistic activity at the human A2A receptor (endogenously ex pressed in PC 12 cells, which were used in the assay) at high concentrations of adenosine. The antagonistic activity was determined by measuring the effect of each compound on agonist-in duced cAM P production using the assay based on time-resolved fluorescence resonance en ergy transfer (TR-FRET).
General reference as regards the cells and background can be made to Gao et al.,“Novel short-acting A2A adenosine receptor agonists for coronary vasodilation: inverse relationship be tween affinity and duration of action ofA21A agonistd’, J. Pharmacol. Exp. Ther., 298, 209.
More specifically, the assay to test each of examples 1 to 133 was performed as follows: The cells were suspended in HBSS buffer (Invitrogen) complemented with 20 mM HEPES (pH 7.4), with 0.1 % BSA ,100 pM Rolipram (a phosphodiesterase-4 inhibitor to block the degradation of cAMP) and 10 pM EHNA - adenosine deaminase inhibitor, then distributed in microplates at a density of 2.0x103 cells/well (in a 384 well plate) in the presence of either (i) HBSS (basal con trol) with 0.2% DMSO, (ii) the test compound, i.e. each of examples 1 to 133, or (iii) the refer ence antagonist ZM 241385.
After 2h incubation at room temperature, the nonselective adenosine receptor agonist - aden osine (e.g. CAS 58-61 -7, Tocris) was added at a final concentration of 100 pM (corresponding to high adenosine concentration in tumor). For basal control measurements, separate assay wells did not contain adenosine.
Following 30 min incubation at room temperature, the cells were lysed and the detection mix was added (standard reagents used according to a standard protocol; LANCE™ cAM P 384 Kit, PerkinElmer).
After 60 min at room temperature, the fluorescence transfer was measured at Aex=340 nm and Aem= 665 nm using a microplate reader according to a standard protocol (Tecan 20M Spark).
For test compounds % of normalized vehicle control was calculated for each data point and plotted against test compound concentration: y = 100 - 100
Figure imgf000155_0001
Sample - mean fluorescence intensity of tested compound
Low control - mean fluorescence intensity of adenosine 100 mM
Vehicle control - mean fluorescence intensity of DMSO 0.2%
EC50, Hill slope and efficacy parameters were determined by fitting a variable-slope sigmoidal function.
For each of example 1 to 133, the apparent dissociation constant (KB) was calculated using the modified Cheng Prusoff equation:
Figure imgf000155_0002
where A = concentration of reference agonist in the assay, and EC50A= EC50 value of the ref erence agonist.
The standard reference antagonist used was ZM 241385, which was tested in each experi ment at several concentrations to generate a concentration-response curve from which its EC50 value was calculated.
A2B activity low adenosine
Examples 1 to 133 (see synthesis part above for the structures and names of these 133 com pounds) were tested for their antagonistic activity at the human A2B receptor (overexpressed in cAMPZen-A2BR-HEK293 cells, which were used in the assay). The antagonistic activity was determined by measuring the effect of each compound on agonist-induced cAM P production us ing the assay based on time-resolved fluorescence resonance energy transfer (TR-FRET).
General reference as regards the cells and background can be made to Cooper et al.,“An en dogenous A2B adenosine receptor coupled to cyclic AMP generation in human embryonic kid ney (HEK-293) ce/id, Brit. J. Pharmacol., 122: 546.
More specifically, the assay to test each of examples 1 to 133 was performed as follows: The cells were suspended in HBSS buffer (Invitrogen) complemented with 20 mM HEPES (pH 7.4), with 0.1 % BSA and adenosine deaminase [0.02 U/ml], then distributed in microplates at a den sity of 2.5x103 cells/well (in a 384 well plate) in the presence of either (i) H BSS (basal control) with 0.2% DMSO, (ii) the test compound, i.e. each of examples 1 to 133, or (iii) the reference antagonist XAC.
Thereafter, the reference adenosine receptor agonist NECA (e.g. CAS 35920-39-9, Calbio- chem) was added at a final concentration of 100 nM (concentration corresponding to ECso). For basal control measurements, separate assay wells did not contain NECA.
Following 30 min incubation at room temperature, the cells were lysed and the detection mix was added (standard reagents used according to a standard protocol; LANCE™ cAM P 384 Kit, PerkinElmer).
After 60 min at room temperature, the fluorescence transfer was measured at Aex=340 nm and Aem= 665 nm using a microplate reader according to a standard protocol (Tecan Spark 20 M).
For test compounds % of normalized vehicle control was calculated for each data point and plotted against test compound concentration: y = 100 - 100
Figure imgf000156_0001
Sample - mean fluorescence intensity of tested compound
Low control - mean fluorescence intensity of NECA 0.1 mM
Vehicle control - mean fluorescence intensity of DMSO 0.2%
EC50, Hill slope and efficacy parameters were determined by fitting a variable-slope sigmoidal function.
For each of example 1 to 133, the apparent dissociation constant (KB) was calculated using the modified Cheng Prusoff equation:
Figure imgf000156_0002
where A = concentration of reference agonist in the assay, and EC50A= EC50 value of the ref erence agonist.
The standard reference antagonist used was XAC, which was tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value was calculated.
A2B activity high adenosine
Examples 1 to 133 (see synthesis part above for the structures and names of these 133 com pounds) were tested for their antagonistic activity at the human A2B receptor (overexpressed in cAMPZen-A2BR-HEK293 cells, which were used in the assay) at high concentrations of adeno sine. The antagonistic activity was determined by measuring the effect of each compound on agonist-induced cAMP production using the assay based on time-resolved fluorescence reso nance energy transfer (TR-FRET).
General reference as regards the cells and background can be made to Cooper et al.,“An en dogenous A2B adenosine receptor coupled to cyclic AMP generation in human embryonic kid ney (HEK-293) ce/id, Brit. J. Pharmacol., 122: 546. More specifically, the assay to test each of examples 1 to 133 was performed as follows: The cells were suspended in HBSS buffer (Invitrogen) complemented with 20 mM HEPES (pH 7.4), with 0.1 % BSA and EHNA - adenosine deaminase inhibitor [10 pM], then distributed in micro plates at a density of 2.5x103 cells/well (in a 384 well plate) in the presence of either (i) HBSS (basal control) with 0.2% DMSO, (ii) the test compound, i.e. each of examples 1 to 133, or (iii) the reference antagonist XAC.
After 2h incubation at room temperature, the nonselective adenosine receptor agonist - aden osine (e.g. CAS 58-61 -7, Tocris) was added at a final concentration of 100 pM (corresponding to high adenosine concentration in tumor). For basal control measurements, separate assay wells did not contain adenosine.
Following 30 min incubation at room temperature, the cells were lysed and the detection mix was added (standard reagents used according to a standard protocol; LANCE™ cAM P 384 Kit, PerkinElmer).
After 60 min at room temperature, the fluorescence transfer was measured at Aex=340 nm and Aem= 665 nm using a microplate reader according to a standard protocol (Tecan Spark 20M).
For test compounds % of normalized vehicle control was calculated for each data point and plotted against test compound concentration:
Sample Low control
y = 100 100 - -
Vehicle control Low control
Sample - mean fluorescence intensity of tested compound
Low control - mean fluorescence intensity of adenosine 100 mM
Vehicle control - mean fluorescence intensity of DMSO 0.2%
EC50, Hill slope and efficacy parameters were determined by fitting a variable-slope sigmoidal function.
For each of example 1 to 133, the apparent dissociation constant (KB) was calculated using the modified Cheng Prusoff equation:
Figure imgf000157_0001
where A = concentration of reference agonist in the assay, and EC50A= EC50 value of the ref erence agonist.
The standard reference antagonist used was XAC, which was tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value was calculated.
Compounds of the present disclosure, as exemplified in the Examples, showed EC50 values in the following ranges: + = EC50 > 1 uM ; ++ = 0.1 uM < EC50 < 1 uM; +++ = EC50 < 0.1 uM ac cording to Table 2. Table 2
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Compounds 123 and 125 show particularly high activities in all four tests.
In particular, the present invention relates to the following further items.
1. A compound of formula (I)
Figure imgf000162_0001
or a salt, stereoisomer, tautomer, isotopologue, or N-oxide thereof,
wherein
G1 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 CH3, F and CN.
G2 is selected from the group consisting of
Figure imgf000162_0002
G3 is selected from the group consisting of of
(i) Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, par tially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated car- bobicyclic 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 heteroatom in the afore mentioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R3;
(ii) C(=0)R5, C(=0)0R6, C(=0)SR6, C(=0)N(R6a)(R6b), OR6, S(=0)nR6, S(=0)nN(R6a)(R6b), S(=0)m0R6, N(R6a)(R6b), N(R6)C(=0)R5, N(R6)C(=0)0R6, N(R6)C(=0)N(R6a)(R6b), N(R6)S(=0)n(R6), N(R6)S(=0)mN(R6a)(R6b), and N(R6)S(=0)m0R6;
R1a is selected from the group consisting of H and Cl;
R1 b is selected from the group consisting of H and Cl;
R1c is selected from the group consisting of H and Cl; R2a 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;
R2b 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;
R2c is Ci-C3-alkyl, wherein each substitutable carbon atom is unsubstituted or substi tuted with one or more F;
R3 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R4;
(ii) C(=0)R7, C(=0)0R8, C(=0)SR8, C(=0)N(R8a)(R8b), OR8, S(=0)nR8,
S(=0)nN(R8a)(R8b), S(=0)m0R8, N(R8a)(R8b), N(R8)C(=0)R7, N(R8)C(=0)0R8, N(R8)C(=0)N(R8a)(R8b), N(R8)S(=0)n(R8), N(R8)S(=0)mN(R8a)(R8b), and N(R8)S(=0)m0R8;
R4 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R9;
(ii) C(=0)R1°, C(=0)0R11, C(=0)SR11, C(=0)N(R11a)(R11b), OR11, S(=0)nR11, S(=0)nN(R11a)(R11b), S(=0)m0R11, N(R11a)(R11b), N(R11)C(=0)R1°, N(R11)C(=0)0R11, N(R11)C(=0)N(R11a)(R11b), N(R11)S(=0)n(R11), N(R11)S(=0)mN(R11a)(R11b), and N(R11)S(=0)m0R11;
R5, R6, R6a, R6b are independently selected from the group consisting of FI, CrC6-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsatu rated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-mem- bered saturated, partially unsaturated or fully unsaturated carbobicyclic or het erobicyclic 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 moieties is unsubstituted or substituted with one or more, same or different substituents R12; R7, R8, R8a, R8b are independently selected from the group consisting of H, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsatu rated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-mem- bered saturated, partially unsaturated or fully unsaturated carbobicyclic or het- erobicyclic 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 moieties is unsubstituted or substituted with one or more, same or different substituents R13;
R9 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C(=0)R14, C(=0)0R15, C(=0)SR15, C(=0)N(R15a)(R15b), OR15, S(=0)nR15, S(=0)nN(R15a)(R15b), S(=0)mOR15, N(R15a)(R15b), N(R15)C(=0)R14, N(R15)C(=0)0R15, N(R15)C(=0)N(R15a)(R15b), N(R15)S(=0)n(R15),
N(R15)S(=0)mN(R15a)(R15b), and N(R15)S(=0)m0R15;
R10, R11, R11a, R11b 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 R17;
R12 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)0R2°, C(=0)SR2°, C(=O)N(R20a)(R20b), OR20, S(=0)nR2°, S(=O)nN(R20a)(R20b), S(=0)mOR2°, N(R20a)(R20b), N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b), N(R20)S(=O)n(R20),
N (R20)S(=O)mN (R20a)(R20b), and N(R20)S(=O)mOR20;
and/or two R12 present on one carbon atom together form =0;
R13 is selected from the group consisting of (i) halogen, CN, NO2, Ci-C6-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 clic 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 R21;
(ii) C(=0)R22, C(=0)0R23, C(=0)SR23, C(=0)N(R23a)(R23b), OR23, S(=0)nR23, S(=0)nN(R23a)(R23b), S(=0)m0R23, N(R23a)(R23b), N(R23)C(=0)R22, N(R23)C(=0)0R23, N(R23)C(=0)N(R23a)(R23b), N(R23)S(=0)n(R23),
N (R23)S(=0)mN (R23a)(R23b), and N(R23)S(=0)m0R23;
R14, R15, R15a, R15b are independently selected from the group consisting of
(i) H, Ci-C6-alkyl, C2-C6-alkenyl, and C2-C6-alkynyl, wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R16;
(ii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated car bocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially un saturated or fully unsaturated carbobicyclic or heterobicyclic 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 heteroatom in the aforementioned cyclic or bicyclic moieties is in dependently unsubstituted or substituted with one or more, same or different substituents R32;
R16 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloal- kenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, N(R33a)(R33b), C(=0)NR33aR33b, S(=0)nNR33aR33b, OR33 and S(=0)nR33;
(ii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated car bocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially un saturated or fully unsaturated carbobicyclic or heterobicyclic 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 heteroatom in the aforementioned cyclic or bicyclic moieties is in dependently unsubstituted or substituted with one or more, same or different substituents R32;
R17 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C -C6-alkenyl, C -C6-haloalkenyl, C -C6-alkynyl, C -C6-haloalkynyl, OH, 0(CrC4-alkyl), NH2, NH(C C4-alkyl), and N(C1-C4-alkyl)(C1-C4-alkyl);
R18 is selected from the group consisting of (i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)SR26, C(=0)N(R26a)(R26b), OR26, S(=0)nR26, S(=0)nN(R26a)(R26b), S(=0)m0R26, N(R26a)(R26b), N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b), N(R26)S(=0)n(R26),
N (R26)S(=0)mN (R26a)(R26b), and N(R26)S(=0)m0R26;
R19, R20, R20a, R20b 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 R27;
R21 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl);
R22, R23, R23a, R23b 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 R28;
R24 is selected from the group consisting of halogen, CN, NO2, Ci-C6-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 R29;
R25, R26, R26a, R26b are independently selected from the group consisting of H, C1-C4- alkyl, Ci-C4-haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, and C2- C4-haloalkynyl;
R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-alkyl),
NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R30;
R28 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-alkyl),
NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R31;
R29, R30, R31 are independently selected from the group consisting of halogen, CN,
NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-al- kynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci- C4-alkyl)(Ci-C4-alkyl);
R32 is selected from the group consisting of halogen, CN, NO2, Ci-C4-alkyl, C1-C4- haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, C(=0)R34, C(=0)0R33, C(=0)SR33, C(=0)N(R33a)(R33b), OR33, S(=0)nR33, S(=0)nN(R33a)(R33b), S(=0)m0R33, N(R33a)(R33b), N(R33)C(=0)R34, N(R33)C(=0)0R33, N(R33)C(=0)N(R33a)(R33b), N(R33)S(=0)n(R33),
N(R33)S(=0)mN(R33a)(R33b), and N(R33)S(=0)m0R33;
R33, R33a, R33b, R34 are independently selected from the group consisting of H, C1-C4- alkyl, Ci-C4-haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, and C2- C4-haloalkynyl;
and wherein
n is 0, 1 or 2; and
m is 1 or 2;
and wherein the compound is not:
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
The compound according to item 1 , wherein G1 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 substitutable carbon or heteroatoms in the aforementioned cyclic moieties is substituted with same or different substituents selected from the group consisting of CF , F and CN, and wherein all other substituents have the mean ing as defined in item 1. The compound according to item 1 , wherein G1 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 aforemen tioned cyclic moieties is substituted with same or different substituents selected from the group consisting of CF , F and CN, and wherein all other substituents have the meaning as defined in item 1. The compound according to any one of items 1 , 2, or 3, whererin R1a is selected from the group consisting of FI and Cl; R1b is selected from the group consisting of FI and Cl; R1c is selected from the group consisting of FI and Cl; R2a is CFh; R2b is CF ; R2c is CH3; and wherein all other substituents have the meaning as defined in item 1. The compound according to any one of items 1 , 2, 3, or 4, wherein G3 is selected from the group consisting of
(i) CrC6-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 R3;
(ii) C(=0)R5, C(=0)OR6, and C(=0)N(R6a)(R6b); wherein R3 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R4;
(ii) C(=0)R7, C(=0)OR8, C(=0)N(R8a)(R8b), OR8, N(R8a)(R8b), N(R8)C(=0)R7, N(R8)C(=0)0R8, and N(R8)C(=0)N(R8a)(R8b);
wherein R4 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R9;
(ii) C(=0)R1°, C(=0)OR11, C(=0)N(R11a)(R11b), OR11, N(R11a)(R11b),
N(R11)C(=0)R1°, N(R11)C(=0)OR11, N(R11)C(=0)N(R11a)(R11b); wherein R5, R6, R6a, R6b 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 R12;
wherein R7, R8, R8a, R8b 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 R13; wherein R9 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4- alkyl);
wherein R10, R11, R11a, R11b are independently selected from the group consisting of H , Ci- C6-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 R17;
wherein R12 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)0R2°, C(=O)N(R20a)(R20b), OR20, N(R20a)(R20b),
N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b); and/or two R12 present on one carbon atom together form =0;
wherein R13 is selected from the group consisting of
(i) halogen, CN, N02, Ci-C6-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 clic 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 R21;
(ii) C(=0)R22, C(=0)0R23, C(=0)N(R23a)(R23b), OR23, N(R23a)(R23b),
N(R23)C(=0)R22, N(R23)C(=0)0R23, N(R23)C(=0)N(R23a)(R23b); wherein R17 is selected from the group consisting of halogen, CN, N02, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(CrC4-alkyi), NH2, NH(C C4-alkyl), and N(C1-C4-alkyl)(C1-C4-alkyl); wherein R18 is selected from the group consisting of (i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)N(R26a)(R26b), OR26, N(R26a)(R26b),
N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b); wherein R19, R20, R20a, R20b are independently selected from the group consisting of H , Ci- C6-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 R27;
wherein R21 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl); wherein R22, R23, R23a, R23b are independently selected from the group consisting of H , Ci- C6-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 R28;
wherein R24 is selected from the group consisting of halogen, CN, N0 , CrC6-alkyl, C -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 R29; wherein R25, R26, R26a, R26b 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;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R30; wherein R28 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R31; wherein R29, R30, R31 are independently selected from the group consisting of halogen,
CN, NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6- alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci- C4-alkyl)(Ci-C4-alkyl), and
wherein all other substituents have the meaning as defined in item 1.
6. The compound according to any one of items 1 , 2, 3, or 4, wherein G3 is selected from the group consisting of C(=0)R5, C(=0)OR6, and C(=0)N(R6a)(R6b);
wherein R5, R6, R6a, R6b are independently selected from the group consisting of H, C1-C6- alkyl, C2-C6-alkenyl, C2-Ce-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 R12;
wherein R12 is selected from the group consisting of (i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)OR2°, C(=O)N(R20a)(R20b), OR20, N(R20a)(R20b),
N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b); and/or two R12 present on one carbon atom together form =0;
wherein R18 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)N(R26a)(R26b), OR26, N(R26a)(R26b),
N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b); wherein R19, R20, R20a, R20b are independently selected from the group consisting of H , Ci- C6-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 R27;
wherein R24 is selected from the group consisting of halogen, CN, N0 , CrC6-alkyl, C -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 R29; wherein R25, R26, R26a, R26b 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;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R30; wherein R29, R30 are independently selected from the group consisting of halogen, CN,
NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-al- kynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci- C4-alkyl)(Ci-C4-alkyl); and
wherein all other substituents have the meaning as defined in item 1.
7. The compound according to item 1 , wherein 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]pyrazin-8-amine; 8-amino-6- (4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(pyridin-2-yl)methyl]imidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(oxan-4- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(4-fluoro- pyrrolidin-3-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-N-[3-(difluoromethoxy)propyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-tert-butyl-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)-N-(2,2,2-trifluoroethyl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(morpholin-2-yl)me- thyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[2-(methyla- mino)ethyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(pyrrolidin-3-yl)imidazo[1 ,2-a]pyrazine- 2-carboxamide 8-amino-N-(1 ,1-dioxo-1 A6-thiolan-3-yl)-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)-N-(2-oxopyrrolidin-3-yl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-6-(4-fluorophenyl)-N-(1-hydroxypropan-2-yl)-5-(4-methylquinolin- 6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 2-(4,4-difluoropiperidine-1 -carbonyl)-6-(4- fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-N-(2,2- difluoroethyl)-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-5-(8-chloro-4-methylquinolin-6-yl)-6-(4-fluoro- phenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-[4-(difluorome- thyl)quinolin-6-yl]-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(propan-2-yl)imidazo[1 ,2-a]py- razine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(2H3)methyl-5-(4-methylquinolin- 6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(3-ethylpyrrolidin-3-yl)-6-(4- fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 2-(2,6- dimethylmorpholine-4-carbonyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazin-8-amine; 8-amino- 5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-6- (4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-N-methyl-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-N-(oxo- lan-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 2-(2,6-dimethylmorpholine-4-car- bonyl)-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazin- 8-amine; 8-amino-N-(4-aminobutyl)-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodia- zol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-{2-[4-(2,4-difluorophenyl)pi- perazin-1-yl]ethyl}-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 2-[4-(2,4-difluorophenyl)piperazine-1-carbonyl]-6- (4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 6-(4-fluoro- phenyl)-2-[4-(2-methoxyethyl)piperazine-1-carbonyl]-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazin-8-amine; 8-amino-6-(4-fluorophenyl)-N-methyl-5-(4-methylquinolin- 6-yl)-N-(propan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-N-(2-methoxyethyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine- 2-carboxamide; 1-[8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 , 3-benzodiazol-6-yl)im- idazo[1 ,2-a]pyrazine-2-carbonyl]pyrrolidin-3-amine; 8-amino-6-(4-fluorophenyl)-5-(1- methyl-1 H-1 ,3-benzodiazol-6-yl)-N-(oxan-4-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(piperidin-4-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-2- (piperazine-1-carbonyl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-N,N-diethyl-6-(4-fluor- ophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(2-methoxyethyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodia- zol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(8-chloroquinolin-6-yl)-6-(4- fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[(1- methylpyrrolidin-3-yl)methyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-N-[3-(dimethylamino)butyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide 8-amino-N-(4,4-difluorocyclohexyl)-6-(4- fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-(2-methoxy- ethyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-[2-(dimethylamino)propyl]-6- (4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(prop-2-yn-1-yl)imidazo[1 ,2-a]py- razine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-N-(1-methylpiperidin-4-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2- carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(oxetan-2-yl)me- thyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-{[6-(2-hy- droxypropan-2-yl)pyridin-2-yl]methyl}-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-
2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-N- (2,2,2-trifluoroethyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)-N-(3,3,3-trifluoropropyl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-6-(4-fluorophenyl)-N-methyl-5-[4-(2H3)methylquinolin-6-yl]imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(4-ethylquinolin-6-yl)-6-(4-fluorophenyl)- N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-[2-(dimethylamino)ethyl]- 6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-N-(1-methoxy-2-methylpropan-2-yl)-5-(4-methylquinolin-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(3-hydroxy- butan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 6-(4-fluorophenyl)-N-[(4-methylmorpholin-2-yl)methyl]-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6- yl)-N-[(oxetan-3-yl)methyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)-N-(oxolan-3-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-N-[1-(methoxymethyl)cyclopropyl]-5-(4-methylquin- olin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1-me- thyl-2-oxopyrrolidin-3-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-{2-[(oxolan-2-yl)meth- oxy]ethyl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(2- methoxy-2-methylpropyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(1 ,1 , 1 -trifluoro-3-hy- droxypropan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-
5-(4-methylquinolin-6-yl)-N-(oxetan-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 1-[8- amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbonyl]-
3-methylpyrrolidin-3-ol; 8-amino- 5-(8-chloro-4-methylquinolin-6-yl)-6-(4-fluorophenyl)- N-(2-methoxyethyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)- N-(1-methylcyclobutyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-N-(2-fluoroethyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 1-[8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-
6-yl)imidazo[1 ,2-a]pyrazine-2-carbonyl]pyrrolidin-3-amine; 8-amino-6-(4-fluorophenyl)- N-(1-methylpyrrolidin-3-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-N-[(1-hydroxycyclopentyl)methyl]-5-(4-methylquino- lin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(2,2-dimethylpropyl)-6-(4- fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-N-(1-methoxypropan-2-yl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol- 6-yl)-N-(2-fluoroethyl)-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-[(1-hy- droxycyclopropyl)methyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(4-chloro- 1 -methyl-1 H-1 , 3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)im- idazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[1-(1-hydroxycyclo- propyl)ethyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-
5-{3-chloroimidazo[1 ,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-[4-(2H3)methylquinolin-6-yl]imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-{8-chloro-3-methylimidazo[1 ,2-a]pyridin-
6-yl}-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4- fluorophenyl)-5-(1-methyl-1 H-1 ,3-benzodiazol-6-yl)-N-(propan-2-yl)imidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(3-hydroxypropyl)-5-(4-methylquin- olin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(2-fluoroethyl)-6-(4-fluoro- phenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-{8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}-6-(4-fluorophenyl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-N- (2,2-difluoroethyl)-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- N-ethyl-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino-5-{8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}-6-(4- fluorophenyl)-N-(propan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-5-{8- chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-[1-(dimethylamino)-2-methylpropan-2- yl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[(1 -methylazetidin-3-yl)methyl]-5-(4-methylquinolin-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-({1-[(2,4-difluorophenyl)me- thyl]piperidin-4-yl}methyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]py- razine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[2-methyl-1-(propan-2-yloxy)pro- pan-2-yl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6- (4-fluorophenyl )-N-methyl-5-(1 -methyl-1 H-1 , 3-benzodiazol-6-yl)-N-(pyrrolidin-3-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[(5-methyl-1 ,3,4- oxadiazol-2-yl)methyl]-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2- carboxamide; 8-amino-N-tert-butyl-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol- 6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(3-cyano-2-methylphenyl)-N- methyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-[1 - (2,2-difluoroethyl)-1 H-1 ,3-benzodiazol-6-yl]-6-(4-fluorophenyl)-N-methylimidazo[1 ,2- a]pyrazine-2-carboxamide; 6-(4-fluorophenyl)-2-[(methylamino)methyl]-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)-N-[2-(pyrrolidin-1-yl)ethyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(cyclopropylmethyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol- 6-yl)-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(2,2-difluo- roethyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(oxetan-3-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-{8-chloro-3-methylimidazo[1 ,2-a]pyridin- 6-yl}-6-(4-fluorophenyl)-N-(1-methylcyclobutyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1-methylcyclobutyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6- yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-{3-methylimid- azo[1 ,2-a]pyridin-6-yl}-N-(propan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 6-(4-fluorophenyl)-N-methyl-5-[1 -(propan-2-yl)-1 H-1 ,3-benzodiazol-6-yl]imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-6-(3-cyanophenyl)-N-methyl-5-(4-methylquinolin- 6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-{3-methylim- idazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-carboxylic acid; 8-amino-6-(3-cyano- phenyl)-N-(2,2-difluoroethyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino-6-(2-fluorophenyl)-N-methyl-5-(4-methylquinolin-6-yl)im- idazo[1 ,2-a]pyrazine-2-carboxamide; and 8-amino-6-(3-cyanophenyl)-5-{3-methylimid- azo[1 ,2-a]pyridin-6-yl}-N-(propan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide.
8. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of items 1 to 7 and optionally a pharmaceutically ac ceptable carrier, diluent or excipient.
9. A compound according to any one of items 1 to 7 and a pharmaceutical composition according to item 8 for use in medicine.
10. A compound for use according to item 9 or a pharmaceutical composition for use ac cording to item 8 or 9, wherein said compound or pharmaceutical composition is for use in the treatment of a disease selected from the group consisting of cancer, Parkin son's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra py ramidal syndrome (in particular dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis (in particular dermal fibrosis in scleroderma), sleep disorders, AIDS, autoimmune diseases, infections, atherosclerosis and ischemia-reperfusion injury.
11. A compound for use according to item 9 or a pharmaceutical composition for use ac cording to item 8 or 9, wherein said compound or pharmaceutical composition is for use in the treatment of cancer, and wherein at least one further anti-neoplastic agent is preferably coadministered with said compound and/or comprised in said pharma ceutical composition.
12. A compound for use according to item 11 or a pharmaceutical composition for use ac cording to item 1 1 , wherein said anti-neoplastic agent is selected from the group con sisting of a chemotherapeutic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone, a hormonal analogue, a signal transduction pathway inhibitor, a non-receptor tyrosine kinase inhibitor, an angiogenesis inhibitor, a proapoptotic agent, a cell cycle signaling inhibitor, a proteasome inhibitor, an inhibitors of cancer metabolism, and an immunotherapeutic agent, wherein said chemothera peutic agent is preferably selected from the group consisting of an anti-microtubule agent, an platinum coordination complex and an antibiotic agent; and wherein said im- munotherapeutic agent is preferably selected from the group considting of a STING pathway modulating compound, a TLR agonist and a checkpoint inhibitor. 13. A compound for use according to item 12 or a pharmaceutical composition for use ac cording to item 12, wherein said checkpoint inhibitor targets PD-1 , PD-L1 , CTLA-4, IDO, KIR, TIM-3, LAG-3, CD39, CD73, ICOS, 0X40, Tim-3, Vista, BTLA, TDO, or TIGIT. 14. A compound for use according to item 12 or 13 or a pharmaceutical composition for use according to item 12 or 13, wherein said checkpoint inhibitor is an antibody, a small molecule inhibitor or an antisense oligonucleotide selected from the group con sisting 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.

Claims

Claims
1. A compound of formula (I)
Figure imgf000182_0001
or a salt, stereoisomer, tautomer, isotopologue, or N-oxide thereof,
wherein
G1 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 CH3, F and CN.
G2 is selected from the group consisting of
Figure imgf000182_0002
G3 is selected from the group consisting of
(i) Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, par tially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated car- bobicyclic 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 heteroatom in the afore mentioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R3;
(ii) C(=0)R5, C(=0)OR6, C(=0)SR6, C(=0)N(R6a)(R6b), OR6, S(=0)nR6, S(=0)nN(R6a)(R6b), S(=0)mOR6, N(R6a)(R6b), N(R6)C(=0)R5, N(R6)C(=0)0R6, N(R6)C(=0)N(R6a)(R6b), N(R6)S(=0)n(R6), N(R6)S(=0)mN(R6a)(R6b), and N(R6)S(=0)m0R6;
R1a is selected from the group consisting of H and Cl;
R1 b is selected from the group consisting of H and Cl; R1c is selected from the group consisting of H and Cl;
R2a 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;
R2b 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;
R2c is Ci-C3-alkyl, wherein each substitutable carbon atom is unsubstituted or substi tuted with one or more F;
R3 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R4;
(ii) C(=0)R7, C(=0)0R8, C(=0)SR8, C(=0)N(R8a)(R8b), OR8, S(=0)nR8,
S(=0)nN(R8a)(R8b), S(=0)m0R8, N(R8a)(R8b), N(R8)C(=0)R7, N(R8)C(=0)0R8, N(R8)C(=0)N(R8a)(R8b), N(R8)S(=0)n(R8), N(R8)S(=0)mN(R8a)(R8b), and N(R8)S(=0)m0R8;
R4 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R9;
(ii) C(=0)R1°, C(=0)0R11, C(=0)SR11, C(=0)N(R11a)(R11b), OR11, S(=0)nR11, S(=0)nN(R11a)(R11b), S(=0)mOR11, N(R11a)(R11b), N(R11)C(=0)R1°, N(R11)C(=0)0R11, N(R11)C(=0)N(R11a)(R11b), N(R11)S(=0)n(R11), N(R11)S(=0)mN(R11a)(R11b), and N(R11)S(=0)m0R11;
R5, R6, R6a, R6b are independently selected from the group consisting of FI, Ci-C6-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsatu rated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-mem- bered saturated, partially unsaturated or fully unsaturated carbobicyclic or het erobicyclic 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 moieties is unsubstituted or substituted with one or more, same or different substituents
R12;
R7, R8, R8a, R8b are independently selected from the group consisting of H, Ci-C6-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, a 3- to 9-membered saturated, partially unsatu rated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-mem- bered saturated, partially unsaturated or fully unsaturated carbobicyclic or het- erobicyclic 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 moieties is unsubstituted or substituted with one or more, same or different substituents R13;
R9 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C(=0)R14, C(=0)OR15, C(=0)SR15, C(=0)N(R15a)(R15b), OR15, S(=0)nR15, S(=0)nN(R15a)(R15b), S(=0)mOR15, N(R15a)(R15b), N(R15)C(=0)R14, N(R15)C(=0)0R15, N(R15)C(=0)N(R15a)(R15b), N(R15)S(=0)n(R15),
N(R15)S(=0)mN(R15a)(R15b), and N(R15)S(=0)m0R15;
R10, R11, R11a, R11b 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 R17;
R12 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)OR2°, C(=0)SR2°, C(=O)N(R20a)(R20b), OR20, S(=0)nR2°, S(=O)nN(R20a)(R20b), S(=0)mOR2°, N(R20a)(R20b), N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b), N(R20)S(=O)n(R20),
N (R20)S(=O)mN (R20a)(R20b), and N(R20)S(=O)mOR20;
and/or two R12 present on one carbon atom together form =0;
R13 is selected from the group consisting of (i) halogen, CN, NO2, Ci-C6-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 clic 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 R21;
(ii) C(=0)R22, C(=0)0R23, C(=0)SR23, C(=0)N(R23a)(R23b), OR23, S(=0)nR23, S(=0)nN(R23a)(R23b), S(=0)m0R23, N(R23a)(R23b), N(R23)C(=0)R22, N(R23)C(=0)0R23, N(R23)C(=0)N(R23a)(R23b), N(R23)S(=0)n(R23),
N (R23)S(=0)mN (R23a)(R23b), and N(R23)S(=0)m0R23;
R14, R15, R15a, R15b are independently selected from the group consisting of
(i) H, Ci-C6-alkyl, C2-C6-alkenyl, and C2-C6-alkynyl, wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R16;
(ii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated car bocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially un saturated or fully unsaturated carbobicyclic or heterobicyclic 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 heteroatom in the aforementioned cyclic or bicyclic moieties is in dependently unsubstituted or substituted with one or more, same or different substituents R32;
R16 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloal- kenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, N(R33a)(R33b), C(=0)NR33aR33b, S(=0)nNR33aR33b, OR33 and S(=0)nR33;
(ii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated car bocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially un saturated or fully unsaturated carbobicyclic or heterobicyclic 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 heteroatom in the aforementioned cyclic or bicyclic moieties is in dependently unsubstituted or substituted with one or more, same or different substituents R32;
R17 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C -C6-alkenyl, C -C6-haloalkenyl, C -C6-alkynyl, C -C6-haloalkynyl, OH, 0(CrC4-alkyl), NH2, NH(C C4-alkyl), and N(C1-C4-alkyl)(C1-C4-alkyl);
R18 is selected from the group consisting of (i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)SR26, C(=0)N(R26a)(R26b), OR26, S(=0)nR26, S(=0)nN(R26a)(R26b), S(=0)m0R26, N(R26a)(R26b), N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b), N(R26)S(=0)n(R26),
N (R26)S(=0)mN (R26a)(R26b), and N(R26)S(=0)m0R26;
R19, R20, R20a, R20b 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 R27;
R21 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl);
R22, R23, R23a, R23b 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 R28;
R24 is selected from the group consisting of halogen, CN, NO2, Ci-C6-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 R29;
R25, R26, R26a, R26b are independently selected from the group consisting of H, C1-C4- alkyl, Ci-C4-haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, and C2- C4-haloalkynyl;
R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-alkyl),
NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R30;
R28 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-alkyl),
NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R31;
R29, R30, R31 are independently selected from the group consisting of halogen, CN,
NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-al- kynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci- C4-alkyl)(Ci-C4-alkyl);
R32 is selected from the group consisting of halogen, CN, NO2, Ci-C4-alkyl, C1-C4- haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, C(=0)R34, C(=0)0R33, C(=0)SR33, C(=0)N(R33a)(R33b), OR33, S(=0)nR33, S(=0)nN(R33a)(R33b), S(=0)m0R33, N(R33a)(R33b), N(R33)C(=0)R34, N(R33)C(=0)0R33, N(R33)C(=0)N(R33a)(R33b), N(R33)S(=0)n(R33),
N(R33)S(=0)mN(R33a)(R33b), and N(R33)S(=0)m0R33;
R33, R33a, R33b, R34 are independently selected from the group consisting of H, C1-C4- alkyl, Ci-C4-haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, and C2- C4-haloalkynyl;
and wherein
n is 0, 1 or 2; and
m is 1 or 2;
2. The compound according to claim 1 , wherein the compound is not:
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
3. The compound according to claim 1 , wherein the compound is not:
5
Figure imgf000190_0002
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
4. The compound according to any one of claims 1 to3, wherein G1 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrim- idin-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 substitutable carbon or heteroatoms in the aforementioned cyclic moieties is substituted with same or different substituents selected from the group consisting of Ch , F and CN, and wherein all other substitu ents have the meaning as defined in claim 1.
5. The compound according to any one of claims 1 to3, wherein G1 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 CF , F and CN, and wherein all other substitu ents have the meaning as defined in claim 1.
6. The compound according to any one of claims 1 to 5 , wherein R1a is selected from the group consisting of H and Cl; R1b is selected from the group consisting of H and Cl; R1c is selected from the group consisting of H and Cl; R2a is CF ; R2b is CF ; R2c is CF ; and wherein all other substituents have the meaning as defined in claim 1.
7. The compound according to any one of claims 1 to 6, wherein G3 is selected from the group consisting of
(i) Ci-C6-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 R3;
(ii) C(=0)R5, C(=0)OR6, and C(=0)N(R6a)(R6b);
wherein R3 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R4;
(ii) C(=0)R7, C(=0)OR8, C(=0)N(R8a)(R8b), OR8, N(R8a)(R8b), N(R8)C(=0)R7, N(R8)C(=0)0R8, and N(R8)C(=0)N(R8a)(R8b);
wherein R4 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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- clic 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 R9;
(ii) C(=0)R1°, C(=0)OR11, C(=0)N(R11a)(R11b), OR11, N(R11a)(R11b),
N(R11)C(=0)R1°, N(R11)C(=0)OR11, N(R11)C(=0)N(R11a)(R11b); wherein R5, R6, R6a, R6b 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 R12;
wherein R7, R8, R8a, R8b 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 R13;
wherein R9 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4- alkyl);
wherein R10, R11, R11a, R11b are independently selected from the group consisting of H , Ci- C6-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 R17;
wherein R12 is selected from the group consisting of
(i) halogen, CN, N0 , CrC6-alkyl, C -C6-alkenyl, C -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 clic 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 R18;
(ii) C(=0)R19, C(=0)0R2°, C(=O)N(R20a)(R20b), OR20, N(R20a)(R20b),
N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b); and/or two R12 present on one carbon atom together form =0;
wherein R13 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R21;
(ii) C(=0)R22, C(=0)0R23, C(=0)N(R23a)(R23b), OR23, N(R23a)(R23b),
N(R23)C(=0)R22, N(R23)C(=0)0R23, N(R23)C(=0)N(R23a)(R23b); wherein R17 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(CrC4-alkyl); wherein R18 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)N(R26a)(R26b), OR26, N(R26a)(R26b),
N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b); wherein R19, R20, R20a, R20b are independently selected from the group consisting of H , Ci- C6-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 R27;
wherein R21 is selected from the group consisting of halogen, CN, NO2, Ci-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl); wherein R22, R23, R23a, R23b are independently selected from the group consisting of H , Ci- C6-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 R28;
wherein R24 is selected from the group consisting of halogen, CN, NO2, Ci-C6-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 R29; wherein R25, R26, R26a, R26b 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;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), CrCe-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 R30; wherein R28 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C -alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-Ce-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 R31; wherein R29, R30, R31 are independently selected from the group consisting of halogen,
CN, NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6- alkynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci- C4-alkyl)(Ci-C4-alkyl), and
wherein all other substituents have the meaning as defined in claim 1.
8. The compound according to any one of claims 1 to 6, wherein G3 is selected from the group consisting of C(=0)R5, C(=0)OR6, and C(=0)N(R6a)(R6b);
wherein R5, R6, R6a, R6b 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 R12;
wherein R12 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R18;
(ii) C(=0)R19, C(=0)OR2°, C(=O)N(R20a)(R20b), OR20, N(R20a)(R20b),
N(R20)C(=O)R19, N(R20)C(=O)OR20, N(R20)C(=O)N(R20a)(R20b); and/or two R12 present on one carbon atom together form =0;
wherein R18 is selected from the group consisting of
(i) halogen, CN, NO2, Ci-C6-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 clic 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 R24;
(ii) C(=0)R25, C(=0)0R26, C(=0)N(R26a)(R26b), OR26, N(R26a)(R26b),
N(R26)C(=0)R25, N(R26)C(=0)0R26, N(R26)C(=0)N(R26a)(R26b); wherein R19, R20, R20a, R20b are independently selected from the group consisting of H , Ci- C6-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 R27;
wherein R24 is selected from the group consisting of halogen, CN, NO2, Ci-C6-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 R29; wherein R25, R26, R26a, R26b 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;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-al- kyl), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl), Ci-C6-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 R30; wherein R29, R30 are independently selected from the group consisting of halogen, CN,
NO2, Ci-C6-alkyl, Ci-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-al- kynyl, C2-C6-haloalkynyl, OH, 0(Ci-C4-alkyl), NH2, NH(Ci-C4-alkyl), and N(Ci- C4-alkyl)(Ci-C4-alkyl); and
wherein all other substituents have the meaning as defined in claim 1.
9. The compound according to any one of claims 1 to 6, wherein G3 is selected from the group consisting of C(=0)N(R6a)(R6b); wherein R6a is H,
wherein R6b is selected from the group consisting of Ci-C6-alkyl, C2-C6-alkynyl, 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 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 R12;
wherein R12 is selected from the group consisting of
(i) 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 R18;
(ii) OR20, N(R20a)(R20b);
and/or two R12 present on one carbon atom together form =0;
wherein R18 is selected from the group consisting of
(i) 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 R24;
(ii) OR26, N(R26a)(R26b);
wherein R20, R20a, R20b 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 clic 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 R27;
wherein R24 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 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 R29; wherein R26, R26a, R26b are independently selected from the group consisting of H, C1-C4- alkyl, and Ci-C4-haloalkyl;
wherein R27 is selected from the group consisting of halogen, CN, NO2, OH, 0(Ci-C4-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 R30;
wherein R29, R30 are independently selected from the group consisting of halogen, CN,
NO2, Ci-C4-alkyl, Ci-C4-haloalkyl, OH, 0(Ci-C4-alkyi), NH2, NH(Ci-C4-alkyl), and N(Ci-C4-alkyl)(Ci-C4-alkyl);
10. The compound according to claim 1 , wherein 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]pyrazin-8-amine; 8-amino-6-(4- fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(pyridin-2-yl)methyl]imidazo[1 ,2-a]pyrazine-2- carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(oxan-4-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(4-fluoropyrrolidin-3- yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-[3- (difluoromethoxy)propyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino-N-tert-butyl-6-(4-fluorophenyl)-5-(4-methylquinolin-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquino- lin-6-yl)-N-(2,2,2-trifluoroethyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4- fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(morpholin-2-yl)methyl]imidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[2-(methylamino)ethyl]-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)- 5-(4-methylquinolin-6-yl)-N-(pyrrolidin-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide 8- amino-N-(1 ,1-dioxo-1A6-thiolan-3-yl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6- yl)-N-(2-oxopyrrolidin-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-N-(1-hydroxypropan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2- carboxamide; 2-(4,4-difluoropiperidine-1-carbonyl)-6-(4-fluorophenyl)-5-(4-methylquino- lin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)- 5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(8-chloro-4-methylquinolin-6-yl)-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-2- carboxamide; 8-amino-5-[4-(difluoromethyl)quinolin-6-yl]-6-(4-fluorophenyl)-N-me- thylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquin- olin-6-yl)-N-(propan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-N-(2H3)methyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(3-ethylpyrrolidin-3-yl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 2-(2,6-dimethylmorpholine-4-carbonyl)-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-5-(4-chloro-1- methyl-1 H-1 ,3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-2- carboxamide; 8-amino-6-(4-fluorophenyl)-N-methyl-5-{3-methylimidazo[1 ,2-a]pyridin-6- yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H- 1 ,3-benzodiazol-6-yl)-N-(oxolan-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 2-(2,6-di- methylmorpholine-4-carbonyl)-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 , 3-benzodiazol-6- yl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-N-(4-aminobutyl)-6-(4-fluorophenyl)-5-(1- methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-{2- [4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 , 3-ben- zodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 2-[4-(2,4-difluorophenyl)pipera- zine-1-carbonyl]-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8- amine; 6-(4-fluorophenyl)-2-[4-(2-methoxyethyl)piperazine-1-carbonyl]-5-(4-methylquin- olin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-6-(4-fluorophenyl)-N-methyl-5-(4- methylquinolin-6-yl)-N-(propan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6- (4-fluorophenyl)-N-(2-methoxyethyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 1-[8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodia- zol-6-yl)imidazo[1 ,2-a]pyrazine-2-carbonyl]pyrrolidin-3-amine; 8-amino-6-(4-fluoro- phenyl)-5-(1 -methyl-1 H-1 , 3-benzodiazol-6-yl)-N-(oxan-4-yl)imidazo[1 ,2-a]pyrazine-2- carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(piperidin-4-yl)im- idazo[1 ,2-a]pyrazine-2-carboxamide; 6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodia- zol-6-yl)-2-(piperazine-1-carbonyl)imidazo[1 ,2-a]pyrazin-8-amine; 8-amino-N,N-diethyl- 6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-6-(4-fluorophenyl)-N-(2-methoxyethyl)-5-(4-methylquinolin-6-yl)im- idazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3- benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N- [(1-methylpyrrolidin-3-yl)methyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 8-amino-N-[3-(dimethylamino)butyl]-6-(4-fluorophenyl)-5-(4-methylquinolin- 6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide 8-amino-N-(4,4-difluorocyclohexyl)-6-(4- fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(4-chloro-1-methyl-1 H-1 ,3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-(2-methoxy- ethyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-[2-(dimethylamino)propyl]-6- (4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(prop-2-yn-1-yl)imidazo[1 ,2-a]py- razine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)- N-(1-methylpiperidin-4-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(oxetan-2-yl)methyl]im- idazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-{[6-(2-hydroxypro- pan-2-yl)pyridin-2-yl]methyl}-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-N-(2,2,2-triflu- oroethyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)-N-(3,3,3-trifluoropropyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-N-methyl-5-[4-(2H3)methylquinolin-6-yl]imidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino- 5-(4-ethylquinolin-6-yl)-6-(4-fluorophenyl)-N-methylimid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-[2-(dimethylamino)ethyl]-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4- fluorophenyl)-N-(1-methoxy-2-methylpropan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(3-hydroxybutan-2-yl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)- N-[(4-methylmorpholin-2-yl)methyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2- carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[(oxetan-3-yl)me- thyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)-N-(oxolan-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6- (4-fluorophenyl)-N-[1-(methoxymethyl)cyclopropyl]-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1-methyl-2-ox- opyrrolidin-3-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-{2-[(oxolan-2-yl)methoxy]ethyl}im- idazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(2-methoxy-2- methylpropyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-(1 ,1 ,1-trifluoro-3-hydroxypropan-2-yl)im- idazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6- yl)-N-(oxetan-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 1 -[8-ami no-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbonyl]-3-methylpyrrolidin- 3-ol; 8-amino-5-(8-chloro-4-methylquinolin-6-yl)-6-(4-fluorophenyl)-N-(2-methoxy- ethyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1 -methyl- cyclobutyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N- (2-fluoroethyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-car- boxamide; 1-[8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyra- zine-2-carbonyl]pyrrolidin-3-amine; 8-amino-6-(4-fluorophenyl)-N-(1-methylpyrrolidin-3- yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluoro- phenyl)-N-[(1-hydroxycyclopentyl)methyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino-N-(2,2-dimethylpropyl)-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)- N-(1-methoxypropan-2-yl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-N-(2-fluoroethyl)-6-(4- fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-5-(4-chloro-1 -methyl-1 H- 1 ,3-benzodiazol-6-yl)-6-(4-fluorophenyl)-N-[(1-hydroxycyclopropyl)methyl]imidazo[1 ,2- a]pyrazine-2-carboxamide; 8-amino- 5-(4-chloro-1 -methyl-1 H-1 ,3-benzodiazol-6-yl)-6- (4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[1-(1-hydroxycyclopropyl)ethyl]-5-(4-methylquinolin-6- yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-5-{3-chloroimidazo[1 ,2-a]pyridin-6- yl}-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4- fluorophenyl)-5-[4-(2H3)methylquinolin-6-yl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-5-{8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-methylimid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-ben- zodiazol-6-yl)-N-(propan-2-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4- fluorophenyl)-N-(3-hydroxypropyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2- carboxamide; 8-amino-N-(2-fluoroethyl)-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodi- azol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-{8-chloro-3-methylimid- azo[1 ,2-a]pyridin-6-yl}-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-5-(4-chloro-1 -methyl-1 H-1 , 3-benzodiazol-6-yl)-N-(2,2-difluoroethyl)-6-(4-fluoro- phenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-ethyl-6-(4-fluorophenyl)-5-(1 - methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-5-{8- chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-(propan-2-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-5-{8-chloro-3-methylimidazo[1 ,2-a]pyridin- 6-yl}-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-N-[1-(dimethylamino)-2-methylpropan-2-yl]-6-(4-fluorophenyl)-5-(4-methylquino- lin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-[(1- methylazetidin-3-yl)methyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-N-({1-[(2,4-difluorophenyl)methyl]piperidin-4-yl}methyl)-6-(4-fluoro- phenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4- fluorophenyl)-N-[2-methyl-1-(propan-2-yloxy)propan-2-yl]-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-methyl-5-(1-methyl- 1 H-1 ,3-benzodiazol-6-yl)-N-(pyrrolidin-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(4-fluorophenyl)-N-[(5-methyl-1 , 3, 4-oxadiazol-2-yl)methyl]-5-(1 -methyl-1 H-1 , 3- benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-tert-butyl-6-(4- fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(3-cyano-2-methylphenyl)-N-methyl-5-(4-methylquinolin-6-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-5-[1-(2,2-difluoroethyl)-1 H-1 ,3-benzodia- zol-6-yl]-6-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-2-carboxamide; 6-(4-fluoro- phenyl)-2-[(methylamino)methyl]-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8- amine; 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)-N-[2-(pyrrolidin-1- yl)ethyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(cyclopropylmethyl)-6-(4- fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5-(4-chloro-1-methyl-1 H-1 ,3-benzodiazol-6-yl)-6-(4-fluorophenyl)imidazo[1 ,2-a]pyra- zine-2-carboxamide; 8-amino-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)-5-(4-methylquino- lin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)-N-(oxetan-3-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino- 5- {8-chloro-3-methylimidazo[1 ,2-a]pyridin-6-yl}-6-(4-fluorophenyl)-N-(1-methylcyclobu- tyl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-(1-methylcy- clobutyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}-N-(propan-2-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-N-methyl-5-[1 -(propan- 2-yl)-1 H-1 ,3-benzodiazol-6-yl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(3-cy- anophenyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyra- zine-2-carboxylic acid; 8-amino-6-(3-cyanophenyl)-N-(2,2-difluoroethyl)-5-{3-methylim- idazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(2-fluoro- phenyl)-N-methyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(3-cyanophenyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}-N-(propan-2-yl)imid- azo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(cyclopropylmethyl)-6-(4-fluorophenyl)-
5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-
6-(3-cyano-4-fluorophenyl)-N-(2,2-difluoroethyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6- yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 1-[8-amino-6-(4-fluorophenyl)-5-(4- methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-2-yl]ethan-1-one; 8-amino-6-(4-fluorophenyl)- N-(1-methoxy-2-methylpropan-2-yl)-5-(1 -methyl-1 H-1 , 3-benzodiazol-6-yl)imidazo[1 , 2- a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodia- zol-6-yl)-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-6-(3-cyano-4-fluorophenyl)-N-(2,2-difluoroethyl)-5-(1 -methyl-1 H-1 ,3-benzodia- zol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(4-fluorophenyl)-5-{3-me- thylimidazo[1 ,2-a]pyridin-6-yl}-N-[1 -(trifluoromethyl)cyclopropyl]imidazo[1 ,2-a]pyrazine- 2-carboxamide; 8-amino-N-(cyclopropylmethyl)-6-(4-fluorophenyl)-5-{3-methylimid- azo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 2-(4,5-dihydro-1 H-imid- azol-2-yl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazin-8-amine; 8- amino-N-(4,4-difluorocyclohexyl)-6-(4-fluorophenyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6- yl}imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(1-cyanocyclopropyl)-6-(4-fluoro- phenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-N-(2,2-difluoroethyl)-6-(4-fluorophenyl)-5-{3-methylimidazo[1 ,2-a]pyridin-6-yl}im- idazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(4,4-difluorocyclohexyl)-6-(4-fluoro- phenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8- amino-N-(1 ,1-difluoropropan-2-yl)-6-(4-fluorophenyl)-5-(1-methyl-1 H-1 ,3-benzodiazol- 6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-6-(3-cyano-4-fluorophenyl)-N-me- thyl-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carboxamide; 8-amino-N-(2-cy- anoethyl)-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imidazo[1 ,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-5-(1 -methyl-1 H-1 ,3-benzodiazol-6-yl)imidazo[1 ,2- a]pyrazine-2-carboxylic acid; and 8-amino-N-tert-butyl-6-(4-fluorophenyl)-5-{3-me- thylimidazo[1 ,2-a]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-2-carboxamide.
11. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 10 and optionally a pharmaceutically ac ceptable carrier, diluent or excipient.
12. A compound according to any one of claims 1 to 10 and a pharmaceutical composition according to claim 11 for use in medicine.
13. A compound for use according to claim 12 or a pharmaceutical composition for use ac cording to claim 11 or 12, wherein said compound or pharmaceutical composition is for use in the treatment of a disease selected from the group consisting of cancer, Parkin son's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra py ramidal syndrome (in particular dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis (in particular dermal fibrosis in scleroderma), sleep disorders, AIDS, au toimmune diseases, infections, atherosclerosis, ischemia-reperfusion injury, idiopathic pulmonary fibrosis, systemic sclerosis, irritable bowel disease and as analgesic.
14. A compound for use according to claim 12 or a pharmaceutical composition for use ac cording to claim 11 or 12, wherein said compound or pharmaceutical composition is for use in the treatment of cancer, and wherein at least one further anti-neoplastic agent is preferably coadministered with said compound and/or comprised in said pharmaceuti cal composition.
15. A compound for use according to claim 14 or a pharmaceutical composition for use ac cording to claim 14, wherein said anti-neoplastic agent is selected from the group con sisting of a chemotherapeutic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone, a hormonal analogue, a signal transduction path way inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, a proapoptotic agent, a cell cycle signaling inhibitor, a proteasome inhibitor, an inhibitors of cancer metabolism, and an immunotherapeutic agent, wherein said chemotherapeutic agent is preferably selected from the group consisting of an anti-microtubule agent, an platinum coordination complex and an antibiotic agent; and wherein said immunotherapeutic agent is preferably selected from the group considting of a STING pathway modulating compound, a TLR agonist and a checkpoint inhibitor.
16. A compound for use according to claim 15 or a pharmaceutical composition for use ac cording to claim 15, wherein said checkpoint inhibitor targets PD-1 , PD-L1 , CTLA-4, IDO, KIR, TIM-3, LAG-3, CD39, CD73, ICOS, 0X40, Tim-3, Vista, BTLA, TDO, or TIGIT.
17. A compound for use according to claim 15 or 16 or a pharmaceutical composition for use according to claim 15 or 16, wherein said checkpoint inhibitor is an antibody, a small molecule inhibitor or an antisense oligonucleotide selected from the group con sisting 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.
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WO2025018901A1 (en) 2023-07-17 2025-01-23 Ryvu Therapeutics S.A. Modulators of the adenosine a2a and a2b receptor

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