[go: up one dir, main page]

WO2025018901A1 - Modulateurs de l'adénosine a2a et du récepteur a2b - Google Patents

Modulateurs de l'adénosine a2a et du récepteur a2b Download PDF

Info

Publication number
WO2025018901A1
WO2025018901A1 PCT/PL2023/050060 PL2023050060W WO2025018901A1 WO 2025018901 A1 WO2025018901 A1 WO 2025018901A1 PL 2023050060 W PL2023050060 W PL 2023050060W WO 2025018901 A1 WO2025018901 A1 WO 2025018901A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
amino
pentan
pyrazine
fluorophenyl
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/PL2023/050060
Other languages
English (en)
Inventor
Michal GALEZOWSKI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biontech SE
Ryvu Therapeutics SA
Original Assignee
Biontech SE
Ryvu Therapeutics SA
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 Biontech SE, Ryvu Therapeutics SA filed Critical Biontech SE
Priority to PCT/PL2023/050060 priority Critical patent/WO2025018901A1/fr
Publication of WO2025018901A1 publication Critical patent/WO2025018901A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to substituted imidazo[1,2 ⁇ a]pyrazine compounds and salts, stereoisomers, tautomers, isotopologues, or N-oxides thereof.
  • the present invention is inter alia further concerned with the use of substituted imidazo[1,2 ⁇ a]pyrazine com- pounds or salts, stereoisomers, tautomers, isotopologues, or N-oxides thereof as medica- ment and a pharmaceutical composition 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 metabolites, which works this way is adenosine.
  • adenosine receptors which are members of the G protein-coupled receptor (GPCR) family and possess seven transmembrane alpha helices.
  • GPCR G protein-coupled receptor
  • A1 and A2A are heavily distributed in immune cells and mainly responsible for immunosuppression me- diated by adenosine. Stressed or injured tissues (i.e. tumor tissue) release endogenous ATP, which works as a proinflammatory agent.
  • This subpopulation of T cells is further activated by adenosine and produces immunosuppressive cytokines such as TGF- ⁇ and IL-10.
  • immunosuppressive cytokines such as TGF- ⁇ and IL-10.
  • Another group of immunosuppressing cells which re- Ryvu Therapeutics S.A. and BioNTech SE R10559WO 2 spond to higher concentration of adenosine are MDSC, which undergo differentiation upon activation by this metabolite (Morrello et al Oncoimmunology. 2016 Mar; 5(3): e1108515).
  • stimulation of adenosine might also lead to decreased cytotoxic activity, e.g.
  • CD8+ lymphocytes lower their secretion of IL-2, Th1 cytokines and IFN- ⁇ , while NK cells produce lower levels of GzmB, NKG2d, CD69 andCD27 [Sitkovsky Trends Immunol 2009;30:102-8].
  • Dendritic cells and macrophages 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 immunostimulatory cytokines such as IL12, TNFa, IFNg. Adenosine also stimulates in macrophages the conversion of M1 to M2. [Allard et al Curr Opin Pharmacol.
  • 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 regulation of dopamine and glutamate release.
  • the A2A receptor antag- onists have been proposed useful in treatment of neurodegenerative disorders such as Parkinson's, Huntington's and Alzheimer's disease causing motor impairment, which can be improved by employment 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 treat- ment of psychosis, stroke, extra pyramidal syndrome, e.g., dystonia, akathisia, pseu- doparkinsonism and tardive dyskinesia (see Jenner P. J Neurol. 2000; 247 Suppl2: 1143-50) and attention related disorders such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD).
  • ADD attention deficit disorder
  • ADHD 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 thera- Immeric potential as neuroprotectants (Stone TW. et al., Drag. Dev.
  • WO 2017/098421 discloses in- hibitors of CD73, wherein CD73 catalyzes the conversion of AMP to adenosine and is thought to be the major contributor to extracellular adenosine, in particular in the tumor mi- croenvironment.
  • CD73 inhibition results in decreased extracellular adenosine such that the activity of the A2A receptor is decreased, resulting in less (or no) immunosuppression – ex- actly the effect achieved with A2A receptor antagonists. It can thus be assumed that the diseases disclosed in WO 2017/098421 may also be treated by A2A antagonists.
  • Ryvu Therapeutics S.A. and BioNTech SE R10559WO 3 There is growing evidence that also the A2B receptor plays an important role in cancer pro- gression, especially in immune suppression in tumor microenvironment, as well as tumor proliferation, angiogenesis, metastasis (Zhan-Guo Gao et al., Int J Mol Sci. 2019; 20(20): 5139).
  • A2BR expression is significantly upregulated under many patho- logical conditions such as hypoxia, inflammation, and cancer (Borea PA et al.,Trends Phar- macol 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 carci- noma expresses high levels of A2BAR and it is suggested to be associated with a poor pa- tient prognosis (Zhou Y et al.; Oncotarget. 2017; 8(30):48755-48768).
  • A2BR controls cellular proliferation via HIF-1 ⁇ 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).
  • A2BR antagonists have already been sug- gested as promising therapeutic approach for other diseases such as idiopathic pulmonary fibrosis (J. Clin. Invest.116:2173–2182 (2006), Liu et al., Journal of Nanobiotechnology.
  • a high agonist e.g. adenosine
  • a disease selected from the group consisting of cancer, Parkinson's dis- ease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syn- drome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibro- sis, a sleep disorder, AIDS, autoimmune diseases
  • the above objects and others can be achieved in particular by the compounds of formula (I) as defined herein in the first aspect, as well as the further aspect disclosed herein.
  • the inventors of the present invention inter alia found that the compounds of formula (I), as defined herein below in the first aspect, antagonize adenosine A2A receptor activity.
  • Fur- thermore the inventors of the present invention inter alia found that the compounds of for- mula (I), as defined herein below in the first aspect, antagonize adenosine A2B receptor ac- tivity.
  • the inventors of the present invention inter alia found that the com- pounds of formula (I), as defined herein below in the first aspect, antagonize both adeno- sine 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 in the 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.
  • the compounds of formula (I) or a pharma- ceutical composition comprising a compound of formula (I) as defined herein below in the second aspect can be used for the treatment of diseases linked to the adenosine A2B re- ceptor, in particular the diseases given herein and most preferably cancer.
  • the compounds of formula (I) or a pharmaceutical composition comprising a compound of for- mula (I) as defined herein below in the second aspect can be used for the treatment of dis- eases linked to both the adenosine A2A and A2B receptors, in particular the diseases given herein and most preferably cancer.
  • the present invention relates to a compound of formula (I) or a salt, stereoisomer, tautomer, isotopologue, or N-oxide thereof, wherein G 1 is phenyl, wherein one or two of the substitutable carbon atoms in the aforementioned phenyl is substituted with same or different substituents selected from the group con- sisting of halogen, CN, NO 2 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 - haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, OH, O(C 1 -C 4 -alkyl), NH 2 , NH(C 1 -C 4 - alkyl), an d N(C 1 -C 4 -alkyl), NH 2 , NH(C 1
  • R 5 (i) is selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsatu- rated carbocyclic or heterocyclic ring, and a 4- 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 het- eroatoms selected from O, N or S, wherein said N- and/or S-atoms
  • R 10 , R 11 , R 11a , R 11b are independently selected from the group consisting of H, C 1 -C 4 - alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, and C 2 -C 4 - haloalkynyl; wherein R 12 is selected from the group consisting of halogen, CN, NO 2 , OH, O(C 1 -C 4 -alkyl), NH 2 , NH(C 1 -C 4 -alkyl), and N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 - C 6 -alkynyl, a 3-
  • G 1 is phenyl, wherein one or two of the substitutable carbon atoms in the aforementioned phenyl is substituted with same or different sub- stituents selected from the group consisting of CH 3 , halogen and CN.
  • G 1 is phenyl, wherein one or two of the substi- tutable carbon atoms in the aforementioned phenyl 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 substi- tutable carbon atoms in the aforementioned phenyl is substituted with F.
  • G 1 is 4-fluorophenyl.
  • R 1a is selected from the group consisting of H and halogen. It can be preferred in this embodiment that R 1a is selected from the group con- sisting of H and Cl.
  • R 1b is selected from the group consisting of H and halogen. It can be preferred in this embodiment that R 1b is selected from the group con- sisting of H and Cl.
  • R 1c is selected from the group consisting of H and halogen. It can be preferred in this embodiment that R 1c is selected from the group con- sisting of H and Cl.
  • R 2a is C 1 -C 3 -alkyl. It can be preferred in this em- bodiment that R 2a is CH 3 .
  • R 2b is C 1 -C 3 -alkyl. It can be preferred in this em- bodiment that R 2b is CH 3 .
  • R 2c is C 1 -C 3 -alkyl. It can be preferred in this em- bodiment that R 2c is CH 3 .
  • R 4a is H.
  • G 1 is phenyl, wherein one or two of the sub- stitutable carbon atoms in the aforementioned phenyl is substituted with same or different substituents selected from the group consisting of CH 3 , F, and CN;
  • 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 3 ;
  • R 2b is CH 3 ;
  • R 2c is CH 3 ; and
  • R 4a is H.
  • G 1 is phenyl, wherein one or two of the substitutable carbon atoms in the aforementioned phenyl is substituted with same or different substituents selected from the group con- sisting of CH 3 , F and CN;
  • 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 3 ;
  • R 2b is CH 3 ;
  • R 2c is CH 3 ;
  • R 4a is H;
  • R 4b is a 5-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N-
  • R10559WO 9 is selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, a 3- to 9-membered saturated, partially unsaturated or fully unsatu- rated carbocyclic or heterocyclic ring, and a 4- 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 het- eroatoms selected from O, N or S, wherein said N- and/or S-atoms are indepen- dently 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 6 ; or (i)
  • R 12 is selected from the group consisting of halogen, CN, NO 2 , OH, O(C 1 -C 4 -alkyl), NH 2 , NH(C 1 -C 4 -alkyl), and N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), C 1 -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 4- to 14-membered saturated, partially unsatu- rated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said hetero- cyclic or heterobicyclic ring comprises one or more, same or different heteroatoms se- lected from O, N or S, wherein said N- and/or S-atom
  • G 2 is selected from the group consisting of In another preferred embodiment of the first aspect, G 2 is In another em ent of the fi rst asp ect, G 2 is selected from the gr oup consisting of wherein R 1a is H; R 1b is H; R 1c is H; R 2a is CH 3 ; R 2b is CH 3 ; and R 2c is CH 3 . In another embodim ent of the first a spect, G 2 is se lected from the group consisting of Ryvu Therapeutics S.A. and BioNTech SE R10559WO 11 wherein R 1b is H; R 1c is H; R 2b is CH 3 ; and R 2c is CH 3 .
  • G 2 is wherein R 1b is H; and R 2b is CH 3 .
  • R 7 , R 8 , R 8a , R 8b 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 unsatu- rated or fully unsaturated carbocyclic or heterocyclic ring, and a 4- 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 in- dependently oxidized or non-oxidized, and wherein each substitutable carbon or het- ero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 12 ;
  • each substitutable carbon or hetero-atom in the aforementioned moieties is unsubstituted or substituted with one or more, same or different substituents R 6 ; wherein R 6 (i) is selected from the group consisting of halogen, C 1 -C 4 -alkyl, a 3- to 9-membered sat- urated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, and a 4- to 14-membered saturated, partially unsaturated or fully unsaturated carbobi- cyclic 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 sub- stituted with one or more,
  • said compound is selected from the group consisting of 8-amino-N- ⁇ 3-[(dimethylamino)methyl]bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4- fluorophenyl)-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- ⁇ 3-[(morpholin-4- yl)methyl]bicyclo[1.1.1]pentan-1-yl ⁇ imidazo[1,2-a]pyrazine
  • said compound is selected from the group consisting of 8-amino-N- ⁇ 3-[(dimethylamino)methyl]bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4- fluorophenyl)-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- ⁇ 3-[(morpholin-4- Ryvu Therapeutics S.A.
  • said compound is selected from the group consisting of 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6-aza- spiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-carboxam- ide; 8-amino-N-(3- ⁇ [(2,2-difluoroethyl)amino]methyl ⁇ bicyclo[1.1.1]pentan-1-yl)-6-(4-fluo- rophenyl)-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-y
  • said compound is selected from the group con- sisting of 8-amino-N- ⁇ 3-[(dimethylamino)methyl]bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluo- rophenyl)-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- ⁇ 3-[(4-methylpiperazin- Ryvu Therapeutics S.A.
  • said compound is selected from the group consisting of 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2- oxa-6-azaspiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2- carboxamide; 8-amino-N-(3- ⁇ [(2,2-difluoroethyl)amino]methyl ⁇ bicyclo[1.1.1]pentan-1-yl)-6- (4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carbox- amide; 8-amino-6-(4-fluorophenyl)-N-[3-(1-hydroxyethyl)
  • said compound is 8-amino-6-(4-fluo- rophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6-azaspiro[3.3]heptan-6- yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-carboxamide.
  • said compound is 8-amino-N-(3- ⁇ [(2,2- difluoroethyl)amino]methyl ⁇ bicyclo[1.1.1]pentan-1-yl)-6-(4-fluorophenyl)-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide.
  • said compound is 8-amino-6-(4-fluo- rophenyl)-N-[3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2- a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide.
  • said compound is 8-amino-6-(4-fluo- rophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2- a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide.
  • said compound is 8-amino-N-[3- (aminomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2- a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide.
  • said compound is 8-amino-N-[3-(ac- etamidomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2- a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide.
  • said compound is 8-amino-N- ⁇ bicy- clo[1.1.1]pentan-1-yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxamide.
  • the present invention relates to a pharmaceutical composition com- prising the compound according to the first aspect and optionally a pharmaceutically ac- ceptable carrier, diluent and/or excipient.
  • the pharmaceutical composition com- prises the compound according to the first aspect in a pharmaceutically effective amount.
  • said pharmaceutical composition comprises 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2- oxa-6-azaspiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2- carboxamide and optionally a pharmaceutically acceptable carrier, diluent and/or excipient.
  • said pharmaceutical composition comprises 8-amino-N-(3- ⁇ [(2,2-difluoroethyl)amino]methyl ⁇ bicyclo[1.1.1]pentan-1-yl)-6-(4- fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide and optionally a pharmaceutically acceptable carrier, diluent and/or excipient.
  • said pharmaceutical composition comprises 8-amino-6-(4-fluorophenyl)-N-[3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- Ryvu Therapeutics S.A. and BioNTech SE R10559WO 19 ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide and optionally a pharmaceutically acceptable carrier, diluent and/or excipient.
  • said pharmaceutical composition comprises 8-amino-N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide and optionally a pharmaceutically acceptable carrier, diluent and/or excipient.
  • said pharmaceutical composition comprises 8-amino-N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)- 5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide and optionally a pharmaceutically acceptable carrier, diluent and/or excipient.
  • said pharmaceutical composition comprises 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide and optionally a pharmaceu- tically acceptable carrier, diluent and/or excipient.
  • the present invention relates to the compound according to the first aspect for use in medicine. All embodiments of the first aspect including of course all preferred embodiments of the first aspect equally apply to the third aspect.
  • the compound for use in medicine is 8- amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6-aza- spiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-carboxam- ide.
  • the compound for use in medicine is 8-amino-N-(3- ⁇ [(2,2-difluoroethyl)amino]methyl ⁇ bicyclo[1.1.1]pentan-1-yl)-6-(4-fluo- rophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide.
  • the compound for use in medicine is 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide.
  • the compound for use in medicine is 8-amino-N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide.
  • the compound for use in medicine is 8-amino-N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide.
  • the compound for use in medicine is 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2- a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide.
  • the compound according to the first aspect is for use in the treatment of cancer.
  • at least one further anti-neoplastic agent is coadministered with said compound of the first aspect.
  • the afore-mentioned anti-neoplastic agent is selected from the group consisting 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 tyrosine kinase inhibitor, an angiogenesis inhibitor, a proapoptotic agent, a cell cycle signaling inhibitor, a proteasome inhibitor, an inhibitor of cancer metabolism, and an immunotherapeutic agent.
  • 8-amino-6-(4-fluorophenyl)-N-[3-(1- hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2- a]pyrazine-2-carboxamide is for use in the treatment of a disease selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psy- chosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an in- fection, atherosclerosis, ischemia-reperfusion injury, idiopathic pulmonary fibrosis, systemic sclerosis, irritable bowel disease
  • a disease selected from the
  • 8-amino-6-(4-fluorophenyl)-N-[3- (hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxamide is for use in the treatment of a disease selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's dis- ease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), atten- tion deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune dis- ease, an infection, atherosclerosis, ischemia-reperfusion injury, idiopathic pulmonary fibro- sis, systemic sclerosis, irritable bowel disease, chronic kidney
  • 8-amino-N-[3-(aminomethyl)bicy- clo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxamide is for use in the treatment of a disease selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's dis- ease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), atten- tion deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune dis- ease, an infection, atherosclerosis, ischemia-reperfusion injury, idiopathic pulmonary fibro- sis, systemic sclerosis, irritable bowel
  • 8-amino-N-[3-(acetamidomethyl)bi- cyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxamide is for use in the treatment of a disease selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's dis- ease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), atten- tion deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune dis- ease, an infection, atherosclerosis, ischemia-reperfusion injury, i
  • 8-amino-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6-azaspiro[3.3]heptan-6-yl ⁇ methyl)bicy- clo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-carboxamide is for use in the treatment of cancer.
  • 8-amino-N-(3- ⁇ [(2,2-difluo- roethyl)amino]methyl ⁇ bicyclo[1.1.1]pentan-1-yl)-6-(4-fluorophenyl)-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide is for use in the treatment of cancer.
  • 8-amino-6-(4-fluorophenyl)-N-[3- (hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxamide is for use in the treatment of cancer.
  • 8-amino-N-[3-(aminomethyl)bicy- clo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxamide is for use in the treatment of cancer.
  • 8-amino-N-[3-(acetamidomethyl)bi- cyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxamide is for use in the treatment of cancer.
  • 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1- yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-car- boxamide is for use in the treatment of cancer.
  • the present invention relates to a method for treating a disease in a subject in need thereof, wherein the method comprises administering a therapeutically ef- fective amount of the compound according to the first aspect to the subject, wherein the disease is selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclero- sis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-reperfusion injury, idio- pathic pulmonary fibrosis, systemic sclerosis, irritable bowel disease, chronic kidney dis- ease and pain.
  • the disease is selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome,
  • the present invention relates to a method for treating cancer in a subject in need thereof, wherein the method comprises administering a thera- Chamberically effective amount of the compound according to the first aspect to the subject.
  • the method further comprises co-administering a therapeutically effective amount of at least one further anti-neoplastic agent with said compound.
  • the anti-neoplastic agent is selected from the group consisting of a chemotherapeutic agent, a topoisomerase II inhibitor, an anti- metabolite, a topoisomerase I inhibitor, a hormone, a hormonal analogue, a signal transduc- tion pathway inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, a proapoptotic agent, a cell cycle signaling inhibitor, a proteasome inhibitor, an inhibitor of cancer metabol- ism, and an immunotherapeutic agent.
  • a chemotherapeutic agent a topoisomerase II inhibitor, an anti- metabolite, a topoisomerase I inhibitor, a hormone, a hormonal analogue, a signal transduc- tion pathway inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, a proapoptotic agent, a cell cycle signaling inhibitor, a proteasome inhibitor, an inhibitor of cancer metabol- ism, and an immunotherapeut
  • the immunotherapeutic agent (and thus the anti- neoplastic agent) may be a checkpoint inhibitor, wherein the checkpoint inhibitor may be selected from the group consisting of an antibody or an antigen-binding fragment thereof, a small molecule inhibitor and an antisense oligonucleotide.
  • the method further comprises diagnosing the disease in a subject prior to administering the therapeutically effective amount of the com- pound according to the first aspect. All embodiments of the first aspect including of course all preferred embodiments of the first aspect equally apply to the fifth aspect.
  • the present invention relates to a method for treating a disease in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of 8-amino-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6-azaspiro[3.3]heptan-6-yl ⁇ methyl)bicy- clo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-carboxamide to the subject, wherein the disease is selected from the group consisting of cancer, Parkinson's disease, Huntington's Ryvu Therapeutics S.A.
  • BioNTech SE R10559WO 24 disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclero- sis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-reperfusion injury, idio- pathic pulmonary fibrosis, systemic sclerosis, irritable bowel disease, chronic kidney dis- ease and pain.
  • ADD attention deficit disorder
  • ADHD attention deficit hyperactivity disorder
  • amyotrophic lateral sclero- sis amyotrophic lateral sclero- sis
  • cirrhosis cirrhosis
  • fibrosis fatty liver
  • addictive behavior dermal fibrosis
  • a sleep disorder AIDS
  • an autoimmune disease an infection, atherosclerosis, ischemia-reperfusion
  • the present invention relates to a method for treating a disease in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of 8-amino-6-(4-fluorophenyl)-N-[3-(hy- droxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2- a]pyrazine-2-carboxamide to the subject, wherein the disease is selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psy- chosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an in- fection, atheros
  • the present invention relates to a method for treating a disease in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of 8-amino-6-(4-fluorophenyl)-N-[3-(hy- droxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2- a]pyrazine-2-carboxamide to the subject, wherein the disease is selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psy- chosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an in- fection, atheros
  • the present invention relates to a method for treating a disease in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of 8-amino-N-[3-(aminomethyl)bicy- Ryvu Therapeutics S.A.
  • the disease is selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-reperfusion injury, idiopathic pulmonary fibrosis, sys- temic sclerosis, irritable bowel disease, chronic kidney disease and pain.
  • the disease is selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder,
  • the present invention relates to a method for treating a disease in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of 8-amino-N-[3-(acetamidomethyl)bicy- clo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxamide to the subject, wherein the disease is selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-
  • the present invention relates to a method for treating a disease in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ - 6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carbox- amide to the subject, wherein the disease is selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, der- mal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-reperfusion injury, idiopathic
  • the present invention relates to a method for treating cancer in a subject in need thereof, wherein the method comprises ad- ministering a therapeutically effective amount of 8-amino-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6-azaspiro[3.3]heptan-6-yl ⁇ methyl)bicy- clo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-carboxamide to the subject.
  • the present invention relates to a method for treating cancer in a subject in need thereof, wherein the method comprises ad- ministering a therapeutically effective amount of 8-amino-6-(4-fluorophenyl)-N-[3-(1-hy- droxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2- a]pyrazine-2-carboxamide to the subject.
  • the present invention relates to a method for treating cancer in a subject in need thereof, wherein the method comprises ad- ministering a therapeutically effective amount of 8-amino-6-(4-fluorophenyl)-N-[3-(hydrox- ymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2- a]pyrazine-2-carboxamide to the subject.
  • the present invention relates to a method for treating cancer in a subject in need thereof, wherein the method comprises ad- ministering a therapeutically effective amount of 8-amino-6-(4-fluorophenyl)-N-[3-(hydrox- ymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2- a]pyrazine-2-carboxamide to the subject.
  • the present invention relates to a method for treating cancer in a subject in need thereof, wherein the method comprises ad- ministering a therapeutically effective amount of 8-amino-N-[3-(aminomethyl)bicy- clo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxamide to the subject.
  • the present invention relates to a method for treating cancer in a subject in need thereof, wherein the method comprises ad- ministering a therapeutically effective amount of 8-amino-N-[3-(acetamidomethyl)bicy- clo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxamide to the subject.
  • the present invention relates to a method for treating cancer in a subject in need thereof, wherein the method comprises ad- ministering a therapeutically effective amount of 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6- (4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carbox- amide to the subject.
  • the present invention relates to the use of the compound according to the first aspect in the manufacture of a medicament 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, attention deficit disorder (ADD), at- tention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibro- sis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-reperfusion injury, idiopathic pulmonary fi- brosis, systemic sclerosis, irritable bowel disease, chronic kidney disease and pain.
  • a disease selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), at- tention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis,
  • the present invention relates to the use of the com- pound according to the first aspect in the manufacture of a medicament for the treatment of cancer.
  • at least one further anti-neoplastic agent is co-administered in the treatment of cancer.
  • the anti-neoplastic agent is selected from the group consisting 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 tyrosine kinase inhibitor, an angiogenesis inhibitor, a proapoptotic agent, a cell cycle signaling inhibitor, a proteasome inhibitor, an inhibitor of cancer metabolism, and an immunotherapeutic agent.
  • a chemotherapeutic agent a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone, a hormonal analogue, a signal transduction pathway inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, a proapoptotic agent, a cell cycle signaling inhibitor, a proteasome inhibitor, an inhibitor of cancer metabolism, and an immunotherapeutic agent.
  • the immunotherapeutic agent (and thus the anti-neoplastic agent) may be a checkpoint inhibitor, wherein the checkpoint inhibitor may be selected from the group consisting of an antibody or an antigen-binding fragment thereof, a small mole- cule inhibitor and an antisense oligonucleotide. All embodiments of the first aspect including of course all preferred embodiments of the first aspect equally apply to the sixth aspect.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6- azaspiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-car- boxamide in the manufacture of a medicament for the treatment of a disease selected from the group consisting of cancer, Parkinson's disease, Huntington's disease, Alzheimer's dis- ease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), atten- tion deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibrosis, a sleep disorder, AIDS, an autoimmune dis- ease, an infection, atherosclerosis,
  • a disease selected from the group consisting
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of a disease selected from the group consisting of can- cer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, der- mal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-reperfusion injury, idiopathic pulmonary fibrosis, systemic
  • a disease selected from the group
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of a disease selected from the group consisting of can- cer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, der- mal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-reperfusion injury, idiopathic pulmonary fibrosis, systemic sclerosis, irri
  • a disease selected from the
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of a disease selected from the group consisting of can- cer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, der- mal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-reperfusion injury,
  • the present invention relates to the use of 8-amino-N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of a disease selected from the group consisting of can- cer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, der- mal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-reperfusion injury, idiopathic pulmonary fibrosis, systemic sclerosis,
  • a disease selected from the
  • the present invention relates to the use of 8-amino-N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of a disease selected from the group consisting of can- cer, Parkinson's disease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, der- mal fibrosis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia-reperfusion injury, idiopathic pulmonary fibrosis, systemic s
  • a disease selected from the
  • the present invention relates to the use of 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2- a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of a disease selected from the group consisting of cancer, Parkinson's dis- ease, Huntington's disease, Alzheimer's disease, psychosis, stroke, extra pyramidal syn- drome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, cirrhosis, fibrosis, fatty liver, addictive behavior, dermal fibro- sis, a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis, ischemia- reperfusion injury, idiopathic pulmonary fibrosis, systemic sclerosis, irritable bowel
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6- Ryvu Therapeutics S.A. and BioNTech SE R10559WO 29 azaspiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-car- boxamide in the manufacture of a medicament for the treatment of cancer.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of cancer.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of cancer.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of cancer.
  • the present invention relates to the use of 8-amino-N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of cancer.
  • the present invention relates to the use of 8-amino-N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of cancer.
  • the present invention relates to the use of 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2- a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide in the manufacture of a medicament for the treatment of cancer.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor, wherein said receptor is exposed to the compound according to the first aspect, wherein said method is preferably performed outside the human or animal body and/or wherein said compound preferably exhibits a low CYP inhibition profile.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor, wherein said receptor is exposed to 8- amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6-aza- spiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-carboxam- ide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor, wherein said receptor is exposed to 8- amino-6-(4-fluorophenyl)-N-[3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor, wherein said receptor is exposed to 8- amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor, wherein said receptor is exposed to 8- amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor, wherein said receptor is exposed to 8- amino-N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor, wherein said receptor is exposed to 8- amino-N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor, wherein said receptor is exposed to 8- amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin- 6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adeno- sine A2B receptor, wherein said receptor is exposed to the compound according to the first aspect, wherein said method is preferably performed outside the human or animal body and/or wherein said compound preferably exhibits a low CYP inhibition profile.
  • All embodiments of the first aspect including of course all preferred embodiments of the first aspect equally apply to the eight aspect.
  • the present invention relates to a method for antagonizing the adenosine A2B receptor, wherein said receptor is exposed to 8- amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6-aza- spiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-carboxam- ide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2B receptor, wherein said receptor is exposed to 8- amino-6-(4-fluorophenyl)-N-[3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2B receptor, wherein said receptor is exposed to 8- amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2B receptor, wherein said receptor is exposed to 8- amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2B receptor, wherein said receptor is exposed to 8- amino-N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2B receptor, wherein said receptor is exposed to 8- amino-N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2B receptor, wherein said receptor is exposed to 8- amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin- 6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adeno- sine A2A receptor and the adenosine A2B receptor, wherein said receptors are exposed to the compound according to the first aspect, wherein said method is preferably performed Ryvu Therapeutics S.A. and BioNTech SE R10559WO 32 outside the human or animal body and/or wherein said compound preferably exhibits a low CYP inhibition profile. All embodiments of the first aspect including of course all preferred embodiments of the first aspect equally apply to the ninth aspect.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor and the adenosine A2B receptor, wherein said receptor is exposed to 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2- a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6-azaspiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1- yl]imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed out- side the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor and the adenosine A2B receptor, wherein said receptor is exposed to 8-amino-6-(4-fluorophenyl)-N-[3-(1-hydroxyethyl)bicy- clo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-car- boxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor and the adenosine A2B receptor, wherein said receptor is exposed to 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicy- clo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-car- boxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor and the adenosine A2B receptor, wherein said receptor is exposed to 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicy- clo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-car- boxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor and the adenosine A2B receptor, wherein said receptor is exposed to 8-amino-N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1- yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-car- boxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor and the adenosine A2B receptor, wherein said receptor is exposed to 8-amino-N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan- 1-yl]-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2- carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to a method for antagonizing the adenosine A2A receptor and the adenosine A2B receptor, Ryvu Therapeutics S.A. and BioNTech SE R10559WO 33 wherein said receptor is exposed to 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluo- rophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, wherein said method is preferably performed outside the human or animal body.
  • the present invention relates to the use of the compound according to the first aspect as adenosine A2A receptor antagonist. All embodiments of the first aspect including of course all preferred embodiments of the first aspect equally apply to the tenth aspect.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6- azaspiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-car- boxamide as adenosine A2A receptor antagonist.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2A receptor antagonist.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2A receptor antagonist.
  • the present invention relates to the use 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide of as adenosine A2A receptor antagonist.
  • the present invention relates to the use of 8-amino-N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2A receptor antagonist.
  • the present invention relates to the use of 8-amino-N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2A receptor antagonist.
  • the present invention relates to the use of 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2- a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2A receptor antago- nist.
  • the present invention relates to the use of the compound accord- ing to the first aspect as adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2- oxa-6-azaspiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2- carboxamide as adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2B receptor antagonist.
  • the present invention relates to the use 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide of as adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)- 5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2B receptor antagonist.
  • the present invention relates to the use of the compound according to the first aspect as adenosine A2A receptor and adenosine A2B receptor antagonist. All embodiments of the first aspect including of course all preferred embodiments of the first aspect equally apply to the twelfth aspect.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N-[3-( ⁇ 2-oxa-6- azaspiro[3.3]heptan-6-yl ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]imidazo[1,2-a]pyrazine-2-car- boxamide as adenosine A2A receptor and adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2A receptor and adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2A receptor and adenosine A2B receptor antagonist.
  • the present invention relates to the use 8-amino-6-(4-fluorophenyl)-N-[3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl]-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide of as adenosine A2A receptor and adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)-5- ⁇ 3- methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2A receptor and adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-6-(4-fluorophenyl)- 5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2A receptor and adenosine A2B receptor antagonist.
  • the present invention relates to the use of 8-amino-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluorophenyl)-5- ⁇ 3-methylimi- dazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide as adenosine A2A receptor and adenosine A2B receptor antagonist.
  • the present invention relates to a method of manufacturing a pharmaceutical composition according to the second aspect, comprising the step of con- tacting the compound according to the first aspect with a pharmaceutically acceptable car- rier, diluent and/or excipient.
  • the method further comprises the step of blending the compound according to the first aspect and/or blending the pharmaceutically acceptable carrier, diluent and/or excipient, wherein the compound according to the first aspect and the pharmaceutically acceptable carrier, diluent and/or excipient may optionally be blended together.
  • the method further comprises the step of milling the compound according to the first aspect and/or milling the pharmaceutically ac- ceptable carrier, diluent and/or excipient, wherein the compound according to the first as- pect and the pharmaceutically acceptable carrier, diluent and/or excipient may optionally be milled together.
  • the method further comprises the step of sieving the compound according to the first aspect and/or sieving the pharmaceutically ac- ceptable carrier, diluent and/or excipient, wherein the compound according to the first as- pect and the pharmaceutically acceptable carrier, diluent and/or excipient may optionally be sieved together.
  • the method further comprises the step of granulating the compound according to the first aspect with a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the method further comprises the step of compressing the compound according to the first aspect with a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the method further comprises the step of compressing a blend of the compound according to the first aspect and a pharmaceutically acceptable carrier, diluent and/or excipient.
  • a pharmaceutically acceptable carrier diluent and/or excipient.
  • All embodiments of the first aspect including of course all preferred embodiments of the first aspect equally apply to the thirteenth aspect.
  • the present invention relates to a method of manufacturing a compound according to the first aspect, wherein the manufacturing essentially follows the synthesis scheme provided in the example section of the present application. All embodiments of the first aspect including of course all preferred embodiments of the first aspect equally apply to the fourteenth aspect.
  • 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, stereoi- somer, tautomer, isotopologue, or N-oxide thereof.
  • the compounds according to the invention may be amorphous or may exist in one or more different crystalline states (polymorphs) which may have different macroscopic properties such as stability or show different biological properties such as activities.
  • the present in- vention 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 accept- able salts, such as those containing counterions present in drug products listed in the US FDA Orange Book database. They can be formed in a customary manner, e.g., by reacting the compound with an acid of the anion in question if the compounds according to the in- vention have a basic functionality or by reacting acidic compounds according to the inven- tion 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 ammonium (NH 4 + ) and substituted ammonium in which one to four of the hy- drogen atoms are replaced by C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy- C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, phenyl or benzyl.
  • the alkali metals preferably lithium, sodium and potassium
  • the alkaline earth metals preferably calcium, magnesium and barium
  • the transition metals preferably manganese, copper, silver, zinc and
  • substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, furthermore the cations of 1,4-piperazine, meglumine, benzathine and lysine.
  • Suitable acidic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, di- hydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hex- afluorosilicate, hexafluorophosphate, benzoate, and the anions of C 1 -C 4 -alkanoic acids, preferably formate, acetate, propionate and butyrate, furthermore lactate, gluconate, and poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, fur- thermore sulfonate anions such as besylate (benzenesulfonate), tosylate (p-toluenesul- fonate), napsylate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanesulfonate), and e
  • the compounds according to the invention can be formed by reacting compounds ac- cording to the invention that have a basic functionality 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 enantiomers 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 possible 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- Ryvu Therapeutics S.A.
  • Tautomers may be formed, if a substituent is present at the compound of formula (I), which allows for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, amide-imidic acid tautomers or the like.
  • An isotopologue is an isotopically enriched compound.
  • the term "isotopically enriched compound" refers to a compound containing at least one atom having an isotopic composi- tion other than the natural isotopic composition of that atom.
  • the isotopologue is a deuterium(i.e. D or 2H)-enriched compound.
  • N-oxide includes any compound of the present invention which has at least one tertiary nitrogen atom that is oxidized to a N-oxide moiety.
  • substituted means that a hydrogen atom bonded to a desig- nated 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.
  • substitutedutable when used in reference to a designated atom, means that at- tached to the atom is a hydrogen, which can be replaced with a suitable substituent.
  • the term “one or more” is intended to cover at least one substituent, e.g. 1 to 10 substituents, preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most preferably 1, or 2 substituents.
  • substituents e.g. 1 to 10 substituents, preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most preferably 1, or 2 substituents.
  • 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 fluorine 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 preferably 1 to 3 or 1 to 2 or 1 carbon atoms.
  • alkyl group examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- dimethylbutyl, 1,2-dimethylbutyl, 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
  • 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 replaced with halogen atoms.
  • Preferred haloalkyl moieties are selected from C 1 - C 4 -haloalkyl, more preferably from C 1 -C 3 -haloalkyl or C 1 -C 2 -haloalkyl, in particular from C 1 - C 2 -fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluo- roethyl, 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, Ryvu Therapeutics S.A.
  • 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 atoms, comprising at least one carbon-carbon triple bond in any position, e.g.
  • 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, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom.
  • alkoxy group examples 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 prefer- ably 1 carbon atom, wherein the hydrogen atoms of this group are partially or totally re- placed with halogen atoms, in particular fluorine atoms.
  • Preferred haloalkoxy moieties in- clude C 1 -haloalkoxy, in particular C 1 -fluoroalkoxy, such as trifluoromethoxy and the like.
  • carbocyclic includes, unless otherwise indicated, in general a 3- to 9-mem- bered, 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 atoms.
  • the carbocycle may be saturated, partially unsaturated, or fully unsatu- rated.
  • the term “carbocycle” covers cycloalkyl and cycloalkenyl groups as de- fined 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 carbocycle.
  • carbobicycle includes in general bicyclic 4- to 14-membered, bicyclic rings comprising 4 to 14, carbon atoms.
  • the carbobicycle may be saturated, partially unsaturated, or fully unsaturated.
  • the term “carbobicycle” covers bicycloalkyl, bicycloalkenyl and bicyclic aromatic groups, for example bicyclobutane (such as bicyclo[1.1.0]butane), bi- cyclopentane (such as bicyclo[1.1.1]pentane), bicyclohexane, bicycloheptane (such as nor- bornane), bicyclooctane (such as bicyclo[2.2.2]octane, bicyclo[3.2.1]octane or bicy- clo[4.2.0]octane), bicyclononane (such as bicyclo[3.3.1]nonane or bicyclo[4.3.0]nonane ), bicyclodecane (such as bicyclo[4.4.0]decane), bicycloundecane (such as bicyclo[3.3.3]un- decane), norbornene, naphthalene and the like.
  • bicyclobutane such
  • heterocyclic includes, unless otherwise indicated, in general a 3- to 9-mem- bered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-mem- bered, in particular 6-membered monocyclic ring.
  • the heterocycle may be saturated, par- tially 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.
  • heterocycles 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 SO 2 .
  • aromatic heterocycles are provided below in connection with the definition of “hetaryl”. “Hetaryls” or “heteroaryls” are covered by the term “heterocycles”.
  • the saturated or par- tially unsaturated heterocycles usually comprise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 het- eroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2.
  • the S atom will not be present in oxidized form in fully unsaturated compounds.
  • Saturated heterocycles include, unless otherwise indicated, in general 3- to 9-membered, preferably 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, tetrahydrofu- ran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.
  • heteroatoms such as pyrrolidine, tetrahydrothiophene, tetrahydrofu- ran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.
  • heteroaryl or “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” includes 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 SO 2
  • S-atoms as ring members may be present as S, SO or SO 2
  • the S atom will not be present in oxidized form in fully unsaturated compounds.
  • Examples of 5- or 6-membered aromatic heterocycles include pyridyl, i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e.
  • heterocyclic includes in general bicyclic 4- to 14-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 SO 2 .
  • the heterobicycle may be satu- rated, partially unsaturated, or fully unsaturated.
  • heterobicycles include benzo- furanyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridyl, pteridyl, pyrido[3,2-d]pyrimidyl, pyridoimidazolyl, triethylenediamine or quinuclidine and the like.
  • 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 embodiments only.
  • pharmaceutically acceptable excipient refers to an excipient commonly comprised in pharmaceutical compositions, which is known to the skilled person. Examples of a suitable excipient 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”.
  • a “treatment” or “treating” this is to be under- stood as “treatment and/or prophylaxis” or “treating and/or preventing”.
  • the term “exhibits a low CYP-inhibition profile” as used herein means a that compound does substantially not inhibit the various members of the Cytochromes P450 (or CYPs), which are enzymes catalyzing the degradation of various (toxic) compounds. This can e.g. indicate a lower risk of drug-drug interactions in case of combination therapies comprising the afore-mentioned compound or co-administration of the afore-mentioned compound with other drugs.
  • 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 preferred. Parenteral application can also be preferred and includes intravenous, in- traarterial, intratumoral, intrathecal, intravesical, intramuscular or subcutaneous administra- tion.
  • the compound according to formula (I) should be applied in a pharmaceutically effec- tive amount, for example in the amount as set out herein below.
  • a pharmaceutical composition of the present invention may also be designated as formu- lation or dosage form.
  • a compound of formula (I) may also be designated in the following as (pharmaceutically) active agent or active compound.
  • a pharmaceutical composition may be a solid or a liquid dosage form or may have an inter- mediate, e.g. gel-like character depending inter alia on the route of administration.
  • the dosage form can comprise at least one pharmaceutically acceptable excipi- ent, which will be selected depending on which functionality is to be achieved for the dosage form.
  • a “pharmaceutically acceptable excipient” in the meaning of the present in- vention can be any substance used for the preparation of a pharmaceutical dosage form, in- cluding a coating material, a film-forming material, a filler, a disintegrating agent, a release- modifying material, a carrier material, a diluent, a binding agent and any other adjuvant.
  • typical pharmaceutically acceptable excipient includes a substance like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and a lubricating agent such as magnesium stearate, a disintegrant and a buffering agent.
  • carrier denotes a pharmaceutically acceptable organic or inorganic carrier sub- stance with which the active ingredient is combined to facilitate the application.
  • a suitable pharmaceutically acceptable carrier includes, for instance, water, an aqueous salt solution, an alcohol, oil, preferably vegetable oil, propylene glycol, polyoxyethelene sorbitan, a poly- ethylene-polypropylene block co-polymer such as poloxamer 188 or poloxamer 407, a poly- ethylene glycol such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amy- lose, magnesium stearate, a surfactant, perfume oil, a fatty acid monoglyceride, a diglyc- eride and a triglycerides, a polyoxyethylated medium or a long chain fatty acid such as rici- noleic acid, and a polyoxyethylated fatty acid mono-, di, and triglyceride such as capric or caprilic acid, petroethral fatty acid ester, hydroxymethyl cellulose such as hydroxymethyl, hydroxye
  • the pharmaceutical composition can be sterile and, if desired, mixed with an auxiliary agent, like a lubricant, a preservative, a stabilizer, a wetting agent , an emulsifier, a salt for influencing osmotic pressure, a buffer, a coloring, a flavoring and/or aromatic substance and the like which does not deleteriously react with the active com- pound.
  • an auxiliary agent like a lubricant, a preservative, a stabilizer, a wetting agent , an emulsifier, a salt for influencing osmotic pressure, a buffer, a coloring, a flavoring and/or aromatic substance and the like which does not deleteriously react with the active com- pound.
  • a liquid dosage form can include a pharma- ceutically acceptable emulsion, a solutions, a suspension and a syrups containing an inert diluent commonly used in the art such as water.
  • mi- crocrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and a sweetener/flavouring agent.
  • a particularly suitable vehicle consists of a solution, preferably an oily or aqueous solution, as well as a suspension, an emulsions, or an implant.
  • a phar- maceutical formulation for parenteral administration is particularly preferred and includes an aqueous solution of the compounds of formula (I) in water-soluble form. Additionally, a suspension of the compounds of formula (I) may be prepared as an appropriate oily injec- tion suspension.
  • a suitable lipophilic solvent or vehicle includes a fatty oil such as sesame oil, soybean oil, or a tocopherol, or a synthetic fatty acid ester, such as ethyl oleate or triglyceride, or a liposome.
  • An aqueous injection suspension may contain a substance which increases the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • a particularly preferred dosage form is an injectable preparation of a compound of formula (I).
  • a sterile injectable aqueous or oleaginous suspension can for example be formu- lated according to the known art using a suitable dispersing agent, a wetting agent and/or a suspending agent.
  • 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 vehicles and solvents that can be used are water and isotonic sodium chlo- ride solution.
  • a sterile oil is also conventionally used as solvent or suspending medium.
  • a suppository for rectal administration of a compound of formula (I) can be prepared by e.g.
  • the compound of formula (I) may be conveniently deliv- ered in the form of an aerosol spray from a pressurized pack or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorote- trafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorote- trafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • gelatin for use in an inhaler or insufflator may be formulated con- taining a powder mix of the compound and a suitable powder base such as lactose or starch.
  • An oral dosage form may be liquid or solid and include e.g. a tablet, a troche, a pill, a cap- sule, a powder, an effervescent formulation, a dragee and a granule.
  • a pharmaceutical preparation for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding a suitable auxiliary agent, if desired, to obtain a tablet or a dragee core.
  • a suitable excipient is, in particular, a filler such as a sugar, including lactose, sucrose, mannitol, or sorbitol; a cellulose preparation such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • a disintegrating agent 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 form may be formulated 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 dosage form may be in the form of a so-called film tablet.
  • a capsule may be a two-piece hard gelatin 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 comprising the compound of formula (I) may be formulated for topical application.
  • a suitable pharmaceutical application form for such an application may be a topical nasal spray, a sublingual administration form and a controlled and/or sustained re- lease skin patch.
  • the composition may take the form of a tablet or lozenge formulated in conventional manner.
  • the composition may conveniently be presented in a unit dosage form and may be pre- pared by any of the methods well known in the art of pharmacy.
  • the method can include the step of bringing the compounds into association with a carrier which constitutes one or more accessory ingredient(s).
  • the composition is prepared by uniformly and inti- mately bringing the compound of formula (I) into association with a liquid carrier, a finely di- vided solid carrier, or both, and then, if necessary, shaping the product.
  • a liquid dose unit is a vial or an ampoule.
  • a solid dose unit is a tablet, a capsule and a suppository.
  • 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 1000 mg per day, which is the effective amount.
  • the phrase “effective amount” means an amount of the compound of formula (I) 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 con- verted under physiological conditions or by solvolysis to any of the compounds of formula Ryvu Therapeutics S.A. and BioNTech SE R10559WO 44 (I).
  • a prodrug 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 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 (ADHD), amyotrophic lateral sclerosis, cirrho- sis, fibrosis, fatty liver, addictive behavior, dermal fibrosis (in particular dermal fibrosis in scleroderma), a sleep disorder, AIDS, an autoimmune disease, an infection, atherosclerosis and ischemia-reperfusion injury.
  • the compounds according to the present in- vention are used for idiopathic pulmonary fibrosis, systemic sclerosis, irritable bowel dis- ease, chronic kidney disease (in particular diabetic nephropathy) 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 treatment of a disease selected from the group consisting of a neurodegenerative disease, a proliferative disease, an inflammatory disease, an infectious disease, sickle cell disease, di- abetic nephropathy, a cognition disease and a CNS disease.
  • the proliferative diseases in- clude cancer.
  • a pharmaceutical composition may comprise the compound of formula (I) as the only pharmaceutically active agent.
  • the compound of formula (I) according to the present invention is administered in combination with an antibody, 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.
  • an antibody 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.
  • the compounds of the present invention may be coadministered with an anti- neoplastic agent and/or an anti-neoplastic agent may be comprised in the pharmaceutical composition according to the present invention.
  • 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.
  • Typical anti-neoplastic agents useful in the present invention include a chemotherapeutic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hor- mone and a hormonal analogue, a signal transduction pathway inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, a proapoptotic agent, a cell cycle signaling inhibitor, a proteasome inhibitor, an inhibitor of cancer metabolism, and an immunotherapeutic agent. It is widely known today that tumors can evade the immune system by suppressing the im- mune response.
  • a strategy against this suppression resides e.g. in the blockade of recep- tors, which act (co-)inhibitory on the immune system (a negative “immune checkpoint” or “checkpoint”).
  • Agents blocking or inhibiting these receptors are commonly referred to as “checkpoint in- hibitors” and this reference is also used herein.
  • checkpoint inhibitor may be selected Ryvu Therapeutics S.A. and BioNTech SE R10559WO 45 from the group consisting of an antibody or an antigen-binding fragment thereof, a small molecule inhibitor and an antisense oligonucleotide.
  • Combination therapy may be achieved by use of a single pharmaceutical composition that includes both agents, or by administering two distinct compositions, preferably 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 treat- ment 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 present invention is administered prior to admin- istration of the distinct cancer treatment.
  • the distinct cancer treat- ment is administered prior to administration of the compound of the present invention.
  • the present invention is further illustrated by the following examples. Examples Part 1: Synthesis General Abbreviations Some abbreviations that may appear in this application are defined hereinafter: Ryvu Therapeutics S.A. and BioNTech SE R10559WO 46 Ryvu Therapeutics S.A. and BioNTech SE R10559WO 47 Ryvu Therapeutics S.A.
  • Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quar- tet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets), td (triplet of doublets), dt (doublet of triplets), br (broad).
  • NMR data were analyzed using MestReNova v10.0.2 and ul- terior (Mestrelab Research S.L., Santiago de Compostela, Spain, www.mestrelab.com).
  • Analytical methods UPLC long elution: Four types of eluent systems were used: Ryvu Therapeutics S.A.
  • Detection DAD, MS single quadrupole with positive and negative ionization, ESCI or ESI ion sources
  • Methods 3 default methods were available for UPLC, flow rate 0.5 mL/min: Polar: Ryvu Therapeutics S.A. and BioNTech SE R10559WO 50
  • Non polar long method Equipment: • I Class Waters UPLC-MS with SQD2 and ESCI ion source. • I Class Waters UPLC-MS with SQD2 and ESI ion source.
  • Preparative HPLC purification The following equipment was used for Preparative HPLC purification: Waters Autopurifica- tion system (Waters 2767 – Sample Manager, Waters 2545 – Binary Gradient Module, Wa- ters SFO – System Fluidics Organizer, Waters Prep Degasser, Waters 515 – HPLC Pump, Waters UV Fraction Manager) with DAD (Waters 2998 – Photodiode Array Detector) and QDa (Waters Acquity QDa) detection using a Gemini®5 ⁇ m NX-C18110 ⁇ (00G-4454-P0-AX LC Column 250 x 21.2 mm, AX).
  • Waters Autopurifica- tion system Waters 2767 – Sample Manager, Waters 2545 – Binary Gradient Module, Wa- ters SFO – System Fluidics Organizer, Waters Prep Degasser, Waters 515 – HPLC Pump, Waters UV Fraction Manager
  • DAD Waters 2998
  • reaction mixture was sparged with argon and Pd(PPh 3 ) 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. Af- ter that time, the reaction mixture was cooled down to RT, filtered through Celite® pad, ex- Ryvu Therapeutics S.A. and BioNTech SE R10559WO 52 tracted with EtOAc/NaHCO 3 solution, organic layer was washed with brine and dried over Na 2 SO 4 . Then the mixture was concentrated in vacuo to dryness.
  • Step 2 3-bromo-6-chloro-5-(4-fluorophenyl)pyrazin-2-amine, Int-A-02 Into a pressure tube N-bromosuccinimide (12.6 g, 70.6 mmol) was added in 3 portions to a solution of 6-chloro-5-(4-fluorophenyl)pyrazin-2-amine (15 g, 64.2 mmol) in CH 3 CN (100 mL) at 0°C.
  • Step 3 ethyl 8-bromo-5-chloro-6-(4-fluorophenyl)imidazo[1,2-a]pyrazine-2-carboxylate, Int-A-03
  • 3-bromo-6-chloro-5-(4-fluorophenyl)pyrazin-2-amine 10 g; 33.06 mmol
  • 3-bromopyruvic acid ethyl ester (19.3 g; 99.17 mmol) was added.
  • the reac- tion was stirred for 1 h at room temperature (appearance of a yellow solid was observed) and then heated to 85 °C for 16 h, under an argon atmosphere.
  • Step 4 ethyl 8-amino-5-chloro-6-(4-fluorophenyl)imidazo[1,2-a]pyrazine-2-carboxylate, Int-A-04 To ethyl 8 ⁇ bromo ⁇ 5 ⁇ chloro ⁇ 6 ⁇ (4 ⁇ fluorophenyl)imidazo[1,2 ⁇ a]pyrazine ⁇ 2 ⁇ car- boxylate (11 g; 31.06 mmol) 0.5M ammonia in dioxane (140 mL) was added, the reaction mixture was heated at 110 °C for 20 h.
  • Step 5 ethyl 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-carboxylate, Int-A-05
  • a two-neck round bottom flask with Findenser TM was charged with 3-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (6.82 g, 25.892 mmol, 2.002 eq.), potassium hydrogen carbonate (2.59 g, 25.871 mmol, 2.0 eq.), NMP (21.0 mL, 1.62 mL/mmol) and water (7.3 mL, 0.56 mL/mmol).
  • the microwave reaction vial was charged with ethyl 8-amino-5- chloro-6-(4-fluorophenyl)imidazo[1,2-a]pyrazine-2-carboxylate (5.39 g, 12.935 mmol, 1.0 eq.) and NMP (24.0 mL, 1.86 mL/mmol), degassed, flushed with N 2 and heated to 120 °C.
  • NMP 24.0 mL, 1.86 mL/mmol
  • the solution from the microwave reaction vial was immediately transferred to the mix- ture in the 2-neck flask using a glass syringe.
  • RM was stirred at 120 °C for 2.5 h.
  • the RM was cooled to RT and diluted with water.
  • the iInsoluble solid was filtered off, washed with Ryvu Therapeutics S.A. and BioNTech SE R10559WO 53 water and heptane and dried under reduced pressure. Then, the solid was suspended in EtOH and refluxed for 7 min. The hot mixture was filtered off and the resulting grey solid was washed with a fresh portion of EtOH. This procedure (reflux in EtOH) was repeated three times.
  • Step 6 lithium(1+) 8-amino-6-(4- yl ⁇ imidazo[1,2-a]pyrazine-2-
  • a suspension of ethyl 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6- yl ⁇ imidazo[1,2-a]pyrazine-2-carboxylate (8.88 g, 18.773 mmol, 1.0 eq.) in ethanol (70 mL)
  • a solution of lithium(1+) hydrate hydroxide (1.19 g, 28.36 mmol, 1.511 eq.) in water (25 mL) was added.
  • the reaction mixture was heated at 90°C for 2 h.
  • Step 1 methyl 3- ⁇ [(benzyloxy)carbonyl]amino ⁇ bicyclo[1.1.1]pentane-1-carboxylate, Int-C- 01 ⁇ solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (5.3 g, 31.146 mmol, 1.0 eq.) in anhydrous toluene (200 mL) was prepared. Triethylamine (10.0 mL, 71.744 mmol, 2.303 eq.) was added to the solution.
  • the mixture was stirred at room temperature while DPPA (10.0 g, 36.337 mmol, 1.167 eq.) was slowly added dropwise over a period of 15 minutes. The temperature was gradually increased in steps of 10°C every 15 minutes until reaching 95°C. The RM was maintained at 95°C for 3 hours. Subsequently, the reaction mixture was cooled to 50°C and a solution of benzyl alcohol (7.0 mL, 67.32 mmol, 1.922 eq.) in toluene (10 mL) was added dropwise. The resulting mixture was heated to 95°C and kept at that temperature for 9 hours, followed by cooling to room temperature. To the mixture at RT aq. sat.
  • Dess-Martin periodi- nane (25.0 g, 58.942 mmol, 1.307 eq.) was added portionwise to the RM to maintain temper- ature below 5°C. After the addition was complete, the reaction mixture was kept at 0°C for 1.5 hours. Afterward, a 10% aqueous Na 2 S 2 O 3 was added to the heterogeneous reaction mixture, followed by aq. sat. NaHCO 3 solution, and the mixture was stirred for 1 h. Then, DCM was added and phases were separated. The organic phase was concentrated.
  • the RM was then diluted with DCM and the solution was washed with aq. 1 N NaOH and brine.
  • the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and evaporated under reduced pressure.
  • the residue was purified by FCC (NH 2 silica, 0 to 10% MeOH gradient in DCM) to give benzyl N- ⁇ 3-[(dimethylamino)methyl]bicyclo[1.1.1]pen- tan-1-yl ⁇ carbamate (0.29 g, 0.951 mmol, 70%).
  • Step 3 8-amino-N- ⁇ 3-[(dimethylamino)methyl]bicyclo[1.1.1]pentan-1-yl ⁇ -6-(4-fluo- rophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, Ex-001, General Procedure 03.
  • the RM was then diluted with DCM and the solution was washed with aq. 1 N NaOH and brine.
  • the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and evaporated under reduced pressure.
  • the crude material was purified by FCC (0 to 10% MeOH gradient in DCM).
  • Step 4 8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ -N- ⁇ 3-[(piper- azin-1-yl)methyl]bicyclo[1.1.1]pentan-1-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxamide, Ex-023, General procedure 04: Tert-butyl 4-( ⁇ 3-[8-amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imi- dazo[1,2-a]pyrazine-2-amido]bicyclo[1.1.1]pentan-1-yl ⁇ methyl)piperazine-1-
  • the RM was stirred at RT overnight and the volatiles were evaporated under reduced pressure. The residue was partitioned between sat. aq. Na 2 CO 3 and DCM. The aqueous phase was extracted with DCM, and the combined organic extracts were dried over anh. Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • acetyl chloride (0.145 mL, 2.033 mmol, 1.5 eq.) and NEt 3 (0.283 mL, 2.033 mmol, 1.5 eq.) were added, RM was stirred overnight. Then the RM was washed with aq. 5% KHSO 4 and brine. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and evaporated under reduced pressure.
  • Step 2 was performed according to General Procedure 02.
  • the crude tert-butyl N-( ⁇ 3- aminobicyclo[1.1.1]pentan-1-yl ⁇ methyl)-N-methylcarbamate (Int-GP2-17, 0.048 g, 0.201 mmol, 73%) was used in the next step without further purification.
  • Step 3 was performed according to General Procedure 03, using lithium(1+) 8-amino-6- (4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxy- late (0.09 g, 0.201 mmol, 1.0 eq.), HATU (0.12 g, 0.302 mmol, 1.5 eq.), tert-butyl N-( ⁇ 3- aminobicyclo[1.1.1]pentan-1-yl ⁇ methyl)-N-methylcarbamate (0.048 g, 0.201 mmol, 1.0 eq.) in NMP.
  • Step 4 was performed according to General procedure 04, using tert-butyl N-( ⁇ 3-[8- amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2- amido]bicyclo[1.1.1]pentan-1-yl ⁇ methyl)-N-methylcarbamate (0.08 g, 0.128 mmol, 1.0 eq.), and TFA (0.295 mL, 3.851 mmol, 30.0 eq.) in DCM.
  • Step 22 (3- ⁇ [(benzyloxy)carbonyl]amino ⁇ bicyclo[1.1.1]pentan-1-yl)acetic acid, Int-E-02.
  • benzyl N-[3-(2,2,2-trichloro-1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]car- bamate 0.838 g, 2.183 mmol, 1.0 eq.
  • NaOH 0.262 g, 6.55 mmol, 3.0 eq.
  • NaBH 4 (0.124 g, 3.278 mmol, 1.501 eq.
  • Step 5 was performed according to General Procedure 02.
  • the crude 1- ⁇ 3-aminobicy- clo[1.1.1]pentan-1-yl ⁇ -2-methylpropan-2-ol (Int-GP2-18, 0.113 g, 0.692 mmol, 100%) was used in the next step without further purification.
  • Step 6 was performed according to General Procedure 03, using lithium(1+) 8-amino-6- (4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxy- late (0.28 g, 0.645 mmol, 1.0 eq), HATU (0.27 g, 0.71 mmol, 1.1 eq.), 1- ⁇ 3-aminobicy- clo[1.1.1]pentan-1-yl ⁇ -2-methylpropan-2-ol (0.111 g, 0.679 mmol, 1.054 eq.) in NMP.
  • Step 3 was performed according to General Procedure 03 using lithium(1+) 8-amino-6- (4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxy- late (0.21 g, 0.483 mmol, 1.0 eq.), HATU (0.193 g, 0.508 mmol, 1.05 eq.), 2- ⁇ 3-aminobicy- clo[1.1.1]pentan-1-yl ⁇ ethan-1-ol (0.07 g, 0.523 mmol, 1.08 eq.) in NMP.
  • the crude material was purified by two consecutive FCC (first: 0 to 10% MeOH gradient in DCM, second: 0 to 10% MeOH gradient in EtOAc) to yield 8-amino-6-(4-fluorophenyl)-N-[3-(2-hydroxyethyl)bi- cyclo[1.1.1]pentan-1-yl]-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2- carboxamide (Ex-028, 0.05 g, 0.097 mmol, 20%, white solid, long elution UPLC purity: 99.07%).
  • Propan-2-yl carbonochloridate (0.121 g, 0.987 mmol, 1.048 eq.) was added to a solution of tert-butyl N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]carbamate (0.2 g, 0.942 mmol, 1.0 eq.) and ethylbis(propan-2-yl)amine (0.33 mL, 1.895 mmol, 2.011 eq.) in anhydrous DCM at 0°C. The RM was stirred for overnight, being allowed to slowly come back to RT. The reac- tion was quenched by addition of aq. sat.
  • Step 2 was performed according to General procedure 04, using tert-butyl N-[3- ( ⁇ [(propan-2-yloxy)carbonyl]amino ⁇ methyl)bicyclo[1.1.1]pentan-1-yl]carbamate (0.13 g, 0.427 mmol, 1.0 eq.) and HCl (4M in dioxane, 2.14 mL, 8.56 mmol, 20.0 eq.) in DCM.
  • the RM was evaporated to dryness to afford propan-2-yl N-( ⁇ 3-aminobicyclo[1.1.1]pentan-1- yl ⁇ methyl)carbamate hydrochloride (Int-GP4-01, 0.116 g, 0.428 mmol, 100%).
  • Step 3 was performed according to General Procedure 03, using lithium(1+) 8-amino-6- (4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxy- late (0.18 g, 0.414 mmol, 1.0 eq.), HATU (0.17 g, 0.447 mmol, 1.079 eq.), propan-2-yl N-( ⁇ 3- aminobicyclo[1.1.1]pentan-1-yl ⁇ methyl)carbamate hydrochloride (0.116 g, 0.428 mmol, 1.032 eq.) in NMP.
  • Step 1 was performed according to General Procedure 03, using lithium(1+) 8-amino-6- (4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxy- late (0.2 g, 0.46 mmol, 1.0 eq.), HATU (0.175 g, 0.46 mmol, 1.0 eq.), tert-butyl 4- ⁇ 3-aminobi- cyclo[1.1.1]pentan-1-yl ⁇ piperazine-1-carboxylate (0.13 g, 0.462 mmol, 1.003 eq.) in NMP.
  • Step 2 was performed according to General procedure 04, using tert-butyl 4- ⁇ 3-[8-amino- 6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2- amido]bicyclo[1.1.1]pentan-1-yl ⁇ piperazine-1-carboxylate (0.205 g, 0.311 mmol, 1.0 eq.) and TFA (0.48 mL, 6.268 mmol, 20.0 eq.) in DCM.
  • Step 2 was performed according to General procedure 04, using tert-butyl N-[3-(mor- pholin-4-yl)bicyclo[1.1.1]pentan-1-yl]carbamate (0.25 g, 0.913 mmol, 1.0 eq.) and HCl (4M in dioxane, 4.6 mL, 18.4 mmol, 20.1 eq.) in DCM.
  • Step 3 was performed according to General Procedure 03, using lithium(1+) 8-amino-6- (4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2-carboxy- late (0.33 g, 0.727 mmol, 1.0 eq.), HATU (0.304 g, 0.8 mmol, 1.1 eq.), 3-(morpholin-4-yl)bicy- clo[1.1.1]pentan-1-amine dihydrochloride (0.211 g, 0.875 mmol, 1.203 eq.) in NMP.
  • Step 2 was performed according to General procedure 04, using tert-butyl N-( ⁇ 3-[8- amino-6-(4-fluorophenyl)-5- ⁇ 3-methylimidazo[1,2-a]pyridin-6-yl ⁇ imidazo[1,2-a]pyrazine-2- amido]bicyclo[1.1.1]pentan-1-yl ⁇ methyl)carbamate (0.265 g, 0.444 mmol, 1.0 eq.) and HCl (3M in MeOH, 2.0 mL, 6.0 mmol, 13.5 eq.) in EtOH.
  • the RM was evaporated to dryness, the residue was partitioned between EtOAc and a solution of aq. sat. Na 2 CO 3 . The organic layer was separated and washed with brine, dried over anhydrous Na 2 SO 4 , filtered and evapo- rated under reduced pressure.
  • Step 2 dazo To a suspension of ethyl 8-amino-6-(4-fluorophenyl)-5-(1-methyl-1H-1,3-benzodiazol-6- yl)imidazo[1,2-a]pyrazine-2-carboxylate (3.5 g, 8.13 mmol, 1.0 eq.) in ethanol (80 mL) a so- lution of LiOH*H 2 O (1.02 g, 24.39 mmol, 3.0 eq.) in water (50 mL) was added. Reaction mix- ture was heated at 70°C for 2 h. Hot reaction mixture was filtered through a pad of Celite®, washed with hot ethanol.
  • Step 3 was performed according to General Procedure 03, using lithio 8-amino-6-(4-fluo- rophenyl)-5-(1-methyl-1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyrazine-2-carboxylate (0.12 g, 0.3 mmol, 1.0 eq.), HATU (0.136 g, 0.36 mmol, 1.2 eq.), bicyclo[1.1.1]pentan-1-amine hy- drochloride (0.043 g, 0.36 mmol, 1.2 eq.) in DMF.
  • Part 2 Activity A2A activity at low agonist concentrations
  • Examples (see synthesis part above for the structures and names of these 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).
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • the assay to test the Examples was performed as follows: The cells were suspended in HBSS buffer (Invitrogen) complemented with 5 mM HEPES (pH 7.4), with 0.1% BSA and 100 ⁇ M Rolipram (a phosphodiesterase-4 inhibitor to block the degradation of cAMP), then distributed in microplates at a density of 2.10 3 cells/well (in a 384 well plate) in the presence of either (i) HBSS (basal control) with 0.2% DMSO, (ii) the test com- pound, i.e. each of the Examples or (iii) the reference antagonist ZM 241385. Thereafter, the reference adenosine receptor agonist NECA (e.g.
  • 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
  • A2A activity at high agonist concentrations Examples (see synthesis part above for the structures and names of these compounds) were tested for their antagonistic activity at the rat A2A receptor (endogenously expressed in PC12 cells, which were used in the assay) at high concentrations of agonist.
  • the antago- nistic activity was determined by measuring the effect of each compound on agonist-in- Jerusalem cAMP production using the assay based on time-resolved fluorescence resonance energy transfer (TR-FRET).
  • the assay to test the Examples was performed as follows: The cells were suspended in HBSS buffer (Invitrogen) complemented with 5 mM HEPES (pH 7.4), with 0.1% BSA , 100 ⁇ M Rolipram (a phosphodiesterase-4 inhibitor to block the degradation of cAMP) and 10 ⁇ M EHNA - adenosine deaminase inhibitor, then distributed in microplates at a density of 2.0x10 3 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 the Examples, or (iii) the refer- ence antagonist ZM 241385.
  • the nonselective adenosine receptor agonist – adenosine (e.g. CAS 58-61-7, Tocris) was added at a final concentration of 100 ⁇ M (corre- sponding to high adenosine concentration in tumor).
  • adenosine e.g. CAS 58-61-7, Tocris
  • sepa- rate assay wells did not contain adenosine.
  • the cells were lysed and the detection mix was added (standard reagents used according to a standard protocol; LANCETM cAMP 384 Kit, PerkinElmer).
  • 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 at low agonist concentrations Examples (see synthesis part above for the structures and names of these compounds) 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 cAMP produc- tion using the assay based on time-resolved fluorescence resonance energy transfer (TR- FRET).
  • the assay to test the Examples was performed as follows: The cells were suspended in HBSS buffer (Invitrogen) complemented with 5 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 2.5x10 3 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, or (iii) the reference antagonist XAC. Thereafter, the reference adenosine receptor agonist NECA (e.g.
  • 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. Ryvu Therapeutics S.A.
  • the assay to test the Examples was performed as follows: The cells were suspended in HBSS buffer (Invitrogen) complemented with 5 mM HEPES (pH 7.4), with 0.1% BSA and EHNA - adenosine deaminase inhibitor [10 ⁇ M], then distributed in mi- croplates at a density of 2.5x10 3 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 the examples, or (iii) the reference antagonist XAC.
  • the nonselective adenosine receptor agonist – adenosine (e.g. CAS 58-61-7, Tocris) was added at a final concentration of 100 ⁇ M (corre- sponding to high adenosine concentration in tumor).
  • adenosine e.g. CAS 58-61-7, Tocris
  • sepa- rate assay wells did not contain adenosine.
  • the cells were lysed and the detection mix was added (standard reagents used according to a standard protocol; LANCETM cAMP 384 Kit, PerkinElmer).
  • 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.
  • Ryvu Therapeutics S.A. and BioNTech SE R10559WO 89 Table 4 As can be derived from Table 4, the compounds of the present invention have very low EC50-values when it comes to A2A- and A2B-binding, respectively.
  • Cytokine secretion induction in human moDCs at high concentrations of agonist Examples Ex-032, Ex-030, and Ex-023 were tested for their antagonistic activity on cytokine pro- Ryvu Therapeutics S.A. and BioNTech SE R10559WO 90 duction by human moDCs (monocyte derived dendritic cells) at high concentrations of ago- nist.
  • the antagonistic activity was determined by measuring the effect of compound on ago- nist-suppressed TNF ⁇ secretion using homogenous AlphaLISA detection method.
  • the assay to test the compounds of the present invention was performed as follows: Human monocyte derived dendritic cells (moDCs) were differentiated in culture with 50 ng/ml GM-CSF (Peprotech) and 100 ng/ml IL-4 (Peprotech) for 6 days. Then cells were seeded in 96 well plates (U-bottom) at density 1.8 mln/ml in culture medium supple- mented with differentiation cytokines and pretreated with i) culture medium with 0.1% DMSO, ii) Ex-032, Ex-030, and Ex-023 at concentrations 10 ⁇ M – 1 nM. After 1h incubation NECA was added at final concentration of 10 ⁇ M.
  • moDCs Human monocyte derived dendritic cells
  • the presented data is (i) the geometrical mean of EC50 values from at least 3 independent experiments for Ex-032, and (ii) the re- sults derived from a single experiment for Ex-030 and Ex-023.
  • Table 5 As can be derived from Table 5, the compounds of the present invention are able to re- verse immunosuppression mediated by an adenosine receptor and rescue proinflammatory TNF ⁇ -production by human moDCs. Ryvu Therapeutics S.A.
  • cytochrome P450 inhibition (single point) assay utilizes human liver microsomes (HLM), a single concentration of test compound, and a single incubation time.
  • CYP1A2, 2B6, 2C8, 2C9, 2D6 and 3A4 The inhibi- tion of CYP1A2, 2B6, 2C8, 2C9, 2D6 and 3A4 is assessed using cocktail containing probe substrates for each CYP (phenacetin for 1A2, bupropion for 2B6, amodiaquine for 2C8, di- clofenac for 2C9, dextromethorphan for 2D6, and testosterone/midazolam for 3A4), while inhibition of CYP2C19 is conducted separately due to requirements of higher protein con- centration and longer incubation time, and the probe substrate is S-mephenytoin.
  • cocktail containing probe substrates for each CYP phenacetin for 1A2, bupropion for 2B6, amodiaquine for 2C8, di- clofenac for 2C9, dextromethorphan for 2D6, and testosterone/midazolam for 3A4
  • the probe substrate is S-mephenytoin.
  • the preincubation plate comprises HLM diluted with phosphate buffer (100 mM, pH 7.4) and aliquots of test compound stock solution (maximum pre-incubation concentration: 50 ⁇ M) or DMSO for the control incubations. Additionally, during each assay run control in- hibitors for each CYP isoform (furafylline for 1A2, ticlopidine for 2B6 and 2C19, gemfibrozil 1-O- ⁇ -glucuronide for 2C8, tienilic acid for 2C9, paroxetine for 2D6, and mifepristone for 3A4), and non-selective reversible inhibitor (atipamezole) for all CYP isoforms are tested.
  • the preincubation is initiated by the addition phosphate buffer (100mM, pH 7.4).
  • the prein- cubation plate is then moved into a thermostatic shaker set at 37°C.
  • an aliquot of the preincubation mixture is removed and diluted 10-fold with phosphate buffer containing the substrate cocktail or single probe in the case of CYP2C19 along with an additional aliquot of NADPH.
  • the secondary incubation progresses for 10 min or 25 min (CYP2C19) in a thermostatic shaker set at 37°C prior to quenching with ice-cold acetonitrile.
  • the metabolites of the probe CYP substrates are analyzed in the samples using LC/MS-MS technique.
  • cytochrome P450 inhibition single point assay was also used to test compounds disclosed in WO 2019/002606 A1 and WO 2020/128036 A1, namely Example 270 of WO 2019/002606 A1 (i.e. 8-amino-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)imi- dazo[1,2-a]pyrazine-2-carboxamide), Example 272 of WO 2019/002606 A1 (i.e.
  • the compounds of the present invention generally show a very low inhibitory activity against the different tested CYP-enzymes, whereas the compounds of WO 2019/002606 and WO 2020/128036 generally display a stronger in- hibitory activity against the different tested CYP-enzymes, in particular when it comes to CYP2C8 and CYP3A4. Accordingly, the compounds of the present invention generally exhibit a lower CYP-inhibition profile compared to the compounds of WO 2019/002606 and WO 2020/128036.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule (I) et des sels, stéréoisomères, tautomères, isotopologues ou N-oxydes de celui-ci. La présente invention concerne en outre, entre autres, l'utilisation d'un tel composé ou sel, stéréoisomère, tautomère, isotopologues ou N-oxyde de celui-ci en tant que médicament et une composition pharmaceutique comprenant ledit composé.
PCT/PL2023/050060 2023-07-17 2023-07-17 Modulateurs de l'adénosine a2a et du récepteur a2b Pending WO2025018901A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/PL2023/050060 WO2025018901A1 (fr) 2023-07-17 2023-07-17 Modulateurs de l'adénosine a2a et du récepteur a2b

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/PL2023/050060 WO2025018901A1 (fr) 2023-07-17 2023-07-17 Modulateurs de l'adénosine a2a et du récepteur a2b

Publications (1)

Publication Number Publication Date
WO2025018901A1 true WO2025018901A1 (fr) 2025-01-23

Family

ID=87696037

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/PL2023/050060 Pending WO2025018901A1 (fr) 2023-07-17 2023-07-17 Modulateurs de l'adénosine a2a et du récepteur a2b

Country Status (1)

Country Link
WO (1) WO2025018901A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058241A2 (fr) 2000-02-10 2001-08-16 New York University Antagonistes des recepteurs d'adenosine a2a pour le traitement et la prevention de la cirrhose hepatique et de la steatose hepatique
WO2006009698A2 (fr) 2004-06-17 2006-01-26 The Regents Of The University Of California Antagonisation d'un recepteur d'adenosine a2a pour ameliorer une ou plusieurs composantes du comportement addictif
US20070037033A1 (en) 2003-09-22 2007-02-15 Nissan Motor Co., Ltd. Separator for fuel cell, fuel cell stack, method for manufacturing separator for fuel cell, and fuel cell vehicle
WO2017098421A1 (fr) 2015-12-08 2017-06-15 Glaxosmithkline Intellectual Property Development Limited Composés benzothiadiazine
WO2019002606A1 (fr) 2017-06-30 2019-01-03 Selvita S.A. Modulateurs de 5,6-bicyclo-imidazo[1,2-a]pyrazine du récepteur a2a de l'adénosine
WO2020128036A1 (fr) 2018-12-21 2020-06-25 Ryvu Therapeutics S.A. Modulateurs du récepteur a2a de l'adénosine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058241A2 (fr) 2000-02-10 2001-08-16 New York University Antagonistes des recepteurs d'adenosine a2a pour le traitement et la prevention de la cirrhose hepatique et de la steatose hepatique
US20070037033A1 (en) 2003-09-22 2007-02-15 Nissan Motor Co., Ltd. Separator for fuel cell, fuel cell stack, method for manufacturing separator for fuel cell, and fuel cell vehicle
WO2006009698A2 (fr) 2004-06-17 2006-01-26 The Regents Of The University Of California Antagonisation d'un recepteur d'adenosine a2a pour ameliorer une ou plusieurs composantes du comportement addictif
WO2017098421A1 (fr) 2015-12-08 2017-06-15 Glaxosmithkline Intellectual Property Development Limited Composés benzothiadiazine
WO2019002606A1 (fr) 2017-06-30 2019-01-03 Selvita S.A. Modulateurs de 5,6-bicyclo-imidazo[1,2-a]pyrazine du récepteur a2a de l'adénosine
WO2020128036A1 (fr) 2018-12-21 2020-06-25 Ryvu Therapeutics S.A. Modulateurs du récepteur a2a de l'adénosine

Non-Patent Citations (36)

* Cited by examiner, † Cited by third party
Title
"Cancer Principles and Practice of Oncology", 15 February 2001, LIPPINCOTT WILLIAMS & WILKINS PUBLISHERS
"CAS", Database accession no. 35920-39-9
ALLARD ET AL., CURR OPIN PHARMACOL, vol. 29, August 2016 (2016-08-01), pages 7 - 16
ALLARD ET AL., IMMUNOL CELL BIOL, vol. 95, no. 4, April 2017 (2017-04-01), pages 333 - 339
BOREA PA ET AL., PHYSIOL REV, vol. 98, no. 3, 2018, pages 1591 - 1625
BOREA PA ET AL., TRENDS PHARMACOL SCI, vol. 37, no. 6, 2016, pages 419 - 434
BRUCE N, CRONSTEIN F1000 BIOL REPORTS, vol. 3, 2011, pages 21
CANCER IMMUNOL RES, vol. 3, no. 5, May 2015 (2015-05-01), pages 506 - 17
CARDENAS ET AL., LAB INVEST, vol. 93, no. 1, January 2013 (2013-01-01), pages 135 - 44
CAS , no. 35920-39-9
CAS, no. 58-61-7
CEKIC CLINDEN, J NAT REV IMMUNO, vol. 16, no. 3, 2016, pages 177 - 92
CHAN ET AL., ARTHRITIS & RHEUMATISM, vol. 54, no. 8, 2006, pages 2632 - 2642
COOPER ET AL.: "XI endogenous A2B adenosine receptor coupled to cyclic AMP generation in human embryonic kidney (HEK-293) cells", BRIT. J. PHARMACOL, vol. 122, pages 546, XP071163479, DOI: 10.1038/sj.bjp.0701401
DALL'LGNA ET AL., EXPERIMENTAL NEUROLOGY, 2007, pages 241 - 245
FREDHOLM ET AL., PROG NEUROBIOL, vol. 83, no. 24, 2007, pages 263 - 76
GAO ET AL.: "Novel short-acting A2A adenosine receptor agonists for coronary vasodilation: inverse relationship between affinity and duration of action of A2A agonists", J. PHARMACOL. EXP. THER, vol. 298, pages 209
GRENZ ET AL., ANTIOXID REDOX SIGNAL, vol. 15, no. 23, 2011, pages 2221 - 34
H KARMOUTY - QUINTANA, ARTHRITIS & REUMATOLOGY, vol. 70, no. 10, 2018, pages 1673 - 1684
J PHARMACOL EXP THER, vol. 308, no. 1, 2004, pages 358 - 66
J. CLIN. / ES7, vol. 116, 2006, pages 2173 - 2182
JENNER P, J NEUROL, vol. 247, no. 2, 2000, pages 1 143 - 50
KARMOUTY-QUINTANA ET AL., FASEB J, vol. 29, 2015, pages 50 - 60
KASAMA H ET AL., BMC CANCER, vol. 15, 2015, pages 563
KUROKOWA ET AL.: "Neuroscience Meeting Planner", 2009, SOCIETY FOR NEUROSCIENCE
LANNONE AM, J CANCER RES, vol. 4, no. 2, 1 March 2014 (2014-03-01), pages 172 - 81
LIU ET AL., JOURNAL OF NANOBIOTECHNOLOGY, vol. 17, no. 45, 2018
MORRELLO ET AL., ONCOIMMUNOLOGY, vol. 5, no. 3, March 2016 (2016-03-01), pages e1108515
POPOLI P ET AL., J NEUROSCI, vol. 22, 2002, pages 1967 - 75
SITKOVSKY TRENDS IMMUNOL, vol. 30, 2009, pages 102 - 8
SITKOVSKY, TRENDS IMMUNOL, vol. 30, 2009, pages 102 - 8
STONE TW ET AL., DRAG. DEV. RES, vol. 52, 2001, pages 323 - 330
TEITA ASANOMITSUKO TAKENAGA, J CLIN MED, vol. 6, no. 11, 2017, pages 104
TUITE P ET AL., J. EXPERT OPIN. INVESTIG. DRUGS, vol. 12, 2003, pages 1335 - 52
ZHAN-GUO GAO ET AL., INT J MOL SCI, vol. 20, no. 20, 2019, pages 5139
ZHOU Y ET AL., ONCOTARGET, vol. 8, no. 30, 2017, pages 48755 - 48768

Similar Documents

Publication Publication Date Title
US12377083B2 (en) Lysophosphatidic acid receptor antagonist and preparation method therefor
US11466013B2 (en) ERK inhibitor and use thereof
TWI356059B (en) Substituted bicyclolactam compounds
US10065962B2 (en) Amino pryan ring derivative and composition and use thereof
KR102707502B1 (ko) Apj 효능제로서의 2,4-디히드록시-니코틴아미드
US11020395B2 (en) Cycloalkyl substituted triazole compounds as agonists of the APJ receptor
CN111094265B (zh) 吡唑衍生化合物及其用途
WO2014191894A1 (fr) Dérivés imidazopyrrolidinone et leur utilisation dans le traitement de maladies
KR20210105375A (ko) Cdk 저해제로서의 대환식 화합물, 이의 제조 방법, 및 의약에서의 이의 용도
US12150941B2 (en) Process for preparing substituted pyrazolo[1,5-a]pyrazines
JP2023528073A (ja) Ｇｐｒ６５モジュレーターとしてのｎ－フェニルアミノカルボニル、ピリジノ－、ピリミジノ及びベンゾトロパン
EA027880B1 (ru) Ингибиторы bace
JP2019537587A (ja) 置換ピリド［３，４−ｂ］インドールおよび医薬品としてのその使用
US20220073476A1 (en) Triazole compounds and preparation method therefor and use thereof
WO2025018901A1 (fr) Modulateurs de l'adénosine a2a et du récepteur a2b
CN109535132A (zh) 2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用
US11149040B2 (en) Fused triazole agonists of the APJ receptor
JP7713954B2 (ja) 核内受容体に対して活性な化合物
TWI640524B (zh) Aminopyran ring derivatives and compositions and uses thereof
CN113943295B (zh) 吡咯并嘧啶类化合物及其用途
JP7713953B2 (ja) 核内受容体に対して活性な化合物
WO2025113806A1 (fr) Dérivés de thiophène et de thiazole utilisés en tant qu'inhibiteurs de wip1
WO2025172706A1 (fr) Composés modulant l'endonucléase flap (fen1)
WO2025172707A1 (fr) Composés hétérocycliques modulant l'exonucléase 1 (exo1)
CN113387989A (zh) 一种氨基吡喃环衍生物及其在医药上的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23757373

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: AU2023454063

Country of ref document: AU