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WO2025215153A1 - Prmt5 inhibitors - Google Patents

Prmt5 inhibitors

Info

Publication number
WO2025215153A1
WO2025215153A1 PCT/EP2025/059884 EP2025059884W WO2025215153A1 WO 2025215153 A1 WO2025215153 A1 WO 2025215153A1 EP 2025059884 W EP2025059884 W EP 2025059884W WO 2025215153 A1 WO2025215153 A1 WO 2025215153A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
methyl
heterocyclyl
same
oxidized
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/EP2025/059884
Other languages
French (fr)
Inventor
Adam RADZIMIERSKI
Aneta BOBOWSKA
Julia Krzywik
Martin Swarbrick
Pavlo LEBED
Szymon PALUCH
Marta OLSZAK-PLACHTA
Oleksander POPIKA
Daria SZUKIEL
Aleksandra WIECKOWSKA
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.)
Ryvu Therapeutics SA
Original Assignee
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 Ryvu Therapeutics SA filed Critical Ryvu Therapeutics SA
Publication of WO2025215153A1 publication Critical patent/WO2025215153A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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 compounds of formula (I) and salts, stereoisomers, atropisomers, rotamers, tautomers or N-oxides thereof that are useful as PRMT5 inhibitors.
  • the present invention further relates to the compounds of formula (I) for use as a medicament and to pharmaceutical compositions comprising said com- pounds.
  • Protein arginine methyltransferases are enzymes that catalyze the transfer of methyl groups from S-adeno- sylmethionine (SAM) to the arginine residues on histones and other proteins.
  • SAM S-adeno- sylmethionine
  • PRMT5 Protein methyltransferase 5
  • MMA omega-N monomethylarginine
  • SDMA symmetrical dimethylarginine
  • PRMT5 conjugated with WD-re- peat containing proteins forms methylosome, which regulates essential cellular functions via symmetric dimethylation of target proteins involved in regulation of gene expression, RNA splicing, signal trans- duction, metabolism and other functions (Koh, Bezzi and Guccione 2015; Wu et al., 2021). Homozygous deletions of p16/CDKN2a (cyclin dependent kinase inhibitor 2A) locus are prevalent in cancer and often involve co-deletion of adjacent genes.
  • p16/CDKN2a cyclin dependent kinase inhibitor 2A
  • Metabolic gene MTAP (methylthioadenosine phosphorylase) is localized at the 9p21 chromosome in the close proximity to p16/CDKN2A tumor-suppressor locus. Co-deletion of MTAP may be observed in 80-90% of all tumors harboring homozygous deletion of CDKN2A, which repre- sents 10 - 15% of all human tumors (Gao et al., 2013, Marjon et al., 2016; Firestone and Schramm 2017,).
  • MTAP a critical enzyme in the methionine salvage pathway
  • MTA methyl- thioadenosine
  • PRMT5 is a well-known essential gene regulating many cellular processes including cell growth and prolifera- tion, apoptosis and DNA damage response.
  • Conditional PRMT5 knockout or siRNA mediated knockdown stud- ies indicate that significant liabilities could be associated with inhibiting PRMT5 in normal tissues.
  • MTA-cooperative PRMT5 inhibitors could provide an improved therapeutic window, by preferential binding to MTA-bound PRMT5, which is enriched in MTAP deficient tumor cells.
  • compounds acting as PRMT5 inhibitors are useful for treating one or more diseases se- lected from the group consisting of cancer and pre-cancerous syndromes. Accordingly, there is a need for compounds acting as PRMT5 inhibitors, preferably for MTA-bound PRMT5, and thus provide a therapeutic impact in the treatment of diseases, in which the inhibition of PRMT5 is benefi- cial.
  • the above objects can be achieved by the compounds of formula (I) as defined herein as well as pharmaceu- tical compositions comprising the same, and by the medical uses thereof.
  • the present invention therefore relates to a compound of formula (I) or a salt, stereoisomer, atropisomer, rotamer, tautomer, or N-oxide thereof; wherein A is ; wherein the wavy line marks the connection to the N-atom of the remainder of the molecule; and wherein Ryvu Therapeutics S.A.
  • RVU305 4 R10945WO groups is independently unsubstituted or substituted with one or more, same or different substituents R Y ;
  • R 3a is H, or D;
  • RVU305 5 R10945WO heterocyclyl-C1-C2-alkyl wherein the aforementioned heterocyclyl rings independently comprise 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents R A3 ; R E1a , R E1b , R E2a , R E2b , R E3a , and R E3b are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; R N1 , R N2 and R N3 are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; R N4 is H, or C1-C4-alkyl; R N5 is H, or C1-C
  • RVU305 8 R10945WO heteroatom in the aforementioned carbocyclyl or heterocyclyl is independently unsubstituted or substi- tuted with one or more, same or different substituents R A2 ;
  • R S1 is C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C5-cycloalkyl, or NR N4 R N5 ;
  • R S2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NR N4 R N5 , C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and
  • E 1 is CR E1a , CHR E1a , or NR N1 ;
  • E 2 is O or N;
  • E 3 is CR E3a , CHR E3a , or NR N3 ; and wherein preferably R E1a , R E3a , R N1 , and R N3 are independently H, C1-C2-alkyl, or C1-C2-haloalkyl.
  • the compound is a compound of formula (Ia’) Ryvu Therapeutics S.A. RVU305 10 R10945WO ; and wherein preferably R E1a is H, CH3, or CF3; and R E3a is H.
  • X 3 is CH or CR X3 , wherein R X3 is halogen; X 4 is CH; and X 5 is CH; and wherein preferably X3 is CH.
  • a 2 is a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 n is 0, 1, or 2.
  • R 2a is H, C1-C2-alkyl, cyclopropyl, or cyclopropyloxy; and R 2b is H, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; and wherein preferably R 2a is H, or C1-C2-alkyl; and R2b is C1-C2-alkyl.
  • R A4 is halogen, C1-C2-alkyl, NR N4 R N5 , C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two R A1 , if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one substituent R A2 ; and R A2 is a 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are oxidized or n on-oxidized; and wherein the aforementioned heterocycly
  • RA1 is C1-C4-hydroxyalkyl, ORO, or a 6- or 7-membered saturated heterocyclyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and Ryvu Therapeutics S.A.
  • RVU305 13 R10945WO wherein the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two substituents R A2 ; and R A2 is C1-C2-alkyl, a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O and
  • R 1 is a 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein said carbocyclyl or heterocy- clyl is independently unsubstituted or substituted with one or more, same or different substituents R Y ; and wherein preferably R 1 is wherein B 1 is CH or N, and B 2 is CH or N.
  • R Y is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; and wherein preferably R Y is F, CN, CH 3 , CF 3 , or cyclopropyl.
  • the compound is a compound of formula (Ia’) Ryvu Therapeutics S.A.
  • RVU305 15 R10945WO lected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforemen- tioned heterocyclyl rings are independently unsubstituted or substituted with one or two, same or differ- ent substituents R A3 ;
  • R A4 is halogen, C1-C2-alkyl, NR N4 R N5 , C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NR N4 R N5 ,
  • the compound of formula (I) is selected from the group consisting of: N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-5-yl]pyridine-3-carboxamide; N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carbox- amide; N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyridine-3-carbox- amide; N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-
  • the compound of formula (I) is selected from the group consisting of: N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 6-[(3,3-difluoropiperidin-4-yl)oxy]-2- methylpyridin-3-yl ⁇ pyrimidine-5-carboxamide; N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 2-methyl-6-[3-(trifluoromethyl)piperazin-1- yl]pyridin-3-yl ⁇ pyrimidine-5-carboxamide; N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 6-[4-(2-hydroxyethyl)-3-(trifluoro
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceuti- cally effective amount of the compound of formula (I) as defined herein, and optionally a pharmaceutically ac- ceptable carrier, diluent or excipient.
  • the present invention relates to a compound of formula (I) as defined herein or a phar- maceutical composition comprising the same as defined herein for use in medicine.
  • the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein for use in modulating PRMT5, in particular (partial) inhibition of PRMT5.
  • the compound of the present invention or a pharmaceutical composition comprising the same is for use in the treatment of a disease selected from the group consisting of cancer and pre-cancerous syndromes.
  • the present invention relates to methods of treatment comprising the administration of a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein to a human or animal body.
  • a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein to a human or animal body.
  • the dashed lines between E 1 and E 2 and be- tween E 2 and E 3 denote that either a double bond is present between E 1 and E 2 , a double bond is present be- tween E 2 and E 3 , or no double bond is present between E 1 , E 2 and E 3 .
  • the compound of formula (I) may there- fore be a compound of formula (Ia), (Ib), or (Ic), preferably a compound of formula (Ia), as shown below: It is to be understood that the substituent meanings for E 1 , E 2 , and E 3 are in each case selected such that suitable valences of the atoms are realized.
  • E 1 is CR E1a R E1b , O, S, or NR N1
  • E 2 is CR E2a R E2b , O, S, or NR N2
  • E 3 is CR E3a R E3b , O, S, or NR N3 ; preferably that E 1 is CR E1a R E1b ; E 2 is O, S, or NR N2 ; E 3 is CR E3a R E3b ; more preferably that E 1 is CHR E1a ; E 2 is O; E 3 is CHR E3a .
  • E 1 is CR E1a R E1b , O, S, or NR N1 ;
  • E 2 is CR E2a or N;
  • E 3 is CR E3a or N; preferably that E 1 is NR N1 ;
  • E 2 is N;
  • E 3 is CR E3a .
  • this means that E 1 is CR E1a or N; Ryvu Therapeutics S.A.
  • RVU305 21 R10945WO E 2 is CR E2a or N; E 3 is CR E3a R E3b , O, S, or NR N3 ; preferably that E 1 is CR E1a ; E 2 is N; E 3 is NR N3 .
  • E 1 is CR E1a , CHR E1a , or NR N1 ; E 2 is O or N; E 3 is CR E3a , CHR E3a , or NR N3 .
  • the compound of formula (I) is a compound of formula (Ia’), (Ib’), or (Ic’), more preferably a compound of formula (Ia’), as shown below:
  • the following preferred embodiments regarding the remaining substituents of the tricyclic core moiety X 3 , X 4 , and X 5 are relevant.
  • each of X 3 , X 4 , and X 5 can be nitrogen (N), unsubstituted carbon (CH), or substituted car- bon (CR X3 , CR X4 , or CR X5 ). If X 3 , X 4 , or X 5 is a substituted carbon (CR X3 , CR X4 , or CR X5 ), the substituent at the carbon atom is represented by R X3 , R X4 , and R X5 , respectively.
  • none, one, or two of X 3 , X 4 , and X 5 are N, more preferably none or one of X 3 , X 4 , and X 5 are N, and even more preferably none of X 3 , X 4 , and X 5 is N.
  • X 4 is CH or CR X4 , preferably CH.
  • X 5 is CH or CR X5 , preferably CH.
  • X 3 is CH or CR X3 , preferably CH.
  • X 4 is CH or CR X4 and X 5 is CH or CR X5 , even more preferably X 4 and X 5 are CH.
  • X 4 and X 5 are CH and X 3 is CH or CR X3 , preferably CH. Therefore, in a preferred embodiment, in the compounds of formula (I), E 1 is CR E1a , CHR E1a , or NR N1 ; Ryvu Therapeutics S.A.
  • RVU305 22 R10945WO E 2 is O or N;
  • E 3 is CR E3a , CHR E3a , or NR N3 ;
  • X 3 is CH, CR X3 , or N;
  • X 4 is CH or CR X4 ;
  • X 5 is CH or CR X5 .
  • E 1 is CR E1a , CHR E1a , or NR N1 ;
  • E 2 is O or N;
  • E 3 is CR E3a , CHR E3a , or NR N3 .
  • X 3 is CH, CR X3 , or N;
  • X 4 is CH;
  • X 5 is CH.
  • E 1 is CR E1a , CHR E1a , or NR N1 ; E 2 is O or N; E 3 is CR E3a , CHR E3a , or NR N3 .
  • X 3 is CH or CR X3 ; X 4 is CH; X 5 is CH.
  • E 1 is CR E1a , CHR E1a , or NR N1 ; E 2 is O or N; E 3 is CR E3a , CHR E3a , or NR N3 .
  • X 3 is CH; X 4 is CH; X 5 is CH.
  • the compound of formula (I) is a compound of formula (Ia*), (Ib*), or (Ic*), preferably a compound of formula (Ia*) or (Ic*), more preferably a compound of formula (Ia*) as shown below: (Ic*) wherein preferably, X 3 is CH or CR X3 , more preferably CH. Ryvu Therapeutics S.A.
  • RVU305 23 R10945WO If present, in connection with the compounds of formula (I), as well as in connection with the compounds of formula (Ia), (Ib), or (Ic), and in connection with the compounds of formula (Ia’), (Ib’), or (Ic’), in particular in connection with the compounds of formula (Ia*), (Ib*), or (Ic*), the following preferred embodiments regarding the substituents R E1a , R E1b , R E2a , R E2b , R E3a , R E3b , R N1 , R N2 , R N3 , R X3 , R X4 , and R X5 are relevant.
  • R E1a , R E1b , R E2a , R E2b , R E3a , and R E3b are independently H, C1-C4-alkyl, or C1-C4-haloalkyl.
  • R E1a , R E1b , R E2a , R E2b , R E3a , and R E3b are independently H, C1-C2-alkyl, or C1-C2-haloalkyl.
  • R E1a , R E1b , R E2a , R E2b , R E3a , and R E3b are independently H or C1-C2-alkyl. In an even more preferred embodiment, R E1a , R E1b , R E2a , R E2b , R E3a , and R E3b are independently H or CH3.
  • R E1b , R E2b , and R E3b are H; and R E1a , R E2a , and R E3a are independently H, C1-C2-alkyl, or C1-C2-haloalkyl, preferably H or C1-C2-alkyl, more pref- erably H or CH3.
  • R E1a , R E2a , and R E3a are H, C1-C2-alkyl, or C1-C2-haloalkyl, preferably H or C1-C2-alkyl, more preferably H or CH3; and the other one of R E1a , R E2a , and R E3a as well as R E1b , R E2b , and R E3b , if present, are H.
  • R E1a , R E1b , R E2a , R E2b , R E3a , and R E3b are H.
  • R N1 , R N2 and R N3 are independently H, C1-C4-alkyl, or C1-C4-haloalkyl.
  • R N1 , R N2 and R N3 are independently H, C1-C2-alkyl, or C1-C2-haloalkyl.
  • R N1 , R N2 and R N3 are independently H or C1-C2-alkyl.
  • R N1 , R N2 and R N3 are independently H or CH3.
  • none or one of R E1a , R E2a , R E3a , R N1 , R N2 and R N3 is C1-C2- alkyl or C1-C2-haloalkyl, preferably C1-C2-alkyl, more preferably CH3; and R E1b , R E2b , R E3b , if present, as well as the remaining ones of RE1a, RE2a, RE3a, RN1, RN2 and RN3, if present, are H.
  • each of R E1a , R E2a , R E3a , R E1b , R E2b , R E3b , R N1 , R N2 and R N3 if pre- sent, is H.
  • R X3 , R X4 , and R X5 are independently halogen, C1-C2-alkyl, C1-C2-alkoxy, or C1-C2-haloalkyl.
  • R X3 , R X4 , and R X5 are independently halogen.
  • none, or only one or two of R X3 , R X4 , and R X5 are present. In a more preferred embodiment, none or only one of R X3 , R X4 , and R X5 is present. In a particularly preferred embodiment, none of R X3 , R X4 , and R X5 is present so that X 3 , X 4 and X 5 are N or CH, preferably CH.
  • R E1a , R E3a , R N1 , and R N3 are independently H or C1-C2-alkyl, more preferably H or CH3.
  • R E1a andR E3a are H or CH3, and R N1 and R N3 are CH3.
  • R E1a , R E3a are H or CH3, preferably R E1a is CH3 and R E3a is H.
  • the compound of formula (I) is a compound of formula (Ia**), preferably a compound of formula (Ia**-1) .
  • the compound of formula (I) is a compound of formula (Ia*-1), prefer- ably a compound of formula (Ia*-1*).
  • the compound of formula (I) is a compound of formula (Ia*-2), preferably a compound of formula (Ia*-2*). If the compound of formula (I) is a compound of formula (Ia**), preferably a compound of formula (Ia**-1), the compound may be a compound of formula (Ia**-A) or (Ia**-B), . In one embodiment, the compound of formula (I) is a compound of formula (Ia**-A), preferably a compound of formula (Ia**-1-A).
  • the compound of formula (I) is a compound of formula (Ia**-B), preferably a com- pound of formula (Ia**-1-B).
  • the compound of formula (I) is a compound of formula (Ia*-2), preferably a compound of formula (Ia*-2*)
  • the compound may be a compound of formula (Ia*-2-A) or (Ia*-2-B), ;
  • the compound of formula (I) is a compound of formula (Ia*-2-A), preferably a compound of formula (Ia*-2*-A).
  • the compound of formula (I) is a compound of formula (Ia*-2-B), preferably a com- pound of formula (Ia*-2*-B).
  • the compounds of formula (I) in connection with the compounds of formula (I), as well as in connection with the compounds of formula (Ia), (Ib), and (Ic), and in connection with the compounds of formula (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), and (Ic*), in particular in connection with the compounds of formula (Ia**), (Ia**-1), (Ia*-1), (Ia*-1*), (Ia*-2), (Ia*-2*), (Ia**-A), (Ia**-B), (Ia**-1-A), (Ia**-1-B), (Ia*-2-A), (Ia*-2-B), (Ia*-2*-A), and (Ia*-2*-B), the following preferred embodiments regard- ing the substituent R 1 are relevant.
  • R 1 is NR N4 R N5 , C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-alkyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, or heter- ocyclyloxy-C1-C2-alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or
  • R 1 is C1-C3-alkyl, C1-C3-alkoxy, C1-C2-alkoxy-C1-C2-alkyl, C1-C3-haloalkyl, C1-C2-aminoalkyl, C1-C2-amino- alkyl, 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, cyclopropyl-C1-C2-alkyl, cyclopropyloxy-C1-C2-alkyl, or 5- to 6-membered aromatic heterocyclyl-C1-C2- alkyl, wherein the aforementioned heterocyclyl rings comprise one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- d ized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is inde- pendently unsubsti
  • RVU305 27 R10945WO R Z is halogen, CN, C1-alkyl, C1-haloalkyl, or C1-alkoxy; preferably halogen or C1-alkyl; and wherein more preferably R Y is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably R Y is F, CN, CH3, CF3, or cyclopropyl, even more preferably R Y is CN, cyclopropyl, or CF3, even more preferably R Y is cyclopropyl or CF3.
  • R 1 is C1-C2-alkyl, or a 5- or 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi- tutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substi- tuted with one or more, same or different substituents R Y ; wherein R Y is as defined above in connection with the compounds of formula (I), and wherein preferably R Y is halogen, CN, C 1 -C 3 -alkyl, C 1 -C 2 -alkoxy, C 1 -C 2 -haloalkyl, or 3- to 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl rings comprise one or more, same or different
  • R 1 is a 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein the aforementioned rings are independently unsubstituted or substituted with one or more, preferably one, same or different substit- u ents RY; wherein R Y is as defined above in connection with the compounds of formula (I), and wherein preferably R Y is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably R Y is F, CN, CH3, CF3, or cyclopropyl, even more preferably R Y is CN, cyclopropyl, or CF3, even more preferably R Y is cyclopropyl or CF3.
  • R 1 is pyridinyl or pyrimidinyl; wherein the pyridinyl or pyrimidinyl is independently unsubstituted or substituted with one or more, pref- erably one, same or different substituents R Y ; wherein R Y is as defined above in connection with the compounds of formula (I), and wherein preferably R Y is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably R Y is F, CN, CH3, CF3, or cyclopropyl, even more preferably R Y is CN, cyclopropyl, or CF3, even more preferably R Y is cyclopropyl or CF3.
  • R 1 is pyridinyl; wherein the pyridinyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents selected from F, CN, CF3, or cyclopropyl.
  • R 1 is pyrimidinyl; wherein the pyrimidinyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents selected from F, CN, CF3, or cyclopropyl, preferably cyclopropyl.
  • R 1 is pyridinyl substituted with one substituent selected from F, CN, CF3, or cyclopropyl.
  • R 1 is pyrimidinyl substituted with one substituent selected from F, CN, CF3, or cyclopropyl, preferably cyclo- propyl.
  • R 1 is wherein B 1 is CH or N, and B 2 is CH or N wherein R Y is as defined above in connection with the compounds of formula (I), and wherein preferably R Y is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably R Y is F, CN, CH 3 , CF 3 , or cyclopropyl, even more preferably R Y is CN, cyclopropyl, or CF3, even more preferably R Y is cyclopropyl or CF3; particularly preferably Ryvu Therapeutics S.A.
  • R Y is cyclopropyl.
  • R 1 is wherein with the compounds of formula (I), and wherein preferably R Y is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably R Y is F, CN, CH3, CF3, or cyclopropyl, even more preferably R Y is CN, cyclopropyl, or CF3, even more preferably R Y is cyclopropyl or CF3; particularly preferably R Y is cyclopropyl.
  • R 1 is wherein R Y is halogen, CN, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, or cyclopropyl; more preferably R Y is F, CN, CH3, CF3, or cyclopropyl, even more preferably R Y is CN, cyclopropyl, or CF3, even more preferably R Y is cyclopropyl or CF3; particularly preferably R Y is cyclopropyl.
  • R 1 is ; wherein R Y is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably R Y is F, CN, CH3, CF3, or cyclopropyl, even more preferably Ryvu Therapeutics S.A. RVU305 30 R10945WO R Y is CN, cyclopropyl, or CF3, even more preferably R Y is cyclopropyl or CF3; particularly preferably R Y is cyclopropyl. In one particularly preferred embodiment, R 1 is .
  • the moiety A may therefore be a moiety (A-1), (A-2), (A-3), (A-4), (A-5), or (A-6), preferably (A-1) or (A-5), more preferably (A-1), as shown below:
  • A is selected from the group consisting of (A-1), (A-2*), (A-3*), (A-4*), (A-5), and (A-6*), preferably (A-1) and (A-5*), more preferably (A-1), as shown below:
  • A is the following moiety wherein Y 1 , A 1 , and R 4a are as defined for the compound of formula (I), preferably as defined in the preferred embodiments below.
  • R4a is H.
  • the substituent meanings for Y 1 are in each case selected such that suitable valences of the atoms are realized.
  • A is the moiety (A-1)
  • A is the moiety (A-5), Y 1 is CR 2a , preferably Y 1 is CR 2a or NR 2b .
  • A is selected from the group consisting of (A-1*) and (A-1**), wherein compound of formula (I), preferably as defined in the pre- ferred embodiments below.
  • R 4a is H.
  • R 4a is H
  • R 2a is H or CH3
  • R 2b is CH3.
  • a 1 is phenyl, pyridinyl, or pyrazolyl, wherein each substi- tutable atom in the aforementioned rings other than the carbon or nitrogen atom(s) shown in the structures above is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A1 .
  • Ryvu Therapeutics S.A. RVU305 34 R10945WO A 1 is phenyl, pyridinyl, or pyrazolyl, wherein each substitutable atom in the aforementioned rings other than Y 1 and Y 2 is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A1 ; wherein preferably Y 1 is CR 2a , N, or NR 2b ; and Y 2 is CR 4a or N, more preferably Y 1 is CR 2a , N, or NR 2b ; and Y 2 is CH or N, even more preferably Y 1 is CR 2a or NR 2b ; and Y 2 is CH.
  • a 1 is phenyl, wherein the phenyl is independently unsubstituted or substituted with one or more, prefera- bly one or two, same or different substituents R A1 ; wherein Y 1 is CR 2a ; and Y 2 is CR 4a .
  • a 1 is pyridinyl, wherein the pyridinyl is independently unsubstituted or substituted with one or more, pref- erably one, same or different substituents R A1 ; wherein preferably Y 1 is CR 2a ; and Y 2 is CR 4a or N, more preferably Y 1 is CR 2a ; and Y 2 is CH or N, even more preferably Y 1 is CR 2a ; and Y 2 is CH.
  • a 1 is pyrazolyl, wherein the pyrazolyl is independently unsubstituted or substituted with one or more, pref- erably one, same or different substituents R A1 ; wherein preferably Y 1 is CR 2a or NR 2b ; and Y 2 is CR 4a , more preferably Y 1 is CR 2a or NR 2b ; and Y2 is CH.
  • A is selected from the group consisting of Ryvu Therapeutics S.A.
  • RVU305 35 R10945WO more preferably from the group consisting of ; , , , ; wherein in the embodiments defined above, n is 0, 1, or 2; and A 2 is a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 preferably A 2 is a fused thiazolyl, imidazolyl, or pyrazolyl; more preferably A 2 is a fused thiazolyl.
  • RVU305 36 R10945WO In connection with the compounds of formula (I), as well as in connection with the compounds of formula (Ia), (Ib), and (Ic), and in connection with the compounds of formula (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), (Ic*), (Ia**), (Ia**-1), (Ia*-1), (Ia*-1*), (Ia*-2), (Ia*-2*), (Ia**-A), (Ia**-B), (Ia**-1-A), (Ia**-1-B), (Ia*-2-A), (Ia*-2-B), (Ia*-2*-A), and (Ia*- 2*-B), in particular in connection with the preferred embodiments regarding R 1 and A or A 1 defined above, pref- erably, A 1 is unsubstituted or substituted with one, two, or three, same or different substituents R A1 , more pref- erably A 1 is unsubstit
  • R 2a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents R A3 .
  • R 2a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy.
  • R 2a is H, C1-C2-alkyl, cyclopropyl, or cyclopropyloxy. In an even more preferred embodiment, R 2a is H or C1-C2-alkyl. In an even more preferred embodiment, R 2a is H or CH3. In one particularly preferred embodiment, R 2a is H. In another particularly preferred embodiment, R 2a is CH3.
  • R 2b is H, C1-C2-alkyl, C1-C2-haloalkyl, or a 3- or 4-membered saturated carbocyclyl.
  • R 2b is H, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl.
  • R 2b is C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl.
  • R 2b is C1-C2-alkyl.
  • R 2b is CH3.
  • R 4a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents R A3 .
  • R 4a is H.
  • R 4b is H, C1-C2-alkyl, C1-C2-haloalkyl, or a 3- or 4-membered saturated carbocyclyl.
  • R 4b is H, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl.
  • R 4b is C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl.
  • R 4b is C1-C2-alkyl.
  • R 4b is CH3.
  • A is selected from the group consisting of Ryvu Therapeutics S.A.
  • RVU305 38 R10945WO group more preferably from the group consisting of ; wherein in the embodiments defined above, n is 0, 1, or 2; and A 2 is a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 preferably A 2 is a fused thiazolyl, imidazolyl, or pyrazolyl; more preferably A 2 is a fused thiazolyl.
  • RVU305 41 R10945WO aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused 5- or 6-membered aro- matic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, same or different substituents R A2 .
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, OR O , cyclopropyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S,
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, OR O , cyclopropyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one o r more, preferably one or two, same or different substituents RA4; or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub
  • R A1 is C1-C2-alkyl, C1-C4-hydroxyalkyl, OR O , or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; wherein the aforementioned heterocyclyl ring is preferably piperidine, piperazine, or 1,4-diazepane; and wherein the aforementioned heterocyclyl ring is inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, where
  • R A1 is C1-C2-alkyl, preferably CH3.
  • a 1 is substituted with two or more, preferably two substituents R A1 ; wherein two R A1 together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, pref- erably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsubstituted or sub- stituted with one or two substituents R A2 .
  • R A1 is a 6- or 7-membered saturated heterocyclyl, preferably piperidine, piperazine, or 1,4-diazepane, wherein the aforementioned heterocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocy- clyl ring is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 .
  • R A1 is a 6-membered saturated heterocyclyl, preferably piperidine or piperazine, wherein the aforemen- tioned heterocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 .
  • R A1 is a 7-membered saturated heterocyclyl, preferably 1,4-diazepane, wherein the aforementioned heter- ocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, preferably one or two, same or different substituents R A4 .
  • R A1 is C1-C4-hydroxyalkyl or OR O .
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two R A1 , if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one substituent R A2 .
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one substituent R A2 .
  • R A1 is C1-C2-alkyl; or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one substituent R A2 .
  • R A1 is C1-C2-alkyl, preferably CH3.
  • a 1 is substituted with two or more, preferably two substituents R A1 ; wherein two R A1 together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, pref- e rably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsubstituted or sub- stituted with one substituent R A2 .
  • R A1 is C1-C4-hydroxyalkyl, OR O , or a 6- or 7-membered saturated heterocyclyl, wherein the aforemen- t ioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; Ryvu Therapeutics S.A.
  • RVU305 44 R10945WO or two R A1 if present, together with the atoms to which they are bonded form a fused 5- or 6-membered aro- matic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A2 .
  • R A1 is C1-C4-hydroxyalkyl, OR O , or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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, wherein the aforementioned heterocyclyl ring is preferably a fused
  • R A1 is C1-C4-hydroxyalkyl, OR O , or a 6- or 7-membered saturated heterocyclyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents R A2 .
  • R A1 is C1-C4-hydroxyalkyl, OR O , piperidine, piperazine, or 1,4-diazepane, wherein the aforementioned het- erocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents R A2 .
  • R A1 is a 6- or 7-membered saturated heterocyclyl, preferably piperidine, piperazine, or 1,4-diazepane, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocy- clyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same o r different substituents RA4.
  • Ryvu Therapeutics S.A is a 6- or 7-membered saturated heterocyclyl, preferably piperidine, piperazine, or 1,4-diazepane, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocy- clyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same
  • RVU305 45 R10945WO R A1 is a 6-membered saturated heterocyclyl, preferably piperidine or piperazine, wherein the aforemen- tioned heterocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 .
  • R A1 is a 7-membered saturated heterocyclyl, preferably 1,4-diazepane, wherein the aforementioned heter- ocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, preferably one or two, same or different substituents R A4 .
  • R A1 is C1-C4-hydroxyalkyl or OR O .
  • a 1 is substituted with two or more, preferably two substituents R A1 ; wherein two R A1 together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, pref- erably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsubstituted or sub- stituted with one or two substituents R A2 .
  • R A2 is C1-C2-alkyl, NR N6 R N7 , a 3- to 6-membered saturated carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2- a lkyl, or a 5- to 7-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or dif- Ryvu Therapeutics S.A.
  • R A2 is C1-C2-alkyl, or a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two, same or different heteroatoms se- lected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforemen- tioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents R A3 .
  • R A2 is C1-alkyl, piperidinyl, or piperidinyl-C1-C2-alkyl, wherein the piperidinyl is independently unsubstituted or substituted with one or two, preferably one, same or different substituents R A3 .
  • R A2 is piperidinyl, wherein the piperidinyl is unsubstituted or substituted with one or two, preferably one, same or different substituents R A3 .
  • R A2 is piperidinyl, wherein the piperidinyl is substituted with one or two, preferably one, same or different substituents selected from C1-C2-alkyl, preferably CH3.
  • R A4 is a 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents R A3 .
  • R A4 is piperidinyl, wherein the piperidinyl is unsubstituted or substituted with one or two, preferably one, same or different substituents R A3 .
  • R A4 is piperidinyl, wherein the piperidinyl is substituted with one or two, preferably one, same or different substituents selected from C1-C2-alkyl, preferably CH3.
  • R A4 is halogen, C1-C2-haloalkyl, or C1-C2-hydroxyalkyl.
  • R A4 is F, CF3, or C1-C2-hydroxyalkyl.
  • R A3 , R C2 , R N6 , R N7 , R O , and R S2 are particularly relevant.
  • R C2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NR N4 R N5 , C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned g roups is independently unsubstituted or substituted with one or more, same or different substituents R A3 .
  • R C2 is C1-C2-hydroxyalkyl, C1-C2-alkyl-NR N4 R N5 , or a 5- or 6-membered saturated carbocyclyl or heterocy- clyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroa- t oms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is inde- pendently unsubstituted or substituted with one or more, same or different substituents R A3 .
  • Ryvu Therapeutics S.A is C1-C2-hydroxyalkyl, C1-C2-alkyl-NR N4 R N5 , or a 5- or 6-membered saturated carbocyclyl or heterocy- clyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroa
  • R C2 is a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R A3 .
  • R C2 is C1-C2-hydroxyalkyl or C1-C2-alkyl-NR N4 R N5 .
  • R C2 is C1-C2-hydroxyalkyl.
  • R N6 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NR N4 R N5 , C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R A3 .
  • R N6 is H or C1-C2-alkyl. In a more preferred embodiment, R N6 is H or CH3.
  • R N7 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NR N4 R N5 , C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstitute
  • R N7 is C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different h eteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R A3 .
  • R N7 is C1-C2-alkyl, C1-C2-hydroxyalkyl, C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or h eterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R A3 .
  • R N7 is C1-C2-alkyl, C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R A3 .
  • R O is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NR N4 R N5 , C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R A3 .
  • R O is H, C1-C2-hydroxyalkyl, C1-C2-alkyl-NR N4 R N5 , cyclopropyl, or a 5- or 6-membered saturated heterocy- clyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R A3 .
  • R O is C1-C2-hydroxyalkyl, C1-C2-alkyl-NR N4 R N5 , cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl ring is inde- pendently unsubstituted or substituted with one or more, same or different substituents R A3 .
  • R O is C1-C2-hydroxyalkyl, C1-C2-alkyl-NR N4 R N5 , cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl ring is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A3 .
  • R O is C1-C2-hydroxyalkyl, C1-C2-alkyl-NR N4 R N5 , cyclopropyl, piperidine, or pyrrolidine-C1-C2-alkyl; wherein the aforementioned cyclopropyl, piperidine, or pyrrolidine is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A3 .
  • R S2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NR N4 R N5 , C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or Ryvu Therapeutics S.A.
  • R A3 is C1-C2-alkyl or N(CH3)2.
  • R A3 is C1-C2-alkyl .
  • R A3 is CH3.
  • RVU305 51 R10945WO aforementioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized; and wherein the aforementioned rings are independently unsubstituted or sub- stituted with one or more, preferably one or two, same or different substituents R A3 ;
  • R A4 is halogen, C1-C2-alkyl, NR N6 R N7
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NR N6 R N7 , OR O , cyclo- propyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected
  • R A4 is halogen, C1-C2-alkyl, NR N4 R N5 , C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NR N4 R N5 , C
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, OR O , cyclopropyl, or a 6- or 7-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned het- erocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, OR O , cyclopropyl, or a 6- or 7-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned het- erocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are independently unsub- stituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, OR O , cyclopropyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or p yrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub-
  • RVU305 54 R10945WO aforementioned cyclopropyl or heterocyclyl rings are independently unsubstituted or substituted with one or more, same or different substituents R A3 ;
  • R N4 is H, or C1-alkyl;
  • R N5 is H, or C1-alkyl;
  • R A4 is halogen, C1-C2-haloalkyl, or C1-C2-hydroxyalkyl.
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, OR O , cyclopropyl, piper- idine, piperazine, or 1,4-diazepane, wherein the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents R A2 ; and R A2 is C1-alkyl, piperidine, or pipe
  • RVU305 55 R10945WO rings are independently unsubstituted or substituted with one or more, same or different substituents R A3 ;
  • R A4 is C1-C2-alkyl, NR N6 R N7 , or a 3- to 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring independently 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 the aforementioned rings are independently unsubstituted or substituted with one or more, same or different substituents R A3 ;
  • R N6 is H, or C1-C2-alkyl;
  • R N7 is C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the afore- mentioned heterocyclyl ring comprises one or more, same or
  • RVU305 56 R10945WO R C2 is a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R A3 ; and wherein preferably R A3 is C1-C2-alkyl or N(CH3)2, more preferably C1-C2-alkyl, particularly preferably CH3.
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two R A1 , if present, together with the atoms to which they are bonded form a fused 5-membered aromatic h eterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one substituent R A2 ; and Ryvu Therapeutics S.A.
  • RVU305 57 R10945WO R A2 is a 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents R A3 ; and wherein preferably R A3 is C1-C2-alkyl or N(CH3)2, more preferably C1-C2-alkyl, particularly preferably CH3.
  • R A1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one substituent R A2 ; and R A2 is a 6-membered saturated heterocyclyl, preferably piperidinyl, wherein the aforementioned heterocy- clyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N- atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with
  • R A1 is C1-C2-alkyl; or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one substituent R A2 ; and R A2 is a 6-membered saturated heterocyclyl, preferably piperidinyl, wherein the aforementioned heterocy- clyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N- atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents R A3 ; and wherein preferably R A3 is C1-C2-alkyl or N(
  • R A1 is C1-C2-alkyl, preferably CH3.
  • a 1 is substituted with two or more, preferably two substituents R A1; wherein two R A1 together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, pref- erably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsubstituted or sub- stituted with one substituent R A2 ; and R A2 is a 6-membered saturated heterocyclyl, preferably piperidinyl, wherein the aforementioned heterocy- c lyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N- atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two
  • R A3 is C1-C2-alkyl or N(CH3)2, more preferably C1-C2-alkyl, particularly preferably CH3.
  • R A1 is C1-C4-hydroxyalkyl, OR O , or a 6- or 7-membered saturated heterocyclyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms
  • R A1 is C1-C4-hydroxyalkyl, OR O , or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- s tituents RA4; or two R A1 , if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstit
  • RVU305 59 R10945WO independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are unsub- stituted or substituted with one or two, same or different substituents R A3 ;
  • R O is C1-C2-hydroxyalkyl, C1-C2-alkyl-NR N4 R N5 , cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl rings are independently unsubstituted or substituted with one or more, same or different substituents R A3 ;
  • R N4 is H, or C1-alkyl;
  • R N5 is H, or C1-alkyl;
  • R A3 is halogen,
  • R A1 is C1-C4-hydroxyalkyl, OR O , or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents R A4 ; or two R A1 , if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents R A2 ; and R A2 is C1-C
  • R A1 is C1-C4-hydroxyalkyl, OR O , piperidine, piperazine, or 1,4-diazepane, wherein the aforementioned het- erocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R A4 ; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents R A2 ; and Ryvu Therapeutics S.A.
  • RVU305 60 R10945WO R A2 is piperidine or piperidine-C1-C2-alkyl; wherein the aforementioned piperidine is independently unsub- stituted or substituted with one or two, same or different substituents R A3 ;
  • R O is C1-C2-hydroxyalkyl, C1-C2-alkyl-NR N4 R N5 , cyclopropyl, piperidine, or pyrrolidine-C1-C2-alkyl; wherein the aforementioned cyclopropyl, piperidine, or pyrrolidine is independently unsubstituted or substituted with one or more, same or different substituents R A3 ;
  • R N4 is H;
  • R N5 is H, or C1-alkyl;
  • R A1 , R A2 , and R A3 may vary depending on whether R A1 , R A2 , or R A3 is attached to a carbon atom or heteroatom of the ring.
  • R A1 , R A2 , or R A3 is at- tached to a heteroatom, such as N
  • R A1 , R A2 , or R A3 is preferably a substituent that is attached to said het- eroatom, such as N, via a carbon atom.
  • A is a moiety selected from the group consisting of In even more preferred embodiments, A is a moiety selected from the group consisting of . In particularly preferred embodiments, A the group consisting of and . In other more preferred embodiments, A is a moiety selected from the group consisting of Ryvu Therapeutics S.A. RVU305 62 R10945WO .
  • the compound of formula (I) is a compound selected from the group consisting of: N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-5-yl]pyridine-3-carboxamide; N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carbox- amide; N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyridine-3-carbox- amide; N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinol
  • the compound of formula (I) is a compound selected from the group consisting of: N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 6-[(3,3-difluoropiperidin-4-yl)oxy]-2- methylpyridin-3-yl ⁇ pyrimidine-5-carboxamide; N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 2-methyl-6-[3-(trifluoromethyl)piperazin-1- yl]pyridin-3-yl ⁇ pyrimidine-5-carboxamide; N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 6-[4-(2-hydroxyethyl)-3-
  • the term “compound(s) of the present invention” is to be understood as equivalent to the term “compound(s) according to the invention", and also covers a salt, stereoisomer, rotamer, atropisomer, tautomer or N-oxide thereof.
  • the compounds according to the invention may be amorphous or may exist in one or more different crystal- line states (polymorphs), which may have different macroscopic properties such as stability or show different biological properties such as activities.
  • the present invention relates to amorphous and crystalline forms of compounds of formula (I), mixtures of different crystalline states of the compounds of formula (I), as well as amorphous or crystalline salts thereof.
  • Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the US FDA 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 Ryvu Therapeutics S.A. RVU305 67 R10945WO compounds according to the invention have a basic functionality, or by reacting acidic compounds according to the invention with a suitable base.
  • Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium, sodium and po- tassium, 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 (NH4 + ) and substituted ammonium in which one to four of the hydrogen atoms are replaced by C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkoxy-C1-C4-alkyl, phenyl or benzyl.
  • substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trime- thylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltri- ethylammonium, furthermore the cations of 1,4-piperazine, meglumine, benzathine and lysine.
  • Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihydrogenphos- phate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophos- phate, benzoate, and the anions of C1-C4-alkanoic acids, preferably formate, acetate, propionate and butyrate, furthermore lactate, gluconate, and the anions of poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, furthermore sulfonate anions such as besylate (benzenesulfonate), tosylate (p-tol- uenesulfonate), napsylate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanes
  • the compounds according to the invention can be formed by reacting compounds according 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 cen- tres of chirality, including axial chirality providing different stereoisomers.
  • the invention provides both, pure en- antiomers or pure diastereomers, of the compounds according to the invention, and their mixtures, including racemic mixtures.
  • a chiral centre of the compounds according to the invention may be present in substituent R 1 .
  • Suitable compounds according to the invention also include all possible geometrical stereoisomers (cis/trans isomers or E/Z isomers) and mixtures thereof.
  • E/Z- isomers may be present with respect to, e.g., an alkene, carbon-nitrogen double-bond or amide group.
  • suitable compounds according to the invention also include conformational stereoisomers (conform- ers), which refers to isomers that interconvert by rotations about single bonds. Rotations about single bonds involve overcoming a rotational energy barrier to interconvert one conformer to another. If the energy barrier is high enough, rotation about the single bond can be hindered so that there is no free rotation and the compound exists as a rotational isomer (rotamer) for a relatively long time.
  • the rota- mers are termed atropisomers.
  • atropisomers refers to conformational stereoi- somers (conformers) resulting from hindered rotation about a single bond, where the energy differences due to steric strain or other contributors create a barrier to rotation, which is high enough to allow for the isolation of the conformers.
  • rotational isomers (rotamers) as used herein also includes atropisomers.
  • Rotational isomers in particular atropisomers, do not require an asymmetric atom but an axis of chirality and thus represent a form of axial chirality. Determining the axial stereochemistry can be accomplished through the use of a Newman projection along the axis of hindered rotation.
  • the four substituents are first assigned priority based on Cahn–Ingold–Prelog priority rules. Starting with the substituent of highest priority on the closest atom in the Newman projection and moving along the shortest path to the substituent of highest priority on the other Ryvu Therapeutics S.A. RVU305 68 R10945WO atom, the absolute configuration is assigned P or ⁇ for clockwise and M or ⁇ for counterclockwise.
  • all four groups can be ranked by Cahn–Ingold–Prelog priority rules, with overall priority given to the sub- stituents on the "front" atom of the Newman projection, i.e., the substituents on the end of the single bond, which is closest in the Newman projection.
  • the two configurations are termed Ra and Sa in analogy to the tradi- tional R/S for a traditional tetrahedral stereocenter as exemplarily illustrated below in case of A having a higher priority than B, and C having a higher priority than D by Cahn–Ingold–Prelog priority rules.
  • rotational isomer rotamer
  • the invention provides both, pure rotational isomers (rota- mers) or atropisomers of the compounds according to the invention, and their mixtures, including racemic mix- tures.
  • rotational isomers (rotamers) of the compounds of the present invention may be present with respect to a restricted rotation about the C-N amide bond and/or a restricted rotation about the C-N bond between the tertiary amide nitrogen and the A moiety.
  • Example 6 For illustration only, exemplary rotational isomers (rota- mers) of the compounds according to the invention potentially resulting from a restricted rotation about the C-N amide bond and/or a restricted rotation about the C-N bond between the tertiary amide nitrogen and the A moi- ety of the compounds are shown below for Example 6:
  • Example 6 For Example 6, a mixture of two rotational isomers (rotamers) resulting from a restricted rotation about the C- N amide bond is observed with NMR analysis at room temperature, but the barrier to rotation is too low to iso- late the rotational isomers (rotamers) so that no stable atropisomers are observed for Example 6.
  • the rotational isomers (rotamers) of the compounds accord- ing to the invention can be separated and isolated and can thus be termed atropisomers.
  • the barrier to rotation about the C-N bond between the tertiary amide nitrogen Ryvu Therapeutics S.A. RVU305 69 R10945WO and the A moiety of the compounds according to the invention may be high enough to form atropisomers, which can be separated and isolated.
  • Atropisomers may, e.g., be formed if the A moiety of the compounds of the present invention is substituted in ortho position on both sides of the carbon connected to the tertiary amide nitrogen of the remainder of the molecule.
  • the barrier to rotation about the C-N amide bond may typically not be high enough to form at- ropisomers.
  • the compounds of the present invention may be present as a mixture of two rotational isomers (rotamers) resulting from one restricted bond rotation, such as a mixture of two rotational iso- mers (rotamers) resulting from a restricted rotation about the C-N amide bond as shown above for Example 6.
  • the mixture may be racemic (1 to 1 mixture) or one of the rotational isomers (rotamers) in the mixture may be enriched over the other rotational isomer (rotamer). If the barrier to rotation is high enough to form atropiso- mers, the two atropisomers may be separated and isolated. Further, the compounds of the present invention may be present as a mixture of stereoisomers resulting from more than one restricted bond rotation. For exam- ple, if there are two restricted bond rotations, there may be four rotational isomers (rotamers), which can be grouped into two “diastereoisomer-like” components that are distinguishable by NMR analysis.
  • diastereoisomer-like mixture such a mixture is referred to as “diastereoisomer-like” mixture and the stereoisomers therein which are distinguishable by NMR analysis are referred to as “diastereoisomer-like” components.
  • the two atropisomers may be separated and isolated. Each of the separated and isolated atropisomers may then be present as a mixture of two rota- tional isomers (rotamers) resulting from the second restricted bond rotation, e.g.
  • a “diastereoisomer-like” mixture with “diastereoisomer-like” distinguishable components may also result if the compounds of the present invention contain a combination of one or more restricted bond rota- tion(s) and one or more asymmetric atom(s) (i.e., chiral centres). For example, there may be one chiral centre resulting in two stereoisomers, and additionally at least one restricted bond rotation, e.g., the restricted rotation about the C-N amide bond, resulting in two additional stereoisomers, i.e. rotational isomers (rotamers).
  • a com- pound of the present invention may thus be present as a mixture of four stereoisomers (or even 8 stereoiso- mers in case of two restricted bond rotations), which can be grouped into “diastereoisomer-like” components that are distinguishable by NMR analysis. If, e.g., the stereoisomers resulting from the chiral centre are sepa- rated and isolated, they may then be present as a mixture of the rotational isomers (rotamers) resulting from the additional restricted bond rotation(s), e.g. the rotation about the C-N amide bond.
  • Atropisomers may be classified according to their stereochemical stabilities as mentioned in doi: 10.4155/fmc-2017-0152: Class 1 atropisomers possess barriers to rotation around the chiral axis of ⁇ 84 kJ/mol(20 kcal/mol) and racemize on the minute or faster time scale at room temperature; class 2 atropisomers possess a barrier to rotation between 84 and 117 kJ/mol (20–28 kcal/mol) and racemize on the hour to month timescale at room temperature; and class 3 atropisomers possess a barrier to rotation>117 kJ/mol (28 kcal/mol) and racemize on the year or greater timescale at room temperature.
  • class 2 and class 3 atropisomers are separable.
  • class 2 or class 3 atropisomers of the com- pounds of the invention may be present, if the A moiety of the compounds of the present invention is substi- tuted in ortho position on both sides of the carbon connected to the tertiary amide nitrogen of the remainder of the molecule.
  • Tautomers may be formed, if a substituent is present at the compound of formula (I), which allows for the for- mation of tautomers such as keto-enol tautomers, imine-enamine tautomers, amide-imidic acid tautomers or the like.
  • N-oxide includes any compound of the present invention which has at least one tertiary nitrogen atom that is oxidized to an N-oxide moiety. Any formula or structure given herein, including compounds of formula (I), is also intended to represent unla- beled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom hav- ing a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 CI and 125 I.
  • radioactive isotopes such as 3 H, 13 C and 14 C provide isotopically labelled compounds useful in meta- bolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the disclosure includes compounds of formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME).
  • Substitution with heavier isotopes such as deuterium may afford certain therapeutic ad- vantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage re- quirements and/or an improvement in therapeutic index.
  • Such compounds are synthe- sized by means well known in the art, for example by employing starting materials in which one or more hydro- gens have been replaced by deuterium.
  • concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • substituted means that a hydrogen atom bonded to a designated atom is re- placed with a specified substituent, provided that the substitution results in a stable or chemically feasible com- pound.
  • a substituted atom may have one or more substituents and each substitu- ent is independently selected.
  • substituted when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent.
  • substituents When it is referred to certain atoms or moieties being substituted with “one or more” substituents, 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.
  • 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-dimethylpro- pyl, 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-ethyl- butyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-
  • haloalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, preferably 1 to 3 or 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms.
  • haloalkyl moieties are selected from C1-C4- haloalkyl, more preferably from C1-C3-haloalkyl or C1-C2-haloalkyl, in particular from C1-C2-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
  • alkoxy denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom to the remainder of the molecule and has usually from 1 to 4 carbon atoms, prefer- ably 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.
  • alkoxyalkyl refers to an alkoxy group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, which is bonded via an alkyl group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more prefer- ably 1 carbon atom, to the remainder of the molecule.
  • alkyl group which is bonded via oxy- gen to a further alkyl group, which is then bonded to the remainder of the molecule.
  • alkoxyalkyl group examples are methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and the like.
  • haloalkoxy denotes in each case a straight-chain or branched alkoxy group having from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, wherein the hydro- gen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms.
  • Pre- ferred haloalkoxy moieties include C1-haloalkoxy, in particular C1-fluoroalkoxy, such as trifluoromethoxy and the like.
  • hydroxyalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms, and being further substituted with 1 to 5, preferably with 1 to 2 hydroxy groups, in particular with 1 hydroxy group, wherein a hydroxy group is a OH group.
  • the one hydroxy group is terminating the straight- chain or branched alkyl group so that the hydroxy group is bonded to an alkyl bridge, which is bonded to the remainder of the molecule.
  • Examples of an hydroxyalkyl group are hydroxymethyl, hydroxyethyl, n-hydroxypro- pyl, 2-hydroxypropyl, n-hydroxybutyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl, and n-hydroxypentyl.
  • Hy- droxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, are preferred, in particular hydroxymethyl and hy- droxyethyl.
  • aminoalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms, and being further substituted with 1 to 5, preferably with 1 to 2 amino groups, in particular with 1 amino group, wherein an amino group is a NH2 group.
  • the one amino group is terminating the straight-chain or branched alkyl group so that the amino group is bonded to an alkyl bridge, which is bonded to the remainder of the molecule.
  • aminoalkyl group examples include aminomethyl, aminoethyl, n-aminopropyl, 2-aminopropyl, n-aminobutyl, 2-aminobutyl, 2-amino-2-methylpropyl, and n-aminopentyl.
  • Aminomethyl, aminoethyl, aminopro- pyl, and aminobutyl, are preferred, in particular aminomethyl and aminoethyl.
  • cycloalkyl denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl, cyclo- butyl, cyclopentyl, and cyclohexyl are preferred.
  • carrier includes, unless otherwise indicated, in general a 3- to 10-membered monocyclic ring, preferably a 4- to 8-membered or a 3- to 6-membered or a 5- to 7-membered monocyclic ring, more preferably a 3-, 4-, 5- or 6-membered monocyclic ring, comprising 3 to 10, preferably 4 to 8 or 3 to 6 or 5 to 7, more preferably 3, 4, 5 or 6 carbon atoms.
  • the carbocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled.
  • aryls are covered by the term “carbocycles”.
  • the term “aryl” or “aromatic carbocycle” refers to aromatic carbocyclic rings based on carbon atoms as ring members, preferably 6-membered aromatic carbocyclic rings based on carbon atoms as ring members. A preferred example is phenyl.
  • aryl further co- vers “aromatic carbobicycles” as defined herein.
  • the term “carbocy-hack” or “carbocyclyl” covers phenyl and cycloalkyl, for example phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • carbobicycle includes in general 6 to 14-membered, preferably 7- to 12-mem- bered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings comprising 6 to 14, preferably 7 to 12 or 8 to 10, more preferably 9 or 10 carbon atoms.
  • the carbobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully un- saturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled.
  • the term “aromatic” in connection with the carbobicyclic ring means that both rings of the bicylic moiety are aromatic, so that, e.g., 8 ⁇ electrons are present in case of a 10-membered aromatic carbobicyclic ring.
  • the term “car- bobicylce” or “carbobicyclyl”, unless otherwise indicated, may therefore cover inter alia bicycloalkyl, bicycloal- kenyl, as well as bicyclic aromatic groups, for example bicyclohexane (decalin), bicycloheptane (such as nor- bornane), bicyclooctane (such as bicyclo[2.2.2]octane, bicyclo[3.2.1]octane or bicyclo[4.2.0]octane), bicy- clononane (such as bicyclo[3.3.1]nonane or bicyclo[4.3.0]nonane ), bicyclodecane (such as bicycl
  • the carbobicycle is a fused carbobicycle, which is preferably aromatic, for example naphthalene.
  • carbocyclylalkyl refers to carbocyclyl as defined herein, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon Ryvu Therapeutics S.A. RVU305 73 R10945WO atom.
  • the term “carbocyclylalkyl” refers to phenylalkyl or cycloalkylalkyl, which refers to the corre- sponding groups being bonded to the remainder of the molecule via an alkyl group.
  • car- bocyclylalkyl examples include benzyl (i.e. phenylmethyl), phenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylme- thyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl.
  • the term “carbocyclyloxy” as used herein denotes in each case a carbocyclyl as defined herein, which is bonded via an oxygen atom to the remainder of the molecule. Examples of carbocyclyloxy include phenyloxy or cyclopropyloxy.
  • aryloxy and “benzyloxy” referring to the corresponding groups, which are bonded to the remainder of the molecule via an oxygen atom.
  • carbocyclyloxyalkyl denotes in each case a carbocyclyloxy group, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 car- bon atom.
  • it refers to a carbocyclyl, which is bonded via an oxygen atom to an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom, which is then bonded to the remainder of the molecule.
  • heterocyclic or “heterocyclyl” includes, unless otherwise indicated, in general a 3- to 10-mem- bered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered, in particular 6- membered monocyclic ring.
  • the heterocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled.
  • the heterocycle typically comprises one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S- atoms as ring members may be present as S, SO or SO2. The remaining ring members are carbon atoms.
  • the heterocycle is an aromatic heterocycle, preferably a 5- or 6-membered aromatic heterocycle comprising one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2.
  • aromatic heterocycles are provided below in connection with the definition of “hetaryl”. “Hetaryls” or “heteroaryls” are covered by the term “heterocycles”.
  • the saturated or partially or fully unsaturated heterocycles usually com- prise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S-at- oms as ring members may be present as S, SO or SO2.
  • S, SO or SO2 is to be understood as follows: Further, a skilled person is aware that resonance structures of the oxidized forms may be possible.
  • Saturated heterocycles include, unless otherwise indicated, in general 3- to 10-membered, preferably 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered monocyclic rings comprising 3 to 10, preferably 4 to 8 or 5 to 7, more preferably 5 or 6 atoms comprising at least one heteroatom, such as pyrrolidine, tetrahydrothio- phene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.
  • heteroatoms such as pyrrolidine, tetrahydrothio- phene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.
  • heterocyclic or “heterobicyclyl” includes, unless otherwise indicated, in general 6 to 14-mem- bered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 8- or 9-membered bicyclic rings.
  • the heterobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled.
  • aromatic it is sufficient if one of the two rings of the bicyclic moi- eties is aromatic, while the other is non-aromatic.
  • the heterobicycle typically comprises one or more, e.g.1, 2, Ryvu Therapeutics S.A. RVU305 74 R10945WO 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2.
  • the remaining ring members are carbon atoms.
  • het- erobicycles examples include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadi- azolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridyl, pteridyl, pyr- ido[3,2-d]pyrimidyl, pyridoimidazolyl, triethylenediamine or quinuclidine and the like.
  • heteroaryl or “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” includes monocy-hack 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO2.
  • Examples of 5- or 6-mem- bered aromatic heterocycles include pyridyl (also referred to as pyridinyl), i.e.2-, 3-, or 4-pyridyl, pyrimidinyl, i.e.2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e.3- or 4-pyridazinyl, thienyl, i.e.2- or 3-thienyl, furyl, i.e.2-or 3-furyl, pyrrolyl, i.e.2- or 3-pyrrolyl, oxazolyl, i.e.2-, 3- or 5-oxazolyl, isoxazolyl, i.e.3-, 4- or 5-isoxazolyl, thia- zolyl, i.e.2-, 3- or 5-thiazolyl, isothiazolyl, i.e.3-, 4- or 5-isothiazo
  • oxadiazolyl e.g.2- or 5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3-oxadiazol)yl, 3- or 5-(1,2,4- oxadiazol)yl, 2- or 5-(1,3,4-thiadiazol)yl, thiadiazolyl, e.g.2- or 5-(1,3,4-thiadiazol)yl, 4- or 5-(1,2,3-thiadiazol)yl, 3- or 5-(1,2,4-thiadiazol)yl, triazolyl, e.g.1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or 4H-1,2,4- triazolyl and tetrazolyl, i.e.1H- or 2H-tetrazolyl.
  • heterocyclylalkyl refers to a heterocyclyl as defined herein, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom.
  • heterocyclylalkyl include pyridinylmethyl, pyrimidinylmethyl, pyrazolylmethyl, piperidinylme- thyl, or pyrrolidineethyl.
  • heterocyclyloxy denotes in each case a heterocyclyl as defined herein, which is bonded via an oxygen atom to the remainder of the molecule.
  • a carbon atom of the heterocyclyl is bonded to the oxygen atom.
  • heterocyclyloxy include pyridinyloxy, pyrimidinyloxy, pyrazolyloxy, and piperidinyloxy.
  • heteroaryloxy referring to the corresponding group, which is bonded to the remainder of the molecule via an oxygen atom.
  • heterocyclyloxyalkyl denotes in each case a heterocyclyloxy group, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom.
  • heterocyclyl which is bonded via an oxygen atom to an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom, which is then bonded to the remainder of the mol- ecule.
  • examples include pyridinyloxymethyl, pyrimidinyloxymethyl, pyrazolyloxymethyl, and piperidinyloxyme- thyl.
  • cyclic moiety can refer to any cyclic groups, which are present in the compounds of formula (I), and which are defined above, e.g., cycloalkyl, cycloalkenyl, carbocyclyl.
  • bicyclic moiety can refer to any bicyclic groups, which are present in the compounds of formula (I), and which are defined above.
  • the singular forms of “a” and “an” also include the corresponding plurals unless the context clearly dictates otherwise. The same applies for plural forms used herein, which also include the singular forms unless the context clearly dictates otherwise.
  • pharmaceutically acceptable excipient refers to compounds commonly comprised in pharmaceutical compositions, which are known to the skilled person. Examples of suitable excipients are exemplary listed below. Typically, a pharmaceutically acceptable excipient can be defined as being pharma- ceutically inactive.
  • treatment is to be understood as also including the option of “prophylaxis”. Thus, whenever refer- ence is made herein to a “treatment” or “treating”, this is to be understood as “treatment and/or prophylaxis” or “treating and/or preventing”.
  • a pharmaceutical composition according to the present invention may be formulated for oral, inhalative, buc- cal, nasal, rectal, topical, transdermal or parenteral application.
  • Preferred non-parenteral routes include muco- sal (e.g., oral, vaginal, nasal, cervical, etc.) routes, of which the oral application may be preferred.
  • Parenteral application may be preferred and includes intravenous, intraarterial, intratumoral, peri-tumoral, intradermal, in- trathecal, intravesical, intramuscular, epidural or subcutaneous administration, but also intranasal and inhala- tive administration.
  • Preferably administration is by subcutaneous, intra-tumoral or peri-tumoral routes, in partic- ular in the treatment of cancer. Particularly preferred is intratumoral administration.
  • intratumoral administration is preferred.
  • inhalative administration may be performed by using an inhaler for delivering the pharmaceutical composition into the body via the lungs. Suitable inhalers include dry powder inhalers, metered-dose inhalers, and nebulizers. Dry powder inhalers provide the active ingredient in the form of a powder, which is then inhaled through the dry powder inhaler.
  • Dry powder inhalers are advantageous because they are breath-actuated and do not require the use of any propel- lants.
  • Nebulizers provide the active ingredient as an aerosol created from an aqueous formulation.
  • Metered- dose inhalers release a fixed dose of medication in aerosol form, wherein a liquefied gas propellant, preferably a hydrofluoroalkane (HFA), is used in the formulation of the active ingredient.
  • a liquefied gas propellant preferably a hydrofluoroalkane (HFA)
  • HFA hydrofluoroalkane
  • the compound according to formula (I) should be applied in pharmaceutically effective amounts, for example in the amounts as set out herein below.
  • a pharmaceutical composition of the present invention may also be designated as formulation or dosage form.
  • a compound of formula (I) may also be designated in the following as (pharmaceutically) active agent or active compound.
  • compositions may be solid or liquid dosage forms or may have an intermediate, e.g. gel-like character depending inter alia on the route of administration.
  • inventive dosage forms can comprise various pharmaceutically acceptable excipients, 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 invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, Ryvu Therapeutics S.A. RVU305 76 R10945WO release-modifying materials, carrier materials, diluents, binding agents, and other adjuvants.
  • Typical pharma- ceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch deriva- tives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents.
  • carrier denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the application.
  • Suitable pharmaceutically acceptable carriers in- clude, for instance, water, aqueous salt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbitans, polyethylene-polypropylene block co-polymers such as poloxamer 188 or polox- amer 407, polyethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and triglycerides, polyox- yethylated medium or long chain fatty acids such as ricinoleic acid, and polyoxyethylated fatty acid mono-, di, and triglycerides such as capric or caprilic acids, petroethral fatty acid esters, hydroxymethyl celluloses such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl acetate succinate
  • the compounds of the present invention are administered in a pharmaceuti- cal composition
  • a pharmaceuti- cal composition comprising of lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L- lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, nanoporous par- ticle-supported lipid bilayers and as a conjugate with an antibody.
  • the pharmaceutical compositions can be sterile and, if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.
  • auxiliary agents like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.
  • carrier also covers an antibody that delivers the compound of formula (I).
  • liquid dosage forms are considered for the present invention, these can include pharmaceutically accepta- ble emulsions, solutions, suspensions and syrups containing inert diluents commonly used in the art such as water. These dosage forms may contain e.g.
  • microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners/flavoring agents.
  • particularly suitable vehicles consist of solutions, preferably oily or aqueous solu- tions, as well as suspensions, emulsions, or implants.
  • Pharmaceutical formulations for parenteral administra- tion are particularly preferred and include aqueous solutions of the compounds of formula (I) in water-soluble form. Additionally, suspensions of the compounds of formula (I) may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain sub- stances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • Particularly preferred dosage forms are injectable preparations of a compound of formula (I).
  • sterile in- jectable aqueous or oleaginous suspensions can for example be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
  • a sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be used are water and isotonic sodium chloride solution.
  • Sterile oils are also conventionally used as solvent or suspending medium.
  • Preferred applications for injectable prepa- rations comprising the compounds of the present invention are intravenous, intratumoral and peritumoral ad- ministration.
  • Ryvu Therapeutics S.A. RVU305 77 R10945WO Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g.
  • the compounds according to the present invention may be conveniently de- livered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propel- lant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propel- lant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, powders, efferves- cent formulations, dragees and granules.
  • compositions for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sug- ars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellu- lose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • fillers such as sug- ars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxy
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral dosage forms may be formulated to ensure an immediate release of the compound of for- mula (I) or a sustained release of the compound of formula (I).
  • a solid dosage form may comprise a film coating.
  • the inventive dosage form may be in the form of a so-called film tablet.
  • a capsule of the invention may be a two-piece hard gelatin capsule, a two-piece hy- droxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose or a two- piece capsule made of polysaccharide.
  • the dosage form according to the invention may be formulated for topical application. Suitable pharmaceuti- cal application forms for such an application may be a topical nasal spray, sublingual administration forms and controlled and/or sustained release skin patches.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compositions may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. The methods can include the step of bringing the compounds into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • Liquid dose units are vials or am- poules. Solid dose units are tablets, capsules and suppositories.
  • the compound of formula (I) may be administered to a patient in an amount of about 0.001 mg to about 5000 mg per day, preferably of about 0.01 mg to about 1000 mg per day, more prefer- ably of about 0.05 mg to about 250 mg per day, which is the effective amount.
  • the phrase “effective amount” means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to treat or prevent a particular disease or condition.
  • the pharmaceutical composition may also contain the compound of formula (I) as a prodrug such as an ester or amide thereof.
  • a prodrug is any compound which is converted under physiological condi- tions or by solvolysis to any of the compounds of the invention.
  • a prodrug may be inactive prior to administra- tion but may be converted to an active compound of the invention in vivo.
  • Ryvu Therapeutics S.A. RVU305 78 R10945WO in a preferred embodiment relating to the pharmaceutical compositions of the present invention, said pharma- ceutical composition comprises said compound as the only pharmaceutically active agent.
  • said pharmaceutical composition comprises at least one further independent pharmaceutically active agent in addi- tion to said compound, wherein said additional active agent is typically used for the intended indication(s) as outlined above.
  • said pharmaceutical composition comprises at least one further independent pharmaceutically active agent in addition to the compound of the present invention.
  • further details in this regard are provided below.
  • Indications, for which the compounds of the present invention may be used The compounds according to the present invention are suitable for use in medicine.
  • the compounds of the present invention are useful for (partially) inhibiting PRMT5, in particular MTA-bound PRMT5, which is enriched in MTAP deficient tumor cells.
  • the compounds according to the present invention are particularly suitable for use in the treatment of a disease associated with MTAP deficiency and/or MTA accumulation, in particular a proliferative disorder such as cancer or pre-cancerous syndromes associated with MTAP deficiency and/or MTA accumulation.
  • the compound of the present invention or a pharmaceutical composition compris- ing the same is for use in the treatment of a disease selected from the group consisting of cancer or pre-can- cerous syndromes.
  • the compound of the present invention or a pharmaceutical com- position comprising the same is for use in the treatment of a disease selected from the group consisting of can- cer or pre-cancerous syndromes associated with MTAP deficiency and/or MTA accumulation.
  • said cancer is selected from the group consisting of Glioblastoma, Non-Small Cell Lung Cancer, B-Lymphoblastic Leukemia/Lymphoma, Pancreatic Cancer, Breast Cancer, Melanoma, Esophagogastric Can- cer, Bladder Cancer, Glioma, Head and Neck Cancer, Hepatobiliary Cancer, Prostate Cancer, Pleural Meso- thelioma, Sarcoma, Ovarian Epithelial Tumor, Soft Tissue Sarcoma, Bone Cancer, Colorectal Cancer, Blad- der/Urinary Tract Cancer, Ovarian Cancer, T-Lymphoblastic Leukemia/Lymphoma, Nerve Sheath Tumor, Ma- ture B-Cell Neoplasms, Renal Non-Clear Cell Carcinoma, Renal Cell Carcinoma, Endometrial Cancer, Mature B-cell lymphoma, High-grade glioma/astrocytoma,
  • said cancer is preferably selected from the group consisting of Glioblastoma Multiforme, B-Lym- phoblastic Leukemia/Lymphoma, Pancreatic Adenocarcinoma, Breast Invasive Ductal Carcinoma, Lung Squa- mous Cell Carcinoma, Bladder Urothelial Carcinoma, Lung Adenocarcinoma, Cutaneous Melanoma, Head and Neck Squamous Cell Carcinoma, Melanoma, Prostate Adenocarcinoma, Esophageal Adenocarcinoma, Astro- cytoma, Serous Ovarian Cancer, Stomach Adenocarcinoma, Esophageal Squamous Cell Carcinoma, Hepato- cellular Carcinoma, Pancreatic Neuroendocrine Tumor, Glioblastoma, Pleural Mesothelioma, Epithelioid Type Diffuse Large B-Cell Lymphoma, Tubular Stom
  • RVU305 79 R10945WO noma T-Lymphoblastic Leukemia/Lymphoma, Leiomyosarcoma, Undifferentiated Pleomorphic Sarcoma/Malig- nant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma, Sarcoma, Osteosarcoma, Renal Clear Cell Car- cinoma, Intestinal Type Stomach Adenocarcinoma, Adenoid Cystic Carcinoma, Oligodendroglioma, Breast In- vasive Lobular Carcinoma, Cholangiocarcinoma, Pediatric High Grade Gliomas, Acral Melanoma, Oligoastro- cytoma, Breast Invasive Carcinoma, Adrenocortical Carcinoma, Breast Mixed Ductal and Lobular Carcinoma, Gastrointestinal Stromal Tumor, Thymoma, Dedifferentiated Liposarcoma, Angiosarcoma, Diff
  • the cancer is selected from the group consisting of Glioblastoma, Non-Small Cell Lung Can- cer, B-Lymphoblastic Leukemia/Lymphoma, Pancreatic Cancer, Breast Cancer, Melanoma, Esophagogastric Cancer, Bladder Cancer, Glioma, Head and Neck Cancer, Hepatobiliary Cancer, Prostate Cancer, Pleural Mesothelioma, Sarcoma, Ovarian Epithelial Tumor, Soft Tissue Sarcoma, Bone Cancer, Colorectal Cancer, Bladder/Urinary Tract Cancer, T-Lymphoblastic Leukemia/Lymphoma.
  • said cancer is more preferably selected from the group consisting of Glioblastoma Multiforme, B- Lymphoblastic Leukemia/Lymphoma, Pancreatic Adenocarcinoma, Breast Invasive Ductal Carcinoma, Lung Squamous Cell Carcinoma, Bladder Urothelial Carcinoma, Lung Adenocarcinoma, Cutaneous Melanoma, Head and Neck Squamous Cell Carcinoma, Melanoma, Prostate Adenocarcinoma, Esophageal Adenocarci- noma, Astrocytoma, Serous Ovarian Cancer, Stomach Adenocarcinoma, Esophageal Squamous Cell Carci- noma, Hepatocellular Carcinoma, Glioblastoma, Pleural Mesothelioma, Epithelioid Type Diffuse Large B-Cell Lymphoma, Tubular Stomach Adenocarcinoma, Bladder/U
  • the compounds according to the present invention are administered in combination with antibodies, radiotherapy, surgical therapy, immunotherapy, chemotherapy, toxin therapy, gene therapy, or any other therapy known to those of ordinary skill in the art for treatment of a particular disease.
  • the compounds of the present invention may be coadministered with Ryvu Therapeutics S.A. RVU305 80 R10945WO an anti-neoplastic agent and/or an anti-neoplastic agent may be comprised in the pharmaceutical composition according to the present invention.
  • the cancer treated by the combination of (i) a compound according to the present invention and (ii) an anti-neoplastic agent may be selected from one of the cancers listed above.
  • 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. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wil- kins Publishers.
  • Typical anti-neoplastic agents useful in the present invention include chemotherapeutic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal ana- logues, signal transduction pathway inhibitors, non-receptor tyrosine kinase inhibitors, angiogenesis inhibitors, proapoptotic agents, cell cycle signaling inhibitors, proteasome inhibitors, inhibitors of cancer metabolism, and immunotherapeutic agents (such as STING pathway modulating compounds, TLR agonists and checkpoint in- hibitors).
  • chemotherapeutic agents such as STING pathway modulating compounds, TLR agonists and checkpoint in- hibitors.
  • chemotherapeutic agents are anti-microtubule or anti-mitotic agents (such as paclitaxel), platinum coordination complexes (such as cisplatin), alkylating agents (such as cyclophosphamide) and antibiotic anti-neoplastics (such as doxorubicin).
  • Combination therapy may be achieved by use of a single pharmaceutical composition that includes both agents, or by administering two distinct compositions at the same time, wherein one composition includes a compound of the present invention, and the other includes the second agent(s).
  • the two therapies may be given in either order and may precede or follow the other treatment by intervals ranging from minutes to weeks.
  • the compound of the present invention is administered prior to administration of the distinct cancer treatment.
  • the distinct cancer treatment is administered prior to administration of the compound of the present invention.
  • the present invention is further illustrated by the following examples. Examples The following abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations are used herein: Abbreviations Meaning ))) with sonication Ac Acetyl ACN/MeCN/ Acetonitrile CH3CN AcOH Acetic acid AIBN Azobisisobutyronitrile alamarBlue Resazurin dye (7-hydroxy-3H-phen
  • RVU305 81 R10945WO Abbreviation Meaning Bn Benzyl (Bpin)2 Bis(pinacolato)diboron BTFFH Fluoro-dipyrrolidinocarbenium hexafluorophosphate (BzO)2, BPO Benzoyl peroxide Boc tert-Butoxycarbonyl BocNH2 tert-Butyl carbamate BSA Bovine serum albumin calc. calculated cataCXium ® C trans-Di( ⁇ -acetato)bis[o-(di-o-tolyl-phosphino)benzyl]dipalladium(II) CDI 1,1'-Carbonyldiimidazole conc.
  • Preparative HPLC purifications The following equipment was used for Preparative HPLC purifications: Waters Autopurification system (Waters 2767 – Sample Manager, Waters 2545 – Binary Gradient Module, Waters 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 Phenomenex Gemini® 5 ⁇ m NX- C18110 ⁇ (00G-4454-P0-AX LC Column 250 x 21.2 mm, AX) column.
  • Waters Autopurification system Waters 2767 – Sample Manager, Waters 2545 – Binary Gradient Module, Waters SFO – System Fluidics Organizer, Waters Prep Degasser, Waters 515 – HPLC Pump, Waters UV Fraction Manager) with DAD (Waters 2998 –
  • Methyl 4-oxo-1H,3H,4H,5H-furo[3,4-c]quinoline-7-carboxylate (Int.2): A mixture of methyl 4-(trifluoromethanesulfonyloxy)-2,5-dihydrofuran-3-carboxylate (Int.1, 15.9 g, 51.806 mmol, 1.1 eq.), 2-amino-4-(methoxycarbonyl)phenylboronic acid hydrochloride (10.9 g, 47.096 mmol, 1.0 eq.), K2CO3 (15.287 g, 110.612 mmol, 4.0 eq.), water (12.5 mL) and 1,4-dioxane (125 mL) was sparged with argon, then Pd(
  • the RM was cooled to RT, diluted with water and extracted with CHCl3/i-PrOH (3:1) mixture (2x). Combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. Crude product was tritu- rated with Et2O and a few drops of i-PrOH and acetone, then filtered and washed with Et2O to obtain methyl 4- oxo-1H,3H,4H,5H-furo[3,4-c]quinoline-7-carboxylate (Int.2, 9.26 g, 36.627 mmol, 78%, light brown solid, m/z [M+H] + : 246.1).
  • the RM was cooled by an ice-bath then quenched by addition of MeOH (dropwise) and 6M HCl was Ryvu Therapeutics S.A. RVU305 89 R10945WO used to adjust pH to 1 (ice bath was used). Organic solvent was evaporated again and additional portion of H2O was added. The resulting solution was then stirred at 0°C for 30 min. The precipitated solid was filtered, washed with water and dried in vacuo to give 7-(hydroxymethyl)-1H,3H,4H,5H-furo[3,4-c]quinolin-4-one (Int.3, 7.212 g, 32.537 mmol, 80%, brown solid, m/z [M+H] + : 218.0).
  • a 7-(hydroxymethyl)-1H,3H,4H,5H-furo[3,4-c]quinolin-4-one (Int.3, 7.212 g, 32.537 mmol, 1.0 eq.) was suspended in dry MeCN (75 mL) and DIPEA (22.66 mL, 130.147 mmol, 4.0 eq.) was added. The obtained slurry was stirred for 5 min. Then, a suspension of POBr3 (27.98 g, 97.61 mmol, 3.0 eq.) in MeCN (25 mL) was added dropwise. Reaction mixture was stirred at RT for 20 min., and then it was heated at 80°C for 100 min.
  • Example 1 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(2-cyclopropylpyridin-3-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide N ⁇ (2 ⁇ cyclopropylpyridin ⁇ 3 ⁇ yl) ⁇ 6 ⁇ (trifluoromethyl)pyridine ⁇ 3 ⁇ carboxamide (Int.6) DMAP (0.048 g, 0.392 mmol, 0.5 eq.), DIPEA (0.362 mL, 1.962 mmol, 2.5 eq.), 2-cyclopropylpyridin-3- amine (0.111 g, 0.824 mmol, 1.05 eq.) and 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.15 g, 0.785 mmol, 1.0 eq.) were taken in DMF (4.0 mL) and propylphosphonic anhydride (50% solution
  • Step 2 To a solution of N-(2-cyclopropylpyridin-3-yl)-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H- furo[3,4-c]quinolin-7-yl)methyl]-6-(trifluoromethyl)pyridine-3-carboxamide (0.164 g, 0.215 mmol, 1.0 eq.) in DCM (1.5 mL) TFA (0.165 mL, 2.151 mmol, 10.0 eq.) was added at 0°C. The reaction was stirred at RT over- night. Ater that the RM was diluted with DCM, quenched by NaHCO3 aq.
  • Example 2 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-(6-methylpyridin-3-yl)pyrimi- dine-5-carboxamide 2 ⁇ cyclopropyl ⁇ N ⁇ (6 ⁇ methylpyridin ⁇ 3 ⁇ yl)pyrimidine ⁇ 5 ⁇ carboxamide (Int.8) 6-methylpyridin-3-amine (0.303 g, 2.802 mmol, 1.0 eq.) was dissolved in toluene (14.0 mL) and 2-cyclo- propylpyrimidine-5-carboxylic acid (0.48 g, 2.924 mmol, 1.044 eq.) was added, followed by DMAP (0.018 g, 0.147 mmol, 0.053 eq.) and DIPEA (1.23 mL, 7.061 mmol, 2.52 eq.).
  • T3P as 50 wt% solution in AcOEt (3.3 mL, 5.544 mmol, 1.979 eq.) was added to RM.
  • the reaction mixture was heated at reflux for 4h and then it was cooled to RT.
  • the reaction was quenched with saturated solution of NaHCO3 in portion to pH 8-9.
  • organic phase was separated and water phase was extracted with ethyl acetate.
  • Organic layers were com- bined and washed with brine, dried with sodium sulfate and filtrated.
  • RVU305 95 R10945WO gradient in hexane) to obtain N-( ⁇ 4-bromo-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-(6-methylpyri- din-3-yl)pyrimidine-5-carboxamide (Int.9, 0.487 g, 0.905 mmol, 78%, light yellow powder, m/z [M+H] + : 517.3).
  • the aqueous phase was extracted with chloroform/isopropanol 3:1 mixture and the combined organic layers were washed with aq. Na2CO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • the crude material was purified by FCC (0% to 10% MeOH gradient in DCM). Fractions containing the pure product were pooled and freeze-dried. Obtained compound was dissolved in DCM and washed with sat. aq. NaHCO3 solution. Organic fraction was collected, dried over sodium sulfate, filtered and evaporated.
  • RVU305 96 R10945WO 2 ⁇ cyclopropyl ⁇ N ⁇ (2 ⁇ methylpyridin ⁇ 3 ⁇ yl)pyrimidine ⁇ 5 ⁇ carboxamide (Int.10) N,N-dimethylpyridin-4-amine (0.169 g, 1.387 mmol, 0.3 eq.), 2-methylpyridin-3-amine (0.5 g, 4.623 mmol, 1.0 eq.) and 2-cyclopropylpyrimidine-5-carboxylic acid (0.911 g, 5.548 mmol, 1.2 eq.) were dissolved in pyridine (15.0 mL) and stirred at ice bath for 5 min.
  • phosphoroyl trichloride (1.418 g, 9.247 mmol, 2.0 eq.) was added dropwise and RM was stirred at ice bath for another 5 min. After that time ice bath was re- moved and the RM was stirred at RT for 2 h. The RM was added to ice cold saturated sodium bicarbonate so- lution (150 mL). and stirred for 30 min. The solution was extracted with ethyl acetate (x2). All organic phase was collected together, washed with brine and dried over sodium sulfate. The solvent was evaporated under low pressure.
  • Step 2 2-cyclopropyl-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2- methylpyridin-3-yl)pyrimidine-5-carboxamide (0.449 g, 0.67 mmol, 1.0 eq.) was dissolved in DCM (10 mL) and TFA (2.567 mL, 33.524 mmol, 50 eq.) was added. Then the RM was stirred overnight at RT. After that time sat. aq. NaHCO3 solution was added and the mixture was stirred for 30 minutes.
  • Example 4 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-(1-methyl-2-oxo-1,2-dihydro- pyridin-3-yl)pyrimidine-5-carboxamide 2 ⁇ cyclopropyl ⁇ N ⁇ (1 ⁇ methyl ⁇ 2 ⁇ oxo ⁇ 1,2 ⁇ dihydropyridin ⁇ 3 ⁇ yl)pyrimidine ⁇ 5 ⁇ carboxamide (Int.12) To a stirred solution of 2-cyclopropylpyrimidine-5-carboxylic acid (0.13 g, 0.792 mmol, 0.983 eq.) in an- hydrous DCM (4.0 mL) was added 3-amino-1-methyl-1,2-dihydropyridin-2-one (0.1 g, 0.806 mmol, 1.0 eq.) fol- lowed by HOBT (0.17 g, 1.258 mmol, 1.562
  • Step 2 To a solution of 2-cyclopropyl-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrimidine-5-carboxamide (0.202 g, 0.313 mmol, 1.0 eq.) in DCM (2.0 mL) TFA (0.6 mL, 7.841 mmol, 25.0 eq.) was added. The rection mixture was stirred overnight at RT. Then the reaction was quenched by NaHCO3 and extracted with DCM.
  • toluene (5 mL) were added in N,N-dimethylpyridin-4- amine (0.015 g, 0.121 mmol, 0.05 eq.) and DIPEA (1.05 mL, 6.041 mmol, 2.5 eq.) followed by propylphosphonic anhydride (50% solution in EtOAc, 2.877 mL, 4.833 mmol, 2.0 eq.) at RT.
  • the RM was then stirred at reflux for 1 h. After that time the mixture was cooled to RT, diluted with water and extracted with EtOAc. Combined organic layers were washed with brine, dried over anh. sodium sulfate, filtered and evapo- rated in vacuo.
  • RM NH4Cl (1.2 mL) solution, zinc (0.894 g, 13.679 mmol, 10.0 eq.) was added portion wise. RM was stirred at RT for 1 h. After that time RM was filtrated through Celite pad and filter was washed with ethyl acetate.
  • 1,1'-Bis(diphenylphosphino)ferrocene-pal- ladium(ii)dichloride dichloromethane (0.025 g, 0.03 mmol, 0.1 eq.) was added and RM was heated at 100°C for 4 h. After this time reaction mixture was allowed to cool to RT, then AcOEt was added and the mixture was fil- tered through a pad of celite. To filtrate water was added and layers were separated. Aqueous layer was ex- tracted with AcOEt. Combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated.
  • Step 2 Microwave reactor was charged under nitrogen with 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesul- fonate (Int. D, 0.656 g, 2.427 mmol, 2.0 eq.), product of step 1 (0.96 g, 1.214 mmol, 1.0 eq.) and dipotassium carbonate (0.503 g, 3.641 mmol, 3.0 eq.) followed by 1,4-dioxane (10.0 mL) and water (1.0 mL).
  • 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesul- fonate Int. D, 0.656 g, 2.427 mmol, 2.0 eq.
  • product of step 1 (0.96 g, 1.214 mmol, 1.0 eq.
  • dipotassium carbonate 0.503 g, 3.641 mmol, 3.0 eq.
  • the reaction mixture was bubbled with argon for 5 min and tetrakis(triphenylphosphane) palladium (0.140 g, 0.121 mmol, 0.1 eq.) was added.
  • RM was microwaved for 30 min at 120°C. After that time RM was diluted with ethyl acetate and water. Aqueous phase was extracted with ethyl acetate (2x). Combined organic layers were washed with brine, then dried over Na2SO4, filtered and concentrated in vacuo.
  • Example 6 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(3,6-dimethylpyrazin-2-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide Ryvu Therapeutics S.A.
  • Phosphorus oxychloride 0.498 g, 3.248 mmol, 2.0 eq.
  • 6-(trifluoro- methyl)pyridine-3-carboxylic acid (0.310 g, 1.624 mmol, 1.0 eq.)
  • 3,6-dimethylpyrazin-2-amine 0.2 g, 1.624 mmol, 1.0 eq.
  • N,N-dimethylpyridin-4-amine 0.060 g, 0.487 mmol, 0.3 eq.
  • the RM was stirred 5 min at 0°C and then 40 min at RT under nitrogen. The reaction was quenched with ice/water and neutralized with sat. aq. NaHCO3 solution. The mixture was transferred to separatory funnel and extracted with EtOAc (3x). Combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
  • Step 1 N-( ⁇ 4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(3,6-dimethylpyrazin-2-yl)-6-(trifluoromethyl)pyri- dine-3-carboxamide (Int.18, 0.485 g, 0.755 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.505 g, 3.02 mmol, 4.0 eq.) were stirred in DMSO (5.0 mL) at 120°C for 4h.
  • Step 2 Step 1 product was dissolved in DCM (5 mL) and trifluoroacetic acid (2.889 mL, 37.75 mmol, 50.0 eq.) was added. The RM was stirred 24 h at RT and evaporated under reduced pressure. Residue was partitioned between mixture of sat. aq. NaHCO3/1M NaOH solutions and DCM. The aqueous phase was extracted with DCM. Combined organic layers were washed with aq.
  • 1,3-dimethyl-1H-pyrazol-4-amine (0.765 g, 6.883 mmol, 1.0 eq.)
  • N,N-dimethylpyridin-4-amine (0.011 g, 0.09 mmol, 0.013 eq.)
  • 6-cyclopropylpyridine-3-carboxylic acid 0.734 g, 4.499 mmol, 0.654 eq.
  • phosphoryl trichloride (1.0 g, 6.522 mmol, 0.948 eq.) was added dropwise. Then the reaction was stirred for additional 5 min in ice bath and 1.5 h at RT. The reaction was quenched by sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (x3). All organic phase was collected together, washed with brine and dried over sodium sulfate. The solvent was removed under low pressure.
  • Step 2 To a solution of 6-cyclopropyl-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (0.453 g, 0.592 mmol, 1.0 eq.) in DCM (3.0 mL) at 0°C ,TFA (0.5 mL, 6.534 mmol, 11.0 eq.) was added. The RM was stirred overnight at RT.
  • Example 8 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin- 3-yl)pyrimidine-5-carboxamide N ⁇ (5 ⁇ bromo ⁇ 2 ⁇ methylpyridin ⁇ 3 ⁇ yl) ⁇ 2 ⁇ cyclopropylpyrimidine ⁇ 5 ⁇ carboxamide (Int.21) Phosphorus oxychloride (0.492 g, 3.208 mmol, 2.0 eq.) was added dropwise to a solution of 2-cyclo- propylpyrimidine-5-carboxylic acid (0.263 g, 1.604 mmol, 1.0 eq.), 5-bromo-2-methylpyridin-3-amine (0.3 g, 1.604 mmol, 1.0 eq.) and N,N-dimethylpyridin-4-amine (0.05879 g, 0.481 mmol, 0.3 eq
  • the RM was stirred 5 min at 0°C and then 40 min at RT under nitrogen atmosphere. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3 solution. The mixture was transferred to separatory funnel and extracted with EtOAc (3x). Combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
  • Step 2 Step 1 product was dissolved in DCM (5 mL) and trifluoroacetic acid (1.348 mL, 17.609 mmol, 50.0 eq.) was added. The RM was stirred 24 h at RT and evaporated under reduced pressure. Residue was partitioned between mixture of sat. aq. NaHCO3/1M NaOH solutions and DCM. The aqueous phase was extracted with DCM. Combined organic layers were washed with aq.
  • RVU305 106 R10945WO Example 8, 0.02 g, 0.04 mmol, 11%, white solid, UPLC long elution (Polar long method, buffer type “FA”) pu- rity: 99.67%, m/z [M+H] + : 493.23).
  • Example 10 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyr- idine-3-carboxamide N ⁇ (2 ⁇ methylpyridin ⁇ 3 ⁇ yl) ⁇ 6 ⁇ (trifluoromethyl)pyridine ⁇ 3 ⁇ carboxamide (Int.27) DMAP (0.064 g, 0.524 mmol, 0.501 eq.), DIPEA (0.470 mL, 2.616 mmol, 2.5 eq.), 2-methylpyridin-3- amine (0.12 g, 1.11 mmol, 1.06 eq.) and 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.2 g, 1.047 mmol, 1.0 eq.) were taken in DMF (6.0 mL) and propylphosphonic anhydride (50% in EtOAc, 1.25 mL, 2.1 mmol
  • RVU305 107 R10945WO (0% to 5% MeOH gradient in DCM) to give N-( ⁇ 4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(2-methylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.28, 0.389 g, 0.749 mmol, 75%, yellow solid, m/z [M+H] + : 497.7).
  • Step 2 To a solution of N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2- methylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (0.317 g, 0.428 mmol, 1.0 eq.) in DCM (3.0 mL) TFA (0.4 mL, 5.227 mmol, 12.214 eq.) was added at 0°C. The reaction was stirred overnight at RT. Ater that time the RM was diluted with DCM and basified with aq. NaHCO3.
  • the RM was cooled to 0°C under nitrogen atmosphere and POCl3 (1.964 g, 12.811 mmol, 2.0 eq.) was added dropwise. The mixture was stirred 5 min at 0°C and then 1 h at RT. RM was diluted with DCM and quenched with aq. Na2CO3 solution to pH ⁇ 9. Obtained mixture was extracted with DCM. Combined organic phases were dried over Na2SO4 and evaporated.
  • Step 1 To the suspension of N-(2-fluoro-5-nitrophenyl)-1-methylpiperidine-4-carboxamide (Int.31, 1.0 g, 3.448 mmol, 1.0 eq.) in toluene (10 mL), Lawesson's reagent (1.395 g, 3.448 mmol, 1.0 eq.) was added. The RM was stirred at reflux for 4 h. The RM was cooled to RT and diluted with DCM. Obtained mixture was washed with sat. aq. Na2CO3 solution.
  • Step 2 Ryvu Therapeutics S.A. RVU305 109 R10945WO The residue was dissolved in NMP (10 mL) and K2CO3 (0.477 g, 3.448 mmol, 1.0 eq.) was added. Ob- tained mixture was stirred at 100°C for 3 h. After that time the RM was cooled to RT, diluted with water and EtOAc, and extracted with EtOAc.
  • Step 1 To the suspension of 6-cyclopropylpyridine-3-carboxylic acid (0.192 g, 1.177 mmol, 1.0 eq.) in DCM (6 mL), oxalyl chloride (0.172 g, 1.353 mmol, 1.15 eq.) was added followed by 1 drop of DMF. The RM was stirred over 1 h at RT. After that time the RM was evaporated to dryness at 30°C.
  • RM was evaporated, diluted with water and extracted by EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (0% to 10% MeOH gradient in DCM) to give 6-cyclopropyl-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin- 7-yl)methyl]-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-5-yl]pyridine-3-carboxamide (0.302 g, 0.363 mmol, 84%, beige solid, m/z [M+H] + : 741.2).
  • Step 2 6-cyclopropyl-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-[2- (1-methylpiperidin-4-yl)-1,3-benzothiazol-5-yl]pyridine-3-carboxamide (0.299 g, 0.359 mmol, 1.0 eq.) was dis- solved in DCM (7 mL) and TFA (1.375 mL, 17.958 mmol, 50.0 eq.) was added. The RM was stirred at RT over- night. After that time the RM was carefully neutralized with 1M NaOH while cooling in an ice bath.
  • Example 13 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyano-N-(6-cyclopropyl-2-methylpyridin-3- yl)pyridine-3-carboxamide
  • Ryvu Therapeutics S.A. RVU305 111 R10945WO 6 ⁇ cyclopropyl ⁇ 2 ⁇ methyl ⁇ 3 ⁇ nitropyridine (Int.36)
  • a pressure reactor 20.0 mL of (10:1) toluene : water mixture was degassed and flushed with argon for 30 minutes.
  • 6 ⁇ cyano ⁇ N ⁇ (6 ⁇ cyclopropyl ⁇ 2 ⁇ methylpyridin ⁇ 3 ⁇ yl)pyridine ⁇ 3 ⁇ carboxamide (Int.38) A suspension of 6-cyanonicotinic acid (0.52 g, 3.511 mmol, 0.993 eq.), N,N-dimethylpyridin-4-amine (0.12 g, 0.982 mmol, 0.278 eq.) and 6-cyclopropyl-2-methylpyridin-3-amine (Int.37, 0.54 g, 3.534 mmol, 1.0 Ryvu Therapeutics S.A. RVU305 112 R10945WO eq.) in pyridine (anh., 10 mL) was cooled in ice-bath.
  • phosphoroyl trichloride (0.65 g, 4.239 mmol, 1.2 eq.) was added dropwise.
  • the reaction mixture was stirred 5 min at 0°C and 1 h at RT. After that time RM was diluted with water and treated with Na2CO3. After 30 min EtOAc was added and the mixture was partitioned. Aqueous phase was extracted with EtOAc (4x). Combined organic phases were washed with 5% KHSO4 (3x), brine (2x), dried over Na2SO4, filtered and concentrated.
  • Step 1 In a reactor were placed 1-(2,4-dimethoxyphenyl)methanamine (0.94 g, 5.622 mmol, 6.737 eq.), N-( ⁇ 4- chloro-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyridine-3-carbox- amide (Int.39, 0.445 g, 0.834 mmol, 1.0 eq.) and DMSO (anh., 12 mL).
  • RM was heated in MW for 2 h at 130°C. After that time RM was diluted with EtOAc, washed with diluted NaHCO3 solution (2x), brine (5x), dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 100% EtOAc gradient in hex- ane) to give 6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ - 1H,3H-furo[3,4-c]quinolin-7-yl)methyl]pyridine-3-carboxamide (0.484 g, 0.703 mmol, 84%, m/z [M+H] + : 627.3).
  • Step 2 TFA (5 mL) was added slowly to a solution of 6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7-yl)methyl]pyridine-3-carboxamide (0.484 g, 0.703 mmol, 1.0 eq.) in DCM (45 mL). The RM was stirred overnight at RT. After that time RM was quenched by addition of i-PrOH (5 mL). Then aqueous Na2CO3 solution was added slowly till pH 9 of water phase.
  • Example 14 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3- yl)pyridine-3-carboxamide 5 ⁇ cyclopropyl ⁇ 2 ⁇ methyl ⁇ 3 ⁇ nitropyridine (Int.40) 20.0 mL of (10:1) toluene : water mixture was degassed and flushed with argon for 30 minutes.
  • Step 1 In a reactor were placed 1-(2,4-dimethoxyphenyl)methanamine (1.3 g, 7.775 mmol, 7.678 eq.), N-( ⁇ 4- chloro-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyridine-3-carbox- amide (Int.43, 0.54 g, 1.013 mmol, 1.0 eq.) and DMSO (anh., 12mL).
  • RM was heated in MW for 2h at 130°C. After that time RM was diluted with EtOAc, washed with diluted NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 100% EtOAc gradient in hexane) to give 6- cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4- c]quinolin-7-yl)methyl]pyridine-3-carboxamide (0.29 g, 0.435 mmol, 43%, m/z [M+H] + : 627.4).
  • Example 15 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluoromethyl)- 1H-pyrazol-5-yl]pyrimidine-5-carboxamide 2 ⁇ cyclopropyl ⁇ N ⁇ [1 ⁇ methyl ⁇ 3 ⁇ (trifluoromethyl) ⁇ 1H ⁇ pyrazol ⁇ 5 ⁇ yl]pyrimidine ⁇ 5 ⁇ carboxamide (Int.44) 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (0.253 g, 1.532 mmol, 1.0 eq.), DMAP (0.077 g, 0.63 mmol, 0.411 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.326 g, 1.986 mmol, 1.296 eq.) and isopropyl ac- etate (10.0 mL) were mixed and degassed for
  • RVU305 116 R10945WO 1 H NMR 400 MHz, DMSO-d6) ⁇ 10.84 (s, 1H), 9.12 (s, 2H), 6.76 (s, 1H), 3.84 (s, 3H), 2.37 – 2.27 (m, 1H), 1.20 – 1.14 (m, 2H), 1.13 – 1.07 (m, 2H).
  • 19 F NMR (376 MHz, DMSO-d6) ⁇ -60.94.
  • Step 1 A solution of 1-(2,4-dimethoxyphenyl)methanamine (0.365 g, 2.181 mmol, 4.0 eq.) and N-( ⁇ 4-chloro- 1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridine-3-carbox- amide (Int.47, 0.285 g, 0.545 mmol, 1.0 eq.) in DMSO (3.0 mL) was stirred overnight at 120°C.
  • RM was diluted with water and extracted with DCM (3x). Combined organic extracts were washed with brine and dried over Na2SO4. Crude product was purified by FCC (0% to 80% EtOAc gradient in hexane). Step 2: Obtained product was dissolved in DCM (3.0 mL) and trifluoroacetic acid (0.834 mL, 10.903 mmol, 20.0 eq.) was added at 0°C. RM was stirred overnight at RT. After that time the mixture was basified with 1M NaOH to obtain pH ⁇ 8 and extracted with DCM (3x). Combined organic extracts were washed with brine and dried over Na2SO4. Crude product was purified by FCC (0% to 5% of MeOH gradient in DCM).
  • Fraction con- taining product was re-purified by FCC (NH2 modified silica, 0% to 2% MeOH gradient in DCM) and lyophilized to give N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide (Example 16, 0.158 g, 0.327 mmol, 60%, light yellow solid, UPLC long elution (Mid polar long method, buffer type “FA”) purity: 100.0%, m/z [M+H] + : 483.23).
  • FCC NH2 modified silica, 0% to 2% MeOH gradient in DCM
  • Example 17 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyano-N-(2-cyclopropylpyridin-3-yl)pyridine- 3-carboxamide 6 ⁇ cyano ⁇ N ⁇ (2 ⁇ cyclopropylpyridin ⁇ 3 ⁇ yl)pyridine ⁇ 3 ⁇ carboxamide (Int.48) DMAP (0.083 g, 0.679 mmol, 0.503 eq.), DIPEA (0.598 mL, 3.378 mmol, 2.5 eq.), 2-cyclopropylpyridin- 3-amine (0.19 g, 1.416 mmol, 1.048 eq.) and 6-cyanonicotinic acid (0.2 g, 1.351 mmol, 1.0 eq.) were taken in DMF (7.0 mL) and propylphosphonic anhydride (50% solution in EtOAc, 1.6 mL, 2.688 mmol, 1.989
  • Step 2 Product of step 1 was dissolved in DCM (6.0 mL) and TFA (0.7 mL, 9.147 mmol, 10.276 eq.) was added at 0°C. The reaction was stirred overnight at RT. Ater that time the RM was diluted with DCM and basified with aq. NaHCO3 solution. Water phase was extracted with DCM and CH3Cl : i-PrOH (3:1) mixture.
  • Example 18 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H- pyrazol-5-yl)pyrimidine-5-carboxamide Ryvu Therapeutics S.A.
  • RVU305 120 R10945WO 2 ⁇ cyclopropyl ⁇ N ⁇ (3 ⁇ cyclopropyl ⁇ 1 ⁇ methyl ⁇ 1H ⁇ pyrazol ⁇ 5 ⁇ yl)pyrimidine ⁇ 5 ⁇ carboxamide (Int.50) N,N-dimethylpyridin-4-amine (0.088 g, 0.722 mmol, 0.3 eq.), 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine (0.33 g, 2.405 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.395 g, 2.406 mmol, 1.0 eq.) and DI- PEA (1.048 mL, 6.014 mmol, 2.5 eq.) were dissolved in toluene (10 mL).
  • Step 2 Step 1 product was dissolved in DCE (9 mL) and trifluoroacetic acid (0.978 mL, 12.775 mmol, 50.0 eq.) was added under vigorous stirring. The RM was stirred for 1 h at 60°C.
  • reaction mixture was poured into Na2CO3 solution (150 mL) and stirred for 30 minutes. Next it was transferred to separatory funnel and extracted with DCM: i-PrOH (4:1) mixture. The combined organic layers were washed with aq. NaHCO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Example 19 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyri- dine-3-carboxamide 6 ⁇ cyclopropyl ⁇ N ⁇ (2 ⁇ methylpyridin ⁇ 3 ⁇ yl)pyridine ⁇ 3 ⁇ carboxamide (Int.52) Ryvu Therapeutics S.A.
  • RVU305 122 R10945WO Pyridine (anh., 8 mL) was added to a mixture of N,N-dimethylpyridin-4-amine (0.067 g, 0.548 mmol, 0.144 eq.), 6-cyclopropylpyridine-3-carboxylic acid (0.623 g, 3.818 mmol, 1.0 eq.) and 2-methylpyridin-3-amine (0.431 g, 3.985 mmol, 1.044 eq.) and the suspension was homogenized on ultrasounds. The mixture was then cooled in an ice bath and phosphoroyl trichloride (0.564 g, 3.677 mmol, 0.963 eq.) was added dropwise.
  • RM was stirred 1 h at RT. After that time the reaction was quenched by addition of water followed by aqueous Na2CO3 solution. Obtained mixture was stirred 15 min and then EtOAc was added. The mixture was parti- tioned. Aqueous phase was extracted with EtOAc (4x). Combined organic layers were washed with aq.5% KHSO4 (2x), brine (3x), dried over Na2SO4, filtered and concentrated.
  • Step 1 A solution of 1-(2,4-dimethoxyphenyl)methanamine (1.35 g, 8.074 mmol, 8.184 eq.) and N-( ⁇ 4-chloro- 1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (Int.53, 0.484 g, 0.987 mmol, 1.0 eq.) in DMSO (anh., 12 mL) was heated to 140°C in microwave for 2 h.
  • Step 2 TFA (5 mL) was added slowly to a mixture of Step 1 compound 6-cyclopropyl-N-[(4- ⁇ [(2,4-dimethoxy- phenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (0.29 g, 0.435 mmol, 1.0 eq.) and DCM (45 mL). RM was stirred overnight at RT. After that time the RM was quenched by addition of i-PrOH (5 mL). Then aqueous Na2CO3 solution was added slowly till pH 9 of water phase.
  • Example 20 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-[2-methyl-6-(trifluorome- thyl)pyridin-3-yl]pyrimidine-5-carboxamide 2 ⁇ cyclopropyl ⁇ N ⁇ [2 ⁇ methyl ⁇ 6 ⁇ (trifluoromethyl)pyridin ⁇ 3 ⁇ yl]pyrimidine ⁇ 5 ⁇ carboxamide (Int.54) To solution of 2-methyl-6-(trifluoromethyl)pyridin-3-amine (0.3 g, 1.703 mmol, 1.0 eq.), 2-cyclopropylpy- rimidine-5-carboxylic acid (0.280 g, 1.703 mmol, 1.0 eq.), DMAP (0.0104 g, 0.085 mmol, 0.05 eq.) in toluene (4.0 mL) was added DIPEA (0.742 mL, 4.258 m
  • Step 2 Step 1 product was dissolved in DCM (4.0 mL) and trifluoroacetic acid (1.135 mL, 14.731 mmol, 20.0 eq.). was added. Reaction mixture was stirred overnight at RT. Reaction mixture was basified with 1M NaOH to obtain pH ⁇ 8 and extracted with DCM.
  • Cs2CO3 (1.89 g, 5.80 mmol, 1.2 eq.) was added to a solution of 2-cyclopropyl-N-(2-methylpyridin-3-yl)py- rimidine-5-carboxamide (Int.10, 1.27 g, 4.84 mmol, 1.0 eq.) in MeCN (20.0 mL).
  • NH4Cl solution (15.0 mL) was added dropwise. Then RM was stirred overnight at RT. RM was diluted with DCM and filtrated through Celite. Next, filtrate was diluted with water and sat. aq. Na2CO3 solution and extracted with DCM (2x).
  • RVU305 126 R10945WO N-[(3-amino-4-bromophenyl)methyl]-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.57, 1.44 g, 3.09mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.57 g, 6.18 mmol, 2.0 eq.) and potassium acetate (0.9 g, 9.17 mmol, 2.97 eq.) were mixed in anh. dioxane (80.0 mL).
  • Step 2 (2-amino-4- ⁇ [1-(2-cyclopropylpyrimidin-5-yl)-N-(2-methylpyridin-3-yl)formamido]methyl ⁇ phenyl)boronic acid (3.14 g, 1.869 mmol, 1.0 eq.), 4-cyano-5-methyl-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Int. F, 2.0 g, 2.33 mmol, 1.2 eq.) and K2CO3 (0.77 g, 5.57 mmol, 2.98 eq.) were mixed in a mixture of dioxane (50.0 mL) and water (5.0 mL).
  • Example 22 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-(6-cyclopropyl-2-methylpyri- din-3-yl)pyrimidine-5-carboxamide Ryvu Therapeutics S.A.
  • RVU305 127 R10945WO 2 ⁇ cyclopropyl ⁇ N ⁇ (6 ⁇ cyclopropyl ⁇ 2 ⁇ methylpyridin ⁇ 3 ⁇ yl)pyrimidine ⁇ 5 ⁇ carboxamide
  • Phosphoroyl trichloride (0.700 g, 4.568 mmol, 2.0 eq.) was added dropwise to a solution of 6-cyclopro- pyl-2-methylpyridin-3-amine (Int.37, 0.349 g, 2.284 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.375 g, 2.284 mmol, 1.0 eq.) and N,N-dimethylpyridin-4-amine (0.084 g, 0.685 mmol, 0.3 eq.) in pyridine (10 mL) at 0°C.
  • the RM was stirred for 5 min at 0°C and then 40 min at RT under nitrogen. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3. Solution was transferred to separatory funnel and extracted with EtOAc (3x). Combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
  • Step 2 Step 1 product was dissolved in DCE (9 mL) and trifluoroacetic acid (1 mL) was added under vigorous stirring. The RM was stirred for 2 h at 60°C. After that time reaction mixture was poured into Na2CO3 solution (150 mL) and stirred for 30 minutes.
  • Example 23 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2-cyclo- propylpyrimidine-5-carboxamide N ⁇ (3 ⁇ chloro ⁇ 1 ⁇ methyl ⁇ 1H ⁇ pyrazol ⁇ 5 ⁇ yl) ⁇ 2 ⁇ cyclopropylpyrimidine ⁇ 5 ⁇ carboxamide (Int.60) Ryvu Therapeutics S.A.
  • RVU305 129 R10945WO DMAP (0.16 g, 1.31 mmol, 0.51 eq.), DIPEA (1.12 mL, 6.43 mmol, 2.5 eq.), 3-chloro-1-methyl-1H-pyra- zol-5-amine (0.34 g, 2.58 mmol, 1.0 eq.) and 2-cyclopropylpyrimidine-5-carboxylic acid (0.42 g, 2.56 mmol, 0.99 eq.) were taken in toluene (10.0 mL, 3.87 mL/mmol) and propylphosphonic anhydride (50% solution in EtOAc, 3.1 mL, 5.21 mmol, 2.02 eq.) was added dropwise at RT.
  • Step 2 TFA (1.7 mL, 22.2 mmol, 50.0 eq.) was added to a solution of N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2- cyclopropyl-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7-yl)methyl]pyrimidine-5- carboxamide (0.3 g, 0.446 mmol, 1.0 eq.) in DCM (5.0 mL). RM was stirred at RT for 4.5 h. After that time RM was poured into sat. Na2CO3/ice and stirred for a few minutes.
  • Example 24 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(tri- fluoromethyl)pyridine-3- N ⁇ (3 ⁇ cyano ⁇ 1 ⁇ methyl ⁇ 1H ⁇ pyrazol ⁇ 5 ⁇ yl) ⁇ 6 ⁇ (trifluoromethyl)pyridine ⁇ 3 ⁇ carboxamide
  • Phosphoryl trichloride 0.03 g, 3.93 mmol, 2.0 eq.
  • 6-(trifluoromethyl)pyridine-3-carboxylic acid 0.76 g, 1.965 mmol, 1.0 eq.
  • 5-amino-1-methyl-1H-pyrazole-3- carbonitrile (0.24 g, 1.965 mmol, 1.0 eq.
  • N,N-dimethylpyridin-4-amine 0.072 g,
  • the RM was stirred for 15 min at 0°C under nitrogen. After that time the reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3. Solution was transferred to separatory funnel and extracted with EtOAc (3x). Combined organic layers were washed with brine, then dried over anhydrous Na 2 SO 4 , filtered, and evaporated under reduced pressure.
  • RVU305 131 R10945WO N ⁇ ( ⁇ 4 ⁇ chloro ⁇ 1H,3H ⁇ furo[3,4 ⁇ c]quinolin ⁇ 7 ⁇ yl ⁇ methyl) ⁇ N ⁇ (3 ⁇ cyano ⁇ 1 ⁇ methyl ⁇ 1H ⁇ pyrazol ⁇ 5 ⁇ yl) ⁇ 6 ⁇ (trifluoromethyl)pyr- idine ⁇ 3 ⁇ carboxamide
  • Int.63 To a mixture of N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.62, 0.505 g, 1.54 mmol, 1.0 eq.) and 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int.
  • Step 2 TFA (1 mL) was added dropwise to a solution of tert-butyl N-(7- ⁇ [N-(3-cyano-1-methyl-1H-pyrazol-5-yl)- 1-[6-(trifluoromethyl)pyridin-3-yl]formamido]methyl ⁇ -1H,3H-furo[3,4-c]quinolin-4-yl)carbamate (0.255 g, 0.378 mmol, 1.0 eq.) in DCE (15.0 mL). RM was stirred at 60°C for 60 minutes. After that time RM was poured onto sat. Na2CO3 /ice and stirred for a few minutes. Obtained mixture was extracted with DCM (3x).
  • RVU305 132 R10945WO Example 25 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3- yl]pyrimidine-5-carboxamide 2 ⁇ cyclopropyl ⁇ N ⁇ [6 ⁇ (trifluoromethyl)pyridin ⁇ 3 ⁇ yl]pyrimidine ⁇ 5 ⁇ carboxamide (Int.64) P hosphorus oxychloride (0.57 g, 3.718 mmol, 2.001 eq.) was added dropwise to a solution of 2-cyclo- propylpyrimidine-5-carboxylic acid (0.305 g, 1.858 mmol, 1.0 eq.), 6-(trifluoromethyl)pyridin-3-amine (0.302 g, 1.863 mmol, 1.003 eq.) and N,N-dimethylpyridin-4-amine (0.067
  • the RM was stirred for 5 min at 0°C and then 40 min at RT under nitrogen. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3/1M NaOH mixture. It was extracted with EtOAc (3x) and the combined organic layers were washed with brine, then dried over anhydrous Na2SO4, fil- tered, and evaporated under reduced pressure.
  • Step 2 Obtained product was dissolved in DCM (7.5 mL) and trifluoroacetic acid (3.0 ml, 39.203 mmol) was added. The RM was stirred for 16 h at RT and evaporated under reduced pressure. Residue was partitioned between mixture of sat. aq. NaHCO3/1M NaOH and DCM. The aqueous phase was extracted with DCM, and the combined organic layers were washed with aq. NaHCO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FCC (0% to 10% EtOH gradient in DCM).
  • Ryvu Therapeutics S.A. RVU305 134 R10945WO NaH (60% dispersion in mineral oil, 0.243 g, 10.557 mmol, 3.0 eq.) was added portion wise to a solution of cyclopropanol (0.307 g, 5.278 mmol, 1.5 eq.) in anhydrous THF (10 mL) at 0°C. The mixture was stirred 30 min. at 0°C and then a solution of 2-fluoro-3-nitropyridine (0.5 g, 3.519 mmol, 1.0 eq.) in THF (3 mL) was added slowly dropwise. The reaction was stirred 30 min at 0°C and 3 h at RT.
  • N ⁇ (2 ⁇ cyclopropoxypyridin ⁇ 3 ⁇ yl) ⁇ 2 ⁇ cyclopropylpyrimidine ⁇ 5 ⁇ carboxamide (Int.68) Phosphorus oxychloride (1.3 g, 8.479 mmol, 2.881 eq.) was added dropwise to a solution of 2-cyclo- propoxypyridin-3-amine (Int.67, 0.52 g, 2.943 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.61 g, 3.716 mmol, 1.263 eq.) and N,N-dimethylpyridin-4-amine (0.1 g, 0.819 mmol, 0.278 eq.) in pyridine (16.0 mL) at 0°C.
  • the RM was stirred for 5 min at 0°C and then 40 min at RT under nitrogen. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3/1M NaOH mixture. It was ex- tracted with EtOAc (3x) and the combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
  • the crude material was purified by FCC (0% to 80% Ryvu Therapeutics S.A. RVU305 135 R10945WO EtOAc gradient in heptane) to give N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.
  • N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.68, 0.605 g, 1.756 mmol, 1.0 eq.) was suspended in acetonitrile (10.0 ml) and cesium carbonate (1.06 g, 3.253 mmol, 1.853 eq.) was added. The mixture was stirred for 5 min at RT.
  • Step 2 N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropyl-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H- furo[3,4-c]quinolin-7-yl)methyl]pyrimidine-5-carboxamide (0.575 g, 0.74 mmol, 1.0 eq.) was dissolved in DCM (10 mL) and trifluoroacetic acid (1.5 mL, 19.601 mmol, 26.48 eq.) was added. The RM was stirred for 16 h at RT and evaporated under reduced pressure.
  • Example 27 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(2-oxo-1,2-dihydropyridin-3-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide N ⁇ (2 ⁇ methoxypyridin ⁇ 3 ⁇ yl) ⁇ 6 ⁇ (trifluoromethyl)pyridine ⁇ 3 ⁇ carboxamide (Int.70) Phosphorus oxychloride (1.25 g, 8.153 mmol, 2.024 eq.) was added dropwise to a solution of 6-(trifluo- romethyl)pyridine-3-carboxylic acid (0.815 g, 4.265 mmol, 1.059 eq.), 2-methoxypyridin-3-amine (0.5 g, 4.028 mmol, 1.0 eq.) and N,N-dimethylpyridin-4-amine (0.145 g, 1.187 mmol, 0.295
  • the RM was stirred for 5 min at 0°C and then 40 min at RT under nitrogen. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3/1M NaOH mixture. It was extracted with EtOAc (3x) and the combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
  • the RM was stirred for 48 h at RT and evaporated under reduced pressure. Residue was partitioned between mixture of sat. aq. NaHCO3/1M NaOH and DCM. The aqueous phase was extracted with DCM, and the combined organic layers were washed with aq. NaHCO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was dissolved in DMSO and purified by preparative HPLC (basic conditions).
  • RVU305 138 R10945WO N ⁇ (6 ⁇ cyano ⁇ 2 ⁇ methylpyridin ⁇ 3 ⁇ yl) ⁇ 2 ⁇ cyclopropylpyrimidine ⁇ 5 ⁇ carboxamide Int.72, In a round bottom flask were placed N,N-dimethylpyridin-4-amine (0.130 g, 1.066 mmol, 0.5 eq.), 2-cy- clopropylpyrimidine-5-carboxylic acid (0.35 g, 2.132 mmol, 1.0 eq.) and 5-amino-6-methylpyridine-2-carbonitrile (0.284 g, 2.132 mmol, 1.0 eq.) followed by anhydrous pyridine (5 mL).
  • N,N-dimethylpyridin-4-amine 0.130 g, 1.066 mmol, 0.5 eq.
  • 2-cy- clopropylpyrimidine-5-carboxylic acid (0.35 g, 2.132 mmol, 1.0 eq.
  • reaction mixture was cooled to 0°C and then phosphoryl trichloride (0.654 g, 4.264 mmol, 2.0 eq.) was added dropwise.
  • RM was stirred at 0°C for 15 minutes and then was allowed to warm up to RT and stirred for 1.5 h. Reaction mixture was quenched with sat. aq. NaHCO3 solution and was extracted with DCM.
  • RVU305 139 R10945WO methylpyridin-3-yl)-2-cyclopropyl-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7- yl)methyl]pyrimidine-5-carboxamide (0.19 g, 0.168 mmol, 31%).
  • Step 2 N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropyl-N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H- furo[3,4-c]quinolin-7-yl)methyl]pyrimidine-5-carboxamide (0.03 g, 0.03 mmol, 1.0 eq.) was dissolved in DCM (2.0 ml) and TFA (1.0 ml) was added. The RM was stirred at RT for 4 h. Reaction mixture was quenched with sat. aq. NaHCO3 and 1N aq. NaOH to pH ⁇ 10. Obtained mixture was extracted with DCM.
  • Example 29 N ⁇ [(3R) ⁇ 4 ⁇ amino ⁇ 3 ⁇ methyl ⁇ 1H,3H ⁇ furo[3,4 ⁇ c]quinolin ⁇ 7 ⁇ yl]methyl ⁇ 2 ⁇ cyclopropyl ⁇ N ⁇ (2 ⁇ methylpyri- din ⁇ 3 ⁇ yl)pyrimidine ⁇ 5 ⁇ carboxamide and
  • Example 30 N ⁇ [(3S) ⁇ 4 ⁇ amino ⁇ 3 ⁇ methyl ⁇ 1H,3H ⁇ furo[3,4 ⁇ c]quinolin ⁇ 7 ⁇ yl]methyl ⁇ 2 ⁇ cyclopropyl ⁇ N ⁇ (2 ⁇ methylpyri- din ⁇ 3 ⁇ yl)pyrimidine ⁇ 5 ⁇ carboxamide
  • the title compounds were obtained from rac-N-( ⁇ 4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2- cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Example 21) by HPLC chiral separation (col- umn
  • Example 31 N-( ⁇ 4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 6-[(3,3-difluoropiperidin-4- yl)oxy]-2-methylpyridin-3-yl ⁇ pyrimidine-5-carboxamide N-(6-chloro-2-methylpyridin-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.74) 6-chloro-2-methylpyridin-3-amine (1.5 g, 10.52 mmol, 1.0 eq.) was dissolved in toluene (20.0 mL) and 2- cyclopropylpyrimidine-5-carboxylic acid (1.72 g, 10.48 mmol, 1.0 eq.) was added, followed by DMAP (0.3 g, 2.46 mmol, 0.23 eq.) and DIPEA (4.6 mL, 26.41 mmol, 2.5
  • T3P as 50 wt% solution in AcOEt (12.5 mL, 21.00 mmol, 2.0 eq.) was added to RM.
  • the reaction mixture was heated at reflux for 1.5 h and then it was cooled to RT.
  • the reaction was quenched with saturated solution of NaHCO3 in portion to pH 8-9.
  • or- ganic phase was separated and water phase was extracted with ethyl acetate (3x).
  • Organic layers were com- bined and washed with brine, dried with sodium sulfate. Drying agent was removed by filtration and washed with DCM and CH3Cl : i-PrOH (3:1) mixture.
  • RVU305 141 R10945WO tert-butyl 4- ⁇ [5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]oxy ⁇ -3,3-difluoropiperidine-1-carboxylate (Int.75) A mixture of tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (0.39 g, 1.644 mmol, 1.187 eq.), N- (6-chloro-2-methylpyridin-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.74, 0.4 g, 1.385 mmol, 1.0 eq.) and cesium carbonate (0.95 g, 2.916 mmol, 2.105 eq.) in Toluene (5.0 mL) and the mixture was sparged with argon for 10 min.
  • Step 1 A solution tert-butyl 4-( ⁇ 5-[N-( ⁇ 4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)2-cyclopropylpyrimidine-5- amido]-6-methylpyridin-2-yl ⁇ oxy)-3,3-difluoropiperidine-1-carboxylate (Int, 76, 0.083 g, 0.094 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.094 g, 0.562 mmol, 5.987 eq.) in DMSO
  • RM was diluted with water and extracted by DCM (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (0% to 60% EtOAc gradient in hexane) to give tert-butyl 4-[(5- ⁇ N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4- Ryvu Therapeutics S.A.
  • Step 2 The product was dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The RM was stirred at RT overnight. Then mixture was quenched with sat. aq. Na2CO3 solution and mixture was stirred at RT for 30 min. The mixture was extracted with DCM (3x).
  • Example 32 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 2-methyl-6-[3-(trifluorome- thyl)piperazin-1-yl]pyridin-3-yl ⁇ pyrimidine-5-carboxamide tert-butyl 4-(6-methyl-5-nitropyridin-2-yl)-2-(trifluoromethyl)piperazine-1-carboxylate (Int.77) A 6-chloro-2-methyl-3-nitropyridine (0.2 g, 1.159 mmol, 1.0 eq.) and tert-butyl 2-(trifluoromethyl)pipera- zine-1-carboxylate (0.33 g, 1.30 mmol, 1.12 eq.) were mixed in DMSO (7.0 mL) and then TEA (0.32 mL, 2.30 mmol, 1.98 eq.) was added.
  • the RM was heated at 80°C for 1 h. The reaction was quenched with sat. aq. Na2CO3 solution and extracted with EtOAc (3x). Organic layers were washed with brine and dried over Na2SO4 and evaporated.
  • RVU305 144 R10945WO ⁇ 4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl
  • 2-cyclopropylpyrimidine-5-amido]-6-methylpyridin-2-yl ⁇ -2-(tri- fluoromethyl)piperazine-1-carboxylate Int.80, 0.29 g, 0.38 mmol, 60%, off-white solid, m/z [M+H] + :724.9).
  • RM was diluted with water/Na2CO3 sat. and extracted with DCM(2x). Combined organic layers were washed with water, brine and dried over Na2SO4. The crude mixture was purified by FCC (0% to 35% MeCN gradient in DCM) to give tert-butyl 4-(5- ⁇ N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4- c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido ⁇ -6-methylpyridin-2-yl)-2-(trifluoromethyl)piperazine-1- carboxylate (Int.81, 0.24 g, 0.261 mmol, 69%, yellowish solid, m/z [M+H] + : 855.9).
  • RM was stirred at RT over- night. After that time RM was poured onto sat. Na2CO3 solution/ice and stirred for 10 min, next brine was added and product was extracted with DCM with addition of CHCl3:i-PrOH (3:1) mixture (3x). Organic layers was com- bined, washed with 1M K2CO3 solution, brine and dried over Na2SO4 and evaporated.
  • 19 F NMR (377 MHz, DMSO-d6) ⁇ -73.99 – -74.16 (m, 3F).
  • Example 33 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 6-[4-(2-hydroxyethyl)-3-(tri- fluoromethyl)piperazin-1-yl]-2-methylpyridin-3-yl ⁇ pyrimidine-5-carboxamide
  • N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 2-methyl-6-[3-(trifluoromethyl) piper- azin-1-yl]pyridin-3-yl ⁇ pyrimidine-5-carboxamide (Example 32, 0.035 g, 0.058 mmol, 1.0 eq.) in MeOH (3.0 mL), 1,4-dioxane-2,5-diol (0.016 g, 0.13 mmol) and acetic acid (
  • RVU305 146 R10945WO tert-butyl 4-(4-amino-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (Int.82) To tert-butyl 4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.6 g, 1.93 mmol, 1.0 eq.) in a mix- ture of EtOH (40.0 mL) and water (13.0 mL), NH4Cl (0.52 g, 9.72 mmol, 5.03 eq.) and iron (0.54 g, 9.67 mmol, 5.00 eq.) were added.
  • RM was stirred at 70°C for 1.5 h. RM was filtered through cotton, washed with EtOH and DCM. Then solvents were evaporated and residues was diluted with sat. aq. NaHCO3 solution and extracted with DCM (3x). Organic layers were combined, washed with brine and dried over Na2SO4 and concentrated in vacuo to give crude product tert-butyl 4-(4-amino-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (Int.82, 0.54 g, 1.48 mmol, 77%, red-brown oil) which was used for next step without purification.
  • tert-butyl 4-[4-(2-cyclopropylpyrimidine-5-amido)-3-methyl-1H-pyrazol-1-yl]piperidine-1-carboxylate (Int.83) A DMAP (0.045 g, 0.37 mmol, 0.25 eq.), DIPEA (0.65 mL, 3.73 mmol, 2.52 eq.), 2-cyclopropylpyrimidine-5-car- boxylic acid (0.27 g, 1.65 mmol, 1.11 eq.) and tert-butyl 4-(4-amino-3-methyl-1H-pyrazol-1-yl)piperidine-1-car- boxylate (Int.82, 0.54 g, 1.48 mmol, 1.0 eq.) were taken in DMF (10.0 mL) and T3P (50% in EtOAc, 1.77 mL, 2.97 mmol, 2.00 eq.) was added at RT dropwise.
  • the RM was diluted with mixture of sat. aq. Na2CO3 solution and water and extracted with DCM (3x). Com- bined organic layers were washed with water, brine and dried over Na2SO4 and evaporated.
  • the crude mixture was purified by FCC (0% to 100% MeCN gradient in DCM) to give tert-butyl 4-(4- ⁇ N-[(4- ⁇ [(3,4-dime- thylphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido ⁇ -3-methyl-1H- pyrazol-1-yl)piperidine-1-carboxylate (Int.85, 0.52 g, 0.523 mmol, 61%, yellow solid, [M+H] + : 775.9).
  • RM was stirred at RT overnight. After that time RM was poured onto sat. aq. Na2CO3 solution/ice and stirred for few minutes, next brine was added and product was extracted with DCM with addition of CHCl3:i-PrOH (3:1) mixture (3x). Organic layers was com- bined, washed with 1M K2CO3 solution, brine and dried over Na2SO4 and evaporated.
  • the RM was stirred at RT for 15 min and then at 80°C for 1 h.
  • the reaction was diluted with ethyl acetate.
  • the mixture was transferred to separatory funnel and extracted by saturated NaHCO3 solution. Combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude [1-(6-methyl-5-nitropyridin-2-yl)piperidin-4-yl]methanol (Int.86, 0.741 g, 2.89 mmol, 135%, yellow solid, m/z [M+H] + : 252.0) which was used for next step without purification.
  • RVU305 149 R10945WO followed by DMAP (0.02 g, 0.164 mmol, 0.086 eq.), and DIPEA (0.6 mL, 3.445 mmol, 1.80 eq.). Then, T3P (50 wt% solution in AcOEt, 1.4 mL, 4.704 mmol, 2.47 eq.) was added to RM. The reaction mixture was heated at reflux for 1 h and then it was cooled to RT. The reaction was quenched with saturated solution of NaHCO3 in portion to pH 8-9. Then, organic phase was separated and water phase was extracted with ethyl acetate (3x).
  • Step 2 To a solution of product in DCM (5 mL) TFA (1 mL) was added at 0°C. The reaction was stirred at RT over- night. Ater that the RM was diluted with DCM, quenched by sat. aq. NaHCO3 solution and extracted with DCM and then with mixture of CHCl3:i-PrOH (3:1). Organic phases was combined, dried over Na2SO4 and filtered. Ryvu Therapeutics S.A. RVU305 150 R10945WO Filtrate was concentrated in vacuum.
  • Example 36 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2- methylpyridin-3-yl]pyrimidine-5-carboxamide 6- ⁇ 2-[(tert-butyldimethylsilyl)oxy]ethoxy ⁇ -2-methyl-3-nitropyridine (Int.90) A 6-chloro-2-methyl-3-nitropyridine (0.31 g, 1.796 mmol, 1.0 eq.), 2-[(tert-butyldimethylsilyl)oxy]ethan-1-ol (0.34 g, 1.928 mmol, 1.073 eq.) and Cs2CO3 (1.1 g, 3.376 mmol, 1.879 eq.) were mixed in toluene (8.0 mL) and the mixture was flushed with argon for 10 min.
  • 6- ⁇ 2-[(tert-butyldimethylsilyl)oxy]ethoxy ⁇ -2-methylpyridin-3-amine (Int.91) To a solution of 6- ⁇ 2-[(tert-butyldimethylsilyl)oxy]ethoxy ⁇ -2-methyl-3-nitropyridine (Int.90, 0.51 g, 1.518 mmol, 1.0 eq.) in acetone (14.0 mL) was added zinc (1.0 g, 15.30 mmol, 10.08 eq.). Next the flask was placed in an ice bath and sat. aq. NH4Cl solution (6.0 mL) was added dropwise. Then RM was stirred for 1 h at RT.
  • RM was diluted with DCM and filtrated through Celite. Next, filtrate was diluted with water and sat. aq. HNaCO3 solution Ryvu Therapeutics S.A. RVU305 151 R10945WO and extracted with DCM (2x). Organic layers were combined, washed with brine, dried over Na2SO4 and evap- orated to give 6- ⁇ 2-[(tert-butyldimethylsilyl)oxy]ethoxy ⁇ -2-methylpyridin-3-amine (Int.91, 0.45 g, 1.21 mmol, 80%, colorless oil, m/z [M+H] + : 283.0).
  • T3P 50 wt% solution in AcOEt, 0.7 mL, 2.33 mmol, 1.93 eq.
  • the reaction mixture was heated at reflux for 1 h and then it was cooled to RT.
  • the reaction was quenched with saturated solution of NaHCO3 in portion to pH 8-9.
  • organic phase was separated and water phase was extracted with ethyl acetate (3x).
  • Organic layers were combined and washed with brine, dried with sodium sulfate and filtrated. All solvents were evaporated.
  • Example 37 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 1-[1-(2-hydroxyethyl)piperi- din-4-yl]-3-methyl-1H-pyrazol-4-yl ⁇ pyrimidine-5-carboxamide
  • N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-[3-methyl-1-(piperidin-4-yl)-1H-pyrazol- 4-yl]pyrimidine-5-carboxamide (Example 34, 0.093 g, 0.168 mmol, 1.0 eq.) in MeOH (2.0 mL), 1,4-dioxane-2,5- diol (0.04 g, 0.333 mmol) and acetic acid (0.048 mL, 0.89 mmol, 5.0 e
  • Example 38 rac-N-( ⁇ 4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-(2-methyl-6- ⁇ [(2R,4R)-2- (trifluoromethyl)piperidin-4-yl]oxy ⁇ pyridin-3-yl)pyrimidine-5-carboxamide Ryvu Therapeutics S.A.
  • RVU305 153 R10945WO tert-Butyl 4-[(6-methyl-5-nitropyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carboxylate (Int.94) A 6-chloro-2-methyl-3-nitropyridine (0.27 g, 1.56 mmol, 1.0 eq.), tert-butyl 4-hydroxy-2-(trifluorome- thyl)piperidine-1-carboxylate (0.48 g, 1.78 mmol, 1.14 eq.) and Cs2CO3 (1.07 g, 3.284 mmol, 2.1 eq.), were mixed in toluene (7.0 mL) and the mixture was flushed with argon for 10min.
  • tert-Butyl 4-[(5-amino-6-methylpyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carboxylate (Int.95)
  • tert-butyl 4-[(6-methyl-5-nitropyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carbox- ylate (Int.94, 0.4 g, 0.95 mmol, 1.0 eq.) in a mixture of MeOH (3.0 mL) and EtOAc (6.0 mL)
  • palladium on car- bon (10%, 50% wet, 0.35 g) was added. Air was removed from the flask and hydrogen was introduced from the balloon.
  • reaction mixture was heated at 75°C for 1.5 h.
  • the reaction mixture was diluted with saturated solution of Na2CO3 and extracted with EtOAc. Combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated.
  • the residue was purified by FCC (0% to 40% MeCN gradient in DCM) to obtain tert-butyl 4- ⁇ [5-(2-cyclopropylpyrimidine-5- amido)-6-methylpyridin-2-yl]oxy ⁇ -2-(trifluoromethyl)piperidine-1-carboxylate (Int.96, 0.36 g, 0.69 mmol, 83%, oil, m/z [M+H] + : 425.50).
  • reaction mixture was stirred at RT overnight.
  • the reaction mixture was poured onto a satu- rated solution of Na2CO3 / ice and stirred for few minutes, next brine was added and the crude product was ex- tracted with DCM with addition of CHCl3/iPrOH 3/1 v/v mixture (3x).
  • Organic layers were combined, washed with 1M K2CO3, brine and and dried over Na2SO4, filtered and evaporated.
  • reaction mixture was stirred at 40°C for 2 h. Then, the reaction mixture was concentrated, di- luted with a saturated solution of Na 2 CO 3 and extracted by EtOAc (3x). The organic layers were washed with cold 1M HCl solution, water and brine and dried over Na2SO4, filtered and evaporated. The crude product was triturated in an approx.100 ml of MTBE/EtOAc (19:1) mixture, filtered and washed with MTBE, then dried.
  • the RM was cooled down to RT, concen- trated to dryness, diluted with DCM and neutralized by a saturated solution of Na2CO3 solution to pH ⁇ 9.
  • the crude product was extracted with CHCl3/i-PrOH (3:1) mixture.
  • the combined organic layers were concentrated and diluted in DCM (100 mL), followed by an addition of a solution of HCl 6N (100 mL) and stirred for 1 h.
  • the water layer was separatedand the organic layer was washed with 1M HCl solution.
  • tert-Butyl 4-(5-amino-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.102) To a solution of tert-butyl 4-(5-nitro-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.101, 4.39 g, 11.959 mmol, 1.0 eq.) in acetone (50 mL), Zn (7.82 g, 119.608 mmol, 10.002 eq.) was added. A saturated solu- tion of NH4Cl (30.0 mL, 2.51 ml/mmol) was added slowly in a manner to not exceed 30°C.
  • tert-Butyl 4-[5-(2-cyclopropylpyrimidine-5-amido)-1,3-benzothiazol-2-yl]piperidine-1-carboxylate (Int.103) To the suspension of tert-butyl 4-(5-amino-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.102, 0.5 g, 1.395 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.240 g, 1.464 mmol, 1.05 eq.) and DMAP (0.043 g, 0.349 mmol, 0.25 eq.) in toluene (15 mL), DIPEA (0.607 mL, 3.486 mmol, 2.5 eq.) was added, fol- lowed by T3P as 50% in EtOAc (1.66 mL, 2.789 mmol, 2.0 eq.).
  • the RM was concentrated, diluted with water and extracted by EtOAc (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCCs (first: 0 to 3% MeOH gradient in DCM; second: 0 to 60% EtOAc gradient in heptane) to obtain tert-butyl 4-(5- ⁇ N-[(4- ⁇ [(2,4-di- methoxyphenyl)methyl]amino ⁇ -1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido ⁇ -1,3-ben- zothiazol-2-yl)piperidine-1-carboxylate (Int.105, 0.48 g, 0.568 mmol, 77%, beige solid, m/z [M+H]+: 828.8).
  • Example 40 N-( ⁇ 4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 2-[1-(2-hydroxyacetyl)piperi- din-4-yl]-1,3-benzothiazol-5-yl ⁇ pyrimidine-5-carboxamide 2-(4- ⁇ 5-[N-( ⁇ 4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)2-cyclopropylpyrimidine-5-amido]-1,3-benzothiazol- 2-yl ⁇ piperidin-1-yl)-2-oxoethyl acetate (Int.106) To a solution of N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-[2-(piperidin-4-yl)- 1,3-benzothiazol
  • the RM was stirred at RT for 1 h. Then, the reaction mixture was diluted with water and extracted with DCM (3x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0 to 7% MeOH gradient in DCM) to get 2-(4- ⁇ 5-[N-( ⁇ 4- amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)2-cyclopropylpyrimidine-5-amido]-1,3-benzothiazol-2-yl ⁇ piperidin- 1-yl)-2-oxoethyl acetate (Int.106, 0.035 g, 0.046 mmol, 55%, white solid, m/z [M+H] + : 679.0).
  • Example 41 N-( ⁇ 4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N- ⁇ 2-[1-(2-hydroxyacetyl)piperi- din-4-yl]-1,3-benzothiazol-5-yl ⁇ pyrimidine-5-carboxamide N-( ⁇ 4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-[2-(1- ⁇ 2-[(tert-butyldimethylsilyl)oxy]ethyl ⁇ piperidin-4-yl)- 1,3-benzothiazol-5-yl]-2-cyclopropylpyrimidine-5-carboxamide (Int.107) To a solution of N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-2-cyclopropyl-N-[2-(piperidin-4-
  • reaction mixture was stirred at RT for 4 h.
  • STAB (0.103 g, 0.486 mmol, 2.507 eq.) was added and the reaction mixture stirred at RT overnight. Then, the reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3 and water.
  • RVU305 161 R10945WO 0.133 mmol, 1.0 eq.) in DCM (10 mL), TFA (1.02 mL, 13.32 mmol, 99.987 eq.) was added and the RM was stirred at RT overnight. TFA was evaporated and then the RM was diluted by CHCl3/i-PrOH (3:1) mixture, cooled down on an ice-bath and was carefully neutralized with 2M NaOH solution to pH 10-11. An organic layer was separated, washed with water, brine, dried over Na2SO4, filtered, and concentrated.
  • Example 42 N ⁇ ( ⁇ 4 ⁇ Amino ⁇ 1H,3H ⁇ furo[3,4 ⁇ c]quinolin ⁇ 7 ⁇ yl ⁇ methyl) ⁇ 2 ⁇ cyclopropyl ⁇ N ⁇ [6 ⁇ (6,6 ⁇ difluoro ⁇ 1,4 ⁇ diazepan ⁇ 1 ⁇ yl) ⁇ 2 ⁇ methylpyridin ⁇ 3 ⁇ yl]pyrimidine ⁇ 5 ⁇ carboxamide Ryvu Therapeutics S.A.
  • RVU305 162 R10945WO tert ⁇ Butyl 6,6 ⁇ difluoro ⁇ 4 ⁇ (6 ⁇ methyl ⁇ 5 ⁇ nitropyridin ⁇ 2 ⁇ yl) ⁇ 1,4 ⁇ diazepane ⁇ 1 ⁇ carboxylate (Int.108) To a solution of 6 ⁇ chloro ⁇ 2 ⁇ methyl ⁇ 3 ⁇ nitropyridine (0.137 g, 0.796 mmol, 1.0 eq.), tert ⁇ butyl 6,6 ⁇ difluoro ⁇ 1,4 ⁇ diazepane ⁇ 1 ⁇ carboxylate (0.188 g, 0.796 mmol, 1.0 eq.) in anhydrous DMSO (4 mL), triethylamine (0.55 ml, 3.98 mmol, 5 eq.) was added.
  • the reaction was stirred at RT for 10 min and at 120°C for 21 h.
  • the reaction mixture was diluted with water and with saturated solution of NaHCO3 was added.
  • the obtained mixture was extracted with ethyl acetate (3x).
  • the combined organic phases were washed with brine and dried over Na2SO4, filtered and evaporated.
  • the crude product was purified by FCC (0% to 33% EtOAc gradient in hex- ane) to obtain tert ⁇ butyl 6,6 ⁇ difluoro ⁇ 4 ⁇ (6 ⁇ methyl ⁇ 5 ⁇ nitropyridin ⁇ 2 ⁇ yl) ⁇ 1,4 ⁇ diazepane ⁇ 1 ⁇ carboxylate (Int.108, 0.164 g, 0.344 mmol, 43%).
  • reaction mixture was stirred at RT under hydrogen balloon for 2 h.
  • the RM was filtered through celite® and washed with methanol.
  • the reaction mixture was concentrated to obtain tert ⁇ butyl 4 ⁇ (5 ⁇ amino ⁇ 6 ⁇ methylpyridin ⁇ 2 ⁇ yl) ⁇ 6,6 ⁇ difluoro ⁇ 1,4 ⁇ diazepane ⁇ 1 ⁇ carboxylate (Int.109, 0.143 g, m/z [M+H] + : 343.5).
  • the crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to obtain tert ⁇ butyl 4 ⁇ (5 ⁇ N ⁇ [(4 ⁇ [(2,4 ⁇ dimethoxyphenyl)me- thyl]amino ⁇ 1H,3H ⁇ furo[3,4 ⁇ c]quinolin ⁇ 7 ⁇ yl)methyl]2 ⁇ cyclopropylpyrimidine ⁇ 5 ⁇ amido ⁇ 6 ⁇ methylpyridin ⁇ 2 ⁇ yl) ⁇ 6,6 ⁇ difluoro ⁇ 1,4 ⁇ diazepane ⁇ 1 ⁇ carboxylate (Int.112, 0.152 g, 0.158 mmol, 81%, solid, m/z [M+H] + : 838.40).
  • 19 F NMR (377 MHz, DMSO) ⁇ -96.61 – -96.89 (m).
  • the RM was stirred at 90°C for 2 h. Then the RM was cooled down, quenched with a saturated solution of NaHCO3 and extracted with EtOAc (3x). The organic layers were washed with water, brine and dried over Na2SO4, filtered and evapo- rated. The crude product was purified by FCC (0 to 60% EtOAc gradient in heptane) to obtain tert-butyl N-[(1- ⁇ [5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]oxy ⁇ cyclopropyl)methyl]-N-methylcarbamate (Int.
  • the RM was evaporated, then diluted with water and extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was puri- fied by FCCs (first: 0 to 5% MeOH gradient in DCM; second: 0 to 50% EtOAc gradient in heptane; third: 0 to Ryvu Therapeutics S.A.
  • RVU305 166 R10945WO 50% EtOAc gradient in DCM) to obtain tert-butyl N-( ⁇ 1-[(5- ⁇ N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H- furo[3,4-c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido ⁇ -6-methylpyridin-2-yl)oxy]cyclopropyl ⁇ methyl)- N-methylcarbamate (Int.117, 0.222 g, 0.249 mmol, 51%, yellow solid, m/z [M+H] + : 803.0).
  • the RM was cooled down, diluted with EtOAc and the organic solution was washed four times with brine, dried over Na2SO4, filtered and concentrated.
  • the crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to obtain tert-butyl 4-(5- ⁇ N-[(4- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -1H,3H- furo[3,4-c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido ⁇ -6-methylpyridin-2-yl)-3-(trifluoromethyl)pipera- zine-1-carboxylate (Int.123, 0.18 g, 0.187 mmol, 76%, yellow solid, m/z [M+H]+: 855.9).
  • the RM was diluted with DCM (80 mL) and carefully basified with a saturated solution of NaHCO3. After 30 minutes of vigorous stirring, the organic layer was separated, washed carefully with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, fil- tered and concentrated.
  • the crude product was purified by FCC (0% to 5% MeOH gradient in DCM).
  • RVU305 170 R10945WO N-(4-methylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.124) To solution of 4-methylpyrimidin-5-amine (0.3 g, 2.749 mmol, 1.0 eq.), 6-(trifluoromethyl)pyridine-3-car- boxylic acid (0.525 g, 2.749 mmol, 1.0 eq.), DMAP (0.016 g, 0.137 mmol, 0.05 eq.) and DIPEA (1.2 mL, 6.889 mmol, 2.506 eq.) in toluene (5.0 mL), T3P as 50% in EtOAc (3.3 mL, 5.544 mmol, 2.017 eq.) was added.
  • 4-methylpyrimidin-5-amine 0.3 g, 2.749 mmol, 1.0 eq.
  • 6-(trifluoromethyl)pyridine-3-car- boxylic acid 0.525
  • RVU305 171 R10945WO A suspension of N-( ⁇ 4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(4-methylpyrimidin-5-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide (Int.125, 0.73 g, 1.344 mmol, 1.0 eq.), tert-butyl carbamate (0.31 g, 2.646 mmol, 1.97 eq.) and Cs2CO3 (1.1 g, 3.376 mmol, 2.513 eq.) in dioxane (10.0 mL) was sparged with argon for 5 min.
  • reaction was stirred at room temperature overnight. Then, the reaction mixture was diluted with DCM and with a satu- rated solution of K2CO3. The crude product was extracted and the water phases were washed by DCM and then organic phases was combined, dried over Na2SO4, filtered and evaporated.
  • Example 47 N-( ⁇ 4-amino-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide Ryvu Therapeutics S.A.
  • RVU305 174 R10945WO N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.129)
  • DMAP 0.096 g, 0.786 mmol, 0.499 eq.
  • DIPEA 0.684 ml, 3.927 mmol, 2.493 eq.
  • 2,4-dimethylpyrim- idin-5-amine (0.204 g, 1.656 mmol, 1.052 eq.
  • 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.301 g, 1.575 mmol, 1.0 eq.) were taken in DMF (8.0 mL) and T3P as 50% solution in EtOAc (1.869 mL, 3.14 mmol, 1.994 eq.) was added dropwise at 0°C.
  • N-( ⁇ 4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl ⁇ methyl)-N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3- carboxamide (Int.130) To a solution of N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.129, 0.46 g, 1.522 mmol, 1.0 eq.) and 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (0.395 g, 1.523 mmol, 1.001 eq.) in ACN (8.0 mL), Cs2CO3 (0.99 g, 3.038 mmol, 1.997 eq.) was added.
  • reaction mixture was stirred at 78°C for 4.5 h.
  • the reaction mixture was cooled down to room temperature, diluted with water, extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evap- orated.
  • Step 2 To a solution of the product in DCM (3.0 mL), trifluoroacetic acid (1.5 ml, 19.601 mmol, 50.492 eq.) was added at 0°C. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was diluted with DCM and quenched by a saturated solution of NaHCO3. The crude product was extracted with DCM, the water phases were washed by DCM and then organic phases was combined, dried over Na2SO4, filtered and evaporated.
  • reaction mixture was flushed with argon for 10min at RT, then 4-chloro-7-(chloromethyl)- 1H,3H-furo[3,4-c]quinoline (Int. C, 0.54 g, 2.08 mmol, 1.2 eq.) was added and the reaction mixture was stirred at 70°C for 2 h.
  • the reaction mixture was diluted with saturated solution of Na2CO3 and extracted with DCM (2x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated.

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Abstract

The present invention relates to compounds of formula (I) and salts, stereoisomers, atrop-isomers, rotamers, tautomers or N-oxides thereof that are useful as PRMT5 inhibitors. The present invention further relates to the compounds of formula (I) for use as a medicament and to pharmaceutical compositions comprising said compounds.

Description

Ryvu Therapeutics S.A. RVU305 1 R10945WO Ryvu Therapeutics S.A. ul. Leona Henryka Sternbacha 2 30-394 Kraków Poland PRMT5 Inhibitors Field of the Invention The present invention relates to compounds of formula (I) and salts, stereoisomers, atropisomers, rotamers, tautomers or N-oxides thereof that are useful as PRMT5 inhibitors. The present invention further relates to the compounds of formula (I) for use as a medicament and to pharmaceutical compositions comprising said com- pounds. Background of the Invention Protein arginine methyltransferases are enzymes that catalyze the transfer of methyl groups from S-adeno- sylmethionine (SAM) to the arginine residues on histones and other proteins. Protein methyltransferase 5 (PRMT5) is an arginine methyltransferase that can catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (SDMA) (Blanc and Richard 2017). PRMT5 conjugated with WD-re- peat containing proteins (MEP50/WDR77) forms methylosome, which regulates essential cellular functions via symmetric dimethylation of target proteins involved in regulation of gene expression, RNA splicing, signal trans- duction, metabolism and other functions (Koh, Bezzi and Guccione 2015; Wu et al., 2021). Homozygous deletions of p16/CDKN2a (cyclin dependent kinase inhibitor 2A) locus are prevalent in cancer and often involve co-deletion of adjacent genes. Metabolic gene MTAP (methylthioadenosine phosphorylase) is localized at the 9p21 chromosome in the close proximity to p16/CDKN2A tumor-suppressor locus. Co-deletion of MTAP may be observed in 80-90% of all tumors harboring homozygous deletion of CDKN2A, which repre- sents 10 - 15% of all human tumors (Gao et al., 2013, Marjon et al., 2016; Firestone and Schramm 2017,). Many of these tumor types, such as non-small cell lung cancer, pancreatic adenocarcinoma, glioblastoma or mesothelioma are associated with poor prognosis, representing a significant unmet medical need. MTAP, a critical enzyme in the methionine salvage pathway, is the only enzyme capable of degrading methyl- thioadenosine (MTA). Data from several genome-wide shRNA drop out screens performed on wide panels of cancer cell lines have revealed a selective requirement for PRMT5 activity in MTAP-deleted cells (Kruykov et al., 2016; Marjon et al, 2016; Markarov et al., 2016). Accumulation of MTA in cells with MTAP deletion causes a partial inhibition of the methylation activity of PRMT5, making those cells vulnerable to further PRMT5 inhibi- tion, which in turn reduces the level of symmetric arginine dimethylation of the whole proteome, and thus an increased sensitivity of cells to modulation of the methylosome activity. PRMT5 is a well-known essential gene regulating many cellular processes including cell growth and prolifera- tion, apoptosis and DNA damage response. Conditional PRMT5 knockout or siRNA mediated knockdown stud- ies indicate that significant liabilities could be associated with inhibiting PRMT5 in normal tissues. Therefore, novel approaches are required to target PRMT5 in cancerous cells while not affecting viability of normal cells Ryvu Therapeutics S.A. RVU305 2 R10945WO (MTAP WT). MTA-cooperative PRMT5 inhibitors could provide an improved therapeutic window, by preferential binding to MTA-bound PRMT5, which is enriched in MTAP deficient tumor cells. In view of the above, compounds acting as PRMT5 inhibitors are useful for treating one or more diseases se- lected from the group consisting of cancer and pre-cancerous syndromes. Accordingly, there is a need for compounds acting as PRMT5 inhibitors, preferably for MTA-bound PRMT5, and thus provide a therapeutic impact in the treatment of diseases, in which the inhibition of PRMT5 is benefi- cial. Objects and Summary of the Invention It is therefore an object of the present invention to provide compounds, which act as PRMT5 inhibitors, prefer- ably with a high activity. It is another object of the present invention to provide compounds, which are suitable for use as a medica- ment. It is another object of the present invention to provide compounds, which are suitable for use in the treat- ment of one or more diseases, in which the inhibition of PRMT5 is beneficial. It is yet another object to provide compounds, which are suitable for use in the treatment of one or more diseases selected from the group con- sisting of cancer and pre-cancerous syndromes. The above objects can be achieved by the compounds of formula (I) as defined herein as well as pharmaceu- tical compositions comprising the same, and by the medical uses thereof. The inventors of the present invention inter alia surprisingly found that the compounds of formula (I) as de- fined herein act as PRMT5 inhibitors, in particular for MTA-bound PRMT5. Accordingly, the compounds of for- mula (I) can be used as a medicament, in particular for the treatment of one or more diseases selected from the group consisting of cancer and pre-cancerous syndromes. In a first aspect, the present invention therefore relates to a compound of formula (I) or a salt, stereoisomer, atropisomer, rotamer, tautomer, or N-oxide thereof; wherein A is ; wherein the wavy line marks the connection to the N-atom of the remainder of the molecule; and wherein Ryvu Therapeutics S.A. RVU305 3 R10945WO A1 is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA1; Y1 is CR2a, CHR2a, C(=O), N, or NR2b; Y2 is CR4a, CHR4a, O, S, N, or NR4b; wherein R2a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3; R2b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; R4a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3; and R4b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and wherein the dashed lines in the ring A1, as well as between E1 and E2, and between E2 and E3, denote that an additional bond may be present, so that a double bond is formed; and wherein E1 is CRE1a, CRE1aRE1b, O, S, N, or NRN1; E2 is CRE2a, CRE2aRE2b, O, S, N, or NRN2; E3 is CRE3a, CRE3aRE3b, O, S, N, or NRN3; X3 is CH, CRX3, or N; X4 is CH, CRX4, or N; X5 is CH, CRX5, or N; R1 is NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-alkyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, or heter- ocyclyloxy-C1-C2-alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned Ryvu Therapeutics S.A. RVU305 4 R10945WO groups is independently unsubstituted or substituted with one or more, same or different substituents RY; R3a is H, or D; R3b is H, or D; and wherein RA1 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, or a 3- to 7-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobi- cyclyl rings independently comprise 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 sub- stitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or substi- tuted with one or more, same or different substituents RA4; or two RA1 together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned carbocyclyl or heterocyclyl is independently unsubstituted or substi- tuted with one or more, same or different substituents RA2; RA2 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobi- cyclyl rings independently comprise 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 sub- stitutable atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA3; RA3 is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4- alkyl-NRN4RN5, C(=O)-C1-C4-hydroxyalkyl, or C(=O)-C1-C4-alkyl-NRN4RN5; RA4 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkyl- NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently comprise 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 atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA3; RC1 is H, or C1-C4-alkyl; RC2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or Ryvu Therapeutics S.A. RVU305 5 R10945WO heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3; RE1a, RE1b, RE2a, RE2b, RE3a, and RE3b are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN1, RN2 and RN3 are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN4 is H, or C1-C4-alkyl; RN5 is H, or C1-C4-alkyl; RN6 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3; RN7 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3; RS1 is C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C5-cycloalkyl, or NRN4RN5; RS2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3; RO is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3; RX3, RX4, and RX5 are independently halogen, CN, NH2, C(=O)NH2, CD3, C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, or C1-C4-hydroxyalkyl; RY is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hy- droxyalkyl, C1-C4-alkoxy-C1-C4-alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, Ryvu Therapeutics S.A. RVU305 6 R10945WO or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy, heterocyclyl, heterocyclyloxy, or heter- ocyclyl-C1-C2-alkyl, or 5- to 10-membered saturated carbobicyclyl or hetereobicyclyl, wherein the afore- mentioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; or two RY attached to the same atom form an oxo group; or two RY together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned het- erocyclyl 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; RZ is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-hydroxyalkyl, or 3- to 6-membered saturated carbocyclyl, carbocyclyloxy, heterocyclyl, or heterocyclyloxy, wherein the aforementioned heterocyclyl rings comprise 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; or two RZ attached to the same atom form an oxo group or cyclopropyl. In one embodiment, A is the following moiety wherein the wavy line marks the connection to the N-atom of the remainder of the molecule; and wherein A1 is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA1; Y1 is CR2a, CHR2a, C(=O), N, or NR2b; Y2 is CR4a, CHR4a, O, S, N, or NR4b; wherein R2a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3; R2b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; Ryvu Therapeutics S.A. RVU305 7 R10945WO R4a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3; and R4b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and wherein the dashed lines in the ring A1, as well as between E1 and E2, and between E2 and E3, denote that an additional bond may be present, so that a double bond is formed; and wherein E1 is CRE1a, CRE1aRE1b, O, S, N, or NRN1; E2 is CRE2a, CRE2aRE2b, O, S, N, or NRN2; E3 is CRE3a, CRE3aRE3b, O, S, N, or NRN3; X3 is CH, CRX3, or N; X4 is CH, CRX4, or N; X5 is CH, CRX5, or N; R1 is NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-alkyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, or heter- ocyclyloxy-C1-C2-alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; R3a is H, or D; R3b is H, or D; and wherein RA1 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, car- bobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings inde- pendently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA4; or two RA1 together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or Ryvu Therapeutics S.A. RVU305 8 R10945WO heteroatom in the aforementioned carbocyclyl or heterocyclyl is independently unsubstituted or substi- tuted with one or more, same or different substituents RA2; RA2 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently com- prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized; and wherein each substitutable atom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different sub- stituents RA3; RA3 is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, or C1-C4-haloalkyl; RA4 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently com- prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized; and wherein each substitutable atom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different sub- stituents RA3; RC1 is H, or C1-C4-alkyl; RC2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RE1a, RE1b, RE2a, RE2b, RE3a, and RE3b are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN1, RN2 and RN3 are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN4 is H, or C1-C4-alkyl; RN5 is H, or C1-C4-alkyl; RN6 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RN7 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl 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; Ryvu Therapeutics S.A. RVU305 9 R10945WO and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RS1 is C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C5-cycloalkyl, or NRN4RN5; RS2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RO is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RX3, RX4, and RX5 are independently halogen, CN, NH2, C(=O)NH2, CD3, C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, or C1-C4-hydroxyalkyl; RY is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hy- droxyalkyl, C1-C4-alkoxy-C1-C4-alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy, heterocyclyl, heterocyclyloxy, or heter- ocyclyl-C1-C2-alkyl, or 5- to 10-membered saturated carbobicyclyl or hetereobicyclyl, wherein the afore- mentioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; or two RY attached to the same atom form an oxo group; or two RY together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned het- erocyclyl 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; RZ is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or 3- to 6-membered saturated carbocyclyl, carbocyclyloxy, heterocyclyl, or heterocyclyloxy, wherein the aforementioned heterocyclyl rings com- prise 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; or two RZ attached to the same atom form an oxo group. In a preferred embodiment, E1 is CRE1a, CHRE1a, or NRN1; E2 is O or N; E3 is CRE3a, CHRE3a, or NRN3; and wherein preferably RE1a, RE3a, RN1, and RN3 are independently H, C1-C2-alkyl, or C1-C2-haloalkyl. In another preferred embodiment, the compound is a compound of formula (Ia’) Ryvu Therapeutics S.A. RVU305 10 R10945WO ; and wherein preferably RE1a is H, CH3, or CF3; and RE3a is H. In another preferred embodiment, X3 is CH or CRX3, wherein RX3 is halogen; X4 is CH; and X5 is CH; and wherein preferably X3 is CH. In another preferred embodiment, the . In another preferred embodiment A1 is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocy- clic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently unsubstituted or substituted with one or more, same or different substituents RA1; wherein Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH or N, preferably CH. and wherein preferably A1 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, or 2-oxo-1,2-dihydropyridinyl; wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently un- substituted or substituted with one or more, same or different substituents RA1; wherein Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH or N, preferably CH. In a more preferred embodiment, A Ryvu Therapeutics S.A. RVU305 11 R10945WO ; ; A2 is a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 n is 0, 1, or 2. In another preferred embodiment, R2a is H, C1-C2-alkyl, cyclopropyl, or cyclopropyloxy; and R2b is H, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; and wherein preferably R2a is H, or C1-C2-alkyl; and R2b is C1-C2-alkyl. In another preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, C(=O)RC2, ORO, cyclopropyl, or a 5- to 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is independently unsubstituted or sub- stituted with one or more, same or different substituents RA2; RA2 is C1-C2-alkyl, NRN6RN7, a 3- to 6-membered saturated carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2- alkyl, or a 5- to 7-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or dif- Ryvu Therapeutics S.A. RVU305 12 R10945WO ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized; and wherein the aforementioned rings are independently unsubstituted or sub- stituted with one or more, preferably one or two, same or different substituents RA3; RA3 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RA4 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RN6 is H, or C1-C2-alkyl; RN7 is C1-C2-alkyl, C1-C2-hydroxyalkyl, C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RC2 is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, or a 5- or 6-membered saturated carbocyclyl or heterocy- clyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3; and RO is H, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocy- clyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or dif- ferent substituents RA3;and wherein preferably RA3 is C1-C2-alkyl or N(CH3)2. In a more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one substituent RA2; and RA2 is a 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents RA3; and wherein preferably RA3 is C1-C2-alkyl. In another more preferred embodiment, RA1 is C1-C4-hydroxyalkyl, ORO, or a 6- or 7-membered saturated heterocyclyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and Ryvu Therapeutics S.A. RVU305 13 R10945WO wherein the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two substituents RA2; and RA2 is C1-C2-alkyl, a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or two, same or different substituents RA3; RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- to 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3; RA3 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; and RA4 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5. In another preferred embodiment, R1 is a 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein said carbocyclyl or heterocy- clyl is independently unsubstituted or substituted with one or more, same or different substituents RY; and wherein preferably R1 is wherein B1 is CH or N, and B2 is CH or N. In another preferred embodiment, RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; and wherein preferably RY is F, CN, CH3, CF3, or cyclopropyl. In another preferred embodiment, the compound is a compound of formula (Ia’) Ryvu Therapeutics S.A. RVU305 14 R10945WO ; wherein RE1a is H, CH3, or CF3; RE3a is H; X3 is CH; X4 is CH; and X5 is CH; A1 is phenyl, or a 5- or 6-membered aromatic heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently unsubstituted or substituted with one or more, same or different substituents RA1; Y1 is CR2a, C(=O), N, or NR2b; Y2 is CH or N; R2a is H, C1-C2-alkyl, cyclopropyl, or cyclopropyloxy; R2b is H, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; R1 is wherein B1 is CH or N; B2 is CH or N; and RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6RN7, ORO, cyclo- propyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is independently unsubstituted or sub- stituted with one or more, same or different substituents RA2; RA2 is C1-C2-alkyl, or a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two, same or different heteroatoms se- Ryvu Therapeutics S.A. RVU305 15 R10945WO lected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforemen- tioned heterocyclyl rings are independently unsubstituted or substituted with one or two, same or differ- ent substituents RA3; RA3 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RA4 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RN6 is H, or C1-alkyl; RN7 is C1-C2-alkyl, or C1-C2-hydroxyalkyl; and RO is C1-C2-hydroxyalkyl, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2- alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different het- eroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized; and wherein the aforementioned cyclopropyl or heterocyclyl rings are independently unsubstituted or substituted with one or more, same or different substituents RA3. In another preferred embodiment, the compound of formula (I) is selected from the group consisting of: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-5-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyridine-3-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-cyclopropylpyridin-3-yl)pyridine-3-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)py- rimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3,6-dimethylpyrazin-2-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; Ryvu Therapeutics S.A. RVU305 16 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2-cyclopropylpyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-oxo-1,2-dihydropyridin-3-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]py- rimidine-5-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropylpyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyr- idine-3-carboxamide; and N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)py- rimidine-5-carboxamide. In another preferred embodiment, the compound of formula (I) is selected from the group consisting of: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[(3,3-difluoropiperidin-4-yl)oxy]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[3-(trifluoromethyl)piperazin-1- yl]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(2-hydroxyethyl)-3-(trifluoromethyl)pi- perazin-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4- yl]pyrimidine-5-carboxamide; Ryvu Therapeutics S.A. RVU305 17 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperidin-1-yl]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2-methylpyridin-3- yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-me- thyl-1H-pyrazol-4-yl}pyrimidine-5-carboxamide; rac-N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-6-{[(2R,4R)-2-(trifluorome- thyl)piperidin-4-yl]oxy}pyridin-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyacetyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(6,6-difluoro-1,4-diazepan-1-yl)-2- methylpyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-6-{1-[(methylamino)methyl]cyclo- propoxy}pyridin-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[2-(trifluoromethyl)piperazin-1- yl]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-methylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethylpyridin-3-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methyl-1,2-thiazol-4-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-ethylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)py- rimidine-5-carboxamide; N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]acetamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]pyr- idine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 18 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3- benzodiazol-6-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6- yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-6-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(piperidin-4-yl)methyl]-1,3-benzothiazol- 5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(1-methylpiperidin-4-yl)methyl]-1,3-ben- zothiazol-5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[3-methyl-2-(1-methylpiperidin-4-yl)-2H- indazol-6-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)eth- oxy]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyr- idine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide; N-{[4-amino-3-(trifluoromethyl)-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]py- rimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)py- rimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1-methyl-1H-pyrazol-5-yl)pyridine-3-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,5-dimethylpyridin-3-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-ethyl-1-methyl-1H-pyrazol-5-yl)pyrimi- dine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyridine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 19 R10945WO N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-methyl-1,2-thiazol-4-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-ethyl-1-methyl-1H-pyrazol-4-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[(1-methylpiperidin-4- yl)oxy]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(propan-2-yl)-1H-pyrazol-4- yl]pyrimidine-5-carboxamide; and N‐({4‐amino‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(3‐cyano‐1‐methyl‐1H‐pyrazol‐5‐yl)‐6‐(trifluoromethyl)pyr- idine‐3‐carboxamide. In a further aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceuti- cally effective amount of the compound of formula (I) as defined herein, and optionally a pharmaceutically ac- ceptable carrier, diluent or excipient. In yet another aspect, the present invention relates to a compound of formula (I) as defined herein or a phar- maceutical composition comprising the same as defined herein for use in medicine. In particular, the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein for use in modulating PRMT5, in particular (partial) inhibition of PRMT5. In one embodiment, the compound of the present invention or a pharmaceutical composition comprising the same is for use in the treatment of a disease selected from the group consisting of cancer and pre-cancerous syndromes. In further aspects, the present invention relates to methods of treatment comprising the administration of a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein to a human or animal body. Detailed Description In the following, preferred embodiments of the substituents in the above formula (I) are described in further detail. It is to be understood that each preferred embodiment is relevant on its own as well as in combination with other preferred embodiments. Furthermore, it is to be understood that the preferences in each case also apply to the salts, stereoisomers, tautomers, atropisomers, rotamers and N-oxides of the compounds of the invention. As indicated above, in the (I) Ryvu Therapeutics S.A. RVU305 20 R10945WO the dashed lines between E1 and E2 and between E2 and E3 denote that an additional bond may be present, so that a double bond is formed. It is to be understood that the bond between E1 and E2 and the bond between E2 and E3 cannot both be a double bond at the same time. Thus, the dashed lines between E1 and E2 and be- tween E2 and E3 denote that either a double bond is present between E1 and E2 , a double bond is present be- tween E2 and E3, or no double bond is present between E1, E2 and E3. The compound of formula (I) may there- fore be a compound of formula (Ia), (Ib), or (Ic), preferably a compound of formula (Ia), as shown below: It is to be understood that the substituent meanings for E1, E2, and E3 are in each case selected such that suitable valences of the atoms are realized. In connection with compounds of formula (Ia), this means that E1 is CRE1aRE1b, O, S, or NRN1; E2 is CRE2aRE2b, O, S, or NRN2; E3 is CRE3aRE3b, O, S, or NRN3; preferably that E1 is CRE1aRE1b; E2 is O, S, or NRN2; E3 is CRE3aRE3b; more preferably that E1 is CHRE1a; E2 is O; E3 is CHRE3a. In connection with the compounds of formula (Ib), this means that E1 is CRE1aRE1b, O, S, or NRN1; E2 is CRE2a or N; E3 is CRE3a or N; preferably that E1 is NRN1; E2 is N; E3 is CRE3a. In connection with the compounds of formula (Ic), this means that E1 is CRE1a or N; Ryvu Therapeutics S.A. RVU305 21 R10945WO E2 is CRE2a or N; E3 is CRE3aRE3b, O, S, or NRN3; preferably that E1 is CRE1a; E2 is N; E3 is NRN3. Thus, in a preferred embodiment, in the compounds of formula (I), E1 is CRE1a, CHRE1a, or NRN1; E2 is O or N; E3 is CRE3a, CHRE3a, or NRN3. Thus, in a preferred embodiment, the compound of formula (I) is a compound of formula (Ia’), (Ib’), or (Ic’), more preferably a compound of formula (Ia’), as shown below: In connection with the compounds of formula (I), as well as in connection with the compounds of formula (Ia), (Ib), (Ic), (Ia’), (Ib’), and (Ic’), the following preferred embodiments regarding the remaining substituents of the tricyclic core moiety X3, X4, and X5 are relevant. As indicated above, each of X3, X4, and X5 can be nitrogen (N), unsubstituted carbon (CH), or substituted car- bon (CRX3, CRX4, or CRX5). If X3, X4, or X5 is a substituted carbon (CRX3, CRX4, or CRX5), the substituent at the carbon atom is represented by RX3, RX4, and RX5, respectively. In a preferred embodiment of the compound of formula (I), none, one, or two of X3, X4, and X5 are N, more preferably none or one of X3, X4, and X5 are N, and even more preferably none of X3, X4, and X5 is N. In another preferred embodiment of the compound of formula (I), X4 is CH or CRX4, preferably CH. In another preferred embodiment of the compound of formula (I), X5 is CH or CRX5, preferably CH. In another preferred embodiment of the compound of formula (I), X3 is CH or CRX3, preferably CH. In a more preferred embodiment of the compound of formula (I), X4 is CH or CRX4 and X5 is CH or CRX5, even more preferably X4 and X5 are CH. In a particularly preferred embodiment, X4 and X5 are CH and X3 is CH or CRX3, preferably CH. Therefore, in a preferred embodiment, in the compounds of formula (I), E1 is CRE1a, CHRE1a, or NRN1; Ryvu Therapeutics S.A. RVU305 22 R10945WO E2 is O or N; E3 is CRE3a, CHRE3a, or NRN3; X3 is CH, CRX3, or N; X4 is CH or CRX4; X5 is CH or CRX5. In a more preferred embodiment, in the compounds of formula (I), E1 is CRE1a, CHRE1a, or NRN1; E2 is O or N; E3 is CRE3a, CHRE3a, or NRN3. X3 is CH, CRX3, or N; X4 is CH; X5 is CH. In an even more preferred embodiment, in the compounds of formula (I), E1 is CRE1a, CHRE1a, or NRN1; E2 is O or N; E3 is CRE3a, CHRE3a, or NRN3. X3 is CH or CRX3; X4 is CH; X5 is CH. In an even more preferred embodiment, in the compounds of formula (I), E1 is CRE1a, CHRE1a, or NRN1; E2 is O or N; E3 is CRE3a, CHRE3a, or NRN3. X3 is CH; X4 is CH; X5 is CH. Thus, in a more preferred embodiment, the compound of formula (I) is a compound of formula (Ia*), (Ib*), or (Ic*), preferably a compound of formula (Ia*) or (Ic*), more preferably a compound of formula (Ia*) as shown below: (Ic*) wherein preferably, X3 is CH or CRX3, more preferably CH. Ryvu Therapeutics S.A. RVU305 23 R10945WO If present, in connection with the compounds of formula (I), as well as in connection with the compounds of formula (Ia), (Ib), or (Ic), and in connection with the compounds of formula (Ia’), (Ib’), or (Ic’), in particular in connection with the compounds of formula (Ia*), (Ib*), or (Ic*), the following preferred embodiments regarding the substituents RE1a, RE1b, RE2a, RE2b, RE3a, RE3b, RN1, RN2, RN3, RX3, RX4, and RX5 are relevant. As indicated above, in connection with the compounds of the present invention, RE1a, RE1b, RE2a, RE2b, RE3a, and RE3b are independently H, C1-C4-alkyl, or C1-C4-haloalkyl. In a preferred embodiment, RE1a, RE1b, RE2a, RE2b, RE3a, and RE3b are independently H, C1-C2-alkyl, or C1-C2-haloalkyl. In a more preferred embodiment, RE1a, RE1b, RE2a, RE2b, RE3a, and RE3b are independently H or C1-C2-alkyl. In an even more preferred embodiment, RE1a, RE1b, RE2a, RE2b, RE3a, and RE3b are independently H or CH3. In an even more preferred embodiment, RE1b, RE2b, and RE3b are H; and RE1a, RE2a, and RE3a are independently H, C1-C2-alkyl, or C1-C2-haloalkyl, preferably H or C1-C2-alkyl, more pref- erably H or CH3. In one particularly preferred embodiment, One of RE1a, RE2a, and RE3a, if present, is H, C1-C2-alkyl, or C1-C2-haloalkyl, preferably H or C1-C2-alkyl, more preferably H or CH3; and the other one of RE1a, RE2a, and RE3a as well as RE1b, RE2b, and RE3b, if present, are H. In another particularly preferred embodiment, RE1a, RE1b, RE2a, RE2b, RE3a, and RE3b are H. Further, in connection with the compounds of the present invention, RN1, RN2 and RN3 are independently H, C1-C4-alkyl, or C1-C4-haloalkyl. In a preferred embodiment, RN1, RN2 and RN3 are independently H, C1-C2-alkyl, or C1-C2-haloalkyl. In a more preferred embodiment, RN1, RN2 and RN3 are independently H or C1-C2-alkyl. In an even more preferred embodiment, RN1, RN2 and RN3 are independently H or CH3. In a particularly preferred embodiment, none or one of RE1a, RE2a, RE3a, RN1, RN2 and RN3, if present, is C1-C2- alkyl or C1-C2-haloalkyl, preferably C1-C2-alkyl, more preferably CH3; and RE1b, RE2b, RE3b, if present, as well as the remaining ones of RE1a, RE2a, RE3a, RN1, RN2 and RN3, if present, are H. In another particularly preferred embodiment, each of RE1a, RE2a, RE3a, RE1b, RE2b, RE3b, RN1, RN2 and RN3, if pre- sent, is H. Further, in connection with the compounds of the present invention, RX3, RX4, and RX5 are independently halogen, CN, OH, NH2, C(=O)NH2, CD3, C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, or C1-C4-hydroxyalkyl. In a preferred embodiment, Ryvu Therapeutics S.A. RVU305 24 R10945WO RX3, RX4, and RX5 are independently halogen, CN, NH2, C(=O)NH2, CD3, C1-C2-alkyl, C1-C2-alkoxy, C1-C2- alkoxy-C1-C2-alkyl, C1-C2-haloalkyl, C1-C2-haloalkoxy, or C1-C2-hydroxyalkyl. In a more preferred embodiment, RX3, RX4, and RX5 are independently halogen, CN, NH2, C(=O)NH2, CD3, C1-C2-alkyl, C1-C2-alkoxy, C1-C2- haloalkyl, or C1-C2-hydroxyalkyl. In an even more preferred embodiment, RX3, RX4, and RX5 are independently halogen, C1-C2-alkyl, C1-C2-alkoxy, or C1-C2-haloalkyl. In an even more preferred embodiment, RX3, RX4, and RX5 are independently halogen. In another preferred embodiment of the compounds of the present invention, none, or only one or two of RX3, RX4, and RX5 are present. In a more preferred embodiment, none or only one of RX3, RX4, and RX5 is present. In a particularly preferred embodiment, none of RX3, RX4, and RX5 is present so that X3, X4 and X5 are N or CH, preferably CH. Overall, in the compounds of formula (Ia’), (Ib’), or (Ic’), in particular in the compounds of formula (Ia*), (Ib*), or (Ic*), preferably, RE1a, RE3a, RN1, and RN3 are independently H or C1-C2-alkyl, more preferably H or CH3. Particu- larly preferably, RE1a andRE3a are H or CH3, and RN1 and RN3 are CH3. Thus, in connection with the compounds of formula (Ia’) or (Ia*), it is particularly preferred that RE1a, RE3a are H or CH3, preferably RE1a is CH3 and RE3a is H. In connection with the compounds of formula (Ib’) or (Ib*), it is particularly preferred that RN1 is CH3 and RE3a is H. In connection with the compounds of formula (Ic’) or (Ic*), it is particularly preferred that RE1a is H and RN3 is CH3. Thus, in a particularly preferred embodiment, the compound of formula (I) is a compound of formula (Ia**), preferably a compound of formula (Ia**-1) . In a more the of formula is a of formula (Ia*-1) or ; (Ia*-1*), (Ia*-2*). In one particularly preferred embodiment, the compound of formula (I) is a compound of formula (Ia*-1), prefer- ably a compound of formula (Ia*-1*). Ryvu Therapeutics S.A. RVU305 25 R10945WO In another particularly preferred embodiment, the compound of formula (I) is a compound of formula (Ia*-2), preferably a compound of formula (Ia*-2*). If the compound of formula (I) is a compound of formula (Ia**), preferably a compound of formula (Ia**-1), the compound may be a compound of formula (Ia**-A) or (Ia**-B), . In one embodiment, the compound of formula (I) is a compound of formula (Ia**-A), preferably a compound of formula (Ia**-1-A). In another embodiment, the compound of formula (I) is a compound of formula (Ia**-B), preferably a com- pound of formula (Ia**-1-B). Similarly, if the compound of formula (I) is a compound of formula (Ia*-2), preferably a compound of formula (Ia*-2*), the compound may be a compound of formula (Ia*-2-A) or (Ia*-2-B), ; . In one embodiment, the compound of formula (I) is a compound of formula (Ia*-2-A), preferably a compound of formula (Ia*-2*-A). In another embodiment, the compound of formula (I) is a compound of formula (Ia*-2-B), preferably a com- pound of formula (Ia*-2*-B). In connection with the compounds of formula (I), as well as in connection with the compounds of formula (Ia), (Ib), and (Ic), and in connection with the compounds of formula (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), and (Ic*), in particular in connection with the compounds of formula (Ia**), (Ia**-1), (Ia*-1), (Ia*-1*), (Ia*-2), (Ia*-2*), (Ia**-A), (Ia**-B), (Ia**-1-A), (Ia**-1-B), (Ia*-2-A), (Ia*-2-B), (Ia*-2*-A), and (Ia*-2*-B), the following preferred embodiments regard- ing the substituent R1 are relevant. Ryvu Therapeutics S.A. RVU305 26 R10945WO As indicated above, in connection with the compounds of the present invention, R1 is NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-alkyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, or heter- ocyclyloxy-C1-C2-alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; wherein RY is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hy- droxyalkyl, C1-C4-alkoxy-C1-C4-alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy, heterocyclyl, heterocyclyloxy, or heter- ocyclyl-C1-C2-alkyl, or 5- to 10-membered saturated carbobicyclyl or hetereobicyclyl, wherein the afore- mentioned heterocyclyl or heterobicyclyl rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; or two RY attached to the same atom form an oxo group; or two RY together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned het- erocyclyl 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; RZ is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or 3- to 6-membered saturated carbocyclyl, carbocyclyloxy, heterocyclyl, or heterocyclyloxy, wherein the aforementioned heterocyclyl rings com- prise 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; or two RZ attached to the same atom form an oxo group. In a preferred embodiment, R1 is C1-C3-alkyl, C1-C3-alkoxy, C1-C2-alkoxy-C1-C2-alkyl, C1-C3-haloalkyl, C1-C2-aminoalkyl, C1-C2-amino- alkyl, 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, cyclopropyl-C1-C2-alkyl, cyclopropyloxy-C1-C2-alkyl, or 5- to 6-membered aromatic heterocyclyl-C1-C2- alkyl, wherein the aforementioned heterocyclyl rings comprise one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is inde- pendently unsubstituted or substituted with one or more, same or different substituents RY; wherein RY is as defined above in connection with the compounds of formula (I), and wherein preferably RY is halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or 3- to 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; or two RY attached to the same atom form an oxo group; wherein Ryvu Therapeutics S.A. RVU305 27 R10945WO RZ is halogen, CN, C1-alkyl, C1-haloalkyl, or C1-alkoxy; preferably halogen or C1-alkyl; and wherein more preferably RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably RY is F, CN, CH3, CF3, or cyclopropyl, even more preferably RY is CN, cyclopropyl, or CF3, even more preferably RY is cyclopropyl or CF3. In a more preferred embodiment, R1 is C1-C2-alkyl, or a 5- or 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substi- tutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substi- tuted with one or more, same or different substituents RY; wherein RY is as defined above in connection with the compounds of formula (I), and wherein preferably RY is halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or 3- to 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; more preferably RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably RY is F, CN, CH3, CF3, or cyclopropyl, even more preferably RY is CN, cyclopropyl, or CF3, even more preferably RY is cyclopropyl or CF3. In an even more preferred embodiment, R1 is a 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein the aforementioned rings are independently unsubstituted or substituted with one or more, preferably one, same or different substit- uents RY; wherein RY is as defined above in connection with the compounds of formula (I), and wherein preferably RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably RY is F, CN, CH3, CF3, or cyclopropyl, even more preferably RY is CN, cyclopropyl, or CF3, even more preferably RY is cyclopropyl or CF3. Ryvu Therapeutics S.A. RVU305 28 R10945WO In an even more preferred embodiment, R1 is pyridinyl or pyrimidinyl; wherein the pyridinyl or pyrimidinyl is independently unsubstituted or substituted with one or more, pref- erably one, same or different substituents RY; wherein RY is as defined above in connection with the compounds of formula (I), and wherein preferably RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably RY is F, CN, CH3, CF3, or cyclopropyl, even more preferably RY is CN, cyclopropyl, or CF3, even more preferably RY is cyclopropyl or CF3. In one even more preferred embodiment, R1 is pyridinyl; wherein the pyridinyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents selected from F, CN, CF3, or cyclopropyl. In another even more preferred embodiment, R1 is pyrimidinyl; wherein the pyrimidinyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents selected from F, CN, CF3, or cyclopropyl, preferably cyclopropyl. In one particularly preferred embodiment, R1 is pyridinyl substituted with one substituent selected from F, CN, CF3, or cyclopropyl. In another particularly preferred embodiment, R1 is pyrimidinyl substituted with one substituent selected from F, CN, CF3, or cyclopropyl, preferably cyclo- propyl. Thus, in a particularly preferred embodiment, R1 is wherein B1 is CH or N, and B2 is CH or N wherein RY is as defined above in connection with the compounds of formula (I), and wherein preferably RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably RY is F, CN, CH3, CF3, or cyclopropyl, even more preferably RY is CN, cyclopropyl, or CF3, even more preferably RY is cyclopropyl or CF3; particularly preferably Ryvu Therapeutics S.A. RVU305 29 R10945WO RY is cyclopropyl. In a more preferred embodiment, R1 is wherein with the compounds of formula (I), and wherein preferably RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably RY is F, CN, CH3, CF3, or cyclopropyl, even more preferably RY is CN, cyclopropyl, or CF3, even more preferably RY is cyclopropyl or CF3; particularly preferably RY is cyclopropyl. In one particularly preferred embodiment, R1 is wherein RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably RY is F, CN, CH3, CF3, or cyclopropyl, even more preferably RY is CN, cyclopropyl, or CF3, even more preferably RY is cyclopropyl or CF3; particularly preferably RY is cyclopropyl. In another particularly preferred embodiment, R1 is ; wherein RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; more preferably RY is F, CN, CH3, CF3, or cyclopropyl, even more preferably Ryvu Therapeutics S.A. RVU305 30 R10945WO RY is CN, cyclopropyl, or CF3, even more preferably RY is cyclopropyl or CF3; particularly preferably RY is cyclopropyl. In one particularly preferred embodiment, R1 is . In connection with the compounds of formula (I), as well as in connection with the compounds of formula (Ia), (Ib), and (Ic), and in connection with the compounds of formula (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), (Ic*), (Ia**), (Ia**-1), (Ia*-1), (Ia*-1*), (Ia*-2), (Ia*-2*), (Ia**-A), (Ia**-B), (Ia**-1-A), (Ia**-1-B), (Ia*-2-A), (Ia*-2-B), (Ia*-2*-A), and (Ia*- 2*-B), in particular in connection with the preferred embodiments regarding R1 defined above, the following pre- ferred embodiments regarding the A moiety are relevant. As indicated above, in connection with the compounds of the present invention, A is the following moiety wherein the wavy line marks the connection to the N-atom of the remainder of the molecule; and wherein A1 is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA1; Y1 is CR2a, CHR2a, C(=O), N, or NR2b; Y2 is CR4a, CHR4a, O, S, N, or NR4b; and wherein the dashed lines in ring A1 denote that an additional bond may be present, so that a double bond is formed. It is to be understood that not both bonds indicated by dashed lines in ring A1 can be a double bond at the same time. Thus, the dashed lines in ring A1 denote that either one of the two bonds is a double bond or none of the two bonds is a double bond. Preferably, one of the two dashed lines in ring A1 indicates the presence of a double bond. Further, it is to be understood that the presence of a double bond and the substituent meanings for Y1 and Y2 are in each case selected such that suitable valences of the atoms are realized. Ryvu Therapeutics S.A. RVU305 31 R10945WO The moiety A may therefore be a moiety (A-1), (A-2), (A-3), (A-4), (A-5), or (A-6), preferably (A-1) or (A-5), more preferably (A-1), as shown below: In a preferred embodiment, A is selected from the group consisting of (A-1), (A-2*), (A-3*), (A-4*), (A-5), and (A-6*), preferably (A-1) and (A-5*), more preferably (A-1), as shown below: Thus, in a particularly preferred embodiment, A is the following moiety wherein Y1, A1, and R4a are as defined for the compound of formula (I), preferably as defined in the preferred embodiments below. In a particularly preferred embodiment, R4a is H. As indicated above, it is to be understood that the substituent meanings for Y1 are in each case selected such that suitable valences of the atoms are realized. Thus, if A is the moiety (A-1), Y1 is CR2a, CHR2a, C(=O), N, or NR2b; preferably Y1 is CR2a, C(=O), N, or NR2b; more preferably Y1 is CR2a or NR2b. Ryvu Therapeutics S.A. RVU305 32 R10945WO If A is the moiety (A-2), (A-3), (A-4), or (A-6), and the dashed lines in ring A1 do not indicate the presence of a double bond, Y1 is CR2a, CHR2a, C(=O), N, or NR2b. If A is the moiety (A-2), (A-3), (A-4), or (A-6), and the dashed lines in ring A1 indicate the presence of a double bond, or in other words, if A is the moiety (A-2*), (A-3*), (A-4*), or (A-6*), Y1 is CR2a or N. If A is the moiety (A-5), Y1 is CR2a, preferably Y1 is CR2a or NR2b. Thus, in a particularly preferred embodiment, A is selected from the group consisting of (A-1*) and (A-1**), wherein compound of formula (I), preferably as defined in the pre- ferred embodiments below. In a particularly preferred embodiment, R4a is H. In a more preferred embodiment, R4a is H, R2a is H or CH3, and R2b is CH3. Preferably, A1 is phenyl, pyridinyl, or pyrazolyl, wherein each substi- tutable atom in the aforementioned rings other than the carbon or nitrogen atom(s) shown in the structures above is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA1. In a preferred embodiment, A1 is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocy- clic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently unsubstituted or substituted with one or more, same or different substituents RA1; wherein preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CR4a or N, more preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH or N, even more preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH. Ryvu Therapeutics S.A. RVU305 33 R10945WO In a more preferred embodiment, A1 is phenyl or a 5- or 6-membered aromatic heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or two heteroatoms selected from N or S, wherein said N-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or N in the aforementioned aromatic rings is independently unsubstituted or substituted with one or more, same or different substituents RA1; wherein preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CR4a or N, more preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH or N, even more preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH. In an even more preferred embodiment, A1 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, triazolyl, isothiazolyl, or 2-oxo-1,2-di- hydropyridinyl, wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA1; wherein preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CR4a or N, more preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH or N, even more preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH. In an even more preferred embodiment, A1 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, or 2-oxo-1,2-dihydropyridinyl, wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA1; wherein preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CR4a or N, more preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH or N, even more preferably Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH. In an even more preferred embodiment, Ryvu Therapeutics S.A. RVU305 34 R10945WO A1 is phenyl, pyridinyl, or pyrazolyl, wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA1; wherein preferably Y1 is CR2a, N, or NR2b; and Y2 is CR4a or N, more preferably Y1 is CR2a, N, or NR2b; and Y2 is CH or N, even more preferably Y1 is CR2a or NR2b; and Y2 is CH. In one particularly preferred embodiment, A1 is phenyl, wherein the phenyl is independently unsubstituted or substituted with one or more, prefera- bly one or two, same or different substituents RA1; wherein Y1 is CR2a; and Y2 is CR4a. In another particularly preferred embodiment, A1 is pyridinyl, wherein the pyridinyl is independently unsubstituted or substituted with one or more, pref- erably one, same or different substituents RA1; wherein preferably Y1 is CR2a; and Y2 is CR4a or N, more preferably Y1 is CR2a; and Y2 is CH or N, even more preferably Y1 is CR2a; and Y2 is CH. In another particularly preferred embodiment, A1 is pyrazolyl, wherein the pyrazolyl is independently unsubstituted or substituted with one or more, pref- erably one, same or different substituents RA1; wherein preferably Y1 is CR2a or NR2b; and Y2 is CR4a, more preferably Y1 is CR2a or NR2b; and Y2 is CH. Thus, in preferred embodiments, A is selected from the group consisting of Ryvu Therapeutics S.A. RVU305 35 R10945WO more preferably from the group consisting of ; , , , ; wherein in the embodiments defined above, n is 0, 1, or 2; and A2 is a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 preferably A2 is a fused thiazolyl, imidazolyl, or pyrazolyl; more preferably A2 is a fused thiazolyl. Ryvu Therapeutics S.A. RVU305 36 R10945WO In connection with the compounds of formula (I), as well as in connection with the compounds of formula (Ia), (Ib), and (Ic), and in connection with the compounds of formula (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), (Ic*), (Ia**), (Ia**-1), (Ia*-1), (Ia*-1*), (Ia*-2), (Ia*-2*), (Ia**-A), (Ia**-B), (Ia**-1-A), (Ia**-1-B), (Ia*-2-A), (Ia*-2-B), (Ia*-2*-A), and (Ia*- 2*-B), in particular in connection with the preferred embodiments regarding R1 and A or A1 defined above, pref- erably, A1 is unsubstituted or substituted with one, two, or three, same or different substituents RA1, more pref- erably A1 is unsubstituted or substituted with one or two, same or different substituents RA1. It is to be under- stood that when ring A1 or any embodiment thereof is referred to herein as being unsubstituted, this refers to said ring A1 or embodiment thereof not being substituted with a substituent RA1, i.e., not having a further substit- uent in addition to R2a, R2b, R4a, and R4b, if present. Further, in connection with the compounds of formula (I), as well as in connection with the compounds of for- mula (Ia), (Ib), and (Ic), and in connection with the compounds of formula (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), (Ic*), (Ia**), (Ia**-1), (Ia*-1), (Ia*-1*), (Ia*-2), (Ia*-2*), (Ia**-A), (Ia**-B), (Ia**-1-A), (Ia**-1-B), (Ia*-2-A), (Ia*-2-B), (Ia*-2*-A), and (Ia*-2*-B), in particular in connection with the preferred embodiments regarding R1 and the preferred em- bodiments of A or A1 defined above, the following preferences regarding R2a, R2b, R4a, and R4b, if present, are relevant. As indicated above, in connection with the compounds of the present invention, if present, R2a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3. In a preferred embodiment, R2a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy. In a more preferred embodiment, R2a is H, C1-C2-alkyl, cyclopropyl, or cyclopropyloxy. In an even more preferred embodiment, R2a is H or C1-C2-alkyl. In an even more preferred embodiment, R2a is H or CH3. In one particularly preferred embodiment, R2a is H. In another particularly preferred embodiment, R2a is CH3. As indicated above, in connection with the compounds of the present invention, if present, R2b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. Ryvu Therapeutics S.A. RVU305 37 R10945WO In a preferred embodiment, R2b is H, C1-C2-alkyl, C1-C2-haloalkyl, or a 3- or 4-membered saturated carbocyclyl. In a more preferred embodiment, R2b is H, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl. In an even more preferred embodiment, R2b is C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl. In an even more preferred embodiment, R2b is C1-C2-alkyl. In a particularly preferred embodiment, R2b is CH3. As indicated above, in connection with the compounds of the present invention, if present, R4a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3. In a particularly preferred embodiment, R4a is H. As indicated above, in connection with the compounds of the present invention, if present, R4b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. In a preferred embodiment, R4b is H, C1-C2-alkyl, C1-C2-haloalkyl, or a 3- or 4-membered saturated carbocyclyl. In a more preferred embodiment, R4b is H, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl. In an even more preferred embodiment, R4b is C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl. In an even more preferred embodiment, R4b is C1-C2-alkyl. In a particularly preferred embodiment, R4b is CH3. Thus, in preferred embodiments, A is selected from the group consisting of Ryvu Therapeutics S.A. RVU305 38 R10945WO group ; more preferably from the group consisting of ; wherein in the embodiments defined above, n is 0, 1, or 2; and A2 is a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 preferably A2 is a fused thiazolyl, imidazolyl, or pyrazolyl; more preferably A2 is a fused thiazolyl. Further, in connection with the compounds of formula (I), as well as in connection with the compounds of for- mula (Ia), (Ib), and (Ic), and in connection with the compounds of formula (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), (Ic*), (Ia**), (Ia**-1), (Ia*-1), (Ia*-1*), (Ia*-2), (Ia*-2*), (Ia**-A), (Ia**-B), (Ia**-1-A), (Ia**-1-B), (Ia*-2-A), (Ia*-2-B), (Ia*-2*-A), and (Ia*-2*-B), in particular in connection with the preferred embodiments regarding R1 and the preferred em- bodiments of A or A1, including the preferred embodiments regarding R2a, R2b, R4a, and R4b, defined above, the following preferences regarding the substituents RA1 and RA2, if present, are relevant. As indicated above, in connection with the compounds of the present invention, if present, Ryvu Therapeutics S.A. RVU305 39 R10945WO RA1 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, or a 3- to 7-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobi- cyclyl rings independently comprise 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 sub- stitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or substi- tuted with one or more, same or different substituents RA4; or two RA1 together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned carbocyclyl or heterocyclyl is independently unsubstituted or substi- tuted with one or more, same or different substituents RA2; RA2 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobi- cyclyl rings independently comprise 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 sub- stitutable atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA3; RA3 is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4- alkyl-NRN4RN5, C(=O)-C1-C4-hydroxyalkyl, or C(=O)-C1-C4-alkyl-NRN4RN5; RA4 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkyl- NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently comprise 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 atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA3; and each of RC2, RN6, RN7, RO, and RS2 is independently H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4- alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned hetero- cyclyl rings independently comprise 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 sub- stitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substi- tuted with one or more, same or different substituents RA3. In a preferred embodiment, Ryvu Therapeutics S.A. RVU305 40 R10945WO RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, C(=O)RC2, ORO, a 3- to 7-membered saturated carbocyclyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, a 5- or 6-membered aromatic carbocyclyl or heterocyclyl, or a 5- to 7-mem- bered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned hetero- cyclyl or heterobicyclyl rings independently comprise one or more, same or different heteroatoms se- lected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein the aforementioned rings are independently unsubstituted or substituted with one or more, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5- or 6-membered aro- matic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, same or different substituents RA2. In a more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, C(=O)RC2, ORO, a 3- to 7-membered saturated carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, a 5- or 6-membered aromatic carbocyclyl or heterocyclyl, or a 5- to 7-mem- bered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned hetero- cyclyl or heterobicyclyl rings independently comprise one or more, same or different heteroatoms se- lected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein the aforementioned rings, preferably the aforementioned aromatic rings, are inde- pendently unsubstituted or substituted with one or more, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5- or 6-membered aro- matic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, same or different substituents RA2. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, C(=O)RC2, ORO, cyclopropyl, or a 5- to 7-membered saturated heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5- or 6-membered aro- matic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, same or different substituents RA2. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, cyclopropyl, or a 6- or 7-membered saturated heterocyclyl, wherein the Ryvu Therapeutics S.A. RVU305 41 R10945WO aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5- or 6-membered aro- matic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, same or different substituents RA2. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, cyclopropyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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, wherein the aforementioned heterocyclyl ring is preferably a fused thiazolyl, imidazolyl, or pyrazolyl, more preferably thiazolyl, and wherein the aforementioned heterocyclyl ring is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA2. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, ORO, cyclopropyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two substituents RA2. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, ORO, cyclopropyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents RA2. Ryvu Therapeutics S.A. RVU305 42 R10945WO In one even more preferred embodiment, RA1 is C1-C2-alkyl, C1-C4-hydroxyalkyl, ORO, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; wherein the aforementioned heterocyclyl ring is preferably piperidine, piperazine, or 1,4-diazepane; and wherein the aforementioned heterocyclyl ring is inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents RA2. In one particularly preferred embodiment, RA1 is C1-C2-alkyl, preferably CH3. In another particularly preferred embodiment, A1 is substituted with two or more, preferably two substituents RA1; wherein two RA1 together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, pref- erably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsubstituted or sub- stituted with one or two substituents RA2. In another particularly preferred embodiment, RA1 is a 6- or 7-membered saturated heterocyclyl, preferably piperidine, piperazine, or 1,4-diazepane, wherein the aforementioned heterocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocy- clyl ring is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4. In another particularly preferred embodiment, RA1 is a 6-membered saturated heterocyclyl, preferably piperidine or piperazine, wherein the aforemen- tioned heterocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4. In another particularly preferred embodiment, RA1 is a 7-membered saturated heterocyclyl, preferably 1,4-diazepane, wherein the aforementioned heter- ocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, preferably one or two, same or different substituents RA4. In another particularly preferred embodiment, RA1 is C1-C4-hydroxyalkyl or ORO. In one aspect of the present invention, in a preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused 5- or 6-membered aro- matic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- Ryvu Therapeutics S.A. RVU305 43 R10945WO ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, same or different substituents RA2. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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, wherein the aforementioned heterocyclyl ring is preferably a fused thiazolyl, imidazolyl, or pyrazolyl, more preferably thiazolyl, and wherein the aforementioned heterocyclyl ring is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA2. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one substituent RA2. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one substituent RA2. In an even more preferred embodiment, RA1 is C1-C2-alkyl; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one substituent RA2. In one particularly preferred embodiment, RA1 is C1-C2-alkyl, preferably CH3. In another particularly preferred embodiment, A1 is substituted with two or more, preferably two substituents RA1; wherein two RA1 together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, pref- erably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsubstituted or sub- stituted with one substituent RA2. In another aspect of the present invention, in a preferred embodiment, RA1 is C1-C4-hydroxyalkyl, ORO, or a 6- or 7-membered saturated heterocyclyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; Ryvu Therapeutics S.A. RVU305 44 R10945WO or two RA1, if present, together with the atoms to which they are bonded form a fused 5- or 6-membered aro- matic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA2. In an even more preferred embodiment, RA1 is C1-C4-hydroxyalkyl, ORO, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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, wherein the aforementioned heterocyclyl ring is preferably a fused thiazolyl, imidazolyl, or pyrazolyl, more preferably thiazolyl, and wherein the aforementioned heterocyclyl ring is inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents RA2. In an even more preferred embodiment, RA1 is C1-C4-hydroxyalkyl, ORO, or a 6- or 7-membered saturated heterocyclyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents RA2. In an even more preferred embodiment, RA1 is C1-C4-hydroxyalkyl, ORO, piperidine, piperazine, or 1,4-diazepane, wherein the aforementioned het- erocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents RA2. In one particularly preferred embodiment, RA1 is a 6- or 7-membered saturated heterocyclyl, preferably piperidine, piperazine, or 1,4-diazepane, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocy- clyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4. In another particularly preferred embodiment, Ryvu Therapeutics S.A. RVU305 45 R10945WO RA1 is a 6-membered saturated heterocyclyl, preferably piperidine or piperazine, wherein the aforemen- tioned heterocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4. In another particularly preferred embodiment, RA1 is a 7-membered saturated heterocyclyl, preferably 1,4-diazepane, wherein the aforementioned heter- ocyclyl ring independently comprises one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, preferably one or two, same or different substituents RA4. In another particularly preferred embodiment, RA1 is C1-C4-hydroxyalkyl or ORO. In another particularly preferred embodiment, A1 is substituted with two or more, preferably two substituents RA1; wherein two RA1 together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, pref- erably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsubstituted or sub- stituted with one or two substituents RA2. As indicated above, in connection with the compounds of the present invention, in particular in connection with the preferred embodiments regarding ring A or A1 and RA1 defined above, if present, RA2 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobi- cyclyl rings independently comprise 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 sub- stitutable atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA3. In a preferred embodiment, RA2 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, a 3- to 6-membered saturated carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, or a 5- to 7-mem- bered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned hetero- cyclyl or heterobicyclyl rings independently comprise one or more, same or different heteroatoms se- lected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein the aforementioned rings are independently unsubstituted or substituted with one or more, same or different substituents RA3. In a more preferred embodiment, RA2 is C1-C2-alkyl, NRN6RN7, a 3- to 6-membered saturated carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2- alkyl, or a 5- to 7-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or dif- Ryvu Therapeutics S.A. RVU305 46 R10945WO ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized; and wherein the aforementioned rings are independently unsubstituted or sub- stituted with one or more, same or different substituents RA3. In an even more preferred embodiment, RA2 is C1-C2-alkyl, or a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two, same or different heteroatoms se- lected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforemen- tioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents RA3. In an even more preferred embodiment, RA2 is C1-alkyl, piperidinyl, or piperidinyl-C1-C2-alkyl, wherein the piperidinyl is independently unsubstituted or substituted with one or two, preferably one, same or different substituents RA3. In an even more preferred embodiment, RA2 is piperidinyl, wherein the piperidinyl is unsubstituted or substituted with one or two, preferably one, same or different substituents RA3. In a particularly preferred embodiment, RA2 is piperidinyl, wherein the piperidinyl is substituted with one or two, preferably one, same or different substituents selected from C1-C2-alkyl, preferably CH3. As indicated above, in connection with the compounds of the present invention, in particular in connection with the preferred embodiments regarding ring A or A1 and RA1 defined above, if present, RA4 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkyl- NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently comprise 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 atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA3. In a preferred embodiment, RA4 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, C(=O)-C1-C2-alkyl-RN4RN5, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, a 3- to 6-membered saturated carbocyclyl or heterocyclyl, or a 5- to 7-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings inde- pendently comprise 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 the aforementioned rings are independently unsubstituted or substituted with one or more, same or different substituents RA3. In a more preferred embodiment, RA4 is halogen, C1-C2-alkyl, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydrox- yalkyl, C(=O)-C1-C2-alkyl-RN4RN5, NRN6RN7, a 3- to 6-membered saturated carbocyclyl or heterocyclyl, or a 5- to 7-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the afore- mentioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or different Ryvu Therapeutics S.A. RVU305 47 R10945WO heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein the aforementioned rings are independently unsubstituted or substituted with one or more, same or different substituents RA3. In one even more preferred embodiment, RA4 is a 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents RA3. In an even more preferred embodiment, RA4 is piperidinyl, wherein the piperidinyl is unsubstituted or substituted with one or two, preferably one, same or different substituents RA3. In a particularly preferred embodiment, RA4 is piperidinyl, wherein the piperidinyl is substituted with one or two, preferably one, same or different substituents selected from C1-C2-alkyl, preferably CH3. In another even more preferred embodiment, RA4 is halogen, C1-C2-alkyl, NRN6RN7, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5. In an even more preferred embodiment, RA4 is halogen, C1-C2-haloalkyl, or C1-C2-hydroxyalkyl. In an even more preferred embodiment, RA4 is F, CF3, or C1-C2-hydroxyalkyl. Further, in connection with the compounds of the present invention, in particular in connection with the pre- ferred embodiments regarding RA1, RA2, and RA4 defined above, the following preferences regarding RA3, RC2, RN6, RN7, RO, and RS2 are particularly relevant. As indicated above, in connection with the compounds of the present invention, if present, RC2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. In a preferred embodiment, RC2 is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, or a 5- or 6-membered saturated carbocyclyl or heterocy- clyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3. In one more preferred embodiment, Ryvu Therapeutics S.A. RVU305 48 R10945WO RC2 is a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. In another more preferred embodiment, RC2 is C1-C2-hydroxyalkyl or C1-C2-alkyl-NRN4RN5. In a particularly preferred embodiment, RC2 is C1-C2-hydroxyalkyl. As indicated above, in connection with the compounds of the present invention, if present, RN6 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. In a preferred embodiment, RN6 is H or C1-C2-alkyl. In a more preferred embodiment, RN6 is H or CH3. As indicated above, in connection with the compounds of the present invention, if present, RN7 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. In a preferred embodiment, RN7 is C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. In a more preferred embodiment, RN7 is C1-C2-alkyl, C1-C2-hydroxyalkyl, C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. Ryvu Therapeutics S.A. RVU305 49 R10945WO In one even more preferred embodiment, RN7 is C1-C2-alkyl, C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. As indicated above, in connection with the compounds of the present invention, if present, RO is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. In a preferred embodiment, RO is H, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocy- clyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. In a more preferred embodiment, RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl ring is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3. In a more preferred embodiment, RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl ring is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA3. In an even more preferred embodiment, RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, piperidine, or pyrrolidine-C1-C2-alkyl; wherein the aforementioned cyclopropyl, piperidine, or pyrrolidine is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA3. As indicated above, in connection with the compounds of the present invention, if present, RS2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or Ryvu Therapeutics S.A. RVU305 50 R10945WO 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3. As indicated above, in connection with the compounds of the present invention, if present, RA3 is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4- alkyl-NRN4RN5, C(=O)-C1-C4-hydroxyalkyl, or C(=O)-C1-C4-alkyl-NRN4RN5. In a preferred embodiment, RA3 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5. In one more preferred embodiment, RA3 is C1-C2-alkyl or N(CH3)2. In an even more preferred embodiment, RA3 is C1-C2-alkyl . In a particularly preferred embodiment, RA3 is CH3. In another more preferred embodiment, RA3 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5. In an even more preferred embodiment, RA3 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, or C(=O)-C1-C2-hydroxyalkyl. In an even more preferred embodiment, RA3 is F, CF3, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, or C(=O)-C1-C2-hydroxyalkyl. Thus, overall, in a preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, C(=O)RC2, ORO, cyclopropyl, or a 5- to 7-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is independently unsubstituted or sub- stituted with one or more, same or different substituents RA2; RA2 is C1-C2-alkyl, NRN6RN7, a 3- to 6-membered saturated carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2- alkyl, or a 5- to 7-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the Ryvu Therapeutics S.A. RVU305 51 R10945WO aforementioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized; and wherein the aforementioned rings are independently unsubstituted or sub- stituted with one or more, preferably one or two, same or different substituents RA3; RA3 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RA4 is halogen, C1-C2-alkyl, NRN6RN7, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RN6 is H, or C1-C2-alkyl; RN7 is C1-C2-alkyl, C1-C2-hydroxyalkyl, C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RC2 is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, or a 5- or 6-membered saturated carbocyclyl or heterocy- clyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3; and RO is H, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocy- clyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3. In a more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6RN7, ORO, cyclo- propyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is independently unsubstituted or sub- stituted with one or more, same or different substituents RA2; RA2 is C1-C2-alkyl, or a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two, same or different heteroatoms se- Ryvu Therapeutics S.A. RVU305 52 R10945WO lected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforemen- tioned heterocyclyl rings are independently unsubstituted or substituted with one or two, same or differ- ent substituents RA3; RA3 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RA4 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RN6 is H, or C1-alkyl; RN7 is C1-C2-alkyl, or C1-C2-hydroxyalkyl; and RO is C1-C2-hydroxyalkyl, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2- alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, ORO, cyclopropyl, or a 6- or 7-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned het- erocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two substituents RA2; and RA2 is C1-C2-alkyl or a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two, same or different heteroatoms se- lected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforemen- tioned heterocyclyl rings are independently unsubstituted or substituted with one or two, same or differ- ent substituents RA3; RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RA3 is halogen, C1-C2-alkyl, N(CH3)2, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; and Ryvu Therapeutics S.A. RVU305 53 R10945WO RA4 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, ORO, cyclopropyl, or a 6- or 7-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned het- erocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are independently unsub- stituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two substituents RA2; and RA2 is C1-C2-alkyl, or a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or two, same or different substituents RA3; RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl ring is independently unsubstituted or substituted with one or more, same or different substituents RA3; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RA3 is halogen, C1-C2-alkyl, N(CH3)2, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; and RA4 is halogen, C1-C2-haloalkyl, or C1-C2-hydroxyalkyl. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, ORO, cyclopropyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents RA2; and RA2 is C1-C2-alkyl, or a 6-membered saturated heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or two, same or different substituents RA3; RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the Ryvu Therapeutics S.A. RVU305 54 R10945WO aforementioned cyclopropyl or heterocyclyl rings are independently unsubstituted or substituted with one or more, same or different substituents RA3; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RA3 is halogen, C1-C2-alkyl, N(CH3)2, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; and RA4 is halogen, C1-C2-haloalkyl, or C1-C2-hydroxyalkyl. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, ORO, cyclopropyl, piper- idine, piperazine, or 1,4-diazepane, wherein the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents RA2; and RA2 is C1-alkyl, piperidine, or piperidine-C1-C2-alkyl; wherein the aforementioned piperidine is inde- pendently unsubstituted or substituted with one or two, same or different substituents RA3; RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, piperidine, or pyrrolidine-C1-C2-alkyl; wherein the aforementioned cyclopropyl, piperidine, or pyrrolidine is independently unsubstituted or substituted with one or more, same or different substituents RA3; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RA3 is F, CF3, CH3, N(CH3)2, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, or C(=O)-C1-C2-hydroxyalkyl; and RA4 is F, CF3, or C1-C2-hydroxyalkyl. In one aspect of the present invention, in a preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, a 3- to 6-membered saturated carbocyclyl or heterocyclyl, or a 5- or 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned rings, preferably the aforemen- tioned aromatic rings, are independently unsubstituted or substituted with one or more, same or differ- ent substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5- or 6-membered aro- matic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, same or different substituents RA2; RA2 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, a 3- to 6-membered saturated carbocyclyl or heterocyclyl, or a 5- to 7-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently comprise 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 the aforementioned Ryvu Therapeutics S.A. RVU305 55 R10945WO rings are independently unsubstituted or substituted with one or more, same or different substituents RA3; RA4 is C1-C2-alkyl, NRN6RN7, or a 3- to 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring independently 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 the aforementioned rings are independently unsubstituted or substituted with one or more, same or different substituents RA3; RN6 is H, or C1-C2-alkyl; RN7 is C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the afore- mentioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and RC2 is a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and wherein preferably RA3 is C1-C2-alkyl or N(CH3)2, more preferably C1-C2-alkyl, particularly preferably CH3. In a more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused 5- or 6-membered aro- matic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein the aforementioned heterocyclyl ring is independently unsubsti- tuted or substituted with one or more, same or different substituents RA2; RA2 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, a 3- to 6-membered saturated carbocyclyl or heterocyclyl, or a 5- to 7-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently comprise 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 the aforementioned rings are independently unsubstituted or substituted with one or more, same or different substituents RA3; RN6 is H, or C1-C2-alkyl; RN7 is C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the afore- mentioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and Ryvu Therapeutics S.A. RVU305 56 R10945WO RC2 is a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and wherein preferably RA3 is C1-C2-alkyl or N(CH3)2, more preferably C1-C2-alkyl, particularly preferably CH3. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is independently unsubstituted or sub- stituted with one or more, same or different substituents RA2; RA2 is C1-C2-alkyl, NRN6RN7, a 3- to 6-membered saturated carbocyclyl or heterocyclyl, or a 5- to 7-mem- bered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned hetero- cyclyl or heterobicyclyl rings independently comprise one or more, same or different heteroatoms se- lected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein the aforementioned rings are independently unsubstituted or substituted with one or more, same or different substituents RA3; RN6 is H, or C1-C2-alkyl; RN7 is C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the afore- mentioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and RC2 is a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and wherein preferably RA3 is C1-C2-alkyl or N(CH3)2, more preferably C1-C2-alkyl, particularly preferably CH3. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one substituent RA2; and Ryvu Therapeutics S.A. RVU305 57 R10945WO RA2 is a 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents RA3; and wherein preferably RA3 is C1-C2-alkyl or N(CH3)2, more preferably C1-C2-alkyl, particularly preferably CH3. In an even more preferred embodiment, RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one substituent RA2; and RA2 is a 6-membered saturated heterocyclyl, preferably piperidinyl, wherein the aforementioned heterocy- clyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N- atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents RA3; and wherein preferably RA3 is C1-C2-alkyl or N(CH3)2, more preferably C1-C2-alkyl, particularly preferably CH3. In an even more preferred embodiment, RA1 is C1-C2-alkyl; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one substituent RA2; and RA2 is a 6-membered saturated heterocyclyl, preferably piperidinyl, wherein the aforementioned heterocy- clyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N- atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents RA3; and wherein preferably RA3 is C1-C2-alkyl or N(CH3)2, more preferably C1-C2-alkyl, particularly preferably CH3. In one particularly preferred embodiment, RA1 is C1-C2-alkyl, preferably CH3. In another particularly preferred embodiment, A1 is substituted with two or more, preferably two substituents RA1; wherein two RA1 together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, pref- erably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsubstituted or sub- stituted with one substituent RA2; and RA2 is a 6-membered saturated heterocyclyl, preferably piperidinyl, wherein the aforementioned heterocy- clyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N- atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents RA3; and wherein preferably Ryvu Therapeutics S.A. RVU305 58 R10945WO RA3 is C1-C2-alkyl or N(CH3)2, more preferably C1-C2-alkyl, particularly preferably CH3. In another aspect of the present invention, RA1 is C1-C4-hydroxyalkyl, ORO, or a 6- or 7-membered saturated heterocyclyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two substituents RA2; and RA2 is C1-C2-alkyl, or a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two, same or different heteroatoms se- lected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforemen- tioned heterocyclyl rings are independently unsubstituted or substituted with one or two, same or differ- ent substituents RA3; RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RA3 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; and RA4 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5. In a more preferred embodiment, RA1 is C1-C4-hydroxyalkyl, ORO, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two substituents RA2; and RA2 is C1-C2-alkyl, or a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are Ryvu Therapeutics S.A. RVU305 59 R10945WO independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are unsub- stituted or substituted with one or two, same or different substituents RA3; RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl rings are independently unsubstituted or substituted with one or more, same or different substituents RA3; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RA3 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; and RA4 is halogen, C1-C2-haloalkyl, or C1-C2-hydroxyalkyl. In an even more preferred embodiment, RA1 is C1-C4-hydroxyalkyl, ORO, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are inde- pendently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different sub- stituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents RA2; and RA2 is C1-C2-alkyl, or a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are inde- pendently unsubstituted or substituted with one or two, same or different substituents RA3; RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two N-atoms, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl rings are independently unsubstituted or substituted with one or more, same or different substituents RA3; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RA3 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; and RA4 is halogen, C1-C2-haloalkyl, or C1-C2-hydroxyalkyl. In an even more preferred embodiment, RA1 is C1-C4-hydroxyalkyl, ORO, piperidine, piperazine, or 1,4-diazepane, wherein the aforementioned het- erocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused thiazolyl, imidazolyl, or pyrazolyl, preferably thiazolyl, wherein the aforementioned thiazolyl, imidazolyl, or pyrazolyl is unsub- stituted or substituted with one or two substituents RA2; and Ryvu Therapeutics S.A. RVU305 60 R10945WO RA2 is piperidine or piperidine-C1-C2-alkyl; wherein the aforementioned piperidine is independently unsub- stituted or substituted with one or two, same or different substituents RA3; RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, piperidine, or pyrrolidine-C1-C2-alkyl; wherein the aforementioned cyclopropyl, piperidine, or pyrrolidine is independently unsubstituted or substituted with one or more, same or different substituents RA3; RN4 is H; RN5 is H, or C1-alkyl; RA3 is F, CF3, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, or C(=O)-C1-C2-hydroxyalkyl; and RA4 is F, CF3, or C1-C2-hydroxyalkyl. It is to be understood that the preferred embodiments for RA1, RA2, and RA3 may vary depending on whether RA1, RA2, or RA3 is attached to a carbon atom or heteroatom of the ring. For example, if RA1, RA2, or RA3 is at- tached to a heteroatom, such as N, then RA1, RA2, or RA3 is preferably a substituent that is attached to said het- eroatom, such as N, via a carbon atom. Accordingly, if RA1, RA2, or RA3 is attached to a heteroatom, such as N, then each of RA1, RA2, or RA3 is preferably independently selected from one of the preferred embodiments re- garding RA1, RA2, or RA3 defined above, but without the substituents that are attached to the remainder of the molecule via an N, O, or S atom, preferably without the substituents that are attached to the remainder of the molecule via an N, O, or S atom, or C(=O) moiety. Overall, in preferred embodiments, A Ryvu Therapeutics S.A. RVU305 61 R10945WO In more preferred embodiments, A is a moiety selected from the group consisting of In even more preferred embodiments, A is a moiety selected from the group consisting of . In particularly preferred embodiments, A the group consisting of and . In other more preferred embodiments, A is a moiety selected from the group consisting of Ryvu Therapeutics S.A. RVU305 62 R10945WO . In other particularly preferred embodiments, the compound of formula (I) is a compound selected from the group consisting of: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-5-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyridine-3-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5- carboxamide; Ryvu Therapeutics S.A. RVU305 63 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-cyclopropylpyridin-3-yl)pyridine-3-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)py- rimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3,6-dimethylpyrazin-2-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2-cyclopropylpyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-oxo-1,2-dihydropyridin-3-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]py- rimidine-5-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; Ryvu Therapeutics S.A. RVU305 64 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropylpyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyr- idine-3-carboxamide; and N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)py- rimidine-5-carboxamide. In other particularly preferred embodiments, the compound of formula (I) is a compound selected from the group consisting of: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[(3,3-difluoropiperidin-4-yl)oxy]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[3-(trifluoromethyl)piperazin-1- yl]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(2-hydroxyethyl)-3-(trifluoromethyl)pi- perazin-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4- yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperidin-1-yl]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2-methylpyridin-3- yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-me- thyl-1H-pyrazol-4-yl}pyrimidine-5-carboxamide; rac-N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-6-{[(2R,4R)-2-(trifluorome- thyl)piperidin-4-yl]oxy}pyridin-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyacetyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(6,6-difluoro-1,4-diazepan-1-yl)-2- methylpyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-6-{1-[(methylamino)methyl]cyclo- propoxy}pyridin-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[2-(trifluoromethyl)piperazin-1- yl]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-methylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; Ryvu Therapeutics S.A. RVU305 65 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethylpyridin-3-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methyl-1,2-thiazol-4-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-ethylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)py- rimidine-5-carboxamide; N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]acetamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]pyr- idine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3- benzodiazol-6-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6- yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-6-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(piperidin-4-yl)methyl]-1,3-benzothiazol- 5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(1-methylpiperidin-4-yl)methyl]-1,3-ben- zothiazol-5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[3-methyl-2-(1-methylpiperidin-4-yl)-2H- indazol-6-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)eth- oxy]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyr- idine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide; Ryvu Therapeutics S.A. RVU305 66 R10945WO N-{[4-amino-3-(trifluoromethyl)-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]py- rimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)py- rimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1-methyl-1H-pyrazol-5-yl)pyridine-3-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,5-dimethylpyridin-3-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-ethyl-1-methyl-1H-pyrazol-5-yl)pyrimi- dine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-methyl-1,2-thiazol-4-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-ethyl-1-methyl-1H-pyrazol-4-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[(1-methylpiperidin-4- yl)oxy]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(propan-2-yl)-1H-pyrazol-4- yl]pyrimidine-5-carboxamide; and N‐({4‐amino‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(3‐cyano‐1‐methyl‐1H‐pyrazol‐5‐yl)‐6‐(trifluoromethyl)pyr- idine‐3‐carboxamide. Definitions The term “compound(s) of the present invention" is to be understood as equivalent to the term "compound(s) according to the invention", and also covers a salt, stereoisomer, rotamer, atropisomer, tautomer or N-oxide thereof. The compounds according to the invention may be amorphous or may exist in one or more different crystal- line states (polymorphs), which may have different macroscopic properties such as stability or show different biological properties such as activities. The present invention relates to amorphous and crystalline forms of compounds of formula (I), mixtures of different crystalline states of the compounds of formula (I), as well as amorphous or crystalline salts thereof. Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the US FDA 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 Ryvu Therapeutics S.A. RVU305 67 R10945WO compounds according to the invention have a basic functionality, or by reacting acidic compounds according to the invention with a suitable base. Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium, sodium and po- tassium, 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 (NH4+) and substituted ammonium in which one to four of the hydrogen atoms are replaced by C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkoxy-C1-C4-alkyl, phenyl or benzyl. Examples of substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trime- thylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltri- ethylammonium, furthermore the cations of 1,4-piperazine, meglumine, benzathine and lysine. Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihydrogenphos- phate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophos- phate, benzoate, and the anions of C1-C4-alkanoic acids, preferably formate, acetate, propionate and butyrate, furthermore lactate, gluconate, and the anions of poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, furthermore sulfonate anions such as besylate (benzenesulfonate), tosylate (p-tol- uenesulfonate), napsylate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanesulfonate), and ethanedisulfonate. They can be formed by reacting compounds according to the invention that have a basic functionality with an acid of the corresponding anion. Depending on the substitution pattern, the compounds according to the invention may have one or more cen- tres of chirality, including axial chirality providing different stereoisomers. The invention provides both, pure en- antiomers or pure diastereomers, of the compounds according to the invention, and their mixtures, including racemic mixtures. For example, a chiral centre of the compounds according to the invention may be present in substituent R1. Suitable compounds according to the invention also include all possible geometrical stereoisomers (cis/trans isomers or E/Z isomers) and mixtures thereof. E/Z- isomers may be present with respect to, e.g., an alkene, carbon-nitrogen double-bond or amide group. Further, suitable compounds according to the invention also include conformational stereoisomers (conform- ers), which refers to isomers that interconvert by rotations about single bonds. Rotations about single bonds involve overcoming a rotational energy barrier to interconvert one conformer to another. If the energy barrier is high enough, rotation about the single bond can be hindered so that there is no free rotation and the compound exists as a rotational isomer (rotamer) for a relatively long time. If the energy barrier to rotation is high enough so that the time scale of interconversion is long enough to allow for isolation of individual rotamers, the rota- mers are termed atropisomers. Thus, the term “atropisomers” as used herein refers to conformational stereoi- somers (conformers) resulting from hindered rotation about a single bond, where the energy differences due to steric strain or other contributors create a barrier to rotation, which is high enough to allow for the isolation of the conformers. The term rotational isomers (rotamers) as used herein also includes atropisomers. Rotational isomers (rotamers), in particular atropisomers, do not require an asymmetric atom but an axis of chirality and thus represent a form of axial chirality. Determining the axial stereochemistry can be accomplished through the use of a Newman projection along the axis of hindered rotation. The four substituents are first assigned priority based on Cahn–Ingold–Prelog priority rules. Starting with the substituent of highest priority on the closest atom in the Newman projection and moving along the shortest path to the substituent of highest priority on the other Ryvu Therapeutics S.A. RVU305 68 R10945WO atom, the absolute configuration is assigned P or Δ for clockwise and M or Λ for counterclockwise. Alterna- tively, all four groups can be ranked by Cahn–Ingold–Prelog priority rules, with overall priority given to the sub- stituents on the "front" atom of the Newman projection, i.e., the substituents on the end of the single bond, which is closest in the Newman projection. The two configurations are termed Ra and Sa in analogy to the tradi- tional R/S for a traditional tetrahedral stereocenter as exemplarily illustrated below in case of A having a higher priority than B, and C having a higher priority than D by Cahn–Ingold–Prelog priority rules. e.g., from rotation about an amide bond may also be defined as cis/trans isomers or E/Z isomers. Thus, such cis/trans isomers and E/Z isomers are also covered by the term rotational isomer (rotamer) or atropisomer. The invention provides both, pure rotational isomers (rota- mers) or atropisomers of the compounds according to the invention, and their mixtures, including racemic mix- tures. For example, rotational isomers (rotamers) of the compounds of the present invention may be present with respect to a restricted rotation about the C-N amide bond and/or a restricted rotation about the C-N bond between the tertiary amide nitrogen and the A moiety. For illustration only, exemplary rotational isomers (rota- mers) of the compounds according to the invention potentially resulting from a restricted rotation about the C-N amide bond and/or a restricted rotation about the C-N bond between the tertiary amide nitrogen and the A moi- ety of the compounds are shown below for Example 6: For Example 6, a mixture of two rotational isomers (rotamers) resulting from a restricted rotation about the C- N amide bond is observed with NMR analysis at room temperature, but the barrier to rotation is too low to iso- late the rotational isomers (rotamers) so that no stable atropisomers are observed for Example 6. However, if the barrier to rotation is high enough, the rotational isomers (rotamers) of the compounds accord- ing to the invention can be separated and isolated and can thus be termed atropisomers. In particular, depend- ing on the substitution pattern, the barrier to rotation about the C-N bond between the tertiary amide nitrogen Ryvu Therapeutics S.A. RVU305 69 R10945WO and the A moiety of the compounds according to the invention may be high enough to form atropisomers, which can be separated and isolated. Without being bound to theory, atropisomers may, e.g., be formed if the A moiety of the compounds of the present invention is substituted in ortho position on both sides of the carbon connected to the tertiary amide nitrogen of the remainder of the molecule. On the other hand, without being bound to theory, the barrier to rotation about the C-N amide bond may typically not be high enough to form at- ropisomers. In view of the above, the compounds of the present invention may be present as a mixture of two rotational isomers (rotamers) resulting from one restricted bond rotation, such as a mixture of two rotational iso- mers (rotamers) resulting from a restricted rotation about the C-N amide bond as shown above for Example 6. The mixture may be racemic (1 to 1 mixture) or one of the rotational isomers (rotamers) in the mixture may be enriched over the other rotational isomer (rotamer). If the barrier to rotation is high enough to form atropiso- mers, the two atropisomers may be separated and isolated. Further, the compounds of the present invention may be present as a mixture of stereoisomers resulting from more than one restricted bond rotation. For exam- ple, if there are two restricted bond rotations, there may be four rotational isomers (rotamers), which can be grouped into two “diastereoisomer-like” components that are distinguishable by NMR analysis. Such a mixture is referred to as “diastereoisomer-like” mixture and the stereoisomers therein which are distinguishable by NMR analysis are referred to as “diastereoisomer-like” components. If one of the two barriers to rotation is high enough to form atropisomers, e.g. the barrier to rotation about the C-N bond between the tertiary amide nitro- gen and the A moiety of the compounds according to the invention, the two atropisomers may be separated and isolated. Each of the separated and isolated atropisomers may then be present as a mixture of two rota- tional isomers (rotamers) resulting from the second restricted bond rotation, e.g. the rotation about the C-N am- ide bond. A “diastereoisomer-like” mixture with “diastereoisomer-like” distinguishable components may also result if the compounds of the present invention contain a combination of one or more restricted bond rota- tion(s) and one or more asymmetric atom(s) (i.e., chiral centres). For example, there may be one chiral centre resulting in two stereoisomers, and additionally at least one restricted bond rotation, e.g., the restricted rotation about the C-N amide bond, resulting in two additional stereoisomers, i.e. rotational isomers (rotamers). A com- pound of the present invention may thus be present as a mixture of four stereoisomers (or even 8 stereoiso- mers in case of two restricted bond rotations), which can be grouped into “diastereoisomer-like” components that are distinguishable by NMR analysis. If, e.g., the stereoisomers resulting from the chiral centre are sepa- rated and isolated, they may then be present as a mixture of the rotational isomers (rotamers) resulting from the additional restricted bond rotation(s), e.g. the rotation about the C-N amide bond. The skilled person is aware that the presence of further centres of chirality and/or further restricted bond rotations (chirality axes) increases the number of stereoisomers present in the mixture up to a maximum of 2n, with n being the number of chiral centres including chiral atoms and chiral axes (restricted bond rotations). Atropisomers may be classified according to their stereochemical stabilities as mentioned in doi: 10.4155/fmc-2017-0152: Class 1 atropisomers possess barriers to rotation around the chiral axis of <84 kJ/mol(20 kcal/mol) and racemize on the minute or faster time scale at room temperature; class 2 atropisomers possess a barrier to rotation between 84 and 117 kJ/mol (20–28 kcal/mol) and racemize on the hour to month timescale at room temperature; and class 3 atropisomers possess a barrier to rotation>117 kJ/mol (28 kcal/mol) and racemize on the year or greater timescale at room temperature. Typically, only class 2 and class 3 atropisomers are separable. Without being bound to theory, class 2 or class 3 atropisomers of the com- pounds of the invention may be present, if the A moiety of the compounds of the present invention is substi- tuted in ortho position on both sides of the carbon connected to the tertiary amide nitrogen of the remainder of the molecule. For class 2 atropisomers, it may be possible to distinguish the atropisomers in NMR or short time Ryvu Therapeutics S.A. RVU305 70 R10945WO LC, but they may nevertheless be inseparable due to the fact that a single atropisomer would reequilibrate to a mixture within a few hours.1H NMR at 80 °C may be useful to identify stable atropisomers if their signals do not significantly coalesce at this temperature. Tautomers may be formed, if a substituent is present at the compound of formula (I), which allows for the for- mation of tautomers such as keto-enol tautomers, imine-enamine tautomers, amide-imidic acid tautomers or the like. The term "N-oxide" includes any compound of the present invention which has at least one tertiary nitrogen atom that is oxidized to an N-oxide moiety. Any formula or structure given herein, including compounds of formula (I), is also intended to represent unla- beled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom hav- ing a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36CI and 125I. For example, radioactive isotopes such as 3H, 13C and 14C provide isotopically labelled compounds useful in meta- bolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. Further, the disclosure includes compounds of formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic ad- vantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage re- quirements and/or an improvement in therapeutic index. See, for example, Poster, "Deuterium Isotope Effects in Studies of DrugMetabolism", Trends Pharmacol. Sei.5(12):524-527 (1984). Such compounds are synthe- sized by means well known in the art, for example by employing starting materials in which one or more hydro- gens have been replaced by deuterium. The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. Unless otherwise stated, when a position is designated spe- cifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium. The term "substituted", as used herein, means that a hydrogen atom bonded to a designated atom is re- placed with a specified substituent, provided that the substitution results in a stable or chemically feasible com- pound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substitu- ent is independently selected. The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent. When it is referred to certain atoms or moieties being substituted with “one or more” substituents, 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. When neither the term “unsubstituted” nor “substituted” is explicitly mentioned concerning a moiety, said moiety is to be consid- ered as unsubstituted. Ryvu Therapeutics S.A. RVU305 71 R10945WO The organic moieties mentioned in the above definitions of the variables are - like the term halogen - collec- tive terms for individual listings of the individual group members. The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group. The term “halogen” denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine, or bromine. The term "alkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably 1 to 5 or 1 to 4 carbon atoms, more preferably 1 to 3 or 1 or 2 carbon at- oms. Examples of an alkyl group are 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-dimethylpro- pyl, 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-ethyl- butyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl. The term "haloalkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, preferably 1 to 3 or 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Preferred haloalkyl moieties are selected from C1-C4- haloalkyl, more preferably from C1-C3-haloalkyl or C1-C2-haloalkyl, in particular from C1-C2-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like. The term "alkoxy" as used herein denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom to the remainder of the molecule and has usually from 1 to 4 carbon atoms, prefer- ably 1 to 2 carbon atoms, more preferably 1 carbon atom. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the like. The term “alkoxyalkyl” as used herein refers to an alkoxy group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, which is bonded via an alkyl group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more prefer- ably 1 carbon atom, to the remainder of the molecule. Thus, it refers to an alkyl group, which is bonded via oxy- gen to a further alkyl group, which is then bonded to the remainder of the molecule. Examples of an alkoxyalkyl group are methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and the like. The term "haloalkoxy" as used herein denotes in each case a straight-chain or branched alkoxy group having from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, wherein the hydro- gen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms. Pre- ferred haloalkoxy moieties include C1-haloalkoxy, in particular C1-fluoroalkoxy, such as trifluoromethoxy and the like. The term “hydroxyalkyl” as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms, and being further substituted with 1 to 5, preferably with 1 to 2 hydroxy groups, in particular with 1 hydroxy group, wherein a hydroxy group is a OH group. Preferably, the one hydroxy group is terminating the straight- chain or branched alkyl group so that the hydroxy group is bonded to an alkyl bridge, which is bonded to the remainder of the molecule. Examples of an hydroxyalkyl group are hydroxymethyl, hydroxyethyl, n-hydroxypro- pyl, 2-hydroxypropyl, n-hydroxybutyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl, and n-hydroxypentyl. Hy- droxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, are preferred, in particular hydroxymethyl and hy- droxyethyl. Ryvu Therapeutics S.A. RVU305 72 R10945WO The term “aminoalkyl” as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms, and being further substituted with 1 to 5, preferably with 1 to 2 amino groups, in particular with 1 amino group, wherein an amino group is a NH2 group. Preferably, the one amino group is terminating the straight-chain or branched alkyl group so that the amino group is bonded to an alkyl bridge, which is bonded to the remainder of the molecule. Examples of an aminoalkyl group are aminomethyl, aminoethyl, n-aminopropyl, 2-aminopropyl, n-aminobutyl, 2-aminobutyl, 2-amino-2-methylpropyl, and n-aminopentyl. Aminomethyl, aminoethyl, aminopro- pyl, and aminobutyl, are preferred, in particular aminomethyl and aminoethyl. The term “cycloalkyl” as used herein denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl, cyclo- butyl, cyclopentyl, and cyclohexyl are preferred. The term “carbocyclic”, “carbocyclyl”, or “carbocycle” includes, unless otherwise indicated, in general a 3- to 10-membered monocyclic ring, preferably a 4- to 8-membered or a 3- to 6-membered or a 5- to 7-membered monocyclic ring, more preferably a 3-, 4-, 5- or 6-membered monocyclic ring, comprising 3 to 10, preferably 4 to 8 or 3 to 6 or 5 to 7, more preferably 3, 4, 5 or 6 carbon atoms. The carbocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled. Also “aryls” are covered by the term “carbocycles”. The term “aryl” or “aromatic carbocycle” refers to aromatic carbocyclic rings based on carbon atoms as ring members, preferably 6-membered aromatic carbocyclic rings based on carbon atoms as ring members. A preferred example is phenyl. Unless otherwise indicated, the term “aryl” further co- vers “aromatic carbobicycles” as defined herein. The term “carbocyclic” or “carbocyclyl”, unless otherwise indi- cated, may therefore cover inter alia cycloalkyl, cycloalkenyl, as well as phenyl. Preferably, the term “carbocy- clic” or “carbocyclyl” covers phenyl and cycloalkyl, for example phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "carbobicyclic" or “carbobicyclyl” includes in general 6 to 14-membered, preferably 7- to 12-mem- bered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings comprising 6 to 14, preferably 7 to 12 or 8 to 10, more preferably 9 or 10 carbon atoms. The carbobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully un- saturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled. Preferably, the term “aromatic” in connection with the carbobicyclic ring means that both rings of the bicylic moiety are aromatic, so that, e.g., 8 π electrons are present in case of a 10-membered aromatic carbobicyclic ring.The term “car- bobicylce” or “carbobicyclyl”, unless otherwise indicated, may therefore cover inter alia bicycloalkyl, bicycloal- kenyl, as well as bicyclic aromatic groups, for example bicyclohexane (decalin), bicycloheptane (such as nor- bornane), bicyclooctane (such as bicyclo[2.2.2]octane, bicyclo[3.2.1]octane or bicyclo[4.2.0]octane), bicy- clononane (such as bicyclo[3.3.1]nonane or bicyclo[4.3.0]nonane ), bicyclodecane (such as bicyclo[4.4.0]dec- ane), bicycloundecane (such as bicyclo[3.3.3]undecane), norbornene, naphthalene and the like. Preferably, the carbobicycle is a fused carbobicycle, which is preferably aromatic, for example naphthalene. The term “carbocyclylalkyl” as used herein, refers to carbocyclyl as defined herein, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon Ryvu Therapeutics S.A. RVU305 73 R10945WO atom. Preferably, the term “carbocyclylalkyl” refers to phenylalkyl or cycloalkylalkyl, which refers to the corre- sponding groups being bonded to the remainder of the molecule via an alkyl group. Preferred examples of car- bocyclylalkyl include benzyl (i.e. phenylmethyl), phenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylme- thyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl. The term “carbocyclyloxy” as used herein denotes in each case a carbocyclyl as defined herein, which is bonded via an oxygen atom to the remainder of the molecule. Examples of carbocyclyloxy include phenyloxy or cyclopropyloxy. The same applies to the terms “aryloxy” and “benzyloxy” referring to the corresponding groups, which are bonded to the remainder of the molecule via an oxygen atom. The term “carbocyclyloxyalkyl” as used herein denotes in each case a carbocyclyloxy group, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 car- bon atom. Thus, it refers to a carbocyclyl, which is bonded via an oxygen atom to an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom, which is then bonded to the remainder of the molecule. Examples of include phenyloxymethyl, phenyloxyethyl, cyclopropyloxymethyl, and cyclopropyloxyethyl. The term “heterocyclic” or “heterocyclyl” includes, unless otherwise indicated, in general a 3- to 10-mem- bered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered, in particular 6- membered monocyclic ring. The heterocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled. The heterocycle typically comprises one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S- atoms as ring members may be present as S, SO or SO2. The remaining ring members are carbon atoms. In a preferred embodiment, the heterocycle is an aromatic heterocycle, preferably a 5- or 6-membered aromatic heterocycle comprising one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. Examples of aromatic heterocycles are provided below in connection with the definition of “hetaryl”. “Hetaryls” or “heteroaryls” are covered by the term “heterocycles”. The saturated or partially or fully unsaturated heterocycles usually com- prise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S-at- oms as ring members may be present as S, SO or SO2. The skilled person is aware that S, SO or SO2 is to be understood as follows: Further, a skilled person is aware that resonance structures of the oxidized forms may be possible. Saturated heterocycles include, unless otherwise indicated, in general 3- to 10-membered, preferably 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered monocyclic rings comprising 3 to 10, preferably 4 to 8 or 5 to 7, more preferably 5 or 6 atoms comprising at least one heteroatom, such as pyrrolidine, tetrahydrothio- phene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine. The term “heterobicyclic” or “heterobicyclyl” includes, unless otherwise indicated, in general 6 to 14-mem- bered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 8- or 9-membered bicyclic rings. The heterobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled. For being “aromatic”, it is sufficient if one of the two rings of the bicyclic moi- eties is aromatic, while the other is non-aromatic. The heterobicycle typically comprises one or more, e.g.1, 2, Ryvu Therapeutics S.A. RVU305 74 R10945WO 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. The remaining ring members are carbon atoms. Examples of het- erobicycles include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadi- azolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridyl, pteridyl, pyr- ido[3,2-d]pyrimidyl, pyridoimidazolyl, triethylenediamine or quinuclidine and the like. The term "hetaryl" or “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” includes monocy- clic 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO2. Examples of 5- or 6-mem- bered aromatic heterocycles include pyridyl (also referred to as pyridinyl), i.e.2-, 3-, or 4-pyridyl, pyrimidinyl, i.e.2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e.3- or 4-pyridazinyl, thienyl, i.e.2- or 3-thienyl, furyl, i.e.2-or 3-furyl, pyrrolyl, i.e.2- or 3-pyrrolyl, oxazolyl, i.e.2-, 3- or 5-oxazolyl, isoxazolyl, i.e.3-, 4- or 5-isoxazolyl, thia- zolyl, i.e.2-, 3- or 5-thiazolyl, isothiazolyl, i.e.3-, 4- or 5-isothiazolyl, pyrazolyl, i.e.1-, 3-, 4- or 5-pyrazolyl, i.e. 1-, 2-, 4- or 5-imidazolyl, oxadiazolyl, e.g.2- or 5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3-oxadiazol)yl, 3- or 5-(1,2,4- oxadiazol)yl, 2- or 5-(1,3,4-thiadiazol)yl, thiadiazolyl, e.g.2- or 5-(1,3,4-thiadiazol)yl, 4- or 5-(1,2,3-thiadiazol)yl, 3- or 5-(1,2,4-thiadiazol)yl, triazolyl, e.g.1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or 4H-1,2,4- triazolyl and tetrazolyl, i.e.1H- or 2H-tetrazolyl. Unless otherwise indicated, the term “hetaryl” further covers “aromatic heterobicycles” as defined above. The term “heterocyclylalkyl” as used herein, refers to a heterocyclyl as defined herein, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom. Examples of heterocyclylalkyl include pyridinylmethyl, pyrimidinylmethyl, pyrazolylmethyl, piperidinylme- thyl, or pyrrolidineethyl. The term “heterocyclyloxy” as used herein denotes in each case a heterocyclyl as defined herein, which is bonded via an oxygen atom to the remainder of the molecule. Preferably, a carbon atom of the heterocyclyl is bonded to the oxygen atom. Examples heterocyclyloxy include pyridinyloxy, pyrimidinyloxy, pyrazolyloxy, and piperidinyloxy. The same applies to the terms “heteroaryloxy” referring to the corresponding group, which is bonded to the remainder of the molecule via an oxygen atom. The term “heterocyclyloxyalkyl” as used herein denotes in each case a heterocyclyloxy group, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom. Thus, it refers to a heterocyclyl, which is bonded via an oxygen atom to an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom, which is then bonded to the remainder of the mol- ecule. Examples include pyridinyloxymethyl, pyrimidinyloxymethyl, pyrazolyloxymethyl, and piperidinyloxyme- thyl. The term “cyclic” moiety can refer to any cyclic groups, which are present in the compounds of formula (I), and which are defined above, e.g., cycloalkyl, cycloalkenyl, carbocyclyl. The term “bicyclic” moiety can refer to any bicyclic groups, which are present in the compounds of formula (I), and which are defined above. As used in the specification and the claims, the singular forms of “a” and “an” also include the corresponding plurals unless the context clearly dictates otherwise. The same applies for plural forms used herein, which also include the singular forms unless the context clearly dictates otherwise. The terms “about” and “approximately” in the context of the present invention denotes an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10% and preferably ±5%. Ryvu Therapeutics S.A. RVU305 75 R10945WO It needs to be understood that the term “comprising” is not limiting. For the purposes of the present invention, the term “consisting of” is considered to be a preferred embodiment of the term “comprising of”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group which preferably consists of these embodiments only. The term “pharmaceutically acceptable excipient” as used herein refers to compounds commonly comprised in pharmaceutical compositions, which are known to the skilled person. Examples of suitable excipients are exemplary listed below. Typically, a pharmaceutically acceptable excipient can be defined as being pharma- ceutically inactive. The term “treatment” is to be understood as also including the option of “prophylaxis”. Thus, whenever refer- ence is made herein to a “treatment” or “treating”, this is to be understood as “treatment and/or prophylaxis” or “treating and/or preventing”. Description of pharmaceutical compositions according to the present invention A pharmaceutical composition according to the present invention may be formulated for oral, inhalative, buc- cal, nasal, rectal, topical, transdermal or parenteral application. Preferred non-parenteral routes include muco- sal (e.g., oral, vaginal, nasal, cervical, etc.) routes, of which the oral application may be preferred. Parenteral application may be preferred and includes intravenous, intraarterial, intratumoral, peri-tumoral, intradermal, in- trathecal, intravesical, intramuscular, epidural or subcutaneous administration, but also intranasal and inhala- tive administration. Preferably administration is by subcutaneous, intra-tumoral or peri-tumoral routes, in partic- ular in the treatment of cancer. Particularly preferred is intratumoral administration. In connection with the treat- ment of pulmonary diseases, such as asthma, chronic obstructive pulmonary disease, lung cancer and idio- pathic pulmonary fibrosis, inhalative administration is preferred. Inhalative administration may be performed by using an inhaler for delivering the pharmaceutical composition into the body via the lungs. Suitable inhalers include dry powder inhalers, metered-dose inhalers, and nebulizers. Dry powder inhalers provide the active ingredient in the form of a powder, which is then inhaled through the dry powder inhaler. Dry powder inhalers are advantageous because they are breath-actuated and do not require the use of any propel- lants. Nebulizers provide the active ingredient as an aerosol created from an aqueous formulation. Metered- dose inhalers release a fixed dose of medication in aerosol form, wherein a liquefied gas propellant, preferably a hydrofluoroalkane (HFA), is used in the formulation of the active ingredient. The compound according to formula (I) should be applied in pharmaceutically effective amounts, for example in the amounts as set out herein below. A pharmaceutical composition of the present invention may also be designated as formulation or dosage form. A compound of formula (I) may also be designated in the following as (pharmaceutically) active agent or active compound. Pharmaceutical compositions may be solid or liquid dosage forms or may have an intermediate, e.g. gel-like character depending inter alia on the route of administration. In general, the inventive dosage forms can comprise various pharmaceutically acceptable excipients, 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 invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, Ryvu Therapeutics S.A. RVU305 76 R10945WO release-modifying materials, carrier materials, diluents, binding agents, and other adjuvants. Typical pharma- ceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch deriva- tives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents. The term “carrier” denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the application. Suitable pharmaceutically acceptable carriers in- clude, for instance, water, aqueous salt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbitans, polyethylene-polypropylene block co-polymers such as poloxamer 188 or polox- amer 407, polyethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and triglycerides, polyox- yethylated medium or long chain fatty acids such as ricinoleic acid, and polyoxyethylated fatty acid mono-, di, and triglycerides such as capric or caprilic acids, petroethral fatty acid esters, hydroxymethyl celluloses such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl acetate succinate, polyvinylpyrrolidone, cross- povidone and the like. Preferably, the compounds of the present invention are administered in a pharmaceuti- cal composition comprising of lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L- lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, nanoporous par- ticle-supported lipid bilayers and as a conjugate with an antibody. The pharmaceutical compositions can be sterile and, if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound. It is to be understood that the term “carrier” also covers an antibody that delivers the compound of formula (I). If liquid dosage forms are considered for the present invention, these can include pharmaceutically accepta- ble emulsions, solutions, suspensions and syrups containing inert diluents commonly used in the art such as water. These dosage forms may contain e.g. microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners/flavoring agents. For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solu- tions, as well as suspensions, emulsions, or implants. Pharmaceutical formulations for parenteral administra- tion are particularly preferred and include aqueous solutions of the compounds of formula (I) in water-soluble form. Additionally, suspensions of the compounds of formula (I) may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain sub- stances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Particularly preferred dosage forms are injectable preparations of a compound of formula (I). Thus, sterile in- jectable aqueous or oleaginous suspensions can for example be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be used are water and isotonic sodium chloride solution. Sterile oils are also conventionally used as solvent or suspending medium. Preferred applications for injectable prepa- rations comprising the compounds of the present invention are intravenous, intratumoral and peritumoral ad- ministration. Ryvu Therapeutics S.A. RVU305 77 R10945WO Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g. mixing the com- pound with a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides and polyethylene gly- cols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the compound according to formula (I) from said suppositories. For administration by inhalation, the compounds according to the present invention may be conveniently de- livered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propel- lant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, powders, efferves- cent formulations, dragees and granules. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sug- ars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellu- lose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The oral dosage forms may be formulated to ensure an immediate release of the compound of for- mula (I) or a sustained release of the compound of formula (I). A solid dosage form may comprise a film coating. For example, the inventive dosage form may be in the form of a so-called film tablet. A capsule of the invention may be a two-piece hard gelatin capsule, a two-piece hy- droxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose or a two- piece capsule made of polysaccharide. The dosage form according to the invention may be formulated for topical application. Suitable pharmaceuti- cal application forms for such an application may be a topical nasal spray, sublingual administration forms and controlled and/or sustained release skin patches. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. The compositions may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. The methods can include the step of bringing the compounds into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. Liquid dose units are vials or am- poules. Solid dose units are tablets, capsules and suppositories. As regards human patients, the compound of formula (I) may be administered to a patient in an amount of about 0.001 mg to about 5000 mg per day, preferably of about 0.01 mg to about 1000 mg per day, more prefer- ably of about 0.05 mg to about 250 mg per day, which is the effective amount. The phrase “effective amount” means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to treat or prevent a particular disease or condition. Furthermore, the pharmaceutical composition may also contain the compound of formula (I) as a prodrug such as an ester or amide thereof. A prodrug is any compound which is converted under physiological condi- tions or by solvolysis to any of the compounds of the invention. A prodrug may be inactive prior to administra- tion but may be converted to an active compound of the invention in vivo. Ryvu Therapeutics S.A. RVU305 78 R10945WO In a preferred embodiment relating to the pharmaceutical compositions of the present invention, said pharma- ceutical composition comprises said compound as the only pharmaceutically active agent. Alternatively, said pharmaceutical composition comprises at least one further independent pharmaceutically active agent in addi- tion to said compound, wherein said additional active agent is typically used for the intended indication(s) as outlined above. In particular, when it comes to cancer, said pharmaceutical composition comprises at least one further independent pharmaceutically active agent in addition to the compound of the present invention. Further details in this regard are provided below. Indications, for which the compounds of the present invention may be used The compounds according to the present invention are suitable for use in medicine. The compounds of the present invention are useful for (partially) inhibiting PRMT5, in particular MTA-bound PRMT5, which is enriched in MTAP deficient tumor cells. Thus, the compounds according to the present invention are particularly suitable for use in the treatment of a disease associated with MTAP deficiency and/or MTA accumulation, in particular a proliferative disorder such as cancer or pre-cancerous syndromes associated with MTAP deficiency and/or MTA accumulation. Thus, in one embodiment, the compound of the present invention or a pharmaceutical composition compris- ing the same is for use in the treatment of a disease selected from the group consisting of cancer or pre-can- cerous syndromes. In another embodiment, the compound of the present invention or a pharmaceutical com- position comprising the same is for use in the treatment of a disease selected from the group consisting of can- cer or pre-cancerous syndromes associated with MTAP deficiency and/or MTA accumulation. Preferably, said cancer is selected from the group consisting of Glioblastoma, Non-Small Cell Lung Cancer, B-Lymphoblastic Leukemia/Lymphoma, Pancreatic Cancer, Breast Cancer, Melanoma, Esophagogastric Can- cer, Bladder Cancer, Glioma, Head and Neck Cancer, Hepatobiliary Cancer, Prostate Cancer, Pleural Meso- thelioma, Sarcoma, Ovarian Epithelial Tumor, Soft Tissue Sarcoma, Bone Cancer, Colorectal Cancer, Blad- der/Urinary Tract Cancer, Ovarian Cancer, T-Lymphoblastic Leukemia/Lymphoma, Nerve Sheath Tumor, Ma- ture B-Cell Neoplasms, Renal Non-Clear Cell Carcinoma, Renal Cell Carcinoma, Endometrial Cancer, Mature B-cell lymphoma, High-grade glioma/astrocytoma, Renal Clear Cell Carcinoma, Prostate Adenocarcinoma, Adrenocortical Carcinoma, Salivary Gland Cancer, Invasive Breast Carcinoma, Cholangiocarcinoma, Gastroin- testinal Stromal Tumor, Lung Cancer, Low-grade glioma/astrocytoma, Thymic Epithelial Tumor, Salivary Can- cer, Intraductal Papillary Mucinous Neoplasm, Leukemia, Mesothelioma, Sex Cord Stromal Tumor, CNS Can- cer, Embryonal Tumor, Skin Cancer, Cervical Cancer, Thyroid Cancer, Anal Cancer, Peripheral Nervous Sys- tem. In particular, said cancer is preferably selected from the group consisting of Glioblastoma Multiforme, B-Lym- phoblastic Leukemia/Lymphoma, Pancreatic Adenocarcinoma, Breast Invasive Ductal Carcinoma, Lung Squa- mous Cell Carcinoma, Bladder Urothelial Carcinoma, Lung Adenocarcinoma, Cutaneous Melanoma, Head and Neck Squamous Cell Carcinoma, Melanoma, Prostate Adenocarcinoma, Esophageal Adenocarcinoma, Astro- cytoma, Serous Ovarian Cancer, Stomach Adenocarcinoma, Esophageal Squamous Cell Carcinoma, Hepato- cellular Carcinoma, Pancreatic Neuroendocrine Tumor, Glioblastoma, Pleural Mesothelioma, Epithelioid Type Diffuse Large B-Cell Lymphoma, Tubular Stomach Adenocarcinoma, Bladder/Urinary Tract Cancer, Invasive Breast Carcinoma, Colon Adenocarcinoma, Hepatocellular Adenoma, Malignant Peripheral Nerve Sheath Tu- mor, Papillary Renal Cell Carcinoma, Pleural Mesothelioma Biphasic Type, Bladder Squamous Cell Carci- Ryvu Therapeutics S.A. RVU305 79 R10945WO noma, T-Lymphoblastic Leukemia/Lymphoma, Leiomyosarcoma, Undifferentiated Pleomorphic Sarcoma/Malig- nant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma, Sarcoma, Osteosarcoma, Renal Clear Cell Car- cinoma, Intestinal Type Stomach Adenocarcinoma, Adenoid Cystic Carcinoma, Oligodendroglioma, Breast In- vasive Lobular Carcinoma, Cholangiocarcinoma, Pediatric High Grade Gliomas, Acral Melanoma, Oligoastro- cytoma, Breast Invasive Carcinoma, Adrenocortical Carcinoma, Breast Mixed Ductal and Lobular Carcinoma, Gastrointestinal Stromal Tumor, Thymoma, Dedifferentiated Liposarcoma, Angiosarcoma, Diffuse Type Stom- ach Adenocarcinoma, Intracholecystic Papillary Neoplasm, Pediatric Low Grade Gliomas, Intrahepatic Cholan- giocarcinoma, Ewing Sarcoma, Intraductal Papillary Mucinous Neoplasm, Myxofibrosarcoma, Chordoma, Pa- pillary Stomach Adenocarcinoma, B-Lymphoblastic Leukemia/Lymphoma BCR-ABL1 Like, Acute Myeloid Leu- kemia, Metaplastic Breast Cancer, High-Grade Serous Ovarian Cancer, Low-Grade Serous Ovarian Cancer, Liposarcoma, Adenocarcinoma of the Gastroesophageal Junction, Granulosa Cell Tumor, Breast Invasive Can- cer, Mucinous Stomach Adenocarcinoma, Medulloblastoma, Adamantinoma, Breast Invasive Mixed Mucinous Carcinoma, Cervical Squamous Cell Carcinoma, Synovial Sarcoma, Adenosquamous Carcinoma of the Pan- creas, Rectal Adenocarcinoma, Mucinous Adenocarcinoma of the Colon and Rectum, Chromophobe Renal Cell Carcinoma, Peritoneal Mesothelioma, Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor, Anal Squamous Cell Carcinoma, Papillary Thyroid Cancer, Oral Cavity Squamous Cell Carcinoma, Pleural Mesothelioma Sarcomatoid Type, Anaplastic Ependymoma, Sweat Gland Carcinoma/Apocrine Eccrine Carci- noma, Poorly differentiated Non-Small Cell Lung Cancer, Sarcomatoid Carcinoma of the Lung, Neuroblastoma, Pleural Mesothelioma, Pilocytic Astrocytoma, Signet Ring Cell Carcinoma of the Stomach, Ganglioglioma, Col- lecting Duct Renal Cell Carcinoma, Small Cell Carcinoma of the Ovary, Non-Small Cell Lung Cancer, Pancre- atoblastoma, Ependymomal Tumor, Adenosquamous Carcinoma of the Stomach, Carcinoma with Osseous Metaplasia, Fibroblastic Osteosarcoma, Adenocarcinoma, B-Lymphoblastic Leukemia/Lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1, Early T-Cell Precursor Lymphoblastic Leukemia. More preferably, the cancer is selected from the group consisting of Glioblastoma, Non-Small Cell Lung Can- cer, B-Lymphoblastic Leukemia/Lymphoma, Pancreatic Cancer, Breast Cancer, Melanoma, Esophagogastric Cancer, Bladder Cancer, Glioma, Head and Neck Cancer, Hepatobiliary Cancer, Prostate Cancer, Pleural Mesothelioma, Sarcoma, Ovarian Epithelial Tumor, Soft Tissue Sarcoma, Bone Cancer, Colorectal Cancer, Bladder/Urinary Tract Cancer, T-Lymphoblastic Leukemia/Lymphoma. In particular, said cancer is more preferably selected from the group consisting of Glioblastoma Multiforme, B- Lymphoblastic Leukemia/Lymphoma, Pancreatic Adenocarcinoma, Breast Invasive Ductal Carcinoma, Lung Squamous Cell Carcinoma, Bladder Urothelial Carcinoma, Lung Adenocarcinoma, Cutaneous Melanoma, Head and Neck Squamous Cell Carcinoma, Melanoma, Prostate Adenocarcinoma, Esophageal Adenocarci- noma, Astrocytoma, Serous Ovarian Cancer, Stomach Adenocarcinoma, Esophageal Squamous Cell Carci- noma, Hepatocellular Carcinoma, Glioblastoma, Pleural Mesothelioma, Epithelioid Type Diffuse Large B-Cell Lymphoma, Tubular Stomach Adenocarcinoma, Bladder/Urinary Tract Cancer, Colon Adenocarcinoma, Hepa- tocellular Adenoma, Malignant Peripheral Nerve Sheath Tumor, Papillary Renal Cell Carcinoma, Pleural Meso- thelioma Biphasic Type, T-Lymphoblastic Leukemia/Lymphoma, Undifferentiated Pleomorphic Sarcoma/Malig- nant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma. It is to be understood that in connection with the medical uses of the invention it can be preferred that the compounds according to the present invention are administered in combination with antibodies, radiotherapy, surgical therapy, immunotherapy, chemotherapy, toxin therapy, gene therapy, or any other therapy known to those of ordinary skill in the art for treatment of a particular disease. This is particularly relevant in connection with the treatment of cancer. Preferably, the compounds of the present invention may be coadministered with Ryvu Therapeutics S.A. RVU305 80 R10945WO an anti-neoplastic agent and/or an anti-neoplastic agent may be comprised in the pharmaceutical composition according to the present invention. The cancer treated by the combination of (i) a compound according to the present invention and (ii) an anti-neoplastic agent may be selected from one of the cancers listed above. 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. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wil- kins Publishers. Typical anti-neoplastic agents useful in the present invention include chemotherapeutic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal ana- logues, signal transduction pathway inhibitors, non-receptor tyrosine kinase inhibitors, angiogenesis inhibitors, proapoptotic agents, cell cycle signaling inhibitors, proteasome inhibitors, inhibitors of cancer metabolism, and immunotherapeutic agents (such as STING pathway modulating compounds, TLR agonists and checkpoint in- hibitors). Examples for chemotherapeutic agents are anti-microtubule or anti-mitotic agents (such as paclitaxel), platinum coordination complexes (such as cisplatin), alkylating agents (such as cyclophosphamide) and antibiotic anti-neoplastics (such as doxorubicin). Combination therapy may be achieved by use of a single pharmaceutical composition that includes both agents, or by administering two distinct compositions at the same time, wherein one composition includes a compound of the present invention, and the other includes the second agent(s). The two therapies may be given in either order and may precede or follow the other treatment by intervals ranging from minutes to weeks. In embodiments where the other agents are applied separately, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the agents would still be able to exert an advantageously combined effect on the patient. In such instances, it is contemplated that one may administer both modalities within about 12-24 h of each other and, more preferably, within about 6-12 h of each other. In some situations, it may be desirable to extend the time period for treat- ment significantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations. In some embodiments, the compound of the present invention is administered prior to administration of the distinct cancer treatment. In other embodiments, the distinct cancer treatment is administered prior to administration of the compound of the present invention. The present invention is further illustrated by the following examples. Examples The following abbreviations are used herein: Abbreviation Meaning ))) with sonication Ac Acetyl ACN/MeCN/ Acetonitrile CH3CN AcOH Acetic acid AIBN Azobisisobutyronitrile alamarBlue Resazurin dye (7-hydroxy-3H-phenoxazin-3-one 10-oxide) Aq. Aqueous Atm. Atmosphere BINAP (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene Ryvu Therapeutics S.A. RVU305 81 R10945WO Abbreviation Meaning Bn Benzyl (Bpin)2 Bis(pinacolato)diboron BTFFH Fluoro-dipyrrolidinocarbenium hexafluorophosphate (BzO)2, BPO Benzoyl peroxide Boc tert-Butoxycarbonyl BocNH2 tert-Butyl carbamate BSA Bovine serum albumin calc. calculated cataCXium® C trans-Di(μ-acetato)bis[o-(di-o-tolyl-phosphino)benzyl]dipalladium(II) CDI 1,1'-Carbonyldiimidazole conc. Concentrate CRISPR/Cas9 Clustered Regularly Interspaced Short Palindromic Repeats / CRISPR-associ- ated endonuclease 9 DAD Diode array detector DAST Diethylaminosulphur trifluoride 2,2'-bipy 2,2'-bipyridine dba Dibenzylideneacetone DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1,2-Dichloroethane DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIBAL-D Diisobutylaluminum deuteride DIPEA N,N-Diisopropylethylamine Dioxane 1,4-Dioxane DMC Dimethylcarbonate DMA N,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DMBA 1-(2,4-dimethoxyphenyl)methanamine DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide dppf 1,1-Bis(diphenylphosphino)ferrocene DMSO Dimethyl sulfoxide DTT Dithiothreitol EC50 Half maximal effective concentration EDC.HCl 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDTA Ethylenediaminetetraacetic acid ELISA Enzyme-linked immunosorbent assay ELSD Evaporative light scattering detector eq. Equivalent EtOAc, AcOEt Ethyl acetate Ex Example Ryvu Therapeutics S.A. RVU305 83 R10945WO Abbreviation Meaning Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) PhCH3 Toluene P(n-Bu)3 Tributylphosphane PMB p-Methoxybenzyl PTSA p-Toluenesulfonic acid Prep HPLC Preparative HPLC PRMT5 Protein methyltransferase 5 Py Pyridine RM Reaction mixture Rochelle salt Potassium sodium tartrate tetrahydrate rpm Revolutions per minute RPMI 1640 Roswell Park Memorial Institute medium 1640 RT Room temperature Rt Retention time s Second SAM S-Adenosyl methionine sat. Saturated SCX Strong cation exchange SDMA Symmetrical dimethylarginine SelectFluorTM N-Chloromethyl-N-fluorotriethylenediammonium bis(tetrafluoroborate) SEM Trimethylsilylethoxymethyl SM Starting material T3P Propylphosphonic anhydride TBAB Tetrabutylammonium bromide TEA Triethylamine TES Triethylsilane Tf Trifluoromethanesulfonate Tf2O trifluoromethanesulfonyl trifluoromethanesulfonate TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TLC Thin layer chromatography TRIS Tris(hydroxymethyl)aminomethane Trt Trityl (Triphenylmethyl) Tween 20 Polyoxyethylene (20) sorbitan monolaurate UPLC Ultra Performance Liquid Chromatography UPLC-MS Ultra Performance Liquid Chromatography coupled to Mass Spectrometry WT Wild type Xantphos 4,5-bis(Diphenylphosphino)-9,9-dimethylxanthene XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl Ryvu Therapeutics S.A. RVU305 85 R10945WO Detection: DAD (Diode Array Detector), CAD (Charged Aerosol Detector) Equipment: H Class Waters UPLC-MS Methods: 3 default methods were available for every eluent system/buffer type (FA, TFA, NH3 and neutral), flow rate 0.5 mL/min: Polar long method: t (min.) Eluant A (%) Eluant B (%) 0 1 99 7 100 0 8 100 0 9 1 99 12 1 99 Mid polar long method: t (min.) Eluant A (%) Eluant B (%) 0 10 90 7 100 0 8 100 0 9 10 90 12 10 90 Non polar long method: t (min.) Eluant A (%) Eluant B (%) 0 20 80 7 100 0 8 100 0 9 20 80 12 20 80 UPLC Eluent composition: Buffer type Eluant A Eluant B ”FA” MeCN 0.1% FA in water Column: Waters ACQUITY UPLC® BEH C181.7um, 2.1 x 100 mm. 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: t (s) Eluant A (%) Eluant B (%) 0 1 99 6 1 99 Ryvu Therapeutics S.A. RVU305 86 R10945WO 66 100 0 120 100 0 150 1 99 Mid polar: t (s) Eluant A (%) Eluant B (%) 0 20 80 6 20 80 66 100 0 120 100 0 150 20 80 Non polar: t (s) Eluant A (%) Eluant B (%) 0 50 50 6 100 0 66 100 0 120 50 50 150 50 50 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 purifications The following equipment was used for Preparative HPLC purifications: Waters Autopurification system (Waters 2767 – Sample Manager, Waters 2545 – Binary Gradient Module, Waters 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 Phenomenex Gemini® 5µm NX- C18110 Å (00G-4454-P0-AX LC Column 250 x 21.2 mm, AX) column. Three types of eluent system were used: Buffer type Eluant A Eluant B ”FA” MeCN 0.1% FA in water ”TFA” MeCN 0.1% TFA in water ”NH3” MeCN 0.1% NH4OH in water General gradient: flow rate 20 mL/min. t (min.) Eluant A (%) Eluant B (%) 0 10 90 1 10 90 10 40 or 60 60 or 40
Ryvu Therapeutics S.A. RVU305 88 R10945WO Methyl 4-(trifluoromethanesulfonyloxy)-2,5-dihydrofuran-3-carboxylate (Int.1): To a stirred solution of methyl 4-oxooxolane-3-carboxylate (9.0 g, 62.445 mmol, 1.0 eq.) in DCM (300 mL), DIPEA (13.05 mL, 74.934 mmol, 1.2 eq.) was added and the RM was cooled to -78°C. Then triflic anhy- dride (21.14 g, 74.934 mmol, 1.2 eq.) was added dropwise. The reaction mixture was stirred at -78°C for 1 h. RM was diluted with water and aqueous layer was extracted with DCM (3x). Combined organic layers were washed with aq. NaHCO3 and brine, dried over Na2SO4 and evaporated. The residue was purified by FCC (0 to 100% DCM gradient in heptane) to obtain methyl 4-(trifluoromethanesulfonyloxy)-2,5-dihydrofuran-3-carbox- ylate (Int.1, 15.9 g, 51.814 mmol, 83%, yellow oil). 1H NMR (400 MHz, Chloroform-d) δ 4.98 – 4.89 (m, 2H), 4.85 – 4.76 (m, 2H), 3.85 (s, 3H). Methyl 4-oxo-1H,3H,4H,5H-furo[3,4-c]quinoline-7-carboxylate (Int.2): A mixture of methyl 4-(trifluoromethanesulfonyloxy)-2,5-dihydrofuran-3-carboxylate (Int.1, 15.9 g, 51.806 mmol, 1.1 eq.), 2-amino-4-(methoxycarbonyl)phenylboronic acid hydrochloride (10.9 g, 47.096 mmol, 1.0 eq.), K2CO3 (15.287 g, 110.612 mmol, 4.0 eq.), water (12.5 mL) and 1,4-dioxane (125 mL) was sparged with argon, then Pd(PPh3)4 (1.088 g, 0.942 mmol, 0.02 eq.) was added and the mixture heated at 100°C for 2.5 h. The RM was cooled to RT, diluted with water and extracted with CHCl3/i-PrOH (3:1) mixture (2x). Combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. Crude product was tritu- rated with Et2O and a few drops of i-PrOH and acetone, then filtered and washed with Et2O to obtain methyl 4- oxo-1H,3H,4H,5H-furo[3,4-c]quinoline-7-carboxylate (Int.2, 9.26 g, 36.627 mmol, 78%, light brown solid, m/z [M+H]+: 246.1). 1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.74 (dd, J = 8.2, 1.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 5.36 – 5.31 (m, 2H), 4.99 (t, J = 4.1 Hz, 2H), 3.90 (s, 3H). 7-(hydroxymethyl)-1H,3H,4H,5H-furo[3,4-c]quinolin-4-one (Int.3): A suspension of methyl 4-oxo-1H,3H,4H,5H-furo[3,4-c]quinoline-7-carboxylate (Int.2, 10.26 g, 40.582 mmol, 1.0 eq.) in anhydrous THF (500 mL) under nitrogen was cooled to 0°C. Then LAH (2 M solution in THF, 30.43 mL, 60.874 mmol, 1.5 eq.) was added dropwise. The RM was stirred at 0°C for 30 min., and then 30 min. at RT. The RM was cooled by an ice-bath then quenched by addition of MeOH (dropwise) and 6M HCl was Ryvu Therapeutics S.A. RVU305 89 R10945WO used to adjust pH to 1 (ice bath was used). Organic solvent was evaporated again and additional portion of H2O was added. The resulting solution was then stirred at 0°C for 30 min. The precipitated solid was filtered, washed with water and dried in vacuo to give 7-(hydroxymethyl)-1H,3H,4H,5H-furo[3,4-c]quinolin-4-one (Int.3, 7.212 g, 32.537 mmol, 80%, brown solid, m/z [M+H]+: 218.0). 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 7.42 (d, J = 9.2 Hz, 2H), 7.14 (d, J = 8.1 Hz, 1H), 5.39 (d, J = 6.7 Hz, 1H), 5.29 (d, J = 4.0 Hz, 2H), 4.96 (t, J = 4.0 Hz, 2H), 4.59 (d, J = 4.2 Hz, 2H). 4-bromo-7-(bromomethyl)-1H,3H-furo[3,4-c]quinoline (Int. A): A 7-(hydroxymethyl)-1H,3H,4H,5H-furo[3,4-c]quinolin-4-one (Int.3, 7.212 g, 32.537 mmol, 1.0 eq.) was suspended in dry MeCN (75 mL) and DIPEA (22.66 mL, 130.147 mmol, 4.0 eq.) was added. The obtained slurry was stirred for 5 min. Then, a suspension of POBr3 (27.98 g, 97.61 mmol, 3.0 eq.) in MeCN (25 mL) was added dropwise. Reaction mixture was stirred at RT for 20 min., and then it was heated at 80°C for 100 min. The reaction mixture was immersed in ice bath and pH was adjusted to 8 using 12 M NaOH. At this point, large amount of solid crashed out. Whole RM was diluted with water and DCM and product was extracted with DCM (3x). Organic layers were combined, dried over MgSO4, and concentrated under vacuo. Crude product was pu- rified by FCC (0 to 80% DCM gradient in hexane) to give 4-bromo-7-(bromomethyl)-1H,3H-furo[3,4-c]quinoline (Int. A, 4.2 g, 11.999 mmol, 37%, white solid, m/z [M+H]+: 343.7). 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.4, 1.7 Hz, 1H), 5.57 (t, J = 3.1 Hz, 2H), 5.20 (q, J = 4.6, 3.0 Hz, 2H), 4.95 (s, 2H). Intermediate B: 7‐(bromomethyl)‐4‐chloro‐1H,3H‐furo[3,4‐c]quinoline Methyl 4‐chloro‐1H,3H‐furo[3,4‐c]quinoline‐7‐carboxylate (Int.4) A 2500 mL flask was charged with acetonitrile (450 mL) and DIPEA (34 mL, 196.054 mmol, 1.0 eq.) un- der flow of N2. The mixture was cooled down in an ice bath and POCl3 (45.1 g, 294.082 mmol, 1.5 eq.) was added portionwise. It was followed by addition of solid methyl 4-oxo-1H,3H,4H,5H-furo[3,4-c]quinoline-7-car- boxylate (Int.2, 50.25 g, 196.054 mmol, 1.0 eq.). The addition funnel was washed with ACN (50 mL) and the cooling bath was replaced with a heating block. RM was heated to reflux and stirred for 3 h. RM was cooled to 0 °C and then quenched with 2 M NaOH (400 mL), while ensuring that the internal temperature remained be- low 10°C. Then, water was added (500 mL) and the mixture was stirred for 30 min at 5-10°C. Then, the solid was filtered off, washed with water (250 mL), ACN (100 mL), water (3x250 mL) and heptane (500 mL) and air- dried for 3 h. The solid was transferred to a crystallizer and dried in oven (0 mbar, 60°C) for 24 h to give methyl 4-chloro-1H,3H-furo[3,4-c]quinoline-7-carboxylate (Int.4, 49.477 g, 185.764 mmol, 95%, light gray solid). Ryvu Therapeutics S.A. RVU305 90 R10945WO 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.19 (dd, J = 8.6, 1.7 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 5.57 (t, J = 3.2 Hz, 2H), 5.33 (t, J = 3.2 Hz, 2H), 4.01 (s, 3H). {4‐Chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methanol (Int.5) The 1.5 L flask equipped with mechanical stirrer, condenser, nitrogen inlet, thermocouple and rubber septum was charged with anhydrous THF (380 mL) followed by methyl 4-chloro-1H,3H-furo[3,4-c]quinoline-7- carboxylate (Int.4, 35.477 g, 133.2 mmol, 1.0 eq.). Then mixture was cooled in ice/salt/water bath to -8°C and 2M LAH solution (53.28 mL, 106.565 mmol, 0.8 eq.) was slowly added via syringe below 0°C. When addition of LAH was completed reaction was stirred for 30 minutes in temperature below 0°C. Reaction mixture was cooled to -5°C and acetone (48.9 mL, 666.0 mmol, 5.0 eq.) was added via syringe keeping temperature below 0°C. After addition mixture was stirred for 15 minutes in 0°C, then mixture was quenched with 2M HCl (700 mL). Mixture was stirred for 10 minutes, then THF was removed on rotavap (~380 mL) and obtained solid was filtered off, washed with water, heptane and dried on filter overnight. First filtrate was extracted with DCM, com- bined organic layers were dried over MgSO4, then drying agent was removed and second portion of the prod- uct was isolated via evaporation {4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methanol (Int.5, 29.629 g, 123.686 mmol, 93%, light gray solid). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 8.4, 1.6 Hz, 1H), 5.56 – 5.48 (m, 3H), 5.21 (t, J = 3.1 Hz, 2H), 4.73 (d, J = 5.8 Hz, 2H). 7‐(Bromomethyl)‐4‐chloro‐1H,3H‐furo[3,4‐c]quinoline (Int. B) A 750mL flask equipped with condenser, mechanical stirrer, rubber septum and thermometer was charged with POBr3 (23 g, 1.2 eq.) followed by slow addition of acetonitrile (200 mL) under flow of nitrogen. Then DIPEA (14 mL, 1.2 eq.) was added. The mixture was stirred for 15 minutes in ice/salt batch to reach tem- perature -10°C. Then {4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methanol (Int.5, 16 g, 1.0 eq.) was added and glassware were washed with ACN (30 mL). The mixture was stirred at 20°C for 60 minutes. RM was cooled to 0°C in ice bath and 240 mL of water was added to the reaction mixture followed by slow addition of 2M NaOH (160 mL). Mixture was stirred at RT for 30 minutes. Obtained precipitate was filtered, washed with water (2x100 mL) and heptane (100 mL) and dried. Obtained solid was suspended in 320 mL of DCM and 100 mL of water and stirred for 10 minutes, then transferred to separation funnel, layers were separated and DCM layer was washed with 2M NaOH (100 mL), 2M HCl (100 mL), saturated NaHCO3 (100 mL) and brine (100 mL). Or- ganic layer was dried over Na2SO4, then drying agent was removed via filtration and solution of product was evaporated to give 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 18.88 g, 61.999 mmol, 93%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.68 – 7.58 (m, 2H), 5.54 (dd, J = 3.1, 3.1 Hz, 2H), 5.31 (dd, J = 3.1, 3.1 Hz, 2H), 4.66 (s, 2H). The 100 mL flask equipped with condenser, magnetic stirrer, rubber septum and thermometer was charged with acetonitrile (20.0 mL) under flow of nitrogen. Then mixture was cooled in ice/salt/water bath to - Ryvu Therapeutics S.A. RVU305 91 R10945WO 8°C and DIPEA (1.486 mL, 8.532 mmol, 1.2 eq.) was added followed by slow addition of POCl3 (1.308 g, 8.532 mmol, 1.2 eq.). The mixture was stirred for 10 minutes in -5°C. Then {4-chloro-1H,3H-furo[3,4-c]quinolin-7- yl}methanol (Int.5, 1.742 g, 7.11 mmol, 1.0 eq.) was added and glassware were washed with MeCN (5 mL). The mixture was stirred at 30°C for 60 minutes. RM was cooled to 0°C in ice bath and 25 mL of DCM was added to the reaction mixture followed by slow addition of 2M NaOH (25 mL). Mixture was stirred at RT for 30 minutes and transferred to separation funnel (~30mL of DCM and 30mL of water added), layers were sepa- rated and aqueous layer was washed with DCM (3 x 30 mL). Combined organic layers were washed with brine (30 mL) dried over Na2SO4, then drying agent was removed via filtration, solution of product was evaporated together with 72 mL of heptane. After evaporation of ~170 mL of DCM precipitate occurs. Solid was filtered off, washed with small amount of heptane to obtain 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 1.704 g, 6.37 mmol, 90%, beige solid, m/z [M+H]+: 255.1). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.64 (s, 2H), 5.55 (t, J = 3.2 Hz, 2H), 5.31 (t, J = 3.1 Hz, 2H), 4.77 (s, 2H). Intermediate D: 4-Cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate 4-Cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Int. D): To a stirred solution of 4-oxooxolane-3-carbonitrile (0.5 g, 4.5 mmol, 1.0 eq.) in dichloromethane (5 mL) was added DIPEA (0.94 mL, 5.40 mmol, 1.2 eq.) and reaction mixture was cooled to -78°C. Then trifluoro- methanesulfonic anhydride (1.27 g, 4.50 mmol, 1.0 eq., 0.76 mL) was added dropwise at -78°C and reaction mixture was stirred for 15 min at that same temperature. After this time reaction mixture was left to warm to RT and held at RT for 5 h. To reaction mixture was then added water and phases were separated. Aqueous layer was extracted with DCM (x2). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. Product was purified by first FCC (0 to 5% MeOH gradient in DCM) and isolated by second FCC (10% to 30% EtOAc gradient in hexane) to give 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Int. D, 0.187 g, 0.769 mmol, 17%, colorless liquid). 1H NMR (400 MHz, Chloroform-d) δ 4.88 – 4.81 (m, 4H). Intermediate F: rac‐ trifluoromethanesulfonate 2-methyl-4-oxooxolane-3-carbonitrile (Int. E): A solution of butyl 2-hydroxyacetate (1.5 g, 16.652 mmol, 1.0 eq.) in THF (1.0 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 0.386 g, 10.074 mmol, 0.605 eq.) in THF (6.0 mL) at 0°C. After bubbles stopped forming, the resulting mixture was heated at 65°C. Once reflux started, a solution of trans-crotononitrile (contains ca.20% cis- isomer, 1.117 g, 16.652 mmol, 1.0 eq.) in THF (1.0 mL) was added dropwise, and the resulting mixture was stirred at 65°C for 3 h. Reaction mixture was cooled to RT, quenched Ryvu Therapeutics S.A. RVU305 92 R10945WO with 1 M NaOH to pH 9 and extracted with EtOAc (3x). The obtained aqueous layer was acidified with to pH 1 with conc. HCl and extracted with DCM (3x). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 2-methyl-4-oxooxolane-3-carbonitrile (Int. E, 1.269 g, 8.113 mmol, 49%, yel- low oil) 1H NMR (400 MHz, Chloroform-d) δ 4.41 – 4.34 (m, 1H), 4.31 (d, J = 17.5, 0.8 Hz, 1H), 4.05 (d, J = 17.5 Hz, 1H), 3.17 (d, J = 10.7 Hz, 1H), 1.63 (d, J = 6.0 Hz, 3H). 4-cyano-5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (Int. F): To a stirred solution of 2-methyl-4-oxooxolane-3-carbonitrile (Int. E, 1.908 g, 12.198 mmol, 1.0 eq.) in DCM (5.0 mL) was added DIPEA (8.50 mL, 48.793 mmol, 4.0 eq.) and reaction mixture was cooled to -78°C. Then trifluoromethanesulfonic anhydride (8.60 g, 30.50 mmol, 2.5 eq., 5.13 mL) was added dropwise at -78°C and reaction mixture was stirred for 15 min at that same temperature. After this time reaction mixture was left to warm to RT and held at RT overnight. To reaction mixture was then added water and phases were separated. Aqueous layer was extracted with DCM (x2). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. Product was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield 4-cyano-5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (Int. F, 0.374 g, 1.309 mmol, 11%, yellow oil). 1H NMR (400 MHz, Chloroform-d)δ 5.16 – 5.08 (m, 1H), 4.93 – 4.83 (m, 2H), 1.52 (d, J = 6.3 Hz, 3H). 19F NMR (376 MHz, Chloroform-d) δ -72.47 (s, 3F). Example 1: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropylpyridin-3-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide N‐(2‐cyclopropylpyridin‐3‐yl)‐6‐(trifluoromethyl)pyridine‐3‐carboxamide (Int.6) DMAP (0.048 g, 0.392 mmol, 0.5 eq.), DIPEA (0.362 mL, 1.962 mmol, 2.5 eq.), 2-cyclopropylpyridin-3- amine (0.111 g, 0.824 mmol, 1.05 eq.) and 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.15 g, 0.785 mmol, 1.0 eq.) were taken in DMF (4.0 mL) and propylphosphonic anhydride (50% solution in EtOAc, 0.95 mL, 1.596 mmol, 2.0 eq.) was added dropwise at 0°C. Then, the RM was heated at 100°C. The reaction was quenched with sat. aq. Na2CO3. Then was extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4. Product was isolated by FCC (0% to 5% MeOH gradient in DCM) to give N-(2-cyclopropylpyridin-3-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide (Int.6, 0.25 g, 0.797 mmol, 102%, m/z [M+H]+: 308.0). Ryvu Therapeutics S.A. RVU305 93 R10945WO 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.31 (d, J = 2.0 Hz, 1H), 8.66 – 8.57 (m, 1H), 8.35 (dd, J = 4.7, 1.6 Hz, 1H), 8.12 (dd, J = 8.2, 0.8 Hz, 1H), 7.75 (dd, J = 8.0, 1.6 Hz, 1H), 7.21 (dd, J = 7.9, 4.7 Hz, 1H), 2.34 – 2.25 (m, 1H), 1.01 – 0.89 (m, 4H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(2‐cyclopropylpyridin‐3‐yl)‐6‐(trifluoromethyl)pyridine‐3‐ carboxamide (Int.7) To a solution of N-(2-cyclopropylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.6, 0.125 g, 0.399 mmol, 1.0 eq.) in MeCN (2.0 mL) were added (4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.107 g, 0.399 mmol, 1.0 eq.) and Cs2CO3 (0.260 g, 0.797 mmol, 2.0 eq.). The reaction mixture was heated in 78°C for 2 h. The RM was cooled to RT, the dissolved in EtOAc and washed with water. Organic phases were collected and dried over Na2SO4, filtrate was concentrated in vacuum. The crude was purified by FCC (0% to 5% MeOH gradient in DCM) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclo- propylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.7, 0.183 g, 0.275 mmol, 69%, m/z [M+H]+: 526.0). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 2.1 Hz, 1H), 8.21 (dd, J = 4.6, 1.6 Hz, 1H), 8.11 – 8.00 (m, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.82 (dd, J = 13.5, 8.2 Hz, 2H), 7.71 (dd, J = 8.5, 1.7 Hz, 1H), 7.65 (dd, J = 8.0, 1.6 Hz, 1H), 7.05 (dd, J = 8.0, 4.7 Hz, 1H), 5.54 (t, J = 3.1 Hz, 2H), 5.42 (d, J = 14.5 Hz, 1H), 5.30 – 5.17 (m, 3H), 2.02 – 1.77 (m, 1H), 0.90 – 0.76 (m, 1H), 0.75 – 0.64 (m, 1H), 0.62 – 0.49 (m, 1H), 0.44 – 0.32 (m, 1H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3- carboxamide (Example 1) Step 1: To a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropylpyridin-3-yl)-6-(tri- fluoromethyl)pyridine-3-carboxamide (Int.7, 0.183 g, 0.275 mmol, 1.0 eq.) in DMSO (2.0 mL) was added DMBA 1-(2,4-dimethoxyphenyl)methanamine (0.236 g, 1.413 mmol, 5.1 eq.). The reaction was heated in 100°C overnight. After that, the reaction mixture was diluted in water and extracted with DCM. Organic phases were washed by brine and dried over Na2SO4. Product was isolated by FCC (0% to 5% MeOH gradient in DCM) to give N-(2-cyclopropylpyridin-3-yl)-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quino- lin-7-yl)methyl]-6-(trifluoromethyl)pyridine-3-carboxamide (0.164 g, 0.215 mmol, 78%). Step 2: To a solution of N-(2-cyclopropylpyridin-3-yl)-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H- furo[3,4-c]quinolin-7-yl)methyl]-6-(trifluoromethyl)pyridine-3-carboxamide (0.164 g, 0.215 mmol, 1.0 eq.) in DCM (1.5 mL) TFA (0.165 mL, 2.151 mmol, 10.0 eq.) was added at 0°C. The reaction was stirred at RT over- night. Ater that the RM was diluted with DCM, quenched by NaHCO3 aq. and extracted with DCM and then with mixture of CH3Cl : i-PrOH (3:1). Organic phases was combined, dried over Na2SO4 and filtered. Filtrate was concentrated in vacuum. Then the residue was treated with i-PrOH and white solid was filtered off. Resi- due was concentrated in vacuum. The product was isolated by FCC (0% to 10% MeOH gradient in DCM) and lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropylpyridin-3-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide (Example 1, 0.15 g, 0.297 mmol, 138%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 100.0%, m/z [M+H]+: 506.2). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.20 (d, J = 4.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.03 (dd, J = Ryvu Therapeutics S.A. RVU305 94 R10945WO 8.0, 4.7 Hz, 1H), 6.47 (s, 2H), 5.37 – 5.24 (m, 3H), 5.08 (d, J = 14.2 Hz, 1H), 5.03 – 4.94 (m, 2H), 1.97 – 1.86 (m, 1H), 0.86 – 0.77 (m, 1H), 0.76 – 0.68 (m, 1H), 0.66 – 0.55 (m, 1H), 0.41 – 0.31 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -66.74. Example 2: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methylpyridin-3-yl)pyrimi- dine-5-carboxamide 2‐cyclopropyl‐N‐(6‐methylpyridin‐3‐yl)pyrimidine‐5‐carboxamide (Int.8) 6-methylpyridin-3-amine (0.303 g, 2.802 mmol, 1.0 eq.) was dissolved in toluene (14.0 mL) and 2-cyclo- propylpyrimidine-5-carboxylic acid (0.48 g, 2.924 mmol, 1.044 eq.) was added, followed by DMAP (0.018 g, 0.147 mmol, 0.053 eq.) and DIPEA (1.23 mL, 7.061 mmol, 2.52 eq.). Then, T3P as 50 wt% solution in AcOEt (3.3 mL, 5.544 mmol, 1.979 eq.) was added to RM. The reaction mixture was heated at reflux for 4h and then it was cooled to RT. The reaction was quenched with saturated solution of NaHCO3 in portion to pH 8-9. Then, organic phase was separated and water phase was extracted with ethyl acetate. Organic layers were com- bined and washed with brine, dried with sodium sulfate and filtrated. All solvents were evaporated to give 2- cyclopropyl-N-(6-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.8, 0.763 g, 2.94 mmol, 105%, m/z [M+H]+: 255.3). 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.10 (s, 2H), 8.76 (d, J = 2.5 Hz, 1H), 8.04 (dd, J = 8.4, 2.6 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 2.45 (s, 3H), 2.35 – 2.28 (m, 1H), 1.19 – 1.13 (m, 2H), 1.12 – 1.07 (m, 2H). N‐({4‐bromo‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐(6‐methylpyridin‐3‐yl)pyrimidine‐5‐carbox- amide (Int.9) A suspension of 2-cyclopropyl-N-(6-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.8, 0.302 g, 1.164 mmol, 1.0 eq.), 4-bromo-7-(bromomethyl)-1H,3H-furo[3,4-c]quinoline (Int. A, 0.427 g, 1.22 mmol, 1.048 eq.) and Cs2CO3 (0.567 g, 1.74 mmol, 1.495 eq.) in anhydrous MeCN (12.0 mL) was stirred at 70°C for 3h. After that time RM was cooled, diluted with water and extracted with DCM. Combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by FCC (50% to 100% EtOAc Ryvu Therapeutics S.A. RVU305 95 R10945WO gradient in hexane) to obtain N-({4-bromo-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methylpyri- din-3-yl)pyrimidine-5-carboxamide (Int.9, 0.487 g, 0.905 mmol, 78%, light yellow powder, m/z [M+H]+: 517.3). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 2H), 8.20 (s, 1H), 7.95 (d, J = 0.9 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.5, 1.7 Hz, 1H), 7.66 (dd, J = 8.3, 2.7 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 5.55 (t, J = 3.0 Hz, 2H), 5.36 (s, 2H), 5.16 (t, J = 3.1 Hz, 2H), 2.33 (s, 3H), 2.20 – 2.09 (m, 1H), 1.09 – 1.02 (m, 2H), 0.99 – 0.92 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methylpyridin-3-yl)pyrimidine-5-carbox- amide (Example 2) Step 1: N-({4-bromo-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methylpyridin-3-yl)pyrimidine-5- carboxamide (Int.9, 0.435 g, 0.809 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.545 g, 3.259 mmol, 4.031 eq.) were stirred in DMSO (4.0 mL) at 120 °C for 3 hours. The reaction mixture was diluted with EtOAc and washed three times with water followed by brine, dried over anhydrous Na2SO4, filtered and con- centrated in vacuo. Crude product was purified by FCC (60% to 100% EtOAc gradient in hexane and then 0% to 10% MeOH gradient in EtOAc). Step 2: Obtained product was dissolved in DCM (8.0 mL) and trifluoroacetic acid (2.0 mL, 26.135 mmol, 32.318 eq.) was added. The RM was stirred for 4 hours at RT and then evaporated under reduced pressure. Residue was partitioned between mixture of sat. aq. NaHCO3 solution and chloroform/isopropanol 3:1 mixture. The aqueous phase was extracted with chloroform/isopropanol 3:1 mixture and the combined organic layers were washed with aq. Na2CO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FCC (0% to 10% MeOH gradient in DCM). Fractions containing the pure product were pooled and freeze-dried. Obtained compound was dissolved in DCM and washed with sat. aq. NaHCO3 solution. Organic fraction was collected, dried over sodium sulfate, filtered and evaporated. The residue was co-evaporated with EtOH and lyophilized to give N-({4-amino-1H,3H-furo[3,4- c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methylpyridin-3-yl)pyrimidine-5-carboxamide (Example 2, 0.182 g, 0.402 mmol, 50%, beige solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 100%, m/z [M+H]+: 453.26). 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 8.10 (s, 1H), 7.58 (dd, J = 8.3, 2.6 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.18 – 7.13 (m, 2H), 6.45 (s, 2H), 5.28 (t, J = 3.4 Hz, 2H), 5.21 (s, 2H), 4.97 (t, J = 3.4 Hz, 2H), 2.33 (s, 3H), 2.17 – 2.09 (m, 1H), 1.08 – 1.02 (m, 2H), 0.96 – 0.92 (m, 2H). Example 3: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide Ryvu Therapeutics S.A. RVU305 96 R10945WO 2‐cyclopropyl‐N‐(2‐methylpyridin‐3‐yl)pyrimidine‐5‐carboxamide (Int.10) N,N-dimethylpyridin-4-amine (0.169 g, 1.387 mmol, 0.3 eq.), 2-methylpyridin-3-amine (0.5 g, 4.623 mmol, 1.0 eq.) and 2-cyclopropylpyrimidine-5-carboxylic acid (0.911 g, 5.548 mmol, 1.2 eq.) were dissolved in pyridine (15.0 mL) and stirred at ice bath for 5 min. Then phosphoroyl trichloride (1.418 g, 9.247 mmol, 2.0 eq.) was added dropwise and RM was stirred at ice bath for another 5 min. After that time ice bath was re- moved and the RM was stirred at RT for 2 h. The RM was added to ice cold saturated sodium bicarbonate so- lution (150 mL). and stirred for 30 min. The solution was extracted with ethyl acetate (x2). All organic phase was collected together, washed with brine and dried over sodium sulfate. The solvent was evaporated under low pressure. The crude was purified by FCC (0% to 10% MeOH gradient in DCM) to give 2-cyclopropyl-N-(2- methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.10, 0.835 g, 3.218 mmol, 70%, beige solid, m/z [M+H]+: 255.3). 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.11 (s, 2H), 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.29 (dd, J = 8.0, 4.7 Hz, 1H), 2.45 (s, 3H), 2.36 – 2.27 (m, 1H), 1.21 – 1.13 (m, 2H), 1.12 – 1.05 (m, 2H). N‐({4‐bromo‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐(2‐methylpyridin‐3‐yl)pyrimidine‐5‐carbox- amide (Int.11) A suspension of 2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.10, 0.2 g, 0.763 mmol, 1.0 eq.), 4-bromo-7-(bromomethyl)-1H,3H-furo[3,4-c]quinoline (Int. A, 0.289 g, 0.801 mmol, 1.05 eq.) and Cs2CO3 (0.497 g, 1.526 mmol, 2.0 eq.) in anhydrous MeCN (6 mL) was stirred at 60°C for 1 h. RM was cooled, diluted with water and extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by FCC (0% to 2% MeOH gradient in DCM) followed by FCC (66% to 100% EtOAc gradient in heptane) to obtain N-({4-bromo-1H,3H-furo[3,4-c]quinolin-7- yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.11, 0.308 g, 0.537 mmol, 70%, beige solid, m/z [M+H]+: 517.2). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carbox- amide (Example 3) Ryvu Therapeutics S.A. RVU305 97 R10945WO Step 1: A solution of N-({4-bromo-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3- yl)pyrimidine-5-carboxamide (Int.11, 0.352 g, 0.609 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.539 g, 3.221 mmol, 5.3 eq.) in dioxane (6 mL) was heated at 150°C in microwave for 4 h. RM was diluted with water and extracted with DCM. Combined organic layer were washed with brine, dried over Na2SO4, fil- tered, and concentrated. The residue was purified by FCC (0% to 2% MeOH gradient in DCM) to obtain 2-cy- clopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2-methylpyri- din-3-yl)pyrimidine-5-carboxamide (0.449 g, 0.67 mmol, 110%, beige solid, m/z [M+H]+: 603.5). Step 2: 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2- methylpyridin-3-yl)pyrimidine-5-carboxamide (0.449 g, 0.67 mmol, 1.0 eq.) was dissolved in DCM (10 mL) and TFA (2.567 mL, 33.524 mmol, 50 eq.) was added. Then the RM was stirred overnight at RT. After that time sat. aq. NaHCO3 solution was added and the mixture was stirred for 30 minutes. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. Obtained residue was purified by FCC (0% to 7% MeOH gradient in DCM). Obtained fraction was triturated with EtOH, dried under reduced pressure, tritu- rated with water and lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2- methylpyridin-3-yl)pyrimidine-5-carboxamide (Example 3, 0.16 g, 0.352 mmol, 52%, beige solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.58%, m/z [M+H]+: 453.26). 1H NMR (400 MHz, DMSO-d6): δ 8.50 (s, 2H), 8.32 (d, J = 4.4 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.35 (s, 1H), 7.28 – 7.08 (m, 2H), 6.49 (s, 2H), 5.30 (s, 2H), 5.22 (d, J = 14.2 Hz, 1H), 5.07 – 4.89 (m, 3H), 2.10 (tt, J = 8.0, 4.6 Hz, 1H), 2.02 (s, 3H), 1.17 – 0.78 (m, 4H). Example 4: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-methyl-2-oxo-1,2-dihydro- pyridin-3-yl)pyrimidine-5-carboxamide 2‐cyclopropyl‐N‐(1‐methyl‐2‐oxo‐1,2‐dihydropyridin‐3‐yl)pyrimidine‐5‐carboxamide (Int.12) To a stirred solution of 2-cyclopropylpyrimidine-5-carboxylic acid (0.13 g, 0.792 mmol, 0.983 eq.) in an- hydrous DCM (4.0 mL) was added 3-amino-1-methyl-1,2-dihydropyridin-2-one (0.1 g, 0.806 mmol, 1.0 eq.) fol- lowed by HOBT (0.17 g, 1.258 mmol, 1.562 eq.) and DIPEA (0.42 mL, 2.411 mmol, 2.993 eq.). The mixture was cooled to 0°C and EDC-HCl (0.24 g, 1.252 mmol, 1.554 eq.) was added. Then the reaction mixture was Ryvu Therapeutics S.A. RVU305 98 R10945WO allowed to warm to RT and was stirred for 12 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM (3x50 mL). Combined organic layers were washed with water (2x50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude was purified by FCC (0% to 5% MeOH gradient in DCM) to give 2-cyclopropyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrimidine-5-carboxamide (Int.12, 0.2 g, 0.696 mmol, 86%, brown solid, m/z [M-H]-: 269.0). 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.03 (s, 2H), 8.22 (dd, J = 7.4, 1.9 Hz, 1H), 7.52 (dd, J = 6.8, 1.9 Hz, 1H), 6.31 (t, J = 7.1 Hz, 1H), 3.54 (s, 3H), 2.29 (tt, J = 7.9, 4.7 Hz, 1H), 1.18 – 1.12 (m, 2H), 1.11 – 1.06 (m, 2H). N‐({4‐bromo‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐(1‐methyl‐2‐oxo‐1,2‐dihydropyridin‐3‐yl)py- rimidine‐5‐carboxamide (Int.13) 4-bromo-7-(bromomethyl)-1H,3H-furo[3,4-c]quinoline (Int. A, 0.118 g, 0.327 mmol, 0.47 eq.), 2-cyclopro- pyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrimidine-5-carboxamide (Int.12, 0.2 g, 0.696 mmol, 1.0 eq.) and Cs2CO3 (0.34 g, 1.044 mmol, 1.5 eq.) were dissolved in ACN (4.0 mL). Reaction mixture was stirred over- night at 78°C. Then RM was cooled to RT, water was added and the mixture was extracted with AcOEt (3x 30 mL). Organic layers were dried over Na2SO4, filtered and evaporated. The crude was purified by FCC (0% to 10% MeOH gradient in DCM) to give N-({4-bromo-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1- methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrimidine-5-carboxamide (Int.13, 0.165 g, 0.294 mmol, 42%, gray solid, m/z [M+H]+: 533.0). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)py- rimidine-5-carboxamide (Example 4) Step 1: To a solution of N-({4-bromo-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-methyl-2-oxo-1,2- dihydropyridin-3-yl)pyrimidine-5-carboxamide (Int.13, 0.165 g, 0.294 mmol, 1.0 eq.) in DMSO (1.5 mL) 1-(2,4- dimethoxyphenyl)methanamine (0.5 g, 2.99 mmol, 10.156 eq.) was added. The rection mixture was heated at 100°C overnight. The RM was diluted with water and extracted with DCM. Organic phases were combined and dried over Na2SO4. After evaporation the crude was purified by FCC (0% to 5% MeOH gradient in DCM) to give 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(1-methyl- 2-oxo-1,2-dihydropyridin-3-yl)pyrimidine-5-carboxamide (0.202 g, 0.313 mmol, 106%, m/z [M+H]+: 619.7). Step 2: To a solution of 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrimidine-5-carboxamide (0.202 g, 0.313 mmol, 1.0 eq.) in DCM (2.0 mL) TFA (0.6 mL, 7.841 mmol, 25.0 eq.) was added. The rection mixture was stirred overnight at RT. Then the reaction was quenched by NaHCO3 and extracted with DCM. Organic layers were combined, dried over Na2SO4 and evaporated. The crude was purified by FCC (0% to 5% MeOH gradient in DCM) to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)py- rimidine-5-carboxamide (Example 4, 0.051 g, 0.109 mmol, 35%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.77%, m/z [M+H]+: 469.24). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 7.61 (d, J = 7.3 Hz, 1H), 7.49 – 7.37 (m, 2H), 7.26 (d, J = 7.4 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.46 (s, 2H), 6.07 (t, J = 7.0 Hz, 1H), 5.42 – 5.13 (m, 3H), 4.98 (s, 2H), 4.77 – 4.61 (m, 1H), 3.35 (s, 3H), 2.21 – 2.08 (m, 1H), 1.10 – 1.01 (m, 2H), 0.99 – 0.92 (m, 2H). Ryvu Therapeutics S.A. RVU305 99 R10945WO Example 5: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimi- dine-5-carboxamide 2‐cyclopropyl‐N‐(6‐methoxypyridin‐3‐yl)pyrimidine‐5‐carboxamide (Int.14) To a solution of 6-methoxypyridin-3-amine (0.3 g, 2.417 mmol, 1.0 eq.) and 2-cyclopropylpyrimidine-5- carboxylic acid (0.41655 g, 2.537 mmol, 1.05 eq.) in anh. toluene (5 mL) were added in N,N-dimethylpyridin-4- amine (0.015 g, 0.121 mmol, 0.05 eq.) and DIPEA (1.05 mL, 6.041 mmol, 2.5 eq.) followed by propylphosphonic anhydride (50% solution in EtOAc, 2.877 mL, 4.833 mmol, 2.0 eq.) at RT. The RM was then stirred at reflux for 1 h. After that time the mixture was cooled to RT, diluted with water and extracted with EtOAc. Combined organic layers were washed with brine, dried over anh. sodium sulfate, filtered and evapo- rated in vacuo. The crude was purified by FCC (0% to 67% EtOAc gradient in heptane) to give 2-cyclopropyl-N- (6-methoxypyridin-3-yl)pyrimidine-5-carboxamide (Int.14, 0.56 g, 2.051 mmol, 85%, violet solid, m/z [M+H]+: 271.3). 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.09 (s, 2H), 8.50 (d, J = 2.8 Hz, 1H), 8.06 – 7.97 (m, 1H), 6.86 (d, J = 8.9 Hz, 1H), 3.84 (s, 3H), 2.31 (tt, J = 7.9, 4.7 Hz, 1H), 1.17 – 1.13 (m, 2H), 1.12 – 1.07 (m, 2H). N‐[(4‐bromo‐3‐nitrophenyl)methyl]‐2‐cyclopropyl‐N‐(6‐methoxypyridin‐3‐yl)pyrimidine‐5‐carboxamide (Int.15) A mixture of 2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimidine-5-carboxamide (Int.14, 0.458 g, 1.678 mmol, 1.0 eq.), Cs2CO3, (0.656 g, 2.013 mmol, 1.2 eq.) and 1-bromo-4-(bromomethyl)-2-nitrobenzene (0.742 g, 2.516 mmol, 1.5 eq.) in ACN (4 mL) was heated at 70°C for 1 h. After that time the mixture was cooled to RT, diluted with water and extracted with EtOAc. Combined organic layers were dried over anh. sodium sulfate, filtrated and evaporated in vacuo. The crude was purified by FCC (0% to 100% EtOAc gradient in heptane) to give N-[(4-bromo-3-nitrophenyl)methyl]-2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimidine-5-carboxamide (Int. 15, 0.691 g, 1.384 mmol, 83%, m/z [M+H]+: 485.3). 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 2H), 7.21 – 7.11 (m, 2H), 7.02 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 8.9, 2.8 Hz, 1H), 6.73 (dd, J = 8.3, 2.1 Hz, 1H), 5.96 (d, J = 8.8 Hz, 1H), 4.30 (s, 2H), 2.94 (s, 3H), 1.31 (tt, J = 8.2, 4.6 Hz, 1H), 0.26 – 0.19 (m, 2H), 0.15 – 0.09 (m, 2H). N‐[(3‐amino‐4‐bromophenyl)methyl]‐2‐cyclopropyl‐N‐(6‐methoxypyridin‐3‐yl)pyrimidine‐5‐carboxamide (Int.16) Ryvu Therapeutics S.A. RVU305 100 R10945WO To a solution of N-[(4-bromo-3-nitrophenyl)methyl]-2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimidine-5- carboxamide (Int.15, 0.683 g, 1.368 mmol, 1.0 eq.) in acetone (6 mL) and aq. sat. NH4Cl (1.2 mL) solution, zinc (0.894 g, 13.679 mmol, 10.0 eq.) was added portion wise. RM was stirred at RT for 1 h. After that time RM was filtrated through Celite pad and filter was washed with ethyl acetate. Filtrate was washed with sodium bi- carbonate solution, brine, dried over Na2SO4, filtered and evaporated to give N-[(3-amino-4-bromophenyl)me- thyl]-2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimidine-5-carboxamide (Int.16, 0.61 g, 1.222 mmol, 89%, m/z [M+H]+: 455.3). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 2H), 7.88 (s, 1H), 7.62 (dd, J = 8.7, 2.7 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.81 – 6.70 (m, 2H), 6.39 (dd, J = 8.2, 2.1 Hz, 1H), 5.30 (s, 2H), 4.89 (s, 2H), 3.76 (s, 3H), 2.19 – 2.06 (m, 1H), 1.08 – 0.99 (m, 2H), 0.97 – 0.88 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimidine-5-car- boxamide (Example 5) Step 1: A suspension of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.153 g, 0.601 mmol, 2.0 eq.), potassium acetate (0.088 g, 0.901 mmol, 3.0 eq.) and N-[(3-amino-4-bromo- phenyl)methyl]-2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimidine-5-carboxamide (Int.16, 0.15 g, 0.3 mmol, 1.0 eq.) in 1,4-dioxane (2.0 mL) and was purge with N2 for 15 min. Then 1,1'-Bis(diphenylphosphino)ferrocene-pal- ladium(ii)dichloride dichloromethane (0.025 g, 0.03 mmol, 0.1 eq.) was added and RM was heated at 100°C for 4 h. After this time reaction mixture was allowed to cool to RT, then AcOEt was added and the mixture was fil- tered through a pad of celite. To filtrate water was added and layers were separated. Aqueous layer was ex- tracted with AcOEt. Combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. Step 2: Microwave reactor was charged under nitrogen with 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesul- fonate (Int. D, 0.656 g, 2.427 mmol, 2.0 eq.), product of step 1 (0.96 g, 1.214 mmol, 1.0 eq.) and dipotassium carbonate (0.503 g, 3.641 mmol, 3.0 eq.) followed by 1,4-dioxane (10.0 mL) and water (1.0 mL). The reaction mixture was bubbled with argon for 5 min and tetrakis(triphenylphosphane) palladium (0.140 g, 0.121 mmol, 0.1 eq.) was added. RM was microwaved for 30 min at 120°C. After that time RM was diluted with ethyl acetate and water. Aqueous phase was extracted with ethyl acetate (2x). Combined organic layers were washed with brine, then dried over Na2SO4, filtered and concentrated in vacuo. Crude was purified by FCC (0% to 3% MeOH gradient in DCM) followed by FCC (NH2 modified silica, 0% to 5% MeOH gradient in DCM) to give 2- cyclopropyl-N-(6-methoxypyridin-3-yl)-N-({4-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)pyrimidine-5-carbox- amide (Example 5, 0.102 g, 0.218 mmol, 18%, beige solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.36%, m/z [M+H]+: 469.25). 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 7.83 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.46 – 7.26 (m, 2H), 7.17 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.47 (s, 2H), 5.28 (t, J = 3.5 Hz, 2H), 5.17 (s, 2H), 4.97 (t, J = 3.3 Hz, 2H), 3.72 (s, 3H), 2.23 – 2.06 (m, 1H), 1.12 – 0.96 (m, 2H), 0.98 – 0.89 (m, 2H). Example 6: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3,6-dimethylpyrazin-2-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 101 R10945WO N‐(3,6‐dimethylpyrazin‐2‐yl)‐6‐(trifluoromethyl)pyridine‐3‐carboxamide (Int.17) Phosphorus oxychloride (0.498 g, 3.248 mmol, 2.0 eq.) was added dropwise to a solution of 6-(trifluoro- methyl)pyridine-3-carboxylic acid (0.310 g, 1.624 mmol, 1.0 eq.), 3,6-dimethylpyrazin-2-amine (0.2 g, 1.624 mmol, 1.0 eq.) and N,N-dimethylpyridin-4-amine (0.060 g, 0.487 mmol, 0.3 eq.) in pyridine (9.0 mL) at 0°C. The RM was stirred 5 min at 0°C and then 40 min at RT under nitrogen. The reaction was quenched with ice/water and neutralized with sat. aq. NaHCO3 solution. The mixture was transferred to separatory funnel and extracted with EtOAc (3x). Combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (0% to 100% EtOAc gradient in hexane) to give N-(3,6-dimethylpyrazin-2-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.17, 0.355 g, 1.186 mmol, 73%, m/z [M+H]+: 297.1). 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.30 (d, J = 2.1 Hz, 1H), 8.61 (dd, J = 8.3, 2.1 Hz, 1H), 8.41 (s, 1H), 8.12 (dd, J = 8.1, 0.9 Hz, 1H), 2.47 (s, 3H), 2.41 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.66. N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(3,6‐dimethylpyrazin‐2‐yl)‐6‐(trifluoromethyl)pyridine‐3‐ carboxamide (Int.18) Cs2CO3 (0.762 g, 2.339 mmol, 2.0 eq.) was added to a suspension of N-(3,6-dimethylpyrazin-2-yl)-6- (trifluoromethyl)pyridine-3-carboxamide (Int.17, 0.35 g, 1.17 mmol, 1.0 eq.) in MeCN (15 mL). The mixture was flushed with argon for 10 min at RT. Then 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.402 g, 1.287 mmol, 1.1 eq.) was added and RM was stirred at 70°C for 60 minutes. Reaction was quenched with NH4Cl solution, transferred to separatory funnel and extracted with ethyl acetate (3x). Combined organic phases were washed with brine, dried over Na2SO4 filtered and evaporated. The crude was purified by FCC (0% to 80% EtOAc gradient in hexane) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3,6-dime- thylpyrazin-2-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.18, 0.49 g, 0.763 mmol, 65%, m/z [M+H]+: 514.4). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.37 (s, 1H), 8.00 (s, 1H), 7.98 – 7.91 (m, 1H), 7.90 – 7.80 (m, 2H), 7.80 – 7.72 (m, 1H), 5.58 – 5.51 (m, 2H), 5.34 (s, 2H), 5.23 – 5.15 (m, 2H), 2.40 (s, 3H), 2.08 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.80. Ryvu Therapeutics S.A. RVU305 102 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3,6-dimethylpyrazin-2-yl)-6-(trifluoromethyl)pyridine-3- carboxamide (Example 6) Step 1: N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3,6-dimethylpyrazin-2-yl)-6-(trifluoromethyl)pyri- dine-3-carboxamide (Int.18, 0.485 g, 0.755 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.505 g, 3.02 mmol, 4.0 eq.) were stirred in DMSO (5.0 mL) at 120°C for 4h. The reaction mixture was diluted with EtOAc and washed three times with water followed by brine, dried over anhydrous Na2SO4, filtered and con- centrated in vacuo. Step 2: Step 1 product was dissolved in DCM (5 mL) and trifluoroacetic acid (2.889 mL, 37.75 mmol, 50.0 eq.) was added. The RM was stirred 24 h at RT and evaporated under reduced pressure. Residue was partitioned between mixture of sat. aq. NaHCO3/1M NaOH solutions and DCM. The aqueous phase was extracted with DCM. Combined organic layers were washed with aq. NaHCO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by reversed phase FCC (C18 column) followed by normal phase FCC (0% to 10% MeOH gradient in AcOEt) to give N-({4-amino- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3,6-dimethylpyrazin-2-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 6, 0.22 g, 0.445 mmol, 58%, white solid, UPLC long elution (Mid polar long method, buffer type “FA”) purity: 99.03%, m/z [M+H]+: 495.2). 10/2 mixture of restricted C-N amide rotation isomers in DMSO-d6 at RT Major rotamer: 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.35 (s, 1H), 7.93 (d, J = 7.1 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.51 – 7.36 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 6.50 (s, 2H), 5.34 – 5.17 (m, 4H), 4.98 (s, 2H), 2.44 (s, 3H), 1.93 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.80. Minor rotamer: 19F NMR (376 MHz, DMSO-d6) δ -66.67. Example 7: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 103 R10945WO 6‐cyclopropyl‐N‐(1,3‐dimethyl‐1H‐pyrazol‐4‐yl)pyridine‐3‐carboxamide (Int.19) 1,3-dimethyl-1H-pyrazol-4-amine (0.765 g, 6.883 mmol, 1.0 eq.), N,N-dimethylpyridin-4-amine (0.011 g, 0.09 mmol, 0.013 eq.) and 6-cyclopropylpyridine-3-carboxylic acid (0.734 g, 4.499 mmol, 0.654 eq.) were taken in anh. pyridine (12.0 mL). The mixture was cooled in ice bath and stirred for 5 min. After that time, phosphoryl trichloride (1.0 g, 6.522 mmol, 0.948 eq.) was added dropwise. Then the reaction was stirred for additional 5 min in ice bath and 1.5 h at RT. The reaction was quenched by sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (x3). All organic phase was collected together, washed with brine and dried over sodium sulfate. The solvent was removed under low pressure. Product was isolated by FCC (MeOH gradi- ent in DCM) to give 6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (Int.19, 0.5 g, 1.853 mmol, 27%, m/z [M+H]+: 257.2). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 8.2, 2.3 Hz, 1H), 7.88 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 3.74 (s, 3H), 2.25 – 2.15 (m, 1H), 2.14 (s, 3H), 1.12 – 0.92 (m, 4H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐6‐cyclopropyl‐N‐(1,3‐dimethyl‐1H‐pyrazol‐4‐yl)pyridine‐3‐ carboxamide (Int.20) To a solution of 6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (Int.19, 0.2 g, 0.741 mmol, 1.0 eq.) in ACN (4.0 mL) were added 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.198 g, 0.741 mmol, 1.0 eq.) and Cs2CO3 (0.484 g, 1.48 mmol, 2 eq). The reaction mixture was heated at 78°C for 2 h. The RM was cooled to RT diluted with EtOAc and washed with water. Aqueous layer was ex- tracted with EtOAc. Organic phases were combined and dried over Na2SO4, filtrate was concentrated in vacuo. The crude was purified by FCC (0% to 5% MeOH gradient in DCM) to give N-({4-chloro-1H,3H-furo[3,4-c]quin- olin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (Int.20, 0.428 g, 0.831 mmol, 112%, m/z [M+H]+: 475.0). 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.89 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.64 – 7.58 (m, 2H), 7.20 (d, J = 8.1 Hz, 1H), 5.54 (t, J = 3.2 Hz, 2H), 5.23 (t, J = 3.1 Hz, 2H), 5.09 (s, 2H), 3.59 (s, 3H), 2.11 – 2.00 (m, 1H), 1.58 (s, 3H), 0.98 – 0.92 (m, 2H), 0.90 – 0.86 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3- carboxamide (Example 7) Step 1: To a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H- pyrazol-4-yl)pyridine-3-carboxamide (Int.20, 0.428 g, 0.831 mmol, 1.0 eq.) in DMSO (5.0 mL) was added 1- (2,4-dimethoxyphenyl)methanamine (1.165 g, 6.967 mmol, 8.386 eq.). The reaction was heated overnight at 100°C. After that the reaction mixture was diluted in water and extracted by DCM. Organic phases were washed by brine and dried over Na2SO4. The crude was purified by FCC (0% to 5% MeOH gradient in DCM) to give 6-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(1,3- dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (0.453 g, 0.592 mmol, 71%, yellow oil, m/z [M+H]+: 605.4). Step 2: To a solution of 6-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (0.453 g, 0.592 mmol, 1.0 eq.) in DCM (3.0 mL) at 0°C ,TFA (0.5 mL, 6.534 mmol, 11.0 eq.) was added. The RM was stirred overnight at RT. Ater that time the RM was diluted with DCM and quenched by NaHCO3 aq. Obtained mixture was extracted with DCM and Ryvu Therapeutics S.A. RVU305 104 R10945WO CH3Cl : i-PrOH (3:1) mixture. Organic phases was combined, dried over Na2SO4 and filtered. Filtrate was con- centrated in vacuo. Then the residue was treated with i-PrOH. Obtained withe solid was filtered off and filtrate was concentrated in vacuo. The residue was purified by FCC (0% to 10% MeOH gradient in DCM) and lyophi- lized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyridine-3-carboxamide (Example 7, 0.077 g, 0.169 mmol, 29%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.99%, m/z [M+H]+: 455.0). 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.41 (s, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.49 (s, 2H), 5.31 (t, J = 3.3 Hz, 2H), 5.00 (t, J = 3.3 Hz, 2H), 4.96 (s, 2H), 3.60 (s, 3H), 2.11 – 1.98 (m, 1H), 1.54 (s, 3H), 1.02 – 0.91 (m, 2H), 0.91 – 0.79 (m, 2H). Example 8: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin- 3-yl)pyrimidine-5-carboxamide N‐(5‐bromo‐2‐methylpyridin‐3‐yl)‐2‐cyclopropylpyrimidine‐5‐carboxamide (Int.21) Phosphorus oxychloride (0.492 g, 3.208 mmol, 2.0 eq.) was added dropwise to a solution of 2-cyclo- propylpyrimidine-5-carboxylic acid (0.263 g, 1.604 mmol, 1.0 eq.), 5-bromo-2-methylpyridin-3-amine (0.3 g, 1.604 mmol, 1.0 eq.) and N,N-dimethylpyridin-4-amine (0.05879 g, 0.481 mmol, 0.3 eq.) in pyridine (5.0 mL) at 0°C. The RM was stirred 5 min at 0°C and then 40 min at RT under nitrogen atmosphere. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3 solution. The mixture was transferred to separatory funnel and extracted with EtOAc (3x). Combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (0% to 100% EtOAc gradient in hexane) to give N-(5-bromo-2-methylpyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide (Int.21, 0.31 g, 0.93 mmol, 58%, m/z [M+H]+: 334.8). 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.11 (s, 2H), 8.49 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 2.45 (s, 3H), 2.37 – 2.29 (m, 1H), 1.20 – 1.14 (m, 2H), 1.14 – 1.08 (m, 2H). 2‐cyclopropyl‐N‐(5‐cyclopropyl‐2‐methylpyridin‐3‐yl)pyrimidine‐5‐carboxamide (Int.22) In a pressure reactor 10:1 mixture of toluene : water (10 mL) was degassed and flushed with argon for 30 minutes. Next cyclopropylboronic acid (0.159 g, 1.849 mmol, 2.0 eq), N-(5-bromo-2-methylpyridin-3-yl)-2- Ryvu Therapeutics S.A. RVU305 105 R10945WO cyclopropylpyrimidine-5-carboxamide (Int.21, 0.308 g, 0.924 mmol, 1.0 eq.) and K2CO3 (0.383 g, 2.773 mmol, 3.0 eq.) were added and the mixture was stirred vigorously under argon atmosphere for 5 minutes. Then 1,1'- bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.007 g, 0.009 mmol, 0.01 eq.) was added and reaction mixture was stirred at 100°C for 48 h. After that time the mixture was charged with 100 mg of Silica Metal Scav- enger and filtered through celite. Filtrate was diluted with DCM:i-PrOH 4:1 mixture and washed with sat. aq. NaHCO3 solution (3x) and brine. Organic layer was dried over sodium sulphate, filtered through silica gel and evaporated to give 2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.22, 0.151 g, 0.513 mmol, 55%, m/z [M+H]+: 295.0). 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.11 (s, 2H), 8.20 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 2.39 (s, 3H), 2.36 – 2.29 (m, 1H), 2.01 – 1.92 (m, 1H), 1.20 – 1.14 (m, 2H), 1.13 – 1.08 (m, 2H), 1.04 – 0.97 (m, 2H), 0.75 – 0.67 (m, 2H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐(5‐cyclopropyl‐2‐methylpyridin‐3‐yl)pyrimi- dine‐5‐carboxamide (Int.23) To the mixture of 2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int. 22, 0.15 g, 0.51 mmol, 1.0 eq.) and 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.159 g, 0.51 mmol, 1.0 eq.) in MeCN (5 mL), Cs2CO3 (0.332 g, 1.019 mmol, 2.0 eq.) was added. The mixture was flushed with nitrogen for 10 min at RT and was stirred at 70°C for 60 minutes. After that time the reaction mixture was diluted with aqueous Na2CO3 solution, transferred to separatory funnel and extracted with ethyl acetate (3x). Combined organic phases were washed with brine, dried over Na2SO4 filtered and evaporated. Crude product was purified by FCC (0% to 100% EtOAc gradient in hexane) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7- yl}methyl)-2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.23, 0.186 g, 0.356 mmol, 70%, m/z [M+H]+: 513.1). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 2H), 8.17 (d, J = 2.1 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 5.53 (t, J = 3.0 Hz, 2H), 5.33 – 5.12 (m, 4H), 2.17 – 2.07 (m, 1H), 1.90 (s, 3H), 1.88 – 1.77 (m, 1H), 1.07 – 1.01 (m, 2H), 0.95 – 0.80 (m, 4H), 0.64 – 0.42 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide (Example 8) Step 1: A solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-cyclopropyl-2- methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.23, 0.184 g, 0.352 mmol, 1.0 eq.) and 1-(2,4-dimethoxy- phenyl)methanamine (0.236 g, 1.409 mmol, 4.0 eq.) in DMSO (5.0 mL) was stirred at 120°C for 8 h. After that time the mixture was cooled to RT, diluted with EtOAc and washed three times with water followed by brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Step 2: Step 1 product was dissolved in DCM (5 mL) and trifluoroacetic acid (1.348 mL, 17.609 mmol, 50.0 eq.) was added. The RM was stirred 24 h at RT and evaporated under reduced pressure. Residue was partitioned between mixture of sat. aq. NaHCO3/1M NaOH solutions and DCM. The aqueous phase was extracted with DCM. Combined organic layers were washed with aq. NaHCO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by reversed phase FCC (C18 column) followed by normal phase FCC (0% to 10% EtOH gradient in DCM) to give N-({4-amino-1H,3H- furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyrimidine-5-carboxamide Ryvu Therapeutics S.A. RVU305 106 R10945WO (Example 8, 0.02 g, 0.04 mmol, 11%, white solid, UPLC long elution (Polar long method, buffer type “FA”) pu- rity: 99.67%, m/z [M+H]+: 493.23). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2H), 8.17 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.2, 1.6 Hz, 1H), 6.47 (s, 2H), 5.33 – 5.27 (m, 2H), 5.16 – 5.05 (m, 2H), 5.01 – 4.96 (m, 2H), 2.17 – 2.07 (m, 1H), 1.92 – 1.84 (m, 1H), 1.82 (s, 3H), 1.08 – 1.00 (m, 2H), 0.96 – 0.88 (m, 4H), 0.67 – 0.61 (m, 1H), 0.56 – 0.48 (m, 1H). Example 10: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyr- idine-3-carboxamide N‐(2‐methylpyridin‐3‐yl)‐6‐(trifluoromethyl)pyridine‐3‐carboxamide (Int.27) DMAP (0.064 g, 0.524 mmol, 0.501 eq.), DIPEA (0.470 mL, 2.616 mmol, 2.5 eq.), 2-methylpyridin-3- amine (0.12 g, 1.11 mmol, 1.06 eq.) and 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.2 g, 1.047 mmol, 1.0 eq.) were taken in DMF (6.0 mL) and propylphosphonic anhydride (50% in EtOAc, 1.25 mL, 2.1 mmol, 2.0 eq.) was added dropwise at 0°C. Then, the RM was heated at 100°C for 1 h. The reaction was quenched with sat. aq. Na2CO3 solution. Then the mixture was extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4. The crude was purified by FCC (0% to 5% MeOH gradient in DCM) to give N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.27, 0.28 g, 0.996 mmol, 95%, yellow oil, m/z [M-H]-: 280.1). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(2‐methylpyridin‐3‐yl)‐6‐(trifluoromethyl)pyridine‐3‐car- boxamide (Int.28) To a solution of 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.266 g, 0.996 mmol, 1.0 eq.), N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.27, 0.28 g, 0.996 mmol, 1.0 eq.) in ACN (5.0 mL) was added Cs2CO3 (0.65 g, 1.995 mmol, 2.0 eq.). The reaction mixture was heated overnight at 78°C. The reaction was cooled to RT and then diluted with water. Obtained mixture was extracted with EtOAc (2x). Combined organic layers were washed with brine and dried over Na2SO4. The crude was purified by FCC Ryvu Therapeutics S.A. RVU305 107 R10945WO (0% to 5% MeOH gradient in DCM) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.28, 0.389 g, 0.749 mmol, 75%, yellow solid, m/z [M+H]+: 497.7). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide (Example 10) Step 1: To a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methylpyridin-3-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide (Int.28, 0.389 g, 0.749 mmol, 1.0 eq.) in DMSO (4.0 mL) 1-(2,4-dimethoxy- phenyl)methanamine (1.0 g, 5.981 mmol, 7.99 eq.) was added. The reaction was stirred overnight at 100°C. The reaction was cooled to RT and then diluted with water. Obtained mixture was extracted with DCM (2x). Combined organic layers were washed with brine and dried over Na2SO4. The crude was purified by FCC (0% to 5% MeOH gradient in DCM) to give N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (0.317 g, 0.428 mmol, 57%, yel- low solid, m/z [M+H]+: 630.4). Step 2: To a solution of N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2- methylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (0.317 g, 0.428 mmol, 1.0 eq.) in DCM (3.0 mL) TFA (0.4 mL, 5.227 mmol, 12.214 eq.) was added at 0°C. The reaction was stirred overnight at RT. Ater that time the RM was diluted with DCM and basified with aq. NaHCO3. Obtained mixture was extracted with DCM and mixture of CH3Cl : i-PrOH (3:1). Organic phases were combined, dried over Na2SO4 and filtered. Filtrate was concentrated in vacuo. The residue was then treated with i-PrOH. Obtained solid was filtered off. Filtrate was concentrated in vacuo and purified by FCC (0% to 10% MeOH gradient in DCM). Obtained fraction was lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methylpyridin-3-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide (Example 10, 0.16 g, 0.333 mmol, 78%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.84%, m/z [M+H]+: 480.21). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.27 (d, J = 4.7 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.27 – 7.09 (m, 2H), 6.49 (s, 2H), 5.34 – 5.23 (m, 3H), 5.02 (d, J = 14.6 Hz, 1H), 4.99 – 4.96 (m, 2H), 2.07 (s, 3H). Example 12: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)- 1,3-benzothiazol-5-yl]pyridine-3-carboxamide
Ryvu Therapeutics S.A. RVU305 108 R10945WO N‐(2‐fluoro‐5‐nitrophenyl)‐1‐methylpiperidine‐4‐carboxamide (Int.31) 2-fluoro-5-nitroaniline (1.0 g, 6.405 mmol, 1.0 eq.), DMAP (0.157 g, 1.281 mmol, 0.2 eq.) and DIPEA (2.789 mL, 16.014 mmol, 2.5 eq.) were dissolved in pyridine (30 mL), followed by an addition of 1-methylpiperi- dine-4-carboxylic acid hydrochloride (1.151 g, 6.405 mmol, 1.0 eq.). The RM was cooled to 0°C under nitrogen atmosphere and POCl3 (1.964 g, 12.811 mmol, 2.0 eq.) was added dropwise. The mixture was stirred 5 min at 0°C and then 1 h at RT. RM was diluted with DCM and quenched with aq. Na2CO3 solution to pH~9. Obtained mixture was extracted with DCM. Combined organic phases were dried over Na2SO4 and evaporated. The resi- due was purified by trituration with Et2O to give N-(2-fluoro-5-nitrophenyl)-1-methylpiperidine-4-carboxamide (Int.31, 1.0 g, 3.448 mmol, 54%, brown solid, m/z [M+H]+: 282.1). The filtrate was evaporated to dryness, dis- solved in DCM and 1M aq. HCl was added to pH=1 and the mixture was extracted with water. Organic layers were discarded and water layer was basified with aq. NaOH to pH~9 and extracted with DCM. Combined or- ganic phases were dried over Na2SO4 and evaporated to give N-(2-fluoro-5-nitrophenyl)-1-methylpiperidine-4- carboxamide (Int.31, 0.45 g, 1.584 mmol, 25%, yellow solid, m/z [M+H]+: 282.2). 2‐(1‐methylpiperidin‐4‐yl)‐5‐nitro‐1,3‐benzothiazole (Int.32) Step 1: To the suspension of N-(2-fluoro-5-nitrophenyl)-1-methylpiperidine-4-carboxamide (Int.31, 1.0 g, 3.448 mmol, 1.0 eq.) in toluene (10 mL), Lawesson's reagent (1.395 g, 3.448 mmol, 1.0 eq.) was added. The RM was stirred at reflux for 4 h. The RM was cooled to RT and diluted with DCM. Obtained mixture was washed with sat. aq. Na2CO3 solution. Aqueous layers were extracted with DCM. Combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. Step 2: Ryvu Therapeutics S.A. RVU305 109 R10945WO The residue was dissolved in NMP (10 mL) and K2CO3 (0.477 g, 3.448 mmol, 1.0 eq.) was added. Ob- tained mixture was stirred at 100°C for 3 h. After that time the RM was cooled to RT, diluted with water and EtOAc, and extracted with EtOAc. Combined organic layers were dried over Na2SO4, filtered and evaporated to obtain 2-(1-methylpiperidin-4-yl)-5-nitro-1,3-benzothiazole (Int.32, 0.86 g, 2.946 mmol, 85%, red solid, m/z [M+H]+: 278.4). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 1.6 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.27 (dd, J = 8.9, 1.7 Hz, 1H), 3.22 – 3.11 (m, 1H), 2.91 – 2.81 (m, 2H), 2.21 (s, 3H), 2.15 – 2.00 (m, 4H), 1.90 – 1.75 (m, 2H). 2‐(1‐methylpiperidin‐4‐yl)‐1,3‐benzothiazol‐5‐amine (Int.33) A mixture of iron (1.011 g, 18.103 mmol, 7.0 eq.), ammonium chloride (1.66 g, 31.034 mmol, 12.0 eq.), 2-(1-methylpiperidin-4-yl)-5-nitro-1,3-benzothiazole (Int.32, 0.755 g, 2.586 mmol, 1.0 eq.) in ethanol (60 mL) and of water (18 mL) was heated to reflux for 1 h. The reaction mixture was filtered through a Celite pad and filter was washed with hot EtOH. The filtrate was concentrated in vacuo. Residue was diluted with water and acidified with 1N HCl. Obtained mixture was washed with EtOAc. Aqueous layer was basified with aq. NaOH to pH=10 and extracted with EtOAc (3x). Combined organic layers were dried over Na2SO4, filtered and evapo- rated to give 2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-5-amine (Int.33, 0.66 g, 2.588 mmol, 100%, brown solid, m/z [M+H]+: 248.3). 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 6.71 (d, J = 8.5 Hz, 1H), 5.22 (s, 2H), 3.02 – 2.89 (m, 1H), 2.89 – 2.78 (m, 2H), 2.19 (s, 3H), 2.09 – 1.94 (m, 4H), 1.84 – 1.64 (m, 2H). 6‐cyclopropyl‐N‐[2‐(1‐methylpiperidin‐4‐yl)‐1,3‐benzothiazol‐5‐yl]pyridine‐3‐carboxamide (Int.34) Step 1: To the suspension of 6-cyclopropylpyridine-3-carboxylic acid (0.192 g, 1.177 mmol, 1.0 eq.) in DCM (6 mL), oxalyl chloride (0.172 g, 1.353 mmol, 1.15 eq.) was added followed by 1 drop of DMF. The RM was stirred over 1 h at RT. After that time the RM was evaporated to dryness at 30°C. Obtained residue was co-evaporate with DCM in the same manner to give 6‐cyclopropylpyridine‐3‐carbonyl chloride Step 2: 2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-5-amine (0.300 g, 1.177 mmol, 1.0 eq.) was dissolved in anh. dioxane (6 mL) and added to the previously prepared acid chloride. The RM was stirred at 80°C overnight. The RM was evaporated to dryness. Residue was basified with 1M NaOH and extracted with EtOAc. Organic layers were combined, washed with water and brine, dried over Na2SO4. Then drying agent was filtered off and filtrate was concentrated in vacuo. The crude was purified by trituration with a mixture of Et2O and w few drops of i- PrOH to give 6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-5-yl]pyridine-3-carboxamide (Int.34, 0.41 g, 1.013 mmol, 86%, brown solid, m/z [M+H]+: 393.5). 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.97 (s, 1H), 8.45 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 3.13 – 3.02 (m, 1H), 2.92 – 2.80 (m, 2H), 2.26 – 2.15 (m, 4H), 2.13 – 2.00 (m, 4H), 1.88 – 1.74 (m, 2H), 1.09 – 0.96 (m, 4H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐6‐cyclopropyl‐N‐[2‐(1‐methylpiperidin‐4‐yl)‐1,3‐benzothia- zol‐5‐yl]pyridine‐3‐carboxamide (Int.35) To a solution of 6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-5-yl]pyridine-3-carboxamide (Int.34, 0.41 g, 1.013 mmol, 1.0 eq.) in anhydrous DMF (5 mL), NaH 60% in oil (0.0384 g, 1.672 mmol, 1.65 eq.) was added under a nitrogen atmosphere and while cooling in an ice bath. The reaction mixture was stirred Ryvu Therapeutics S.A. RVU305 110 R10945WO at 0°C for 20 min. Then a solution of 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.3056 g, 1.013 mmol, 1.0 eq.) in anhydrous DMF (10 mL) was added dropwise. The reaction mixture was stirred at 0°C for 30 min. The reaction was quenched with diluted NH4Cl solution, transferred to a separatory funnel and ex- tracted with ethyl acetate (3x). Organic layers were combined, washed with brine, dried over anhydrous sodium sulphate and evaporated under vacuum. The crude mixture was purified by FCC (0% to 10% MeOH gradient in DCM) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)- 1,3-benzothiazol-5-yl]pyridine-3-carboxamide (Int.35, 0.3 g, 0.487 mmol, 48%, beige solid, m/z [M+H]+: 611.2). 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.92 (s, 1H), 7.88 – 7.83 (m, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.19 – 7.10 (m, 2H), 5.51 (s, 2H), 5.44 (s, 2H), 5.23 – 5.15 (m, 2H), 3.06 – 2.94 (m, 1H), 2.84 (d, J = 11.1 Hz, 2H), 2.20 (s, 3H), 2.10 – 1.99 (m, 5H), 1.82 – 1.68 (m, 2H), 0.95 – 0.88 (m, 2H), 0.85 – 0.79 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-5-yl]pyridine-3-carboxamide (Example 12) Step 1: A solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4- yl)-1,3-benzothiazol-5-yl]pyridine-3-carboxamide (Int.35, 0.265 g, 0.43 mmol, 1.0 eq.) and 1-(2,4-dimethoxy- phenyl)methanamine (0.431 g, 2.58 mmol, 6.0 eq.) in DMSO (8 mL) was heated at 140°C in microwave for 6 h. RM was evaporated, diluted with water and extracted by EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (0% to 10% MeOH gradient in DCM) to give 6-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin- 7-yl)methyl]-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-5-yl]pyridine-3-carboxamide (0.302 g, 0.363 mmol, 84%, beige solid, m/z [M+H]+: 741.2). Step 2: 6-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-[2- (1-methylpiperidin-4-yl)-1,3-benzothiazol-5-yl]pyridine-3-carboxamide (0.299 g, 0.359 mmol, 1.0 eq.) was dis- solved in DCM (7 mL) and TFA (1.375 mL, 17.958 mmol, 50.0 eq.) was added. The RM was stirred at RT over- night. After that time the RM was carefully neutralized with 1M NaOH while cooling in an ice bath. Obtained mixture was stirred for 30 minutes. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (0% to 50% MeOH gradient in DCM) followed by preparative HPLC and lyophilization. Obtained compound was re-purified by FCC (0% to 30% MeOH gradient in DCM) followed by trituration with EtOH and water. Product was dried by lyophilization to give N-({4-amino- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-5-yl]pyri- dine-3-carboxamide (Example 12, 0.06 g, 0.102 mmol, 28%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 100.0%, m/z [M+H]+: 591.2). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 1.9 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.58 (dd, J = 8.1, 2.2 Hz, 1H), 7.46 – 7.35 (m, 2H), 7.20 (dd, J = 8.2, 1.6 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.09 (dd, J = 8.5, 1.8 Hz, 1H), 6.45 (s, 2H), 5.30 (s, 2H), 5.29 – 5.23 (m, 2H), 5.04 – 4.89 (m, 2H), 2.99 (tt, J = 11.4, 3.6 Hz, 1H), 2.87 – 2.76 (m, 2H), 2.17 (s, 3H), 2.07 – 1.92 (m, 5H), 1.73 (qd, J = 12.6, 3.7 Hz, 2H), 0.97 – 0.75 (m, 4H). Example 13: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(6-cyclopropyl-2-methylpyridin-3- yl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 111 R10945WO 6‐cyclopropyl‐2‐methyl‐3‐nitropyridine (Int.36) In a pressure reactor 20.0 mL of (10:1) toluene : water mixture was degassed and flushed with argon for 30 minutes. Next 6-chloro-2-methyl-3-nitropyridine (2.0 g, 11.589 mmol, 1.0 eq.), cyclopropylboronic acid (1.991 g, 23.179 mmol, 2.0 eq.), K2CO3 (4.805 g, 34.768 mmol, 3.0 eq.) were added to the mixture and it was stirred vigorously under argon atmosphere for 5 minutes. Then 1,1'-Bis(diphenylphosphino)ferrocene dichloro- palladium (II) (0.085 g, 0.116 mmol, 0.01 eq.) was added and reaction mixture was stirred overnight at 100°C. After that time another portion of 1,1'-Bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.085 g, 0.116 mmol, 0.01 eq.) was added and stirring was continued up to the total of 24 h. Reaction mixture was charged with 250 mg of Silica Metal Scavenger and filtered through celite. The filtrate was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution (3x) and brine. Combined organic layers were dried over Na2SO4, filtered and evaporated. The crude was purified by FCC (0% to 50% EtOAc gradient in hexane) to give 6-cyclopropyl-2-methyl-3-nitropyridine (Int.36, 1.85 g, 10.278 mmol, 89%, m/z [M+H]+: 178.7). 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 2.1 Hz, 1H), 2.66 (s, 3H), 2.09 (tt, J = 8.3, 5.1 Hz, 1H), 1.11 – 1.00 (m, 2H), 0.91 – 0.77 (m, 2H). 6‐cyclopropyl‐2‐methylpyridin‐3‐amine (Int.37) 6-cyclopropyl-2-methyl-3-nitropyridine (Int.36, 1.748 g, 9.712 mmol, 1.0 eq.) and 2,2'-bipyridine (0.152 g, 0.971 mmol, 0.1 eq.) were dissolved in DMF (30 mL). The mixture was cooled to 0°C and (dihydroxy- boranyl)boronic acid (4.353 g, 48.558 mmol, 5.0 eq.) was added portion wise. The reaction mixture was stirred at room temperature for 30 min under air atmosphere. After that time the mixture was diluted with water and extracted with DCM:i-PrOH (4:1) mixture. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under high vacuum. The crude was purified by FCC (0% to 100% EtOAc gradient in hexane) to give 6-cyclopropyl-2-methylpyridin-3-amine (Int.37, 1.39 g, 9.097 mmol, 94%, m/z [M+H]+: 149.0). 1H NMR (400 MHz, DMSO-d6) δ 6.80 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 4.70 (s, 2H), 2.18 (s, 3H), 1.89 – 1.80 (m, 1H), 0.78 – 0.71 (m, 2H), 0.71 – 0.67 (m, 2H). 6‐cyano‐N‐(6‐cyclopropyl‐2‐methylpyridin‐3‐yl)pyridine‐3‐carboxamide (Int.38) A suspension of 6-cyanonicotinic acid (0.52 g, 3.511 mmol, 0.993 eq.), N,N-dimethylpyridin-4-amine (0.12 g, 0.982 mmol, 0.278 eq.) and 6-cyclopropyl-2-methylpyridin-3-amine (Int.37, 0.54 g, 3.534 mmol, 1.0 Ryvu Therapeutics S.A. RVU305 112 R10945WO eq.) in pyridine (anh., 10 mL) was cooled in ice-bath. Then phosphoroyl trichloride (0.65 g, 4.239 mmol, 1.2 eq.) was added dropwise. The reaction mixture was stirred 5 min at 0°C and 1 h at RT. After that time RM was diluted with water and treated with Na2CO3. After 30 min EtOAc was added and the mixture was partitioned. Aqueous phase was extracted with EtOAc (4x). Combined organic phases were washed with 5% KHSO4 (3x), brine (2x), dried over Na2SO4, filtered and concentrated. During concentration i-PrOH was added and obtained crystals were collected to give 6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyridine-3-carboxamide (Int.38, 0.705 g, 2.432 mmol, 69%, orange solid, m/z [M+H]+: 279.2). 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.23 (d, J = 2.0 Hz, 1H), 8.52 (dd, J = 8.0, 2.2 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 2.36 (s, 3H), 2.15 – 2.02 (m, 1H), 0.99 – 0.81 (m, 4H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐6‐cyano‐N‐(6‐cyclopropyl‐2‐methylpyridin‐3‐yl)pyridine‐3‐ carboxamide (Int.39) In a reactor were placed Cs2CO3 (1.47 g, 4.512 mmol, 1.855 eq.), 7-(bromomethyl)-4-chloro-1H,3H- furo[3,4-c]quinoline (Int. B, 0.7 g, 2.321 mmol, 0.955 eq.), 6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyri- dine-3-carboxamide (Int.38, 0.705 g, 2.432 mmol, 1.0 eq.) and ACN (50 mL). The reaction was stirred at 65°C for 2 h. After that time RM was diluted with EtOAc (150mL) and water. The mixture was partitioned. Aqueous phase was extracted with EtOAc (2x). Combined organic phases were washed with brine (3x), dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 100% EtOAc gradient in hexane and then 0% to 10% MeOH gradient in EtOAc) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano- N-(6-cyclopropyl-2-methylpyridin-3-yl)pyridine-3-carboxamide (Int.39, 0.445 g, 0.834 mmol, 34%, beige solid, m/z [M+H]+: 496.9). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.01 (dd, J = 8.0, 2.1 Hz, 1H), 7.98 – 7.91 (m, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 5.54 (s, 2H), 5.45 (d, J = 14.7 Hz, 1H), 5.22 (s, 2H), 4.98 (d, J = 14.7 Hz, 1H), 2.08 (s, 3H), 1.98 – 1.85 (m, 1H), 0.97 – 0.67 (m, 4H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyridine-3- carboxamide (Example 13) Step 1: In a reactor were placed 1-(2,4-dimethoxyphenyl)methanamine (0.94 g, 5.622 mmol, 6.737 eq.), N-({4- chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyridine-3-carbox- amide (Int.39, 0.445 g, 0.834 mmol, 1.0 eq.) and DMSO (anh., 12 mL). RM was heated in MW for 2 h at 130°C. After that time RM was diluted with EtOAc, washed with diluted NaHCO3 solution (2x), brine (5x), dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 100% EtOAc gradient in hex- ane) to give 6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}- 1H,3H-furo[3,4-c]quinolin-7-yl)methyl]pyridine-3-carboxamide (0.484 g, 0.703 mmol, 84%, m/z [M+H]+: 627.3). Step 2: TFA (5 mL) was added slowly to a solution of 6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)-N-[(4- {[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]pyridine-3-carboxamide (0.484 g, 0.703 mmol, 1.0 eq.) in DCM (45 mL). The RM was stirred overnight at RT. After that time RM was quenched by addition of i-PrOH (5 mL). Then aqueous Na2CO3 solution was added slowly till pH 9 of water phase. Ob- tained mixture was extracted with DCM (150 mL). Organic layer was washed with Na2CO3 (2x), water, brine (2x), dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 20% EtOH gradient Ryvu Therapeutics S.A. RVU305 113 R10945WO in EtOAc). Obtained fraction was co-evaporated with i-PrOH, EtOH (2x), ACN (2x) and lyophilized to give N- ({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyridine-3-car- boxamide (Example 13, 0.144 g, 0.302 mmol, 43%, cream solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 100.0%, m/z [M+H]+: 477.25). 100:6 mixture of restricted C-N amide rotation isomers in DMSO-d6 at RT Major rotamer: 1H NMR (400 MHz, DMSO-d6) δ 8.65 (dd, J = 2.0, 1.0 Hz, 1H), 8.01 – 7.91 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H), 7.41 – 7.32 (m, 2H), 7.18 (dd, J = 8.2, 1.7 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.55 – 6.39 (m, 2H), 5.33 – 5.19 (m, 3H), 5.04 – 4.95 (m, 2H), 4.90 (d, J = 14.3 Hz, 1H), 2.00 (s, 3H), 1.93 (tt, J = 8.1, 4.8 Hz, 1H), 0.95 – 0.81 (m, 2H), 0.81 – 0.68 (m, 2H). Example 14: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3- yl)pyridine-3-carboxamide 5‐cyclopropyl‐2‐methyl‐3‐nitropyridine (Int.40) 20.0 mL of (10:1) toluene : water mixture was degassed and flushed with argon for 30 minutes. Next 5- bromo-2-methyl-3-nitropyridine (2.0 g, 9.216 mmol, 1.0 eq.), cyclopropylboronic acid (1.583 g, 18.431 mmol, 2.0 eq.) and K2CO3 (3.821 g, 27.647 mmol, 3.0 eq.) were added and the mixture was stirred vigorously under argon atmosphere for 5 minutes. Then 1,1'-Bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.674 g, 0.922 mmol, 0.1 eq.) was added and reaction mixture was stirred overnight at 100°C. After that time another portion of 1,1'-Bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.674 g, 0.922 mmol, 0.1 eq.) was added to the mixture and stirring was continued up to the total of 24 h. The mixture was charged with 250 mg of Silica Metal Scavenger and filtered through celite. Filtrate was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution (3x) and brine. Organic layer was dried over sodium sulphate, filtered and evaporated. The crude was purified by FCC (0% to 50% EtOAc gradient in hexane) to give 5-cyclopropyl-2- methyl-3-nitropyridine (Int.40, 1.388 g, 7.789 mmol, 85%, m/z [M+H]+: 178.7). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 8.5, 0.6 Hz, 1H), 2.68 (s, 3H), 2.25 (tt, J = 8.0, 4.8 Hz, 1H), 1.12 – 1.05 (m, 2H), 1.05 – 1.00 (m, 2H). 5‐cyclopropyl‐2‐methylpyridin‐3‐amine (Int.41) To a mixture of 2,2'-bipyridine (0.095 g, 0.608 mmol, 0.081 eq.) and 5-cyclopropyl-2-methyl-3-nitro- pyridine (Int.40, 1.331 g, 7.47 mmol, 1.0 eq.) in DMF (16 mL) was added portion wise (dihydroxyboranyl)bo- Ryvu Therapeutics S.A. RVU305 114 R10945WO ronic acid (2.05 g, 22.867 mmol, 3.061 eq.). The mixture was stirred 2 h at RT. After that time (dihydroxy- boranyl)boronic acid (2.05 g, 22.867 mmol, 3.061 eq.) was added and the mixture was stirred overnight at RT. Then the mixture was diluted with 5M NaOH and extracted with EtOAc. Combined organic layers were washed with NaHCO3, brine and dried. The crude was purified by FCC to give 5-cyclopropyl-2-methylpyridin-3-amine (Int.41, 1.033 g, 6.621 mmol, 89%, colorless oil that solidifies after time, m/z [M+H]+: 149.0). 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 6.51 (s, 1H), 4.88 (s, 2H), 2.19 (s, 3H), 1.83 – 1.68 (m, 1H), 0.97 – 0.85 (m, 2H), 0.62 – 0.50 (m, 2H). 6‐cyano‐N‐(5‐cyclopropyl‐2‐methylpyridin‐3‐yl)pyridine‐3‐carboxamide (Int.42) N,N-dimethylpyridin-4-amine (0.075 g, 0.614 mmol, 0.192 eq.), 6-cyanonicotinic acid (0.532 g, 3.592 mmol, 1.121 eq.) and 5-cyclopropyl-2-methylpyridin-3-amine (Int.41, 0.5 g, 3.205 mmol, 1.0 eq.) were sus- pended in anhydrous pyridine (8 mL) and homogenized using ultrasounds. The suspension was then cooled in ice bath and phosphoroyl trichloride (0.5 g, 3.261 mmol, 1.018 eq.) was added dropwise. The mixture was al- lowed to warm to RT and was stirred at this temperature for 1 h. After that time reaction was quenched by addi- tion of water followed by addition of Na2CO3 aq. Obtained mixture was stirred 15 min and EtOAc was added. The mixture was partitioned. Aqueous phase was extracted with EtOAc (4x). Combined organic layers were washed with aq.5% KHSO4 (2x), brine (3x), dried over Na2SO4, filtered and concentrated. The crude was puri- fied by FCC (0% to 100% EtOAc gradient in hexane) to give 6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyr- idine-3-carboxamide (Int.42, 0.716 g, 2.47 mmol, 77%, m/z [M+H]+: 279.2). 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.24 (s, 1H), 8.59 – 8.48 (m, 1H), 8.28 – 8.19 (m, 2H), 7.42 (s, 1H), 2.39 (s, 3H), 2.03 – 1.92 (m, 1H), 1.08 – 0.95 (m, 2H), 0.76 – 0.66 (m, 2H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐6‐cyano‐N‐(5‐cyclopropyl‐2‐methylpyridin‐3‐yl)pyridine‐3‐ carboxamide (Int.43) In a reactor were placed Cs2CO3 (0.64 g, 1.964 mmol, 1.424 eq.), 7-(bromomethyl)-4-chloro-1H,3H- furo[3,4-c]quinoline (Int. B, 0.442 g, 1.466 mmol, 1.062 eq.), 6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyr- idine-3-carboxamide (Int.42, 0.4 g, 1.38 mmol, 1.0 eq.) and ACN (20 mL). The reaction was stirred at 70°C for 2h. After that time RM was diluted with EtOAc and water. The mixture was partitioned. Aqueous phase was ex- tracted with EtOAc. Combined organic phases were washed with brine, dried over Na2SO4, filtered and concen- trated. The crude was purified by FCC (0% to 100% EtOAc gradient in hexane) to give N-({4-chloro-1H,3H- furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyridine-3-carboxamide (Int.43, 0.54 g, 1.013 mmol, 73%, m/z [M+H]+: 496.9). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyridine-3- carboxamide (Example 14) Step 1: In a reactor were placed 1-(2,4-dimethoxyphenyl)methanamine (1.3 g, 7.775 mmol, 7.678 eq.), N-({4- chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyridine-3-carbox- amide (Int.43, 0.54 g, 1.013 mmol, 1.0 eq.) and DMSO (anh., 12mL). RM was heated in MW for 2h at 130°C. After that time RM was diluted with EtOAc, washed with diluted NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 100% EtOAc gradient in hexane) to give 6- cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4- c]quinolin-7-yl)methyl]pyridine-3-carboxamide (0.29 g, 0.435 mmol, 43%, m/z [M+H]+: 627.4). Ryvu Therapeutics S.A. RVU305 115 R10945WO Step 2: TFA (5 mL) was added slowly at RT to a solution of 6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)-N- [(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]pyridine-3-carboxamide (0.29 g, 0.435 mmol, 1.0 eq.) in DCM (45 mL). The RM was stirred overnight at RT. After that time the reaction was quenched by addition of i-PrOH (5 mL). Then aq. Na2CO4 was added slowly till pH 9 of water phase. Obtained mixture was extracted with DCM (150 mL). Organic layer was washed with Na2CO3 (2x), water (2x), brine (2x), dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 20% EtOH gradient in Ac- OEt). Obtained fraction was co-evaporated with EtOH (1x), ACN (2x) and lyophilized to give N-({4-amino- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyridine-3-carboxamide (Example 14, 0.191 g, 0.398 mmol, 91%, cream solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.27%, m/z [M+H]+: 477.26). 1H NMR (400 MHz, DMSO-d6) δ 8.66 (dd, J = 2.1, 0.9 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.99 (dd, J = 8.1, 2.1 Hz, 1H), 7.93 (dd, J = 8.1, 0.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.2, 1.7 Hz, 1H), 6.48 (s, 2H), 5.34 – 5.28 (m, 2H), 5.18 – 5.05 (m, 2H), 5.03 – 4.94 (m, 2H), 1.88 (s, 3H), 1.80 (tt, J = 8.4, 5.0 Hz, 1H), 1.00 – 0.82 (m, 2H), 0.62 – 0.54 (m, 1H), 0.52 – 0.43 (m, 1H). Example 15: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluoromethyl)- 1H-pyrazol-5-yl]pyrimidine-5-carboxamide 2‐cyclopropyl‐N‐[1‐methyl‐3‐(trifluoromethyl)‐1H‐pyrazol‐5‐yl]pyrimidine‐5‐carboxamide (Int.44) 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (0.253 g, 1.532 mmol, 1.0 eq.), DMAP (0.077 g, 0.63 mmol, 0.411 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.326 g, 1.986 mmol, 1.296 eq.) and isopropyl ac- etate (10.0 mL) were mixed and degassed for 10 min. After that pyridine (0.38 mL, 4.717 mmol, 3.079 eq.) was added, followed by T3P 50% solution in EtOAc (3.5 mL, 5.879 mmol, 3.837 eq.). Then mixture was heated at 50°C for 4h. After that time the mixture was diluted with water and extracted with EtOAc. Organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo. Remining solid was purified by FCC (10% to 50% EtOAc gradient in hexane) to give 2-cyclopropyl-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]pyrimidine-5-carboxamide (Int.44, 0.473 g, 1.444 mmol, 94%, white solid, m/z [M+H]+: 312.2). Ryvu Therapeutics S.A. RVU305 116 R10945WO 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.12 (s, 2H), 6.76 (s, 1H), 3.84 (s, 3H), 2.37 – 2.27 (m, 1H), 1.20 – 1.14 (m, 2H), 1.13 – 1.07 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -60.94. N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐[1‐methyl‐3‐(trifluoromethyl)‐1H‐pyrazol‐5‐ yl]pyrimidine‐5‐carboxamide (Int.45) A suspension of 2-cyclopropyl-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]pyrimidine-5-carboxamide (Int.44, 0.235 g, 0.717 mmol, 1.0 eq.), 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.226 g, 0.749 mmol, 1.045 eq.) and Cs2CO3 (0.348 g, 1.068 mmol, 1.489 eq.) in anhydrous ACN (10.0 mL) was stirred at 70°C for 2 h. RM was cooled to RT, diluted with water and extracted with ethyl acetate. Combined organic layers were dried over Na2SO4, filtered, and evaporated. The residue was purified by FCC (20% to 60% EtOAc gradient in hexane) to obtain N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3- (trifluoromethyl)-1H-pyrazol-5-yl]pyrimidine-5-carboxamide (Int.45, 0.33 g, 0.549 mmol, 77%, white solid, m/z [M+H]+: 529.9). 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 8.00 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 6.76 (s, 1H), 5.54 (t, J = 3.2 Hz, 2H), 5.43 – 5.28 (m, 1H), 5.22 (t, J = 3.1 Hz, 2H), 5.18 – 5.01 (m, 1H), 3.63 (s, 3H), 2.24 – 2.13 (m, 1H), 1.12 – 1.04 (m, 2H), 1.02 – 0.93 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -61.17. N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]pyrimidine-5-carboxamide (Example 15) Step 1: N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluoromethyl)-1H-py- razol-5-yl]pyrimidine-5-carboxamide (Int.45, 0.3 g, 0.499 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methana- mine (0.3 g, 1.794 mmol, 3.595 eq.) were stirred in DMSO (2.5 mL) at 120 °C for 2 h. The reaction mixture was diluted with EtOAc and washed with water (3x), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crude product was purified by FCC (25% to 66% EtOAc gradient in hexane). Step 2: Obtained product was dissolved in DCM (5.0 mL) and TFA (1.15 mL, 15.028 mmol, 30.108 eq.) was added. The RM was stirred overnight at RT. Then sat. aq. NaHCO3 solution (5 mL) was added and the mixture was stirred for 15 minutes. Obtained mixture was partitioned between sat. aq. NaHCO3 solution and DCM. The aqueous phase was extracted with DCM. Combined organic layers were washed with aq. Na2CO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mate- rial was purified by FCC (0% to 10% MeOH gradient in DCM). Obtained compound was co-evaporated with EtOH (3x) and lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-me- thyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]pyrimidine-5-carboxamide (Example 15, 0.088 g, 0.173 mmol, 35%, light yellow solid, UPLC long elution (Mid polar long method, buffer type “FA”) purity: 100.0%, m/z [M+H]+: 510.24). 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.45 – 7.42 (m, 1H), 7.18 – 7.11 (m, 1H), 6.75 (s, 1H), 6.51 (s, 2H), 5.30 (t, J = 3.3 Hz, 2H), 5.09 (s, 2H), 4.99 (t, J = 3.4 Hz, 2H), 3.46 (s, 3H), 2.24 – 2.12 (m, 1H), 1.14 – 1.04 (m, 2H), 1.01 – 0.89 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -61.13. Ryvu Therapeutics S.A. RVU305 117 R10945WO Example 16: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide N‐(1,3‐dimethyl‐1H‐pyrazol‐4‐yl)‐6‐(trifluoromethyl)pyridine‐3‐carboxamide (Int.46) To a suspension of 1,3-dimethyl-1H-pyrazol-4-amine dihydrochloride (0.35 g, 1.902 mmol, 1.0 eq.), 6- (trifluoromethyl)pyridine-3-carboxylic acid (0.112 g, 0.584 mmol, 0.307 eq.) and DMAP (0.012 g, 0.095 mmol, 0.05 eq.) in anhydrous toluene (5.0 mL) was added DIPEA (0.830 mL, 4.754 mmol, 2.5 eq.) followed by propylphosphonic anhydride (50% solution in EtOAc, 2.264 mL, 3.803 mmol, 2.0 eq.). Reaction mixture was refluxed for 1 hour. After that time the mixture was diluted with NaHCO3 and extracted with EtOAc. Organic lay- ers were combined, washed with brine and dried over Na2SO4 , filtered and concentrated in vacuo. The crude was purified by trituration with i-PrOH to give N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide (Int.46, 0.4 g, 0.999 mmol, 53%, m/z [M+H]+: 285.2). Filtrate was concentrated in vacuo and purified by FCC (0% to 80% EtOAc gradient in hexane) to give N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyri- dine-3-carboxamide (Int.46, 0.2 g, 0.697 mmol, 37%, m/z [M+H]+: 285.2). 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.21 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.95 (s, 1H), 3.76 (s, 3H), 2.17 (s, 3H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(1,3‐dimethyl‐1H‐pyrazol‐4‐yl)‐6‐(trifluoromethyl)pyridine‐ 3‐carboxamide (Int.47) To a solution of N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.46.0.25 g, 0.624 mmol, 1.0 eq.) in anhydrous MeCN (3.0 mL) was added Cs2CO3 (0.244 g, 0.749 mmol, 1.2 eq.) fol- lowed by 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.207 g, 0.687 mmol, 1.1 eq.). Reaction mixture was heated at 70°C for 1 h. Reaction mixture was quenched with NaHCO3 and extracted with EtOAc. Combined organic layers was washed with brine and dried over Na2SO4, filtrated and concentrated in vacuo. The crude was purified by trituration with i-PrOH to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N- (1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.47, 0.335 g, 0.641 mmol, 103%, m/z [M+H]+: 503.0). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 2.1 Hz, 1H), 8.10 (dd, J = 7.9, 2.1 Hz, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.70 (dd, J = 8.5, 1.7 Hz, 1H), 7.63 (s, 1H), 5.54 (t, J = 3.1 Hz, 2H), 5.22 (t, J = 3.1 Hz, 2H), 5.14 (s, 2H), 3.57 (s, 3H), 1.62 (s, 3H). Ryvu Therapeutics S.A. RVU305 118 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide (Example 16) Step 1: A solution of 1-(2,4-dimethoxyphenyl)methanamine (0.365 g, 2.181 mmol, 4.0 eq.) and N-({4-chloro- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridine-3-carbox- amide (Int.47, 0.285 g, 0.545 mmol, 1.0 eq.) in DMSO (3.0 mL) was stirred overnight at 120°C. RM was diluted with water and extracted with DCM (3x). Combined organic extracts were washed with brine and dried over Na2SO4. Crude product was purified by FCC (0% to 80% EtOAc gradient in hexane). Step 2: Obtained product was dissolved in DCM (3.0 mL) and trifluoroacetic acid (0.834 mL, 10.903 mmol, 20.0 eq.) was added at 0°C. RM was stirred overnight at RT. After that time the mixture was basified with 1M NaOH to obtain pH~8 and extracted with DCM (3x). Combined organic extracts were washed with brine and dried over Na2SO4. Crude product was purified by FCC (0% to 5% of MeOH gradient in DCM). Fraction con- taining product was re-purified by FCC (NH2 modified silica, 0% to 2% MeOH gradient in DCM) and lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide (Example 16, 0.158 g, 0.327 mmol, 60%, light yellow solid, UPLC long elution (Mid polar long method, buffer type “FA”) purity: 100.0%, m/z [M+H]+: 483.23). 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 2.1 Hz, 1H), 8.05 (dd, J = 7.8, 2.1 Hz, 1H), 7.88 – 7.82 (m, 1H), 7.59 (s, 1H), 7.49 – 7.40 (m, 2H), 7.18 (dd, J = 8.2, 1.7 Hz, 1H), 6.47 (s, 2H), 5.31 (t, J = 3.3 Hz, 2H), 5.04 - 4.94 (m, 4H), 3.57 (s, 3H), 1.56 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.63. Example 17: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-cyclopropylpyridin-3-yl)pyridine- 3-carboxamide 6‐cyano‐N‐(2‐cyclopropylpyridin‐3‐yl)pyridine‐3‐carboxamide (Int.48) DMAP (0.083 g, 0.679 mmol, 0.503 eq.), DIPEA (0.598 mL, 3.378 mmol, 2.5 eq.), 2-cyclopropylpyridin- 3-amine (0.19 g, 1.416 mmol, 1.048 eq.) and 6-cyanonicotinic acid (0.2 g, 1.351 mmol, 1.0 eq.) were taken in DMF (7.0 mL) and propylphosphonic anhydride (50% solution in EtOAc, 1.6 mL, 2.688 mmol, 1.989 eq.) was added dropwise at 0°C. Then, the RM was heated at 100°C for 1 h. The reaction was quenched with sat. aq. Na2CO3 solution. Obtained mixture was extracted with EtOAc (2x). Combined organic layers were washed with Ryvu Therapeutics S.A. RVU305 119 R10945WO brine and dried over Na2SO4. The crude was purified by FCC (0% to 5% MeOH gradient in DCM) to give 6-cy- ano-N-(2-cyclopropylpyridin-3-yl)pyridine-3-carboxamide (Int.48, 0.35 g, 1.324 mmol, 98%, brown oil, m/z [M- H]-: 263.1). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐6‐cyano‐N‐(2‐cyclopropylpyridin‐3‐yl)pyridine‐3‐carbox- amide (Int.49) To a solution of 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.354 g, 1.324 mmol, 1.0 eq.) and 6-cyano-N-(2-cyclopropylpyridin-3-yl)pyridine-3-carboxamide (Int.48, 0.35 g, 1.324 mmol, 1.0 eq.) in ACN (6.0 mL) was added Cs2CO3, (0.863 g, 2.649 mmol, 2.0 eq.). The reaction mixture was heated overnight at 78°C. After that time the reaction was cooled to RT and then diluted with water. Obtained mixture was ex- tracted with EtOAc (2x). Combined organic layers were washed with brine and dried over Na2SO4. The crude was purified by FCC (0% to 5% MeOH gradient in DCM) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}me- thyl)-6-cyano-N-(2-cyclopropylpyridin-3-yl)pyridine-3-carboxamide (Int.49, 0.66 g, 0.89 mmol, 67%, yellow solid, m/z [M-H]-: 480.4). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-cyclopropylpyridin-3-yl)pyridine-3-carbox- amide (Example 17) Step 1: To a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-cyclopropylpyridin-3- yl)pyridine-3-carboxamide (Int.49, 0.66 g, 0.89 mmol, 1.0 eq.) in DMSO (5.0 mL) 1-(2,4-dimethoxy- phenyl)methanamine (0.952 g, 5.694 mmol, 6.397 eq.) was added under nitrogen atmosphere. The reaction mixture was stirred overnight at in 100°C. After that time the RM was cooled to RT and diluted by DCM. Ob- tained mixture was washed with sat. NaHCO3 solution, water, brine and then dried over Na2SO4, filtrated and concentrated. The crude was purified by FCC. Step 2: Product of step 1 was dissolved in DCM (6.0 mL) and TFA (0.7 mL, 9.147 mmol, 10.276 eq.) was added at 0°C. The reaction was stirred overnight at RT. Ater that time the RM was diluted with DCM and basified with aq. NaHCO3 solution. Water phase was extracted with DCM and CH3Cl : i-PrOH (3:1) mixture. Organic phases were combined, dried over Na2SO4 filtered and concentrated in vacuo. Residue was treated with i-PrOH. Ob- tained solid was filtered off. Filtrate was concentrated in vacuo and purified by FCC to give N-({4-amino-1H,3H- furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-cyclopropylpyridin-3-yl)pyridine-3-carboxamide (Example 17, 0.04 g, 0.085 mmol, 10%, off-white solid, UPLC long elution (Mid polar long method, buffer type “FA”) purity: 98.71%, m/z [M+H]+: 463.22). 1H NMR (400 MHz, DMSO-d6) δ 8.68 (dd, J = 2.1, 0.9 Hz, 1H), 8.20 (dd, J = 4.7, 1.6 Hz, 1H), 7.98 (dd, J = 8.1, 2.1 Hz, 1H), 7.92 (dd, J = 8.1, 0.9 Hz, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.18 (dd, J = 8.2, 1.7 Hz, 1H), 7.03 (dd, J = 8.0, 4.6 Hz, 1H), 6.48 (s, 2H), 5.36 – 5.23 (m, 3H), 5.08 (d, J = 14.2 Hz, 1H), 4.98 (t, J = 3.4 Hz, 2H), 1.95 – 1.82 (m, 1H), 0.87 – 0.76 (m, 1H), 0.76 – 0.65 (m, 1H), 0.65 – 0.51 (m, 1H), 0.48 – 0.31 (m, 1H). Example 18: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H- pyrazol-5-yl)pyrimidine-5-carboxamide Ryvu Therapeutics S.A. RVU305 120 R10945WO 2‐cyclopropyl‐N‐(3‐cyclopropyl‐1‐methyl‐1H‐pyrazol‐5‐yl)pyrimidine‐5‐carboxamide (Int.50) N,N-dimethylpyridin-4-amine (0.088 g, 0.722 mmol, 0.3 eq.), 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine (0.33 g, 2.405 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.395 g, 2.406 mmol, 1.0 eq.) and DI- PEA (1.048 mL, 6.014 mmol, 2.5 eq.) were dissolved in toluene (10 mL). Then propylphosphonic anhydride (50% solution in EtOAc 1.417 mL, 4.811 mmol, 2.0 eq.) was added dropwise and RM was stirred for 120 minutes at 60°C. After that time the mixture was poured into saturated NaHCO3 solution (100 mL), transferred to separatory fun- nel and extracted with ethyl acetate (3x). Organic layers were collected, combined, washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated. Crude product was purified by FCC (0% to 50% EtOAc gradient in hexane) to give 2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)pyrimidine-5-car- boxamide (Int.50, 0.577 g, 1.833 mmol, 76%, m/z [M+H]+: 284.0). 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.08 (s, 2H), 5.98 (s, 1H), 3.61 (s, 3H), 2.37 – 2.29 (m, 1H), 1.84 – 1.78 (m, 1H), 1.17 – 1.14 (m, 2H), 1.11 – 1.07 (m, 2H), 0.87 – 0.77 (m, 2H), 0.63 – 0.60 (m, 2H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐(3‐cyclopropyl‐1‐methyl‐1H‐pyrazol‐5‐yl)py- rimidine‐5‐carboxamide (Int.51) To a mixture of 2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)pyrimidine-5-carboxamide (Int. 50, 0.31 g, 0.985 mmol, 1.0 eq.) and 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.297 g, 0.985 mmol, 1.0 eq.) in MeCN (12 mL) Cs2CO3 (0.642 g, 1.969 mmol, 2.0 eq.) was added. Mixture was flushed with nitrogen for 10 min at RT. Then RM was stirred at 70°C for 60 minutes. After that time reaction mixture was diluted with water, transferred to separatory funnel and extracted with DCM (3x). Combined organic phases were washed with brine, dried over Na2SO4 filtered and evaporated. The crude was purified by FCC (0% to 100% EtOAc gradient in hexane) followed by FCC (0% to 50% MeCN gradient in DCM) to give N-({4- chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)pyrimi- dine-5-carboxamide (Int.51, 0.161 g, 0.257 mmol, 26%, m/z [M+H]+: 501.8). Ryvu Therapeutics S.A. RVU305 121 R10945WO 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 7.95 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 5.91 (s, 1H), 5.59 – 5.53 (m, 2H), 5.35 – 5.25 (m, 1H), 5.25 – 5.20 (m, 2H), 5.09 – 4.97 (m, 1H), 3.31 (s, 3H), 2.23 – 2.13 (m, 1H), 1.72 – 1.61 (m, 1H), 1.14 – 1.06 (m, 2H), 1.02 – 0.94 (m, 2H), 0.78 – 0.69 (m, 2H), 0.49 – 0.41 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)py- rimidine-5-carboxamide (Example 18) Step 1: N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H-pyrazol- 5-yl)pyrimidine-5-carboxamide (Int.51, 0.16 g, 0.255 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.171 g, 1.022 mmol, 4.0 eq.) were stirred in DMSO (5.0 mL) at 110°C for 4 h. After that time the reaction mix- ture was diluted with water, transferred to separatory funnel and extracted with (4:1 v/v) DCM: i-PrOH mixture (5x). Organic layers were combined and washed with brine, dried over anhydrous Na2SO4, filtered and concen- trated in vacuo . Crude product was purified by FCC (0% to 100% EtOAc gradient in hexane) to give 100 mg of yellow solid. Step 2: Step 1 product was dissolved in DCE (9 mL) and trifluoroacetic acid (0.978 mL, 12.775 mmol, 50.0 eq.) was added under vigorous stirring. The RM was stirred for 1 h at 60°C. After that time reaction mixture was poured into Na2CO3 solution (150 mL) and stirred for 30 minutes. Next it was transferred to separatory funnel and extracted with DCM: i-PrOH (4:1) mixture. The combined organic layers were washed with aq. NaHCO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC (basic conditions) to give N-({4-amino-1H,3H-furo[3,4-c]quino- lin-7-yl}methyl)-2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)pyrimidine-5-carboxamide (Example 18, 0.02 g, 0.041 mmol, 16%, white solid, UPLC long elution (Mid polar long method, buffer type “FA”) purity: 99.82%, m/z [M+H]+: 482.27). 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.51 (s, 2H), 5.91 (s, 1H), 5.31 (t, J = 3.2 Hz, 2H), 5.08 – 4.92 (m, 4H), 3.19 (s, 3H), 2.23 – 2.12 (m, 1H), 1.74 – 1.62 (m, 1H), 1.14 – 1.04 (m, 2H), 1.04 – 0.92 (m, 2H), 0.81 – 0.71 (m, 2H), 0.51 – 0.41 (m, 2H). Example 19: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyri- dine-3-carboxamide 6‐cyclopropyl‐N‐(2‐methylpyridin‐3‐yl)pyridine‐3‐carboxamide (Int.52) Ryvu Therapeutics S.A. RVU305 122 R10945WO Pyridine (anh., 8 mL) was added to a mixture of N,N-dimethylpyridin-4-amine (0.067 g, 0.548 mmol, 0.144 eq.), 6-cyclopropylpyridine-3-carboxylic acid (0.623 g, 3.818 mmol, 1.0 eq.) and 2-methylpyridin-3-amine (0.431 g, 3.985 mmol, 1.044 eq.) and the suspension was homogenized on ultrasounds. The mixture was then cooled in an ice bath and phosphoroyl trichloride (0.564 g, 3.677 mmol, 0.963 eq.) was added dropwise. RM was stirred 1 h at RT. After that time the reaction was quenched by addition of water followed by aqueous Na2CO3 solution. Obtained mixture was stirred 15 min and then EtOAc was added. The mixture was parti- tioned. Aqueous phase was extracted with EtOAc (4x). Combined organic layers were washed with aq.5% KHSO4 (2x), brine (3x), dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 100% EtOAc gradient in hexane) to give 6-cyclopropyl-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (Int.52, 0.393 g, 1.489 mmol, 39%, brown solid, m/z [M+H]+: 254.1). 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.97 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 4.8 Hz, 1H), 8.17 (dd, J = 8.2, 2.3 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.28 (dd, J = 8.1, 4.8 Hz, 1H), 2.44 (s, 3H), 2.27 – 2.17 (m, 1H), 1.10 – 0.95 (m, 4H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐6‐cyclopropyl‐N‐(2‐methylpyridin‐3‐yl)pyridine‐3‐carbox- amide (Int.53) MeCN (15 mL) was added to a mixture of Cs2CO3 (0.99 g, 3.038 mmol, 2.04 eq.), 7-(bromomethyl)-4- chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.452 g, 1.499 mmol, 1.0 eq.) and 6-cyclopropyl-N-(2-methylpyridin-3- yl)pyridine-3-carboxamide (Int.52, 0.393 g, 1.489 mmol, 1.0 eq.). RM was stirred 2 h at 70°C. After that time RM was diluted with EtOAc and water. Organic phase was separated, washed with NaHCO3 (2x), brine (2x), dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 100% EtOAc gradient in hexane) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyri- dine-3-carboxamide (Int.53, 0.484 g, 0.987 mmol, 66%, m/z [M+H]+: 471.9). 1H NMR (400 MHz, DMSO-d6) δ 8.34 – 8.25 (m, 2H), 7.87 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.60 – 7.49 (m, 2H), 7.20 – 7.10 (m, 2H), 5.56 – 5.49 (m, 2H), 5.40 (d, J = 14.6 Hz, 1H), 5.24 – 5.17 (m, 2H), 5.05 (d, J = 14.6 Hz, 1H), 2.08 (s, 3H), 2.04 – 1.96 (m, 1H), 1.01 – 0.87 (m, 2H), 0.87 – 0.77 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyridine-3-carbox- amide (Example 19) Step 1: A solution of 1-(2,4-dimethoxyphenyl)methanamine (1.35 g, 8.074 mmol, 8.184 eq.) and N-({4-chloro- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (Int.53, 0.484 g, 0.987 mmol, 1.0 eq.) in DMSO (anh., 12 mL) was heated to 140°C in microwave for 2 h. After that time the RM was diluted with EtOAc and washed with diluted brine, water (3x), brine (3x), dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 100% EtOAc gradient in hexane) to give 6-cyclopro- pyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2-methylpyridin-3- yl)pyridine-3-carboxamide (0.43 g, 0.665 mmol, 67%, m/z [M+H]+: 602.3). Step 2: TFA (5 mL) was added slowly to a mixture of Step 1 compound 6-cyclopropyl-N-[(4-{[(2,4-dimethoxy- phenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (0.29 g, 0.435 mmol, 1.0 eq.) and DCM (45 mL). RM was stirred overnight at RT. After that time the RM was quenched by addition of i-PrOH (5 mL). Then aqueous Na2CO3 solution was added slowly till pH 9 of water phase. DCM (150 mL) was added and phases were separated. Organic phase was washed with Na2CO3 (2x), Ryvu Therapeutics S.A. RVU305 123 R10945WO water (2x), brine (2x), dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (0% to 20% EtOH gradient in EtOAc). Obtained fraction was concentrated, co-evaporated with EtOH (1x), ACN (2x) and lyophilized. Obtained solid was suspended in water, heated to reflux, sonicated and lyophilized. Obtained solid was dissolved in a mixture of t-BuOH, acetone, EtOAc and heated. Acetone and EtOAc were evaporated under reduced pressure. Residue was diluted with water and lyophilized. Obtained solid was suspended in wa- ter, heated, sonicated and lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl- N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (Example 19, 0.19 g, 0.417 mmol, 63%, yellow solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.28%, [M+H]+: 452.2). 1H NMR (400 MHz, DMSO-d6) δ 8.33 – 8.21 (m, 2H), 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 (dd, J = 8.1, 2.3 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.20 – 7.08 (m, 3H), 6.53 – 6.42 (m, 2H), 5.33 – 5.25 (m, 2H), 5.21 (d, J = 14.3 Hz, 1H), 5.02 – 4.93 (m, 3H), 2.06 – 1.94 (m, 4H), 0.95 – 0.86 (m, 2H), 0.85 – 0.77 (m, 2H). Example 20: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-methyl-6-(trifluorome- thyl)pyridin-3-yl]pyrimidine-5-carboxamide 2‐cyclopropyl‐N‐[2‐methyl‐6‐(trifluoromethyl)pyridin‐3‐yl]pyrimidine‐5‐carboxamide (Int.54) To solution of 2-methyl-6-(trifluoromethyl)pyridin-3-amine (0.3 g, 1.703 mmol, 1.0 eq.), 2-cyclopropylpy- rimidine-5-carboxylic acid (0.280 g, 1.703 mmol, 1.0 eq.), DMAP (0.0104 g, 0.085 mmol, 0.05 eq.) in toluene (4.0 mL) was added DIPEA (0.742 mL, 4.258 mmol, 2.5 eq.) followed by T3P (50% solution in EtOAc, 2.028 mL, 3.406 mmol, 2.0 eq.). Reaction mixture was refluxed for 1 hour. After that time the mixture was diluted with water and extracted with EtOAc. Organic layers were combined, washed with brine and dried over Na2SO4, fil- trated and concentrated in vacuo. Crude product was triturated with i-PrOH to give 2-cyclopropyl-N-[2-methyl- 6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide (Int.54, 0.63 g, 1.759 mmol, 103%, white solid, m/z [M+H]+: 323.2). 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.12 (s, 2H), 8.18 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 2.57 (s, 3H), 2.36 – 2.29 (m, 1H), 1.20 – 1.14 (m, 2H), 1.13 – 1.08 (m, 2H). Ryvu Therapeutics S.A. RVU305 124 R10945WO N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐[2‐methyl‐6-(trifluoromethyl)pyridin‐3‐yl]py- rimidine‐5‐carboxamide (Int.55) To a solution of 2-cyclopropyl-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide (Int. 54, 0.3 g, 0.838 mmol, 1.0 eq.) and Cs2CO3 (0.328 g, 1.005 mmol, 1.2 eq.) in anhydrous ACN (3.0 mL) was added 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.2781 g, 0.922 mmol, 1.1 eq.). Reaction mixture was heated at 70°C for 1 hour. Reaction mixture was diluted with water and extracted with EtOAc. Or- ganic layers were combined, washed with brine and dried over Na2SO4, filtrated and concentrated in vacuo. Crude product was purified by FCC (0% to 80% EtOAc gradient in hexane) to give N-({4-chloro-1H,3H-furo[3,4- c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide (Int. 55, 0.46 g, 0.826 mmol, 99%, beige solid, m/z [M+H]+: 541.1). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 8.00 – 7.90 (m, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.77 – 7.67 (m, 2H), 5.56 – 5.51 (m, 2H), 5.48 (d, J = 14.8 Hz, 1H), 5.21 (t, J = 3.0 Hz, 2H), 5.08 (d, J = 14.8 Hz, 1H), 2.26 (s, 3H), 2.16 – 2.07 (m, 1H), 1.08 – 1.00 (m, 2H), 0.95 – 0.88 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]py- rimidine-5-carboxamide (Example 20) Step 1: To a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-methyl-6-(trifluo- romethyl)pyridin-3-yl]pyrimidine-5-carboxamide (Int.55, 0.41 g, 0.737 mmol, 1.0 eq.) in anhydrous DMSO (4.0 mL) was added 1-(2,4-dimethoxyphenyl)methanamine (0.493 g, 2.946 mmol, 4.0 eq.). Reaction was heated at 120°C for 2 h. After that time the mixture was diluted with water and extracted with EtOAc. Organic layers was combined, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Crude product was purified by FCC (0% to 80% EtOAc gradient in hexane). Step 2: Step 1 product was dissolved in DCM (4.0 mL) and trifluoroacetic acid (1.135 mL, 14.731 mmol, 20.0 eq.). was added. Reaction mixture was stirred overnight at RT. Reaction mixture was basified with 1M NaOH to obtain pH~8 and extracted with DCM. Organic layers were combined, washed with brine and dried over Na2SO4, filtrated and evaporated in vacuo. Crude product was purified by FCC (0% to 5% MeOH gradient in DCM, NH2 modified silica) to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-me- thyl-6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide (Example 20, 0.095 g, 0.182 mmol, 25%, yellow solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.65%, m/z [M+H]+: 521.21). 10/1 mixture of restricted C-N amide rotation isomers in DMSO-d6 at RT Major rotamer: 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 7.93 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.47 – 7.37 (m, 2H), 7.16 (d, J = 8.2 Hz, 1H), 6.48 (s, 2H), 5.32 – 5.24 (m, 3H), 5.06 – 4.95 (m, 3H), 2.15 (s, 3H), 2.14 – 2.06 (m, 1H), 1.10 – 0.99 (m, 2H), 0.99 – 0.85 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -66.33. Minor rotamer: 19F NMR (376 MHz, DMSO-d6) δ -66.25 Example 21: rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyri- din-3-yl)pyrimidine-5-carboxamide Ryvu Therapeutics S.A. RVU305 125 R10945WO N‐[(4‐bromo‐3‐nitrophenyl)methyl]‐2‐cyclopropyl‐N‐(2‐methylpyridin‐3‐yl)pyrimidine‐5‐carboxamide (Int.56) Cs2CO3 (1.89 g, 5.80 mmol, 1.2 eq.) was added to a solution of 2-cyclopropyl-N-(2-methylpyridin-3-yl)py- rimidine-5-carboxamide (Int.10, 1.27 g, 4.84 mmol, 1.0 eq.) in MeCN (20.0 mL). The mixture was flushed with argon for a 20 min at RT and then 1-bromo-4-(bromomethyl)-2-nitrobenzene (1.86 g, 6.31 mmol, 1.30 eq.) was added. RM was heated at 70°C for 1.5 h. RM was diluted with water and sat. aq. Na2CO3 solution. Obtained mixture was extracted with EtOAc (2x). Organic layers were combined, washed with brine, dried over Na2SO4 and evaporated. The crude was purified by trituration with hot i-PrOH/EtOAc mixture to give N-[(4-bromo-3-ni- trophenyl)methyl]-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.56, 1.7 g, 3.521 mmol, 73%, light brown solid, m/z [M+H]+: 469.2). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 2H), 8.37 (d, J = 4.7 Hz, 1H), 7.98 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.21 (dd, J = 8.0, 4.8 Hz, 1H), 5.34 (d, J = 15.0 Hz, 1H), 4.79 (d, J = 15.0 Hz, 1H), 2.24 (s, 3H), 2.17 – 2.07 (m, 1H), 1.11 – 1.00 (m, 2H), 0.98 – 0.88 (m, 2H). N‐[(3‐amino‐4‐bromophenyl)methyl]‐2‐cyclopropyl‐N‐(2‐methylpyridin‐3‐yl)pyrimidine‐5‐carboxamide (Int.57) To a solution of N-[(4-bromo-3-nitrophenyl)methyl]-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5- carboxamide (Int.56, 1.65 g, 3.418 mmol, 1.0 eq.) in acetone (25.0 mL) was added zinc (2.23 g, 34.108 mmol, 9.98 eq.). Next the flask was placed in an ice bath and sat. aq. NH4Cl solution (15.0 mL) was added dropwise. Then RM was stirred overnight at RT. RM was diluted with DCM and filtrated through Celite. Next, filtrate was diluted with water and sat. aq. Na2CO3 solution and extracted with DCM (2x). Organic layers were combined, washed with brine, dried over Na2SO4 and evaporated to give N-[(3-amino-4-bromophenyl)methyl]-2-cyclopro- pyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carboxamide slightly brown foam (Int.57, 1.49 g, 3.195 mmol, 93%, light brown foam, m/z [M+H]+: 439.2). 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 2H), 8.34 (d, J = 4.7 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.31 – 7.17 (m, 2H), 6.75 (s, 1H), 6.35 (d, J = 8.0 Hz, 1H), 5.32 (s, 2H), 5.05 (d, J = 14.5 Hz, 1H), 4.64 (d, J = 14.5 Hz, 1H), 2.18 – 2.06 (m, 4H), 1.09 – 1.00 (m, 2H), 0.98 – 0.87 (m, 2H). rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide (Example 21) Step 1: Ryvu Therapeutics S.A. RVU305 126 R10945WO N-[(3-amino-4-bromophenyl)methyl]-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.57, 1.44 g, 3.09mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.57 g, 6.18 mmol, 2.0 eq.) and potassium acetate (0.9 g, 9.17 mmol, 2.97 eq.) were mixed in anh. dioxane (80.0 mL). The mixture was flushed with argon for 10min and then 1,1'-Bis(diphe- nylphosphino)ferrocene dichloropalladium (II) (0.27 g, 0.37 mmol, 0.12 eq.) was added. RM was heated at 100°C for 4 h. Then new portion of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (0.39 g, 1.54 mmol, 0.5 eq.) and 1,1'-Bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.11 g, 0.15 mmol, 0.05 eq.) were added and the reaction was heated at 100°C for 45 min. Solvent was evap- orated and then residue was dissolved in DCM and filtered through Celite. The filtrate was diluted with water and extracted with DCM (2x). The organic phases were combined, washed with brine, dried over Na2SO4, fil- tered, and concentrated in vacuo to give (2-amino-4-{[1-(2-cyclopropylpyrimidin-5-yl)-N-(2-methylpyridin-3- yl)formamido]methyl}phenyl)boronic acid (3.59 g, 2.137 mmol, black solid). Step 2: (2-amino-4-{[1-(2-cyclopropylpyrimidin-5-yl)-N-(2-methylpyridin-3-yl)formamido]methyl}phenyl)boronic acid (3.14 g, 1.869 mmol, 1.0 eq.), 4-cyano-5-methyl-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Int. F, 2.0 g, 2.33 mmol, 1.2 eq.) and K2CO3 (0.77 g, 5.57 mmol, 2.98 eq.) were mixed in a mixture of dioxane (50.0 mL) and water (5.0 mL). The mixture was flushed with argon for 10 min and then Pd(PPh3)4 (0.32 g, 0.28 mmol, 0.15 eq.) was added. RM was heated at 100°C for 1 h. After that time RM was diluted with DCM and filtered through Celite. The filtrate was diluted with water and extracted with DCM (3x). Organic layers were combined, washed with sat. aq. Na2CO3 solution, brine, dried over Na2SO4 and evaporated. The crude was purified by two FCC (0% to 20% EtOH gradient in DCM). Obtained fraction was co-evaporated with EtOH and lyophilized to give rac-(N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)py- rimidine-5-carboxamide (Example 21, 0.6 g, 1.247 mmol, 67%, grayish solid). 110 mg of the product was re-purified by reverse phase FCC (C18 column, 0% to 60% MeCN gradient in wa- ter) to give rac-(N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin- 3-yl)pyrimidine-5-carboxamide (Example 21, 0.090 g, 0.176 mmol, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 100%, m/z [M+H]+: 467.26). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2H), 8.37 – 8.29 (m, 1H), 7.68 – 7.55 (m, 1H), 7.44 (dd, J = 8.2, 3.6 Hz, 1H), 7.34 (d, J = 12.4 Hz, 1H), 7.24 – 7.12 (m, 2H), 6.41 (s, 2H), 5.45 – 5.19 (m, 4H), 5.00 (d, J = 14.2 Hz, 1H), 2.16 – 2.06 (m, 1H), 2.03 (d, J = 3.0 Hz, 3H), 1.39 (d, J = 6.1 Hz, 3H), 1.08 – 0.99 (m, 2H), 0.96 – 0.86 (m, 2H). Example 22: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-cyclopropyl-2-methylpyri- din-3-yl)pyrimidine-5-carboxamide Ryvu Therapeutics S.A. RVU305 127 R10945WO 2‐cyclopropyl‐N‐(6‐cyclopropyl‐2‐methylpyridin‐3‐yl)pyrimidine‐5‐carboxamide (Int.58) Phosphoroyl trichloride (0.700 g, 4.568 mmol, 2.0 eq.) was added dropwise to a solution of 6-cyclopro- pyl-2-methylpyridin-3-amine (Int.37, 0.349 g, 2.284 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.375 g, 2.284 mmol, 1.0 eq.) and N,N-dimethylpyridin-4-amine (0.084 g, 0.685 mmol, 0.3 eq.) in pyridine (10 mL) at 0°C. The RM was stirred for 5 min at 0°C and then 40 min at RT under nitrogen. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3. Solution was transferred to separatory funnel and extracted with EtOAc (3x). Combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (0% to 100% EtOAc gradient in hexane) to give 2-cyclopropyl-N-(6-cyclopropyl-2-methylpyridin-3-yl)py- rimidine-5-carboxamide (Int.58, 0.33 g, 1.087 mmol, 48%, white solid, m/z [M+H]+: 295.2). 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.11 (s, 2H), 7.60 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 2.36 (s, 3H), 2.34 – 2.27 (m, 1H), 2.08 (tt, J = 7.9, 5.0 Hz, 1H), 1.20 – 1.13 (m, 2H), 1.10 (dt, J = 4.6, 2.8 Hz, 2H), 0.95 – 0.87 (m, 4H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐(6‐cyclopropyl‐2‐methylpyridin‐3‐yl)pyrimi- dine‐5‐carboxamide (Int.59) To a mixture of 2-cyclopropyl-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.58, 0.33 g, 1.087 mmol, 1.0 eq.) and 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.328 g, 1.087 mmol, 1.0 eq.) in MeCN (12 mL) Cs2CO3 (0.709 g, 2.175 mmol, 2.0 eq.) was added. Mixture was flushed with nitrogen for 10 min at RT and then RM was stirred at 70°C for 30 minutes. After that time reaction mixture was diluted with water, transferred to separatory funnel and extracted with DCM (3x). Combined organic phases were washed with brine, dried over Na2SO4 filtered and evaporated. The crude was purified by FCC (0% to 50% EtOAc gradient in hexane) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6- cyclopropyl-2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Int.59, 0.286 g, 0.531 mmol, 49%, m/z [M+H]+: 512.6). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 2H), 7.92 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.6 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 5.54 (t, J = 3.1 Hz, 2H), 5.42 (d, J = 14.7 Hz, 1H), 5.22 Ryvu Therapeutics S.A. RVU305 128 R10945WO (t, J = 3.1 Hz, 2H), 4.97 (d, J = 14.7 Hz, 1H), 2.17 – 2.08 (m, 1H), 2.05 (s, 3H), 1.99 – 1.93 (m, 1H), 1.09 – 1.01 (m, 2H), 0.98 – 0.85 (m, 4H), 0.81 – 0.72 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide (Example 22) Step 1: N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-cyclopropyl-2-methylpyridin-3- yl)pyrimidine-5-carboxamide (Int.59, 0.286 g, 0.531 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.355 g, 2.123 mmol, 4.0 eq.) were stirred in DMSO (5.0 mL) at 120°C for 5 h. The reaction mixture was di- luted with water (200 mL), transferred to separatory funnel and extracted with (4:1 v/v) DCM: i-PrOH mixture (5 x 50 mL). Organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and con- centrated in vacuo. Crude product was purified by FCC (0% to 50% EtOAc gradient in hexane). Step 2: Step 1 product was dissolved in DCE (9 mL) and trifluoroacetic acid (1 mL) was added under vigorous stirring. The RM was stirred for 2 h at 60°C. After that time reaction mixture was poured into Na2CO3 solution (150 mL) and stirred for 30 minutes. Obtained mixture was transferred to separatory funnel and extracted with DCM: i-PrOH (4:1) mixture. The combined organic layers were washed with aq. NaHCO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was puri- fied by preparative HPLC. Fractions containing product were combined and concentrated under vacuum to re- move organic solvents. Residue was diluted with water and neutralized with saturated aqueous Na2CO3 solu- tion. Obtained mixtures was extracted with DCM. Combined organic layers were concentrated in vacuo to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide (Example 22, 0.058 g, 0.116 mmol, 22%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 98.94%, m/z [M+H]+: 493.2). 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.16 (dd, J = 8.2, 1.7 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.47 (s, 2H), 5.29 (t, J = 3.3 Hz, 2H), 5.21 (d, J = 14.2 Hz, 1H), 4.98 (t, J = 3.4 Hz, 2H), 4.90 (d, J = 14.3 Hz, 1H), 2.15 – 2.07 (m, 1H), 2.02 – 1.96 (m, 1H), 1.95 (s, 3H), 1.07 – 1.01 (m, 2H), 0.95 – 0.90 (m, 2H), 0.90 – 0.84 (m, 2H), 0.80 – 0.72 (m, 2H). Example 23: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2-cyclo- propylpyrimidine-5-carboxamide N‐(3‐chloro‐1‐methyl‐1H‐pyrazol‐5‐yl)‐2‐cyclopropylpyrimidine‐5‐carboxamide (Int.60) Ryvu Therapeutics S.A. RVU305 129 R10945WO DMAP (0.16 g, 1.31 mmol, 0.51 eq.), DIPEA (1.12 mL, 6.43 mmol, 2.5 eq.), 3-chloro-1-methyl-1H-pyra- zol-5-amine (0.34 g, 2.58 mmol, 1.0 eq.) and 2-cyclopropylpyrimidine-5-carboxylic acid (0.42 g, 2.56 mmol, 0.99 eq.) were taken in toluene (10.0 mL, 3.87 mL/mmol) and propylphosphonic anhydride (50% solution in EtOAc, 3.1 mL, 5.21 mmol, 2.02 eq.) was added dropwise at RT. Then, the RM was heated at 55°C for 1.5 h. The reaction was quenched with sat. aq. Na2CO3 solution. Obtained mixture was extracted with EtOAc (2x). Combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The crude was purified by trituration with i-PrOH/hexane mixture to give N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2- cyclopropylpyrimi- dine-5-carboxamide (Int.60, 0.37 g, 1.332 mmol, 52%, white solid, m/z [M+H]+: 278.9). Filtrate was purified by FCC (0% to 5% MeOH gradient in DCM) to give N-(3-chloro-1-methyl-1H-pyrazol-5-yl)- 2- cyclopropylpyrimidine-5-carboxamide (Int.60, 0.2 g, 0.72 mmol, 28%, white solid, m/z [M+H]+: 278.9). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.11 (s, 2H), 6.39 (s, 1H), 3.71 (s, 3H), 2.32 (tt, J = 7.9, 4.7 Hz, 1H), 1.23 – 1.05 (m, 4H). N‐(3‐chloro‐1‐methyl‐1H‐pyrazol‐5‐yl)‐N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropylpyrimi- dine‐5‐carboxamide (Int 61) To a solution of N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.60, 0.47 g, 1.69 mmol, 1.0 eq.) in MeCN (15.0 mL) Cs2CO3 (1.1 g, 3.38 mmol, 2.0 eq.) was added. Mixture was flushed with argon for 10 min at RT. Then 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.56 g, 1.86 mmol, 1.1 eq.) was added and RM was heated at 70°C for 2 h. After that time RM was diluted with sat. aq. Na2CO3 solution and obtained mixture was extracted with DCM (2x). Combined organic phases were washed with brine dried over Na2SO4 and evaporated. The crude was purified by FCC (0% to 30% EtOAc gradient in DCM) to give N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cy- clopropylpyrimidine-5-carboxamide (Int.61, 0.4 g, 0.791 mmol, 47%, white solid, m/z [M+H]+: 496.5). 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 2H), 7.99 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 8.4, 1.7 Hz, 1H), 6.34 (s, 1H), 5.55 (t, J = 3.1 Hz, 2H), 5.44 – 5.28 (m, 1H), 5.23 (t, J = 3.1 Hz, 2H), 5.17 – 5.00 (m, 1H), 3.48 (s, 3H), 2.26 – 2.13 (m, 1H), 1.15 – 0.97 (m, 4H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2-cyclopropylpyrimi- dine-5-carboxamide (Example 23) Step 1: N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclo- propylpyrimidine-5-carboxamide (Int.61, 0.4 g, 0.791 mmol, 1.0 eq.), 1-(2,4-dimethoxyphenyl)methanamine (0.79 g, 4.725 mmol, 6.0 eq.) and DIPEA (0.41 mL, 2.354 mmol, 3.0 eq.) were mixed in anh. DMSO (10.0 mL) and stirred 2 h at 130°C and overnight at RT. After that time RM was diluted with water/Na2CO3 sat. and ex- tracted with EtOAc (2x). Combined organic layers were washed with water, brine, dried over Na2SO4 and evap- orated. The crude was purified by FCC (0% to 25% MeCN gradient in DCM) to give N-(3-chloro-1-methyl-1H- pyrazol-5-yl)-2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)me- thyl]pyrimidine-5-carboxamide (0.3 g, 0.446 mmol, 56%, yellow solid, m/z [M+H]+: 627.2). Step 2: TFA (1.7 mL, 22.2 mmol, 50.0 eq.) was added to a solution of N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2- cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]pyrimidine-5- carboxamide (0.3 g, 0.446 mmol, 1.0 eq.) in DCM (5.0 mL). RM was stirred at RT for 4.5 h. After that time RM was poured into sat. Na2CO3/ice and stirred for a few minutes. Obtained mixture was extracted with DCM (2x). Ryvu Therapeutics S.A. RVU305 130 R10945WO Organic layers were combined, washed with 1M K2CO3, brine, dried over Na2SO4 and evaporated. Residue was treaded with a mixture of MeOH, CHCl3 and i-PrOH. Obtained mixture was heated and sonicated. Solid was filtered off and filtrate was purified by FCC (0% to 8% EtOH gradient in DCM) to give N-({4-amino-1H,3H- furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2-cyclopropylpyrimidine-5-carboxamide (Example 23, 0.085 g, 0.178 mmol, 40%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.86%, m/z [M+H]+: 476.16). 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.54 – 7.39 (m, 2H), 7.15 (d, J = 7.8 Hz, 1H), 6.52 (s, 2H), 6.33 (s, 1H), 5.31 (t, J = 3.4 Hz, 2H), 5.12 – 5.03 (m, 2H), 5.00 (t, J = 3.4 Hz, 2H), 3.32 (s, 3H), 2.29 – 2.12 (m, 1H), 1.13 – 1.06 (m, 2H), 1.02 – 0.96 (m, 2H). Example 24: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(tri- fluoromethyl)pyridine-3- N‐(3‐cyano‐1‐methyl‐1H‐pyrazol‐5‐yl)‐6‐(trifluoromethyl)pyridine‐3‐carboxamide (Int.62) Phosphoryl trichloride (0.603 g, 3.93 mmol, 2.0 eq.) was added dropwise to a vigorously stirred solution of 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.376 g, 1.965 mmol, 1.0 eq.), 5-amino-1-methyl-1H-pyrazole-3- carbonitrile (0.24 g, 1.965 mmol, 1.0 eq.) and N,N-dimethylpyridin-4-amine (0.072 g, 0.59 mmol, 0.3 eq.) in pyr- idine (10 mL) at 0°C. The RM was stirred for 15 min at 0°C under nitrogen. After that time the reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3. Solution was transferred to separatory funnel and extracted with EtOAc (3x). Combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (0% to 100% EtOAc gradient in hexane) to give N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide (Int.62, 0.515 g, 1.57 mmol, 80%, yellow solid, m/z [M+H]+: 296.0). 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.28 (d, J = 2.1 Hz, 1H), 8.59 (dd, J = 8.2, 2.1 Hz, 1H), 8.15 (dd, J = 8.2, 0.9 Hz, 1H), 7.04 (s, 1H), 3.88 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.70. Ryvu Therapeutics S.A. RVU305 131 R10945WO N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(3‐cyano‐1‐methyl‐1H‐pyrazol‐5‐yl)‐6‐(trifluoromethyl)pyr- idine‐3‐carboxamide (Int.63) To a mixture of N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.62, 0.505 g, 1.54 mmol, 1.0 eq.) and 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.464 g, 1.54 mmol, 1.0 eq.) in MeCN (15 mL) Cs2CO3 (1.00 g, 3.079 mmol, 2.0 eq.) was added. Mixture was flushed with nitrogen for 10 min at RT and then RM was stirred at 70°C for 30 minutes. After that time reaction mixture was poured into water (100 mL), transferred to separatory funnel and extracted with ethyl acetate (3x 50 mL). Or- ganic fractions were combined, washed with brine, dried over sodium sulphate, filtered and evaporated. The crude was purified by FCC (0% to 50% EtOH gradient in hexane) to give N-({4-chloro-1H,3H-furo[3,4-c]quino- lin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.63, 0.278 g, 0.488 mmol, 32%, m/z [M+H]+: 513.5). 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.98 – 7.89 (m, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 6.90 (s, 1H), 5.55 (t, J = 3.2 Hz, 2H), 5.49 – 5.38 (m, 1H), 5.23 (t, J = 3.1 Hz, 2H), 5.16 – 5.03 (m, 1H), 3.69 (s, 3H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyr- idine-3-carboxamide (Example 24) Step 1: N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide (Int.63, 0.26 g, 0.456 mmol, 1.0 eq.), tert-butyl carbamate (0.107 g, 0.913 mmol, 2.0 eq.) and Cs2CO3 (0.372 g, 1.141 mmol, 2.5 eq.) were mixed in anh. dioxane (10.0 mL). The mixture was flushed with argon for 5 min and then tris((1E,4E)-1,5-diphenylpenta-1,4-dien-3-one) dipalladium (0.084 g, 0.091 mmol, 0.2 eq.) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.079 g, 0.137 mmol, 0.3 eq.) were added. RM was heated at 70°C for 60 min. After that time RM was diluted with EtOAc and filtered through celite. The filtrate was washed with sat. aq. Na2CO3 solution, water, brine, dried over Na2SO4, filtered and evaporated. The crude compound was purified by FCC (0% to 50% EtOAc gradient in hexane) to give tert-butyl N-(7-{[N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-1-[6-(trifluoromethyl)pyridin-3-yl]formamido]methyl}-1H,3H- furo[3,4-c]quinolin-4-yl)carbamate (0.257 g, 0.381 mmol, 84%). Step 2: TFA (1 mL) was added dropwise to a solution of tert-butyl N-(7-{[N-(3-cyano-1-methyl-1H-pyrazol-5-yl)- 1-[6-(trifluoromethyl)pyridin-3-yl]formamido]methyl}-1H,3H-furo[3,4-c]quinolin-4-yl)carbamate (0.255 g, 0.378 mmol, 1.0 eq.) in DCE (15.0 mL). RM was stirred at 60°C for 60 minutes. After that time RM was poured onto sat. Na2CO3 /ice and stirred for a few minutes. Obtained mixture was extracted with DCM (3x). Organic layers were combined, washed with sat. aq. Na2CO3 solution, brine , dried over Na2SO4 filtered and evaporated. The crude was purified by preparative HPLC to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano- 1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 24, 0.055 g, 0.111 mmol, 29%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.72%, m/z [M+H]+: 494.16). 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.90 (s, 1H), 6.52 (s, 2H), 5.30 (t, J = 3.3 Hz, 2H), 5.24 – 5.13 (m, 1H), 5.13 – 5.01 (m, 1H), 4.99 (t, J = 3.5 Hz, 2H), 3.55 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.77. Ryvu Therapeutics S.A. RVU305 132 R10945WO Example 25: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3- yl]pyrimidine-5-carboxamide 2‐cyclopropyl‐N‐[6‐(trifluoromethyl)pyridin‐3‐yl]pyrimidine‐5‐carboxamide (Int.64) Phosphorus oxychloride (0.57 g, 3.718 mmol, 2.001 eq.) was added dropwise to a solution of 2-cyclo- propylpyrimidine-5-carboxylic acid (0.305 g, 1.858 mmol, 1.0 eq.), 6-(trifluoromethyl)pyridin-3-amine (0.302 g, 1.863 mmol, 1.003 eq.) and N,N-dimethylpyridin-4-amine (0.067 g, 0.548 mmol, 0.295 eq.) in pyridine (9.0 mL) at 0°C. The RM was stirred for 5 min at 0°C and then 40 min at RT under nitrogen. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3/1M NaOH mixture. It was extracted with EtOAc (3x) and the combined organic layers were washed with brine, then dried over anhydrous Na2SO4, fil- tered, and evaporated under reduced pressure. The crude material was triturated with i-PrOH, product was fil- tered off, washed with i-PrOH and dried to give 2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5- carboxamide (Int.64, 0.43 g, 1.395 mmol, 75%, beige solid, m/z [M+H]+: 309.3). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.14 (s, 2H), 9.07 (d, J = 2.4 Hz, 1H), 8.47 (dd, J = 8.5, 2.5 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 2.33 (tt, J = 8.0, 4.6 Hz, 1H), 1.20 – 1.13 (m, 2H), 1.13 – 1.08 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -65.73. N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐[6‐(trifluoromethyl)pyridin‐3‐yl]pyrimidine‐5‐ carboxamide (Int.65) 2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide (Int.64, 0.43 g, 1.395 mmol, 1.0 eq.) was suspended in acetonitrile (7.0 ml) and cesium carbonate (0.55 g, 1.688 mmol, 1.21 eq.) was added. The mixture was stirred for 5 min at RT. Then, 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.443 g, 1.469 mmol, 1.053 eq.) was added. Reaction mixture was heated at 70°C for 2 h. Reaction mixture was quenched with saturated aqueous NH4Cl solution, diluted with water and extracted with DCM. Or- ganic layers were combined, washed with brine and then dried over Na2SO4 and evaporated. Crude product was triturated with cold isopropanol, filtered off and dried in vacuo to give N-({4-chloro-1H,3H-furo[3,4-c]quino- lin-7-yl}methyl)-2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide (Int.65, 0.61 g, 1.137 mmol, 81%, dark beige solid, m/z [M+H]+: 527.0). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 2.4 Hz, 1H), 8.64 (s, 2H), 8.11 (dd, J = 8.5, 2.5 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.5, 1.7 Hz, 1H), 5.52 (t, J = 3.1 Ryvu Therapeutics S.A. RVU305 133 R10945WO Hz, 2H), 5.48 (s, 2H), 5.20 (t, J = 3.1 Hz, 2H), 2.17 (tt, J = 8.4, 4.7 Hz, 1H), 1.11 – 1.03 (m, 2H), 1.01 – 0.94 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -66.19. N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5- carboxamide (Example 25) Step 1: N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimi- dine-5-carboxamide (Int.65, 0.61 g, 1.137 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.86 g, 5.143 mmol, 4.525 eq.) were stirred in DMSO (6.0 mL) at 120°C for 24 h. The reaction mixture was diluted with EtOAc and washed three times with water followed by brine, dried over anhydrous Na2SO4, filtered and con- centrated in vacuo. Crude product was purified by FCC (0% to 80% EtOAc gradient in heptane) to give 2-cyclo- propyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-[6-(trifluorome- thyl)pyridin-3-yl]pyrimidine-5-carboxamide (0.628 g, 0.851 mmol, 75%). Step 2: Obtained product was dissolved in DCM (7.5 mL) and trifluoroacetic acid (3.0 ml, 39.203 mmol) was added. The RM was stirred for 16 h at RT and evaporated under reduced pressure. Residue was partitioned between mixture of sat. aq. NaHCO3/1M NaOH and DCM. The aqueous phase was extracted with DCM, and the combined organic layers were washed with aq. NaHCO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FCC (0% to 10% EtOH gradient in DCM). The fractions containing the pure product were pooled and freeze-dried to give N-({4-amino- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide (Example 25, 0.164 g, 0.319 mmol, 28%, yellow solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 98.57%, m/z [M+H]+: 507.2). 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 8.61 – 8.59 (m, 1H), 8.04 (dd, J = 2.5, 8.3 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 1.7, 8.2 Hz, 1H), 6.47 (s, 2H), 5.34 (s, 2H), 5.28 (t, J = 3.3 Hz, 2H), 4.97 (t, J = 3.3 Hz, 2H), 2.16 (tt, J = 4.6, 8.2 Hz, 1H), 1.07 (dt, J = 3.3, 7.8 Hz, 2H), 0.97 (dt, J = 3.1, 4.4 Hz, 2H). 19F NMR (376 MHz, DMSO-d6) δ -66.16. Example 26: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropoxypyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide
Ryvu Therapeutics S.A. RVU305 134 R10945WO NaH (60% dispersion in mineral oil, 0.243 g, 10.557 mmol, 3.0 eq.) was added portion wise to a solution of cyclopropanol (0.307 g, 5.278 mmol, 1.5 eq.) in anhydrous THF (10 mL) at 0°C. The mixture was stirred 30 min. at 0°C and then a solution of 2-fluoro-3-nitropyridine (0.5 g, 3.519 mmol, 1.0 eq.) in THF (3 mL) was added slowly dropwise. The reaction was stirred 30 min at 0°C and 3 h at RT. After that time RM was quenched with aq. NH4Cl followed by aq. NaHCO3 and obtained mixture was extracted with EtOAc. Combined organic layers were washed with brine, filtered and concentrated. The residue in the flask was treated with di- ethyl ether, brown solid was filtered off and the filtrate was evaporated to give 2-cyclopropoxy-3-nitropyridine (Int.66, 0.856 g, 3.516 mmol, 100%, brown liquid). 1H NMR (400 MHz, DMSO-d6) δ 8.61 – 8.50 (m, 1H), 8.48 – 8.36 (m, 1H), 7.29 (dd, J = 7.9, 4.9 Hz, 1H), 4.52 – 4.41 (m, 1H), 0.86 – 0.79 (m, 2H), 0.79 – 0.72 (m, 2H). 2‐cyclopropoxypyridin‐3‐amine (Int.67) 10% Pd/C (225 mg) was added to a solution 2-cyclopropoxy-3-nitropyridine (Int.66, 0.856 g, 3.516 mmol, 1.0 eq.) in ethanol (18.0 mL) and the atmosphere was first replaced by argon, with three cycles of vac- uum/argon, then by hydrogen by three cycles of vacuum/hydrogen. Stirring under hydrogen (1 atm) was pur- sued for 2 days at RT. After that time the mixture was filtered through a pad of Celite® and the filtrate was evaporated under reduced pressure. Obtained residue was dissolved in ethyl acetate and washed with water. Organic phase washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give 2-cyclo- propoxypyridin-3-amine (Int.67, 0.6 g, 3.396 mmol, 97%, dark brown oil, m/z [M+H]+: 151.0). 1H NMR (400 MHz, DMSO-d6) δ 7.38 (dd, J = 4.9, 1.7 Hz, 1H), 6.86 (dd, J = 7.5, 1.7 Hz, 1H), 6.72 (dd, J = 7.5, 4.9 Hz, 1H), 4.82 (s, 2H), 4.29 – 4.20 (m, 1H), 0.76 – 0.69 (m, 2H), 0.68 – 0.61 (m, 2H). N‐(2‐cyclopropoxypyridin‐3‐yl)‐2‐cyclopropylpyrimidine‐5‐carboxamide (Int.68) Phosphorus oxychloride (1.3 g, 8.479 mmol, 2.881 eq.) was added dropwise to a solution of 2-cyclo- propoxypyridin-3-amine (Int.67, 0.52 g, 2.943 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.61 g, 3.716 mmol, 1.263 eq.) and N,N-dimethylpyridin-4-amine (0.1 g, 0.819 mmol, 0.278 eq.) in pyridine (16.0 mL) at 0°C. The RM was stirred for 5 min at 0°C and then 40 min at RT under nitrogen. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3/1M NaOH mixture. It was ex- tracted with EtOAc (3x) and the combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (0% to 80% Ryvu Therapeutics S.A. RVU305 135 R10945WO EtOAc gradient in heptane) to give N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int. 68, 0.605 g, 1.756 mmol, 60%, brown solid, m/z [M+H]+: 297.4). 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.04 (s, 2H), 8.12 (dd, J = 7.7, 1.8 Hz, 1H), 8.05 (dd, J = 4.9, 1.8 Hz, 1H), 7.08 (dd, J = 7.7, 4.9 Hz, 1H), 4.38 – 4.29 (m, 1H), 2.31 (tt, J = 8.0, 4.7 Hz, 1H), 1.17 – 1.12 (m, 2H), 1.12 – 1.03 (m, 2H), 0.81 – 0.70 (m, 4H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(2‐cyclopropoxypyridin‐3‐yl)‐2‐cyclopropylpyrimidine‐5‐ carboxamide (Int.69) N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.68, 0.605 g, 1.756 mmol, 1.0 eq.) was suspended in acetonitrile (10.0 ml) and cesium carbonate (1.06 g, 3.253 mmol, 1.853 eq.) was added. The mixture was stirred for 5 min at RT. Then, 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.83 g, 2.724 mmol, 1.552 eq.) was added. Reaction mixture was heated at 70°C for 4 h. Reaction mixture was quenched with saturated aqueous NH4Cl solution, diluted with water and extracted with DCM. Organic layers were combined, washed with brine and then dried over Na2SO4 and evaporated. Crude product was triturated with cold isopropanol, filtered off and dried in vacuo to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)- N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.69, 0.945 g, 1.618 mmol, 92%, brownish solid, m/z [M+H]+: 514.2). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.03 (dd, J = 4.9, 1.7 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.89 – 7.82 (m, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 8.5, 1.7 Hz, 1H), 7.02 (dd, J = 7.7, 4.9 Hz, 1H), 5.52 (t, J = 3.0 Hz, 2H), 5.30 – 5.23 (m, 1H), 5.21 (t, J = 3.1 Hz, 2H), 5.13 (d, J = 14.9 Hz, 1H), 3.94 – 3.87 (m, 1H), 2.19 – 2.08 (m, 1H), 1.08 – 0.99 (m, 2H), 0.96 – 0.91 (m, 2H), 0.60 – 0.52 (m, 2H), 0.35 – 0.25 (m, 1H), 0.14 – 0.03 (m, 1H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimidine-5- carboxamide (Example 26) Step 1: N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimi- dine-5-carboxamide (Int.69, 0.575 g, 0.984 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.68 g, 4.067 mmol, 4.131 eq.) were stirred in DMSO (5.0 mL) at 140°C for 2 h under microwave conditions. The reac- tion mixture was diluted with EtOAc and washed three times with water followed by brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crude product was purified by FCC (0% to 100% EtOAc gradient in heptane) to give N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}- 1H,3H-furo[3,4-c]quinolin-7-yl)methyl]pyrimidine-5-carboxamide (0.575 g, 0.74 mmol, 75%). Step 2: N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H- furo[3,4-c]quinolin-7-yl)methyl]pyrimidine-5-carboxamide (0.575 g, 0.74 mmol, 1.0 eq.) was dissolved in DCM (10 mL) and trifluoroacetic acid (1.5 mL, 19.601 mmol, 26.48 eq.) was added. The RM was stirred for 16 h at RT and evaporated under reduced pressure. The residue was dissolved in MeOH and the solution was passed down a SCX column, washing with MeOH and eluting with 2 M ammonia in MeOH. The crude material was pu- rified by FCC (0% to 10% EtOH gradient in DCM). The fractions containing the pure product were pooled and freeze-dried to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropoxypyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide (Example 26, 0.17 g, 0.34 mmol, 35%, yellowish solid, UPLC long elution (Mid polar long method, buffer type “FA”) purity: 98.94%, m/z [M+H]+: 495.25). Ryvu Therapeutics S.A. RVU305 136 R10945WO 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2H), 8.01 (dd, J = 1.8, 4.9 Hz, 1H), 7.73 (dd, J = 1.8, 7.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 1.7 Hz, 1H), 7.12 (dd, J = 1.7, 8.2 Hz, 1H), 6.99 (dd, J = 4.9, 7.7 Hz, 1H), 6.45 (s, 2H), 5.34 – 5.24 (m, 2H), 5.08 (d, J = 15.0 Hz, 1H), 5.03 (d, J = 13.7 Hz, 1H), 5.00 – 4.95 (m, 2H), 3.96 – 3.86 (m, 1H), 2.13 (tt, J = 4.7, 8.3 Hz, 1H), 1.09 – 1.01 (m, 2H), 0.98 – 0.87 (m, 2H), 0.64 – 0.46 (m, 2H), 0.32 – 0.22 (m, 1H), 0.15 – 0.01 (m, 1H). Example 27: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-oxo-1,2-dihydropyridin-3-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide N‐(2‐methoxypyridin‐3‐yl)‐6‐(trifluoromethyl)pyridine‐3‐carboxamide (Int.70) Phosphorus oxychloride (1.25 g, 8.153 mmol, 2.024 eq.) was added dropwise to a solution of 6-(trifluo- romethyl)pyridine-3-carboxylic acid (0.815 g, 4.265 mmol, 1.059 eq.), 2-methoxypyridin-3-amine (0.5 g, 4.028 mmol, 1.0 eq.) and N,N-dimethylpyridin-4-amine (0.145 g, 1.187 mmol, 0.295 eq.) in pyridine (15.0 mL) at 0°C. The RM was stirred for 5 min at 0°C and then 40 min at RT under nitrogen. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. NaHCO3/1M NaOH mixture. It was extracted with EtOAc (3x) and the combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude material was triturated with isopropanol, product was filtered off, washed with i-PrOH and dried to yield N-(2-methoxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.70, 0.59 g, 1.945 mmol, 48%, beige solid, m/z [M+H]+: 298.3). 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.23 (s, 1H), 8.56 (d, J = 8.2 Hz, 1H), 8.17 – 8.10 (m, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.05 (dd, J = 5.1, 1.6 Hz, 1H), 7.08 (dd, J = 7.7, 5.0 Hz, 1H), 3.94 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.62. N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(2‐methoxypyridin‐3‐yl)‐6‐(trifluoromethyl)pyridine‐3‐car- boxamide (Int.71) N-(2-methoxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.70, 0.59 g, 1.945 mmol, 1.0 eq.) was suspended in acetonitrile (10.0 mL) and cesium carbonate (0.765 g, 2.348 mmol, 1.207 eq.) was added. It was mixed for 5 min at RT. Then, 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.616 g, 2.043 mmol, 1.05 eq.) was added. Reaction mixture was heated at 70°C for 2 h. Reaction mixture was quenched with saturated aqueous NH4Cl solution, diluted with water and extracted with DCM. Organic layers were combined, washed with brine and then dried over Na2SO4 and evaporated. Crude product was triturated with cold isopropanol, filtered off and dried in vacuo to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)- Ryvu Therapeutics S.A. RVU305 137 R10945WO N-(2-methoxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.71, 0.95 g, 1.808 mmol, 93%, white solid, m/z [M+H]+: 516.0). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.98 – 7.92 (m, 2H), 7.85 – 7.80 (m, 2H), 7.73 – 7.68 (m, 2H), 6.90 (dd, J = 7.6, 4.9 Hz, 1H), 5.53 (t, J = 3.1 Hz, 2H), 5.37 (d, J = 15.2 Hz, 1H), 5.22 (t, J = 3.0 Hz, 2H), 5.15 (d, J = 14.9 Hz, 1H), 3.65 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.72. N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-oxo-1,2-dihydropyridin-3-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide (Example 27) Step 1: N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methoxypyridin-3-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide (Int.71, 0.95 g, 1.808 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (1.3 g, 7.775 mmol, 4.3 eq.) were stirred in DMSO (9.0 mL) at 120°C for 24 h. The reaction mixture was diluted with EtOAc and washed three times with water followed by brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crude product was purified by FCC (0% to 100% EtOAc gradient in heptane) to give N-[(4-{[(2,4-di- methoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2-oxo-1,2-dihydropyridin-3-yl)-6-(tri- fluoromethyl)pyridine-3-carboxamide (0.3 g, 0.413 mmol, 23%) Step 2: N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2-oxo-1,2-dihydro- pyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (0.3 g, 0.413 mmol, 1.0 eq.) was dissolved in DCM (3 mL) and trifluoroacetic acid (1.5 ml, 19.601 mmol, 47.434 eq.) was added. The RM was stirred for 48 h at RT and evaporated under reduced pressure. Residue was partitioned between mixture of sat. aq. NaHCO3/1M NaOH and DCM. The aqueous phase was extracted with DCM, and the combined organic layers were washed with aq. NaHCO3 solution, brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was dissolved in DMSO and purified by preparative HPLC (basic conditions). The fractions containing the pure product were pooled and freeze-dried to give N-({4-amino-1H,3H-furo[3,4-c]quino- lin-7-yl}methyl)-N-(2-oxo-1,2-dihydropyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 27, 0.025 g, 0.051 mmol, 12%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 98.38%, m/z [M+H]+: 482.21). 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.07 (dd, J = 2.1, 8.2 Hz, 1H), 7.85 (dd, J = 0.9, 8.1 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.38 (dd, J = 2.0, 7.2 Hz, 1H), 7.24 (dd, J = 1.7, 6.2 Hz, 1H), 7.22 (dd, J = 1.7, 8.4 Hz, 1H), 6.46 (s, 2H), 6.05 (t, 6.8 Hz, 1H), 5.30 (t, J = 3.4 Hz, 2H), 5.25 (s, 1H), 4.99 (t, J = 3.4 Hz, 2H), 4.92 – 4.79 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -66.61. Example 28: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(6-cyano-2-methylpyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide Ryvu Therapeutics S.A. RVU305 138 R10945WO N‐(6‐cyano‐2‐methylpyridin‐3‐yl)‐2‐cyclopropylpyrimidine‐5‐carboxamide (Int.72) In a round bottom flask were placed N,N-dimethylpyridin-4-amine (0.130 g, 1.066 mmol, 0.5 eq.), 2-cy- clopropylpyrimidine-5-carboxylic acid (0.35 g, 2.132 mmol, 1.0 eq.) and 5-amino-6-methylpyridine-2-carbonitrile (0.284 g, 2.132 mmol, 1.0 eq.) followed by anhydrous pyridine (5 mL). The reaction mixture was cooled to 0°C and then phosphoryl trichloride (0.654 g, 4.264 mmol, 2.0 eq.) was added dropwise. RM was stirred at 0°C for 15 minutes and then was allowed to warm up to RT and stirred for 1.5 h. Reaction mixture was quenched with sat. aq. NaHCO3 solution and was extracted with DCM. Organic phase was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropylpy- rimidine-5-carboxamide (Int.72, 0.500 g, 1.739 mmol, 81%, m/z [M+H]+: 280.2). 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.12 (s, 2H), 8.21 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 2.57 (s, 3H), 2.38 – 2.28 (m, 1H), 1.20 – 1.06 (m, 4H). N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(6‐cyano‐2‐methylpyridin‐3‐yl)‐2‐cyclopropylpyrimidine‐5‐ carboxamide (Int.73) Cs2CO3 (0.32 g, 0.982 mmol, 1.201 eq.), 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.247 g, 0.818 mmol, 1.0 eq.) and N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.72.0.233 g, 0.818 mmol, 1.0 eq.) were dissolved in acetonitrile (7 mL) and stirred at 70°C for 2h. Reaction was quenched with aq. NH4Cl solution and diluted with ethyl acetate. Aqueous phase was extracted with EtOAc (3x). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(6-cyano-2-methylpyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide (Int.72, 0.429 g, 0.552 mmol, 68%, m/z [M+H]+: 497.7). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropylpyrimidine-5- carboxamide (Example 28) Step 1: 1-(2,4-dimethoxyphenyl)methanamine (0.092 g, 0.549 mmol, 1.0 eq.), DIPEA (0.478 mL, 2.743 mmol, 5.0 eq.) and N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(6-cyano-2-methylpyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide (Int.72, 0.426 g, 0.549 mmol, 1.0 eq.) were mixed with 1,4-dioxane (5 mL) and stirred at 100°C for 4 h. After that time the mixture was diluted with EtOAC and NaHCO3. Obtained mixture was extracted with EtOAc. Combined organic layers were washed with brine, filtered through silica pad and dried over Na2SO4. The crude was purified by FCC (0% to 10% MeOH gradient in DCM) to give N-(6-cyano-2- Ryvu Therapeutics S.A. RVU305 139 R10945WO methylpyridin-3-yl)-2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]pyrimidine-5-carboxamide (0.19 g, 0.168 mmol, 31%). Fractions containing low purity product were re-purified by FCC (0% to 100% EtOAc gradient in hexane) to give N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4- c]quinolin-7-yl)methyl]pyrimidine-5-carboxamide (0.03 g, 0.03 mmol, 5%). Step 2: N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H- furo[3,4-c]quinolin-7-yl)methyl]pyrimidine-5-carboxamide (0.03 g, 0.03 mmol, 1.0 eq.) was dissolved in DCM (2.0 ml) and TFA (1.0 ml) was added. The RM was stirred at RT for 4 h. Reaction mixture was quenched with sat. aq. NaHCO3 and 1N aq. NaOH to pH~10. Obtained mixture was extracted with DCM. Combined organic layers were dried and evaporated. The crude was purified by FCC (0% to 10% MeOH gradient in EtOAc) to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropylpyrimi- dine-5-carboxamide (Example 28, 0.005 g, 0.01 mmol, 34%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 97.5%, m/z [M+H]+: 478.2). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 7.98 – 7.88 (m, 2H), 7.44 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.49 (s, 2H), 5.32 – 5.28 (m, 2H), 5.24 (d, J = 14.8 Hz, 1H), 5.07 (d, J = 14.0 Hz, 1H), 5.02 – 4.96 (m, 2H), 2.16 – 2.08 (m, 4H), 1.10 – 1.02 (m, 2H), 0.98 – 0.91 (m, 2H). Example 29: N‐{[(3R)‐4‐amino‐3‐methyl‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl]methyl}‐2‐cyclopropyl‐N‐(2‐methylpyri- din‐3‐yl)pyrimidine‐5‐carboxamide and Example 30: N‐{[(3S)‐4‐amino‐3‐methyl‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl]methyl}‐2‐cyclopropyl‐N‐(2‐methylpyri- din‐3‐yl)pyrimidine‐5‐carboxamide The title compounds were obtained from rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2- cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carboxamide (Example 21) by HPLC chiral separation (col- umn: ADH; mobile phase: isocratic hexanes/(EtOH/MeOH 1/1 v/v) = 60%/(40%); flow rate: 20 mL/min.; elution time: 120 min.). R and S configurations were attributed arbitrarily. N‐{[(3R)‐4‐amino‐3‐methyl‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl]methyl}‐2‐cyclopropyl‐N‐(2‐methylpyridin‐3‐yl)pyrimi- dine‐5‐carboxamide (Example 29, 80 mg, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.90%, chiral purity: 100.0%, m/z [M+H]+: 467.2). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2H), 8.40 – 8.26 (m, 1H), 7.68 – 7.55 (m, 1H), 7.44 (dd, J = 8.2, 3.6 Hz, 1H), 7.35 (d, J = 12.3 Hz, 1H), 7.25 – 7.11 (m, 2H), 6.39 (s, 2H), 5.43 – 5.37 (m, 1H), 5.31 (dd, J = 13.7, 3.9 Hz, 1H), 5.25 – 5.18 (m, 2H), 4.99 (d, J = 14.2 Hz, 1H), 2.16 – 2.08 (m, 1H), 2.04 (d, J = 3.0 Hz, 3H), 1.39 (d, J = 6.2 Hz, 3H), 1.09 – 1.00 (m, 2H), 0.96 – 0.85 (m, 2H). Ryvu Therapeutics S.A. RVU305 140 R10945WO N‐{[(3S)‐4‐amino‐3‐methyl‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl]methyl}‐2‐cyclopropyl‐N‐(2‐methylpyridin‐3‐yl)pyrimi- dine‐5‐carboxamide (Example 30, 80 mg, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.88%, chiral purity: 100.0%, m/z [M+H]+: 467.2). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2H), 8.38 – 8.26 (m, 1H), 7.66 – 7.57 (m, 1H), 7.44 (dd, J = 8.2, 3.6 Hz, 1H), 7.35 (d, J = 12.2 Hz, 1H), 7.23 – 7.12 (m, 2H), 6.39 (s, 2H), 5.44 – 5.36 (m, 1H), 5.31 (dd, J = 13.7, 3.9 Hz, 1H), 5.27 – 5.18 (m, 2H), 4.99 (d, J = 14.2 Hz, 1H), 2.10 (tt, J = 8.3, 4.6 Hz, 1H), 2.04 (d, J = 3.0 Hz, 3H), 1.39 (d, J = 6.2 Hz, 3H), 1.11 – 1.01 (m, 2H), 0.95 – 0.84 (m, 2H). Example 31: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[(3,3-difluoropiperidin-4- yl)oxy]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide N-(6-chloro-2-methylpyridin-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.74) 6-chloro-2-methylpyridin-3-amine (1.5 g, 10.52 mmol, 1.0 eq.) was dissolved in toluene (20.0 mL) and 2- cyclopropylpyrimidine-5-carboxylic acid (1.72 g, 10.48 mmol, 1.0 eq.) was added, followed by DMAP (0.3 g, 2.46 mmol, 0.23 eq.) and DIPEA (4.6 mL, 26.41 mmol, 2.5 eq.). Then, T3P as 50 wt% solution in AcOEt (12.5 mL, 21.00 mmol, 2.0 eq.) was added to RM. The reaction mixture was heated at reflux for 1.5 h and then it was cooled to RT. The reaction was quenched with saturated solution of NaHCO3 in portion to pH 8-9. Then, or- ganic phase was separated and water phase was extracted with ethyl acetate (3x). Organic layers were com- bined and washed with brine, dried with sodium sulfate. Drying agent was removed by filtration and washed with DCM and CH3Cl : i-PrOH (3:1) mixture. The solvents were not completely evaporated and the residue was diluted with EtOAc and the precipitate was filtered off and washed with EtOAc to give N-(6-chloro-2-methylpyri- din-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.74, 2.37 g, 8.208 mmol, 78%, beige solid, m/z [M+H]+: 290.10). 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.12 (s, 2H), 7.89 (d, J = 8.3 Hz, 1H), 7.42 (dd, J = 8.3, 0.7 Hz, 1H), 2.44 (s, 3H), 2.32 (tt, J = 8.0, 4.7 Hz, 1H), 1.16 (dt, J = 8.0, 2.9 Hz, 2H), 1.11 (dt, J = 4.6, 2.8 Hz, 2H). Ryvu Therapeutics S.A. RVU305 141 R10945WO tert-butyl 4-{[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]oxy}-3,3-difluoropiperidine-1-carboxylate (Int.75) A mixture of tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (0.39 g, 1.644 mmol, 1.187 eq.), N- (6-chloro-2-methylpyridin-3-yl)-2-cyclopropylpyrimidine-5-carboxamide (Int.74, 0.4 g, 1.385 mmol, 1.0 eq.) and cesium carbonate (0.95 g, 2.916 mmol, 2.105 eq.) in Toluene (5.0 mL) and the mixture was sparged with argon for 10 min. Then JohnPhos (0.124 g, 0.416 mmol, 0.3 eq.) and Palladium (II) Acetate (0.062 g, 0.276 mmol, 0.199 eq.) were added and RM was heated at 85°C for 4 h. After that time, reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was extracted with DCM (5x). Combined organic layers was washed with brine and dried over Na2SO4 and evaporated. Crude product was purifier by FCC (0 to 70% EtOAc gradient in hexane) to give tert-butyl 4-{[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]oxy}- 3,3-difluoropiperidine-1-carboxylate (Int.75, 0.103 g, 0.179 mmol, 13%, beige solid, m/z [M+H]+: 490.50). 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.10 (s, 2H), 7.69 (d, J = 8.6 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 5.67 – 5.54 (m, 1H), 4.02 – 3.92 (m, 1H), 3.75 – 3.64 (m, 2H), 2.35 (s, 3H), 2.33 – 2.28 (m, 1H), 2.12 – 2.04 (m, 1H), 1.81 – 1.71 (m, 1H), 1.42 (s, 9H), 1.18 – 1.13 (m, 3H), 1.11 – 1.07 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -112.50 (dd, J = 240.4, 138.6 Hz, 1F), -118.83 (dd, J = 239.9, 134.9 Hz, 1F). tert-butyl 4-({5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6- methylpyridin-2-yl}oxy)-3,3-difluoropiperidine-1-carboxylate (Int.76) A suspension of cesium carbonate (0.084 g, 0.258 mmol, 1.485 eq.), potassium iodide (0.03 g, 0.181 mmol, 1.041 eq.), 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.049 g, 0.191 mmol, 1.099 eq.) and tert-butyl 4-{[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]oxy}-3,3-difluoropiperidine-1-carbox- ylate (Int.75, 0.1 g, 0.174 mmol, 1.0 eq.) in Acetonitrile (1.0 mL) was stirred at 70°C for 2 h. After that time RM was diluted with water and extracted with EtOAc (3x). Combined organic layers were dried over Na2SO4 and evaporated. Crude was purified by FCC (0% to 60% EtOAc gradient in hexane) to tert-butyl 4-({5-[N-({4-chloro- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6-methylpyridin-2-yl}oxy)-3,3-difluoropi- peridine-1-carboxylate (Int.76, 0.083 g, 0.094 mmol, 54%, orange oil). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 3.2 Hz, 2H), 7.95 – 7.88 (m, 1H), 7.87 – 7.79 (m, 1H), 7.74 – 7.67 (m, 1H), 7.62 – 7.56 (m, 1H), 6.69 (dd, J = 8.7, 3.3 Hz, 1H), 5.57 – 5.42 (m, 4H), 5.41 – 5.31 (m, 1H), 5.24 – 5.18 (m, 2H), 5.07 – 4.97 (m, 1H), 3.96 – 3.85 (m, 1H), 3.69 – 3.53 (m, 2H), 3.29 – 3.18 (m, 1H), 2.16 – 2.06 (m, 1H), 1.98 – 1.93 (m, 2H), 1.70 – 1.58 (m, 1H), 1.39 (s, 9H), 1.07 – 1.01 (m, 2H), 0.97 – 0.88 (m, 2H), 0.88 – 0.80 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -112.66 (ddd, J = 235.1, 147.9, 82.4 Hz, 1F), -119.06 (dd, J = 241.4, 134.0 Hz, 1F). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[(3,3-difluoropiperidin-4-yl)oxy]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide (Example 31) Step 1: A solution tert-butyl 4-({5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5- amido]-6-methylpyridin-2-yl}oxy)-3,3-difluoropiperidine-1-carboxylate (Int, 76, 0.083 g, 0.094 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.094 g, 0.562 mmol, 5.987 eq.) in DMSO (1 mL) was heated at 130°C for 6 h. RM was diluted with water and extracted by DCM (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (0% to 60% EtOAc gradient in hexane) to give tert-butyl 4-[(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4- Ryvu Therapeutics S.A. RVU305 142 R10945WO c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido}-6-methylpyridin-2-yl)oxy]-3,3-difluoropiperidine-1-car- boxylate (0.07 g, 0.063 mmol, 79%, orange solid, m/z [M+H]+: 839.0). Step 2: The product was dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The RM was stirred at RT overnight. Then mixture was quenched with sat. aq. Na2CO3 solution and mixture was stirred at RT for 30 min. The mixture was extracted with DCM (3x). Organic layers were washed with brine, dried over Na2SO4 and evaporated. Crude product was purified by FCC (NH2 functionalized silica; 0 to 3.5% MeOH gradient in DCM) to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[(3,3-difluoropiperidin-4-yl)oxy]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide (Example 31, 0.015 g, 0.025 mmol, 27%, yellow solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 98.75%, m/z [M+H]+: 588.6). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 1.1 Hz, 2H), 7.58 – 7.51 (m, 1H), 7.47 – 7.33 (m, 2H), 7.21 – 7.12 (m, 1H), 6.68 (d, J = 8.6 Hz, 1H), 6.55 – 6.40 (m, 2H), 5.39 – 5.24 (m, 3H), 5.22 – 5.09 (m, 1H), 5.01 – 4.91 (m, 3H), 3.11 – 2.96 (m, 1H), 2.92 – 2.73 (m, 3H), 2.62 – 2.53 (m, 1H), 2.15 – 2.05 (m, 1H), 1.97 – 1.81 (m, 4H), 1.67 – 1.49 (m, 1H), 1.07 – 0.97 (m, 2H), 0.98 – 0.85 (m, 2H). Example 32: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[3-(trifluorome- thyl)piperazin-1-yl]pyridin-3-yl}pyrimidine-5-carboxamide tert-butyl 4-(6-methyl-5-nitropyridin-2-yl)-2-(trifluoromethyl)piperazine-1-carboxylate (Int.77) A 6-chloro-2-methyl-3-nitropyridine (0.2 g, 1.159 mmol, 1.0 eq.) and tert-butyl 2-(trifluoromethyl)pipera- zine-1-carboxylate (0.33 g, 1.30 mmol, 1.12 eq.) were mixed in DMSO (7.0 mL) and then TEA (0.32 mL, 2.30 mmol, 1.98 eq.) was added. The reaction was stirred at RT for 10 min and then at 80°C for 3 h. RM was diluted with water and sat. aq. NaHCO3 solution and extracted with EtOAc(3x). The combined organic layers were washed with brine and dried over Na2SO4. The crude mixture was purified by FCC (0% to 100% DCM gradient Ryvu Therapeutics S.A. RVU305 143 R10945WO in heptane) to give tert-butyl 4-(6-methyl-5-nitropyridin-2-yl)-2-(trifluoromethyl)piperazine-1-carboxylate (Int.77, 0.36 g, 0.904 mmol, 78%, yellowish crystals) 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 9.4 Hz, 1H), 6.87 (d, J = 9.4 Hz, 1H), 4.89 (d, J = 17.8 Hz, 2H), 4.49 – 4.24 (m, 1H), 4.07 – 3.87 (m, 1H), 3.62 – 3.44 (m, 1H), 3.26 – 3.00 (m, 2H), 2.68 (s, 3H), 1.45 (s, 9H). 19F NMR (377 MHz, DMSO-d6) δ -70.20 (d, J = 8.9 Hz, 3F). tert-butyl 4-(5-amino-6-methylpyridin-2-yl)-2-(trifluoromethyl)piperazine-1-carboxylate (Int.78) To the solution of tert-butyl 4-(6-methyl-5-nitropyridin-2-yl)-2-(trifluoromethyl)piperazine-1-carboxylate (Int.76, 0.349 g, 0.88 mmol, 1.0 eq.) in a mixture of MeOH (6.0 mL) and EtOAc (3.0 mL) was sparged with nitrogen. Then Pd/C (10%, 50% wet, 0.31 g) was added. Air was removed from the flask and hydrogen was introduced from the balloon. RM was stirred at RT for 2 h. Catalyst was removed on celite, washed with EtOH, EtOAc and DCM. Filtrate was evaporated to obtain tert-butyl 4-(5-amino-6-methylpyridin-2-yl)-2-(trifluoromethyl)piperazine- 1-carboxylate (Int.78, 0.32 g, 0.879 mmol, 100%, green-black oil, m/z [M+H]+: 361.2) 1H NMR (400 MHz, DMSO-d6) δ 6.93 (d, J = 8.5 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 4.91 – 4.51 (m, 3H), 4.32 (d, J = 14.2 Hz, 1H), 4.01 – 3.83 (m, 2H), 3.24 – 2.99 (m, 1H), 2.90 (d, J = 13.9 Hz, 1H), 2.59 (td, J = 12.3, 3.8 Hz, 1H), 2.19 (s, 3H), 1.44 (s, 9H). 19F NMR (377 MHz, DMSO-d6) δ -69.00 (s, 3F). tert-butyl 4-[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]-2-(trifluoromethyl)piperazine-1-carbox- ylate (Int.79) A DMAP (0.026 g, 0.21 mmol, 0.25 eq.), DIPEA (0.36 mL, 2.07 mmol, 2.47 eq.), 2-cyclopropylpyrimidine-5-car- boxylic acid (0.14 g, 0.853 mmol, 1.018 eq.) and tert-butyl 4-(5-amino-6-methylpyridin-2-yl)-2-(trifluorome- thyl)piperazine-1-carboxylate (Int.78, 0.305 g, 0.838 mmol, 1.0 eq.) were taken in toluene (7.0 mL) and T3P (50% in EtOAc, 1.0 mL, 1.68 mmol, 2.00 eq.) was added at RT dropwise. Then, the RM was heated at 80°C for 1 h. The reaction was quenched with sat. aq. Na2CO3 solution and extracted with EtOAc (3x). Organic layers were washed with brine and dried over Na2SO4 and evaporated. The crude mixture was purified by FCC (0% to 4% MeOH gradient in DCM) to give tert-butyl 4-[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]-2- (trifluoromethyl)piperazine-1-carboxylate (Int.79, 0.38 g, 0.735 mmol, 88%, brownish solid, m/z [M+H]+: 507.4) 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.10 (s, 2H), 7.50 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.00 – 4.74 (m, 1H), 4.64 (d, J = 14.5 Hz, 1H), 4.29 – 4.07 (m, 1H), 4.07 – 3.93 (m, 1H), 3.31 – 3.20 (m, 1H), 3.20 – 3.01 (m, 1H), 2.98 – 2.88 (m, 1H), 2.35 – 2.30 (m, 1H), 2.29 (s, 3H), 1.45 (s, 9H), 1.20 – 1.06 (m, 4H). 19F NMR (377 MHz, DMSO-d6) δ -69.64 (d, J = 8.5 Hz, 3F). tert-butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6- methylpyridin-2-yl}-2-(trifluoromethyl)piperazine-1-carboxylate (Int.80) A tert-butyl 4-[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]-2-(trifluoromethyl) piperazine-1-carbox- ylate (Int.79, 0.33 g, 0.64 mmol, 1.0 eq.) and Cs2CO3 (0.44 g, 1.35 mmol, 2.12 eq.) in MeCN (15.0 mL) was flushed with argon for 10 min at RT, then 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.21 g, 0.818 mmol, 1.28 eq.) was added and RM was stirred at 75°C for 2.5 h. The RM was diluted with sat. Na2CO3 solution and water and extracted with DCM(3x). Then to aqueous layer brine was added and extraction with DCM (2x) was repeated. Combined organic phases were washed with brine and dried over Na2SO4 and evapo- rated. The crude mixture was purified by FCC (0% to 40% EtOAc gradient in DCM) to give tert-butyl 4-{5-[N- Ryvu Therapeutics S.A. RVU305 144 R10945WO ({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6-methylpyridin-2-yl}-2-(tri- fluoromethyl)piperazine-1-carboxylate (Int.80, 0.29 g, 0.38 mmol, 60%, off-white solid, m/z [M+H]+:724.9). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.54 (s, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 8.5, 1.7 Hz, 1H), 7.32 (t, J = 9.0 Hz, 1H), 6.58 (d, J = 8.9 Hz, 1H), 5.54 (t, J = 3.1 Hz, 2H), 5.36 (dd, J = 17.6, 14.5 Hz, 1H), 5.22 (t, J = 3.1 Hz, 2H), 4.94 (dd, J = 17.8, 14.5 Hz, 1H), 4.84 – 4.61 (m, 1H), 4.60 – 4.44 (m, 1H), 4.08 (s, 1H), 3.90 (s, 1H), 3.23 (d, J = 14.3 Hz, 1H), 3.08 (s, 1H), 2.97 – 2.83 (m, 1H), 2.16 – 2.05 (m, 1H), 1.93 (d, J = 21.2 Hz, 3H), 1.41 (s, 9H), 1.09 – 0.98 (m, 2H), 0.95 – 0.88 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -69.98 (d, J = 8.5 Hz), -70.09 (d, J = 8.9 Hz). tert-butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclo- propylpyrimidine-5-amido}-6-methylpyridin-2-yl)-2-(trifluoromethyl)piperazine-1-carboxylate (Int.81) A tert-butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6- methylpyridin-2-yl}-2-(trifluoromethyl)piperazine-1-carboxylate (Int.80, 0.29 g, 0.38 mmol, 1.0 eq.), 1-(2,4-di- methoxyphenyl)methanamine (0.38 g, 2.27 mmol, 5.97 eq.) were mixed in DMSO (10.0 mL) and heated at 140°C for 2.5h. RM was diluted with water/Na2CO3 sat. and extracted with DCM(2x). Combined organic layers were washed with water, brine and dried over Na2SO4. The crude mixture was purified by FCC (0% to 35% MeCN gradient in DCM) to give tert-butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4- c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido}-6-methylpyridin-2-yl)-2-(trifluoromethyl)piperazine-1- carboxylate (Int.81, 0.24 g, 0.261 mmol, 69%, yellowish solid, m/z [M+H]+: 855.9). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 5.1 Hz, 2H), 7.48 – 7.39 (m, 2H), 7.25 (dd, J = 16.2, 8.9 Hz, 1H), 7.16 (ddd, J = 15.3, 8.3, 1.4 Hz, 2H), 7.01 (t, J = 5.7 Hz, 1H), 6.61 – 6.53 (m, 2H), 6.42 (ddd, J = 8.4, 2.4, 1.1 Hz, 1H), 5.31 (t, J = 3.4 Hz, 2H), 5.21 (dd, J = 26.2, 14.1 Hz, 1H), 5.08 – 4.99 (m, 2H), 4.81 (dd, J = 28.1, 14.1 Hz, 1H), 4.73 – 4.64 (m, 1H), 4.58 – 4.52 (m, 2H), 4.52 – 4.43 (m, 1H), 4.16 – 3.97 (m, 1H), 3.90 (s, 1H), 3.81 (s, 3H), 3.74 – 3.69 (m, 3H), 3.22 (d, J = 14.3 Hz, 1H), 3.16 – 2.94 (m, 1H), 2.94 – 2.80 (m, 1H), 2.15 – 2.05 (m, 1H), 1.89 (d, J = 25.5 Hz, 3H), 1.42 (s, 9H), 1.07 – 0.98 (m, 2H), 0.95 – 0.89 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -69.96, -70.08 (d, J = 8.6 Hz). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[3-(trifluoromethyl)piperazin-1- yl]pyridin-3-yl}pyrimidine-5-carboxamide (Example 32) To tert-butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclo- propylpyrimidine-5-amido}-6-methylpyridin-2-yl)-2-(trifluoromethyl)piperazine-1-carboxylate (Int.81, 0.24 g, 0.26 mmol, 1.0 eq.) in DCM (1.2 mL)TFA (0.6 mL, 7.84 mmol, 30.0 eq.) was added. RM was stirred at RT over- night. After that time RM was poured onto sat. Na2CO3 solution/ice and stirred for 10 min, next brine was added and product was extracted with DCM with addition of CHCl3:i-PrOH (3:1) mixture (3x). Organic layers was com- bined, washed with 1M K2CO3 solution, brine and dried over Na2SO4 and evaporated. The residue was purified by preparative HPLC and lyophilization to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopro- pyl-N-{2-methyl-6-[3-(trifluoromethyl)piperazin-1-yl]pyridin-3-yl}pyrimidine-5-carboxamide (Example 32, 0.06 g, 0.099 mmol, 38%, white solid, UPLC long elution (polar long method, buffer type “FA”) purity 100%, m/z [M+H]+: 605.7) 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 1.6 Hz, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 3.3, 1.6 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 7.19 (dt, J = 8.2, 1.4 Hz, 1H), 6.62 (dd, J = 9.0, 1.8 Hz, 1H), 6.48 (s, 2H), 5.31 (t, J = 3.4 Hz, 2H), 5.18 (dd, J = 14.2, 4.6 Hz, 1H), 4.99 (t, J = 3.4 Hz, 2H), 4.86 (dd, J = 14.2, 7.2 Hz, 1H), 4.25 (t, Ryvu Therapeutics S.A. RVU305 145 R10945WO J = 11.1 Hz, 1H), 3.80 (t, J = 10.3 Hz, 1H), 2.96 – 2.87 (m, 2H), 2.87 – 2.75 (m, 2H), 2.67 – 2.60 (m, 1H), 2.12 (tt, J = 8.3, 4.7 Hz, 1H), 1.87 (d, J = 4.1 Hz, 3H), 1.08 – 1.01 (m, 2H), 0.98 – 0.91 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -73.99 – -74.16 (m, 3F). Example 33: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(2-hydroxyethyl)-3-(tri- fluoromethyl)piperazin-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide To N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[3-(trifluoromethyl) piper- azin-1-yl]pyridin-3-yl}pyrimidine-5-carboxamide (Example 32, 0.035 g, 0.058 mmol, 1.0 eq.) in MeOH (3.0 mL), 1,4-dioxane-2,5-diol (0.016 g, 0.13 mmol) and acetic acid (0.013 mL, 0.23 mmol, 4.0 eq.) were added. The re- sulting mixture was stirred at RT for 1 h, then NaBH3CN (0.007 g, 0.12 mmol, 2.0 eq.) was added in one por- tion. After 2.5 h additional amount of 1,4-dioxane-2,5-diol (0.0035 g, 0.029 mmol) and acetic acid (0.004 mL, 0.069 mmol, 1.2 eq.) were added and after 30 min NaBH3CN (0.004 g, 0.069 mmol, 1.2 eq). After 1h RM was quenched with water and then diluted with sat. aq. Na2CO3. Next extraction with DCM and addition of CHCl3:i- PrOH (3:1)(3x) was done. Combined organic fractions was washed with brine and dried over Na2SO4 and evaporated. The crude mixture was purified by preparative HPLC and lyophilization to give N-({4-amino-1H,3H- furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(2-hydroxyethyl)-3-(trifluoromethyl)piperazin-1-yl]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide as its formate salt (Example 33, 0.02 g, 0.03 mmol, 52%, white solid, UPLC long elution (polar long method, buffer type “FA”) purity 97.19%, m/z [M+H]+: 649.7). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 6.8 Hz, 2H), 7.43 (ddd, J = 14.8, 8.3, 1.5 Hz, 2H), 7.27 (dd, J = 21.0, 8.9 Hz, 1H), 7.21 – 7.15 (m, 1H), 6.52 – 6.44 (m, 3H), 5.31 (t, 2H), 5.18 (dd, J = 33.9, 14.2 Hz, 1H), 4.99 (t, J = 3.5 Hz, 2H), 4.85 (dd, J = 38.2, 14.2 Hz, 1H), 4.51 (s, 1H), 4.15 – 3.99 (m, 1H), 3.62 – 3.47 (m, 5H), 3.28 – 3.17 (m, 1H), 3.00 – 2.85 (m, 2H), 2.85 – 2.70 (m, 2H), 2.17 – 2.06 (m, 1H), 1.85 (d, J = 32.9 Hz, 3H), 1.09 – 0.99 (m, 2H), 0.98 – 0.87 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -69.45 (dd, J = 101.7, 8.4 Hz, 3F). Example 34: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[3-methyl-1-(piperidin-4-yl)- 1H-pyrazol-4-yl]pyrimidine-5-carboxamide Ryvu Therapeutics S.A. RVU305 146 R10945WO tert-butyl 4-(4-amino-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (Int.82) To tert-butyl 4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.6 g, 1.93 mmol, 1.0 eq.) in a mix- ture of EtOH (40.0 mL) and water (13.0 mL), NH4Cl (0.52 g, 9.72 mmol, 5.03 eq.) and iron (0.54 g, 9.67 mmol, 5.00 eq.) were added. RM was stirred at 70°C for 1.5 h. RM was filtered through cotton, washed with EtOH and DCM. Then solvents were evaporated and residues was diluted with sat. aq. NaHCO3 solution and extracted with DCM (3x). Organic layers were combined, washed with brine and dried over Na2SO4 and concentrated in vacuo to give crude product tert-butyl 4-(4-amino-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (Int.82, 0.54 g, 1.48 mmol, 77%, red-brown oil) which was used for next step without purification. 1H NMR (400 MHz, DMSO-d6) δ 6.99 (s, 1H), 4.07 – 3.94 (m, 3H), 3.70 – 3.46 (m, 2H), 2.84 (s, 2H), 1.98 (s, 3H), 1.92 – 1.83 (m, 2H), 1.64 (qd, J = 12.4, 4.4 Hz, 2H), 1.41 (s, 9H). tert-butyl 4-[4-(2-cyclopropylpyrimidine-5-amido)-3-methyl-1H-pyrazol-1-yl]piperidine-1-carboxylate (Int.83) A DMAP (0.045 g, 0.37 mmol, 0.25 eq.), DIPEA (0.65 mL, 3.73 mmol, 2.52 eq.), 2-cyclopropylpyrimidine-5-car- boxylic acid (0.27 g, 1.65 mmol, 1.11 eq.) and tert-butyl 4-(4-amino-3-methyl-1H-pyrazol-1-yl)piperidine-1-car- boxylate (Int.82, 0.54 g, 1.48 mmol, 1.0 eq.) were taken in DMF (10.0 mL) and T3P (50% in EtOAc, 1.77 mL, 2.97 mmol, 2.00 eq.) was added at RT dropwise. Then the RM was heated at 70°C for 1 h. The reaction was quenched with sat. aq. Na2CO3 solution and extracted with EtOAc (3x). Organic layers were washed with wa- ter, brine and dried over Na2SO4 and evaporated. The crude mixture was purified by FCC (0% to 8% MeOH gradient in DCM) to give tert-butyl 4-[4-(2-cyclopropylpyrimidine-5-amido)-3-methyl-1H-pyrazol-1-yl]piperidine- 1-carboxylate (Int.83, 0.5 g, 1.149 mmol, 77%, pink solid, [M-H]-: 425.5). 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.05 (s, 2H), 7.99 (s, 1H), 4.32 – 4.19 (m, 1H), 4.04 (d, J = 13.2 Hz, 2H), 2.88 (s, 2H), 2.38 – 2.25 (m, 1H), 2.16 (s, 3H), 2.02 – 1.90 (m, 2H), 1.74 (qd, J = 12.3, 4.4 Hz, 2H), 1.42 (s, 9H), 1.19 – 1.05 (m, 4H). tert-butyl 4-{4-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-3-methyl- 1H-pyrazol-1-yl}piperidine-1-carboxylate (Int.84) Tert-butyl 4-[4-(2-cyclopropylpyrimidine-5-amido)-3-methyl-1H-pyrazol-1-yl]piperidine-1-carboxylate (Int.83, 0.49 g, 1.13 mmol, 1.0 eq.) and Cs2CO3 (0.77 g, 2.36 mmol, 2.10 eq.) in MeCN (15.0 mL) was flushed with ar- gon for 10 min at RT, then 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.36 g, 1.40 mmol, 1.25 eq.) was added and RM was stirred at 75°C for 3 h. Then the RM was diluted with mixture of sat. aq. Na2CO3 solution and water and extracted with DCM (3x). Then to aqueous layer brine was added and extraction with Ryvu Therapeutics S.A. RVU305 147 R10945WO DCM (2x) was repeated. Combined organic phases were washed with brine and dried over Na2SO4 and evapo- rated. The crude mixture was purified by FCC (0% to 70% MeCN gradient in DCM) to give tert-butyl 4-{4-[N- ({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-3-methyl-1H-pyrazol-1-yl}pi- peridine-1-carboxylate (Int.84, 0.62 g, 0.876 mmol, 78%, white solid, [M+H]+: 645.0). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 2H), 7.91 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.66 (dd, J = 8.5, 1.7 Hz, 1H), 5.54 (t, J = 3.2 Hz, 2H), 5.23 (t, J = 3.1 Hz, 2H), 5.11 (s, 2H), 4.17 – 4.03 (m, 1H), 3.86 (d, J = 13.1 Hz, 2H), 2.83 (s, 2H), 2.21 – 2.09 (m, 1H), 1.75 (d, J = 12.8 Hz, 2H), 1.66 (s, 3H), 1.59 – 1.47 (m, 2H), 1.40 (s, 9H), 1.08 – 1.03 (m, 2H), 0.97 – 0.93 (m, 2H). tert-butyl 4-(4-{N-[(4-{[(3,4-dimethylphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclo- propylpyrimidine-5-amido}-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (Int.85) Tert-butyl 4-{4-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-3- methyl-1H-pyrazol-1-yl}piperidine-1-carboxylate (Int.84, 0.61 g, 0.86 mmol, 1.0 eq.), 1-(2,4-dimethoxy- phenyl)methanamine (0.86 g, 5.14 mmol, 5.97 eq.) were mixed in DMSO (10.0 mL) and heated at 140°C for 3 h. The RM was diluted with mixture of sat. aq. Na2CO3 solution and water and extracted with DCM (3x). Com- bined organic layers were washed with water, brine and dried over Na2SO4 and evaporated. The crude mixture was purified by FCC (0% to 100% MeCN gradient in DCM) to give tert-butyl 4-(4-{N-[(4-{[(3,4-dime- thylphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido}-3-methyl-1H- pyrazol-1-yl)piperidine-1-carboxylate (Int.85, 0.52 g, 0.523 mmol, 61%, yellow solid, [M+H]+: 775.9). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.67 (s, 1H), 7.46 – 7.39 (m, 2H), 7.15 (t, J = 7.6 Hz, 2H), 7.02 (t, J = 5.7 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 5.31 (t, J = 3.4 Hz, 2H), 5.05 (t, J = 3.4 Hz, 2H), 4.96 (s, 2H), 4.56 (d, J = 5.6 Hz, 2H), 4.15 – 4.04 (m, 1H), 3.92 – 3.84 (m, 2H), 3.83 (s, 3H), 3.73 (s, 3H), 2.83 (s, 3H), 2.12 (dd, J = 8.2, 4.6 Hz, 1H), 1.75 (d, J = 12.3 Hz, 2H), 1.63 (d, J = 25.7 Hz, 4H), 1.54 (d, J = 12.3 Hz, 3H), 1.40 (d, J = 1.4 Hz, 9H), 1.09 – 1.00 (m, 2H), 0.94 (td, J = 4.6, 2.2 Hz, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4- yl]pyrimidine-5-carboxamide (Example 34) To tert-butyl 4-(4-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclo- propylpyrimidine-5-amido}-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (Int.85, 0.52 g, 0.52 mmol, 1.0 eq.) in DCM (2.4 mL), TFA (1.2 mL, 15.67 mmol, 29.9 eq.) was added. RM was stirred at RT overnight. After that time RM was poured onto sat. aq. Na2CO3 solution/ice and stirred for few minutes, next brine was added and product was extracted with DCM with addition of CHCl3:i-PrOH (3:1) mixture (3x). Organic layers was com- bined, washed with 1M K2CO3 solution, brine and dried over Na2SO4 and evaporated. The crude mixture was purified by FCC (NH2 functionalized silica, 0% to 5% gradient MeOH in DCM) to N-({4-amino-1H,3H-furo[3,4- c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyrimidine-5-carboxamide (Example 34, 0.15 g, 0.275 mmol, 53%, yellow solid, UPLC long elution (polar long method, buffer type “FA”) purity 98.79%, [M+H]+: 525.6). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.67 (s, 1H), 7.51 – 7.35 (m, 2H), 7.14 (dd, J = 8.2, 1.7 Hz, 1H), 6.48 (s, 2H), 5.31 (t, J = 3.4 Hz, 2H), 5.06 – 4.92 (m, 4H), 3.99 – 3.83 (m, 1H), 2.92 (d, J = 12.6 Hz, 2H), 2.47 – 2.39 (m, 2H), 2.14 (tt, J = 8.2, 4.6 Hz, 1H), 1.69 (d, J = 12.0 Hz, 2H), 1.58 (s, 3H), 1.56 – 1.48 (m, 2H), 1.10 – 1.01 (m, 2H), 0.97 – 0.89 (m, 2H). Ryvu Therapeutics S.A. RVU305 148 R10945WO Example 35: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperi- din-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide [1-(6-methyl-5-nitropyridin-2-yl)piperidin-4-yl]methanol (Int.86) TEA (0.6 mL, 4.305 mmol, 2.00 eq.) was added dropwise to a solution of 6-chloro-2-methyl-3-nitropyridine (0.37 g, 2.144 mmol, 1.0 eq.) and (piperidin-4-yl)methanol (0.285 g, 2.474 mmol, 1.154 eq.) in DMSO (5.0 mL). The RM was stirred at RT for 15 min and then at 80°C for 1 h. The reaction was diluted with ethyl acetate. The mixture was transferred to separatory funnel and extracted by saturated NaHCO3 solution. Combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude [1-(6-methyl-5-nitropyridin-2-yl)piperidin-4-yl]methanol (Int.86, 0.741 g, 2.89 mmol, 135%, yellow solid, m/z [M+H]+: 252.0) which was used for next step without purification. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 9.5 Hz, 1H), 6.81 (d, J = 9.5 Hz, 1H), 4.58 – 4.54 (m, 1H), 4.51 (t, J = 5.3 Hz, 2H), 3.26 (t, J = 5.6 Hz, 2H), 2.97 (td, J = 12.8, 2.6 Hz, 2H), 2.66 (s, 3H), 1.76 (dd, J = 13.7, 3.2 Hz, 2H), 1.72 – 1.64 (m, 1H), 1.16 – 1.03 (m, 2H). [1-(5-amino-6-methylpyridin-2-yl)piperidin-4-yl]methanol (Int.87) To a solution of [1-(6-methyl-5-nitropyridin-2-yl)piperidin-4-yl]methanol (Int.86, 0.741 g, 2.89 mmol, 1.0 eq.) in acetone (10.0 mL) and aq. sat. NH4Cl (5.0 mL) solution, zinc (1.85 g, 28.296 mmol, 9.792 eq.) was added por- tion wise. RM was stirred at RT for 1 h. After that time RM was filtrated through Celite pad and filter was washed with ethyl acetate. Filtrate was washed with sodium bicarbonate solution, brine, dried over Na2SO4 and concentrated in vacuo to give crude [1-(5-amino-6-methylpyridin-2-yl)piperidin-4-yl]methanol (Int.87, 0.439 g, 1.904 mmol, 66%, orange solid, m/z [M+H]+: 222.0) which was used for next step without purification. 1H NMR (400 MHz, DMSO-d6) δ 6.86 (d, J = 8.6 Hz, 1H), 6.44 (d, J = 8.6 Hz, 1H), 4.56 – 4.39 (m, 1H), 4.26 (s, 2H), 3.99 (d, J = 12.5 Hz, 2H), 3.27 – 3.19 (m, 2H), 2.66 – 2.58 (m, 2H), 2.15 (s, 3H), 1.70 (s, 2H), 1.56 – 1.43 (m, 1H), 1.17 – 1.02 (m, 2H). 2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperidin-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide (Int.88) ([1-(5-amino-6-methylpyridin-2-yl)piperidin-4-yl]methanol) (Int.87, 0.439 g, 1.904 mmol, 1.0 eq.) was dissolved in DMF (5.0 mL) and 2-cyclopropylpyrimidine-5-carboxylic acid (0.386 g, 2.351 mmol, 1.235 eq.) was added, Ryvu Therapeutics S.A. RVU305 149 R10945WO followed by DMAP (0.02 g, 0.164 mmol, 0.086 eq.), and DIPEA (0.6 mL, 3.445 mmol, 1.80 eq.). Then, T3P (50 wt% solution in AcOEt, 1.4 mL, 4.704 mmol, 2.47 eq.) was added to RM. The reaction mixture was heated at reflux for 1 h and then it was cooled to RT. The reaction was quenched with saturated solution of NaHCO3 in portion to pH 8-9. Then, organic phase was separated and water phase was extracted with ethyl acetate (3x). Organic layers were combined and washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude 2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperidin-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide (Int. 88, 0.616 g, 1.576 mmol, 83%, orange solid, m/z [M+H]+: 368.0) which was used for next step without purifica- tion. 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.09 (s, 2H), 7.40 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 4.54 – 4.39 (m, 1H), 4.30 (d, 2H), 3.27 (d, 2H), 2.81 – 2.68 (m, 2H), 2.37 – 2.26 (m, 1H), 2.25 (s, 3H), 1.76 – 1.67 (m, 2H), 1.66 – 1.52 (m, 1H), 1.16 – 1.11 (m, 2H), 1.10 – 1.07 (m, 2H). N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperidin-1-yl]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide (Int.89) A suspension 2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperidin-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carbox- amide (Int.88, 0.616 g, 1.576 mmol, 1.0 eq.), and 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.43 g, 1.675 mmol, 1.063 eq.) in MeCN (14.0 mL) was added Cs2CO3 (0.9 g, 2.762 mmol, 1.753 eq.) and KI (0.25 g, 1.506 mmol, 0.956 eq.). The reaction mixture was stirred at 70°C for 2 h. After that time RM was cooled, diluted with water and extracted with DCM (3x). Combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 10% MeOH gradient in DCM) to obtain N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(hydroxymethyl)piper- idin-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide (Int.89, 0.826 g, 1.242 mmol, 79%, yellow solid, m/z [M+H]+: 586.0). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.91 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 6.53 (d, J = 9.0 Hz, 1H), 5.54 (s, 2H), 5.22 (s, 2H), 4.45 (t, J = 5.3 Hz, 1H), 4.24 – 4.14 (m, 2H), 3.22 (t, J = 5.8 Hz, 2H), 2.69 – 2.61 (m, 2H), 2.35 – 2.29 (m, 2H), 2.15 – 2.06 (m, 2H), 1.88 (s, 3H), 1.65 (d, J = 13.1 Hz, 2H), 1.58 – 1.48 (m, 1H), 1.07 – 1.01 (m, 2H), 0.98 – 0.91 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperidin-1-yl]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide (Example 35) Step 1: To a solution N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperi- din-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide (Int.89, 0.626 g, 0.941 mmol, 1.0 eq.) in DMSO (12.0 mL) was added 1-(2,4-dimethoxyphenyl)methanamine (1.6 g, 9.569 mmol, 10.164 eq.). The reaction was heated in 100°C overnight. After that the reaction mixture was diluted in water and extracted with DCM (3x). Organic phases were washed by brine and dried over Na2SO4 and evaporated. Product was isolated by FCC (5% to 10% MeOH gradient in DCM) to give 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H- furo[3,4-c]quinolin-7-yl)methyl]-N-{6-[4-(hydroxymethyl)piperidin-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carbox- amide (0.568 g, 0.627 mmol, 67%, yellow oil, m/z [M+H]+: 716.0). Step 2: To a solution of product in DCM (5 mL) TFA (1 mL) was added at 0°C. The reaction was stirred at RT over- night. Ater that the RM was diluted with DCM, quenched by sat. aq. NaHCO3 solution and extracted with DCM and then with mixture of CHCl3:i-PrOH (3:1). Organic phases was combined, dried over Na2SO4 and filtered. Ryvu Therapeutics S.A. RVU305 150 R10945WO Filtrate was concentrated in vacuum. The crude product was isolated by FCC (5% to 10% MeOH gradient in DCM) and co-evaporated with EtOH and lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)- 2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperidin-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide (Example 35, 0.097 g, 0.171 mmol, 33%, white solid, UPLC long elution (polar long method, buffer type “FA”) purity 99.71%, [M+H]+: 566.0). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2H), 7.44 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.25 – 7.13 (m, 2H), 6.54 (d, J = 9.0 Hz, 1H), 6.46 (s, 1H), 5.34 – 5.26 (m, 2H), 5.15 (d, J = 14.2 Hz, 1H), 5.05 – 4.95 (m, 2H), 4.85 (d, J = 14.1 Hz, 1H), 4.45 (t, J = 5.3 Hz, 1H), 4.19 (d, J = 12.7 Hz, 2H), 3.23 (t, J = 5.8 Hz, 2H), 2.71 – 2.60 (m, 2H), 2.17 – 2.06 (m, 1H), 1.81 (s, 3H), 1.65 (d, J = 12.8 Hz, 2H), 1.58 – 1.47 (m, 1H), 1.10 – 0.98 (m, 4H), 0.98 – 0.87 (m, 2H). Example 36: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2- methylpyridin-3-yl]pyrimidine-5-carboxamide 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-2-methyl-3-nitropyridine (Int.90) A 6-chloro-2-methyl-3-nitropyridine (0.31 g, 1.796 mmol, 1.0 eq.), 2-[(tert-butyldimethylsilyl)oxy]ethan-1-ol (0.34 g, 1.928 mmol, 1.073 eq.) and Cs2CO3 (1.1 g, 3.376 mmol, 1.879 eq.) were mixed in toluene (8.0 mL) and the mixture was flushed with argon for 10 min. Then Pd(OAc)2 (0.045 g, 0.2 mmol, 0.11 eq.) and JohnPhos (0.08 g, 0.268 mmol, 0.15 eq.) were added and RM was heated at 85°C for 1.5 h. Then, RM was diluted with DCM and filtered through cotton. The filtrate was washed with saturated solution of Na2CO3, brine and dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 5% MeOH gradient in DCM) to ob- tain 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-2-methyl-3-nitropyridine (Int.90, 0.51 g, 1.518 mmol, 85%, color- less oil). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 9.0 Hz, 1H), 6.86 (d, J = 0.6 Hz, 1H), 4.49 – 4.38 (m, 2H), 3.97 – 3.85 (m, 2H), 2.71 (s, 3H), 0.84 (s, 9H), 0.04 (s, 6H). 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-2-methylpyridin-3-amine (Int.91) To a solution of 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-2-methyl-3-nitropyridine (Int.90, 0.51 g, 1.518 mmol, 1.0 eq.) in acetone (14.0 mL) was added zinc (1.0 g, 15.30 mmol, 10.08 eq.). Next the flask was placed in an ice bath and sat. aq. NH4Cl solution (6.0 mL) was added dropwise. Then RM was stirred for 1 h at RT. RM was diluted with DCM and filtrated through Celite. Next, filtrate was diluted with water and sat. aq. HNaCO3 solution Ryvu Therapeutics S.A. RVU305 151 R10945WO and extracted with DCM (2x). Organic layers were combined, washed with brine, dried over Na2SO4 and evap- orated to give 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-2-methylpyridin-3-amine (Int.91, 0.45 g, 1.21 mmol, 80%, colorless oil, m/z [M+H]+: 283.0). 1H NMR (400 MHz, DMSO-d6) δ 6.97 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 4.48 (s, 2H), 4.13 (dd, J = 5.9, 4.6 Hz, 2H), 3.84 (dd, J = 5.9, 4.5 Hz, 2H), 2.17 (s, 3H), 0.85 (d, J = 1.7 Hz, 9H), 0.04 (d, J = 1.7 Hz, 6H). 2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2-methylpyridin-3-yl]pyrimidine-5-carboxamide (Int.92) A 2-methyl-6-(2-{[2-(trimethylsilyl)propan-2-yl]oxy}ethoxy)pyridin-3-amine (Int.91, 0.45 g, 1.21 mmol, 1.0 eq.) was dissolved in DMF (6.0 mL) and 2-cyclopropylpyrimidine-5-carboxylic acid (0.19 g, 1.16 mmol, 0.96 eq.) was added, followed by DMAP (0.075 g, 0.614 mmol, 0.51 eq.) and DIPEA (0.5 mL, 2.84 mmol, 2.33 eq.). Then, T3P (50 wt% solution in AcOEt, 0.7 mL, 2.33 mmol, 1.93 eq.) was added to RM. The reaction mixture was heated at reflux for 1 h and then it was cooled to RT. The reaction was quenched with saturated solution of NaHCO3 in portion to pH 8-9. Then, organic phase was separated and water phase was extracted with ethyl acetate (3x). Organic layers were combined and washed with brine, dried with sodium sulfate and filtrated. All solvents were evaporated. The residue was purified by FCC (0% to 2% MeOH gradient in DCM) to obtain 2- cyclopropyl-N-[6-(2-hydroxyethoxy)-2-methylpyridin-3-yl]pyrimidine-5-carboxamide (Int.92, 0.24 g, 0.305 mmol, 25%, white solid, m/z [M+H]+: 429.5). 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.10 (s, 2H), 7.62 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 4.83 (t, J = 5.5 Hz, 1H), 4.38 – 4.21 (m, 2H), 3.71 (q, J = 5.4 Hz, 2H), 2.35 – 2.26 (m, 4H), 1.19 – 1.11 (m, 2H), 1.13 – 1.05 (m, 2H). N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2-methylpyridin-3- yl]pyrimidine-5-carboxamide (Int.93) A suspension of 2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2-methylpyridin-3-yl]pyrimidine-5-carboxamide (Int.92, 0.24 g, 0.305 mmol, 1.0 eq.), 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.12 g, 0.47 mmol, 1.53 eq.) in anhydrous MeCN (2.0 mL) was added Cs2CO3 (0.19 g, 0.583 mmol, 1.91 eq.). The reaction mixture was stirred at 76°C for 2 h. After that time RM was cooled, diluted with water and extracted with DCM (3x). Combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 5% MeOH gradient in DCM) to obtain N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}me- thyl)-2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2-methylpyridin-3-yl]pyrimidine-5-carboxamide (Int.93, 0.259 g, 0.409 mmol, 134%, yellow solid, m/z [M+H]+: 533.1). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2-methylpyri- din-3-yl]pyrimidine-5-carboxamide (Example 36) Step 1: To a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2- methylpyridin-3-yl]pyrimidine-5-carboxamide (Int.93, 0.259 g, 0.409 mmol, 1.0 eq.) in DMSO (2.2 mL) was added 1-(2,4-dimethoxyphenyl)methanamine (0.6 g, 3.59 mmol, 8.76 eq.). The reaction was heated in 100°C overnight. After that the reaction mixture was diluted in water and extracted with DCM (3x). Organic phases were washed by brine and dried over Na2SO4. Product was isolated by FCC (0% to 10% MeOH gradient in DCM) to give 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]- N-[6-(2-hydroxyethoxy)-2-methylpyridin-3-yl]pyrimidine-5-carboxamide (0.3 g, 0.385 mmol, 94%, yellow oil, m/z [M+H]+: 663.8). Ryvu Therapeutics S.A. RVU305 152 R10945WO Step 2: To a solution of product from step 1 in DCM (3.0 mL), TFA (0.35 mL, 4.60 mmol, 11.97 eq.) was added at 0°C. The reaction was stirred at RT overnight. Ater that the RM was diluted with DCM, quenched by sat. aq. Na- HCO3 solution and extracted with DCM and then with mixture of CHCl3:i-PrOH (3:1). Organic phases was com- bined, dried over Na2SO4 and filtered. Filtrate was concentrated in vacuum. Then the residue was treated with i-PrOH and white solid was filtered off. Residue was concentrated in vacuum. The product was isolated by pre- parative HPLC, co-evaporated with EtOH and lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7- yl}methyl)-2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2-methylpyridin-3-yl]pyrimidine-5-carboxamide (Example 36, 0.012 g, 0.023 mmol, 6%, white powder, UPLC long elution (polar long method, buffer type “FA”) purity 99.84%, m/z [M+H]+: 513.26). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 2H), 7.50 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.16 (dd, J = 8.2, 1.7 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 6.47 (s, 2H), 5.29 (d, J = 3.7 Hz, 2H), 5.13 (d, J = 14.1 Hz, 1H), 4.96 (d, J = 14.3 Hz, 3H), 4.77 (t, J = 5.5 Hz, 1H), 4.21 – 4.05 (m, 2H), 3.68 – 3.54 (m, 2H), 2.19 – 2.05 (m, 1H), 2.01 – 1.76 (m, 3H), 1.05 – 1.01 (m, 2H), 0.93 (s, 2H). Example 37: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{1-[1-(2-hydroxyethyl)piperi- din-4-yl]-3-methyl-1H-pyrazol-4-yl}pyrimidine-5-carboxamide To N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[3-methyl-1-(piperidin-4-yl)-1H-pyrazol- 4-yl]pyrimidine-5-carboxamide (Example 34, 0.093 g, 0.168 mmol, 1.0 eq.) in MeOH (2.0 mL), 1,4-dioxane-2,5- diol (0.04 g, 0.333 mmol) and acetic acid (0.048 mL, 0.89 mmol, 5.0 eq.) were added. The resulting mixture was stirred at RT for 1 h, then NaBH3CN (0.025 g, 0.42 mmol, 2.5 eq.) was added. After 2 h at RT, RM was quenched with water, diluted with sat. aq. Na2CO3 solution, and extracted with DCM(3x). Next brine was added and extraction with DCM was repeated twice. Combined organic fractions were washed with brine and dried over Na2SO4 and evaporated. The crude mixture was purified by FCC (NH2 functionalized silica, 0% to 4% MeOH gradient in DCM) and then by preparative HPLC and lyophilization to give N-({4-amino-1H,3H-furo[3,4- c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-1H-pyrazol-4-yl}pyrimi- dine-5-carboxamide as its formate salt (Example 37, 0.005 g, 0.008 mmol, 5%, light brown crystals UPLC long elution (polar long method, buffer type “FA”) purity 98.88%, m/z [M+H]+: 569.6). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.21 (s, 1H), 7.70 (s, 1H), 7.48 – 7.38 (m, 2H), 7.19 – 7.08 (m, 1H), 6.47 (s, 2H), 5.30 (t, J = 3.3 Hz, 2H), 5.03 – 4.93 (m, 4H), 3.91 – 3.81 (m, 1H), 3.47 (t, J = 6.3 Hz, 4H overlapped with water signal), 2.82 (d, J = 11.2 Hz, 2H), 2.37 (t, J = 6.3 Hz, 2H), 2.19 – 2.10 (m, 1H), 2.10 – 2.00 (m, 2H), 1.79 – 1.69 (m, 4H), 1.58 (s, 3H), 1.09 – 1.01 (m, 2H), 0.98 – 0.90 (m, 2H). Example 38: rac-N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-6-{[(2R,4R)-2- (trifluoromethyl)piperidin-4-yl]oxy}pyridin-3-yl)pyrimidine-5-carboxamide Ryvu Therapeutics S.A. RVU305 153 R10945WO tert-Butyl 4-[(6-methyl-5-nitropyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carboxylate (Int.94) A 6-chloro-2-methyl-3-nitropyridine (0.27 g, 1.56 mmol, 1.0 eq.), tert-butyl 4-hydroxy-2-(trifluorome- thyl)piperidine-1-carboxylate (0.48 g, 1.78 mmol, 1.14 eq.) and Cs2CO3 (1.07 g, 3.284 mmol, 2.1 eq.), were mixed in toluene (7.0 mL) and the mixture was flushed with argon for 10min. Then Pd(OAc)2 (0.08 g, 0.36 mmol, 0.23 eq.) and JohnPhos (0.14 g, 0.47 mmol, 0.3 eq.) were added and the reaction mixture was stirred at 85°C for 3 h and overnight at RT. Then, the reaction mixture was diluted with DCM and filtered through cotton. The filtrate was washed with a saturated solution of Na2CO3. Aqueous layer was washed with DCM with addi- tion of CHCl3/iPrOH 3/1 mixture. The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 100% DCM gradient in heptane) to obtain tert-butyl 4-[(6-methyl-5-nitropyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carboxylate (Int.94, 0.41 g, 0.97 mmol, 62%, yellowish crystals, m/z [M-H]-: 404.30). 1H NMR (400 MHz, DMSO-d6) mixture of stereoisomers (ratio 10:3); major: δ 8.38 (d, J = 8.9 Hz, 1H)., 6.79 (d, J = 9.0 Hz, 1H), 5.41 (p, J = 3.7 Hz, 1H), 5.08 – 4.79 (m, 1H), 4.01 – 3.95 (m, 1H), 3.28 – 2.91 (m, 1H), 2.72 (s, 3H), 2.31 – 2.18 (m, 2H), 1.95 – 1.81 (m, 2H), 1.43 (s, 9H) 19F NMR (377 MHz, DMSO-d6); mixture of stereoisomers: δ -69.91, -70.32 (d, J = 10.1 Hz). tert-Butyl 4-[(5-amino-6-methylpyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carboxylate (Int.95) To the solution of tert-butyl 4-[(6-methyl-5-nitropyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carbox- ylate (Int.94, 0.4 g, 0.95 mmol, 1.0 eq.) in a mixture of MeOH (3.0 mL) and EtOAc (6.0 mL), palladium on car- bon (10%, 50% wet, 0.35 g) was added. Air was removed from the flask and hydrogen was introduced from the balloon. Then, the reaction mixture was stirred at RT for 2.5 h. The catalyst was removed on a syringe filter and washed with EtOH. Filtrate was evaporated to obtain tert-butyl 4-[(5-amino-6-methylpyridin-2-yl)oxy]-2-(trifluo- romethyl)piperidine-1-carboxylate (Int.95, 0.32 g, 0.84 mmol, Y=88%, P=98%, brownish oil, m/z [M+H]+: 376.30). Ryvu Therapeutics S.A. RVU305 154 R10945WO 1H NMR (400 MHz, DMSO-d6): mixture of stereoisomers; major: δ 6.99 (d, J = 8.5 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 5.11 (t, J = 3.8 Hz, 1H), 4.79 (t, J = 9.3 Hz, 1H), 4.64 (s, 2H), 3.93 (d, J = 13.6 Hz, 1H), 3.27 – 3.13 (m, 1H), 2.19 (s, 3H), 2.14 (t, J = 3.2 Hz, 1H), 2.12 – 2.07 (m, 1H), 1.83 – 1.73 (m, 2H), 1.43 (s, 9H). 19F NMR (377 MHz, DMSO-d6); mixture of streoisomers; δ -69.87, -70.44 (d, J = 8.9 Hz). tert-Butyl 4-{[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]oxy}-2-(trifluoromethyl)piperidine-1-car- boxylate (Int.96) DMAP (0.026 g, 0.21 mmol, 0.26 eq.), DIPEA (0.36 ml, 2.07 mmol, 2.47 eq.), tert-butyl 4-[(5-amino-6- methylpyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carboxylate (Int.95, 0.32 g, 0.84 mmol, 1.0 eq.) and 2- cyclopropylpyrimidine-5-carboxylic acid (0.14 g, 0.85 mmol, 1.02 eq.) were taken in toluene (10.0 mL) and T3P as 50% in EtOAc (0.75 mL, 1.26 mmol, 1.51 eq.) was added at RT. Then, the reaction mixture was heated at 75°C for 1.5 h. The reaction mixture was diluted with saturated solution of Na2CO3 and extracted with EtOAc. Combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 40% MeCN gradient in DCM) to obtain tert-butyl 4-{[5-(2-cyclopropylpyrimidine-5- amido)-6-methylpyridin-2-yl]oxy}-2-(trifluoromethyl)piperidine-1-carboxylate (Int.96, 0.36 g, 0.69 mmol, 83%, oil, m/z [M+H]+: 425.50). 1H NMR (400 MHz, DMSO-d6): mixture of streoisomers; major: δ 10.13 (s, 1H), 9.11 (s, 2H), 7.64 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 5.34 – 5.26 (m, 1H), 4.92 – 4.79 (m, 1H), 3.99 (d, J = 13.7 Hz, 1H), 3.30 – 3.14 (m, 1H), 2.34 (s, 3H), 2.32 – 2.27 (m, 1H), 2.25 (d, J = 2.7 Hz, 1H), 2.22 – 2.12 (m, 1H), 1.93 – 1.78 (m, 2H), 1.44 (s, 9H), 1.20 – 1.07 (m, 4H). 19F NMR (377 MHz, DMSO-d6): mixture of streoisomers: δ -69.88, -70.35 (d, J = 9.5 Hz). tert-Butyl 4-({5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6- methylpyridin-2-yl}oxy)-2-(trifluoromethyl)piperidine-1-carboxylate (Int.97) tert-Butyl 4-{[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]oxy}-2-(trifluoromethyl)piperidine- 1-carboxylate (Int.96, 0.345 g, 0.66 mmol, 1.0 eq.) and Cs2CO3 (0.45 g, 1.38 mmol, 2.09 eq.) in MeCN (15.0 mL) was flushed with argon for 10 min at RT, then 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.2 g, 0.78 mmol, 1.18 eq.) was added and the reaction mixture was stirred at 75°C for 2.5 h.. The reaction mixture was diluted with saturated solution of Na2CO3 and extracted with DCM. Combined organic phases were washed with brine and dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 20% MeCN gradient in DCM) to obtain tert-butyl 4-({5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2- cyclopropylpyrimidine-5-amido]-6-methylpyridin-2-yl}oxy)-2-(trifluoromethyl)piperidine-1-carboxylate (Int.97, 0.41 g, 0.505 mmol, 76%, whitish solidified oil, m/z [M+H]+: 740.00). 1H NMR (400 MHz, DMSO-d6); mixture of stereoisomers, major: δ 8.55 (s, 1H), 8.53 (s, 1H), 7.92 – 7.88 (m, 1H), 7.84 (dd, J = 10.0, 8.3 Hz, 1H), 7.75 – 7.64 (m, 1H), 7.52 (dd, J = 15.9, 8.7 Hz, 1H), 6.59 – 6.43 (m, 1H), 5.58 – 5.49 (m, 2H), 5.34 (dd, J = 14.5, 7.5 Hz, 1H), 5.22 (t, J = 3.1 Hz, 2H), 5.15 – 5.06 (m, 1H), 5.06 – 4.99 (m, 1H), 4.82 – 4.70 (m, 1H), 3.92 (d, J = 13.2 Hz, 1H), 3.21 – 3.04 (m, 1H), 2.16 – 2.09 (m, 2H), 2.07 – 2.00 (m, 1H), 1.95 (d, J = 9.4 Hz, 3H), 1.80 – 1.69 (m, 2H), 1.41 (s, 9H), 1.03 (td, J = 8.8, 3.0 Hz, 2H), 0.96 – 0.89 (m, 2H). 19F NMR (377 MHz, DMSO-d6); mixture of streoisomers: δ -70.02 (d, J = 10.3 Hz), -70.55 (d, J = 9.8 Hz). tert-Butyl 4-[(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclo- propylpyrimidine-5-amido}-6-methylpyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carboxylate (Int.98) Ryvu Therapeutics S.A. RVU305 155 R10945WO tert-Butyl 4-({5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6- methylpyridin-2-yl}oxy)-2-(trifluoromethyl)piperidine-1-carboxylate (Int.97, 0.4 g, 0.49 mmol, 1.0 eq.), 1-(2,4- dimethoxyphenyl)methanamine (0.49 g, 2.93 mmol, 5.95 eq.) were mixed in DMSO anh. (7.0 mL) and heated at 140°C for 3.5h. then, the reaction mixture was diluted with saturated solution of Na2CO3 and extracted with DCM (2x. Combined organic layers were washed with water, brine and dried over Na2SO4, filtered and evapo- rated. The residue was purified by FCC (0% to 40% MeCN gradient in DCM) to obtain tert-butyl 4-[(5-{N-[(4- {[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido}- 6-methylpyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carboxylate (0.22 g, 0.235 mmol, Y=48%, yellowish solid, m/z [M+H]+: 870.90) 1H NMR (400 MHz, DMSO-d6); mixture of streoisomers, major: δ 8.56 – 8.47 (m, 2H), 7.44 (dd, J = 7.4, 4.8 Hz, 2H), 7.22 – 7.08 (m, 2H), 7.08 – 6.97 (m, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.52 – 6.40 (m, 2H), 5.33 – 5.26 (m, 2H), 5.24 – 5.07 (m, 2H), 5.05 (t, J = 3.6 Hz, 2H), 4.92 (t, J = 14.0 Hz, 1H), 4.85 – 4.69 (m, 1H), 4.55 (d, J = 5.8 Hz, 2H), 3.99 – 3.87 (m, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 3.14 (s, 1H), 2.17 – 2.09 (m, 2H), 2.06 – 1.95 (m, 1H), 1.95 – 1.86 (m, 3H), 1.74 (d, J = 14.1 Hz, 2H), 1.41 (s, 9H), 1.02 (td, J = 8.7, 2.9 Hz, 2H), 0.98 – 0.89 (m, 2H). 19F NMR (377 MHz, DMSO); mixture of streoisomers: δ -70.00 (d, J = 10.2 Hz), -70.55 (d, J = 10.3 Hz). The two isomers were separated by HPLC preparative (MeCN/water system + NH3/ammonia) to obtain one undefined isomer (Int.98, 0.050 g, 0.056 mmol, Y=25%, P=97% , white solid, m/z [M+H]+: 870.90). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.50 (s, 1H), 7.52 – 7.40 (m, 3H), 7.20 – 7.08 (m, 2H), 7.02 (q, J = 6.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.51 – 6.40 (m, 2H), 5.30 (t, 2H), 5.24 – 5.07 (m, 2H), 5.04 (t, J = 3.5 Hz, 2H), 4.92 (t, J = 14.0 Hz, 1H), 4.84 – 4.69 (m, 1H), 4.62 – 4.48 (m, 2H), 3.92 (d, J = 11.9 Hz, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 3.14 (s, 1H), 2.18 – 2.00 (m, 3H), 1.91 (d, J = 16.6 Hz, 3H), 1.74 (d, J = 14.1 Hz, 2H), 1.41 (s, 9H), 1.08 – 0.98 (m, 2H), 0.97 – 0.84 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -70.50 – -70.61 (3F). rac-N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-6-{[(2R,4R)-2-(trifluorome- thyl)piperidin-4-yl]oxy}pyridin-3-yl)pyrimidine-5-carboxamide (Example 38) To rac-tert-butyl (2R,4R)-4-[(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]2-cyclopropylpyrimidine-5-amido}-6-methylpyridin-2-yl)oxy]-2-(trifluoromethyl)piperidine-1-carboxylate (Int.98, 0.05 g, 0.056 mmol, 1.0 eq.) in DCM (0.8 ml, 14.4 ml/mmol), TFA (0.2 ml, 2.612 mmol, 46.9 eq.) was added. Then, the reaction mixture was stirred at RT overnight. The reaction mixture was poured onto a satu- rated solution of Na2CO3 / ice and stirred for few minutes, next brine was added and the crude product was ex- tracted with DCM with addition of CHCl3/iPrOH 3/1 v/v mixture (3x). Organic layers were combined, washed with 1M K2CO3, brine and and dried over Na2SO4, filtered and evaporated. The residue was purified by prepar- ative HPLC and lyophilization to give rac-N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N- (2-methyl-6-{[(2R,4R)-2-(trifluoromethyl)piperidin-4-yl]oxy}pyridin-3-yl)pyrimidine-5-carboxamide; formic acid (Example 38, 0.013 g, 0.019 mmol, Y=34%, white solid, UPLC long elution (polar long method, buffer type “FA”) purity 99.67%, m/z [M+H]+: 620.50). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 1.0 Hz, 2H), 7.51 (dd, J = 16.5, 8.6 Hz, 1H), 7.44 (dd, J = 8.2, 1.6 Hz, 1H), 7.39 (dd, J = 4.9, 1.6 Hz, 1H), 7.18 (dt, J = 8.2, 1.7 Hz, 1H), 6.57 (dd, J = 8.7, 5.7 Hz, 1H), 6.49 (s, 2H), 5.30 (t, J = 3.4 Hz, 2H), 5.15 (dd, J = 17.2, 14.2 Hz, 1H), 4.99 (t, J = 3.5 Hz, 2H), 4.97 – 4.88 (m, 2H), 2.98 (d, J = 12.3 Hz, 1H), 2.62 – 2.53 (m, 2H overlapped with DMSO signal), 2.17 – 2.07 (m, 2H), 1.99 (dd, J = 33.3, 12.1 Hz, 1H), 1.87 (d, J = 18.0 Hz, 3H), 1.39 – 1.21 (m, 2H), 1.07 – 1.00 (m, 2H), 0.98 – 0.87 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -75.62 (dd, J = 26.2, 7.3 Hz). Ryvu Therapeutics S.A. RVU305 156 R10945WO Example 39: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-benzo- thiazol-5-yl]pyrimidine-5-carboxamide tert-Butyl 4-[(2-fluoro-5-nitrophenyl)carbamoyl]piperidine-1-carboxylate (Int.99) To the suspension of 2-fluoro-5-nitroaniline (3.0 g, 19.216 mmol, 1.0 eq.), 1-[(tert-butoxy)carbonyl]piperi- dine-4-carboxylic acid (4.538 g, 19.793 mmol, 1.03 eq.), DIPEA (8.368 mL, 48.04 mmol, 2.5 eq.) and DMAP (0.587 g, 4.805 mmol, 0.25 eq.) in toluene (40 mL), T3P as 50% in EtOAc (17.16 mL, 28.826 mmol, 1.5 eq.) was added. The reaction mixture was stirred at 40°C for 2 h. Then, the reaction mixture was concentrated, di- luted with a saturated solution of Na2CO3 and extracted by EtOAc (3x). The organic layers were washed with cold 1M HCl solution, water and brine and dried over Na2SO4, filtered and evaporated. The crude product was triturated in an approx.100 ml of MTBE/EtOAc (19:1) mixture, filtered and washed with MTBE, then dried. The filtrate was concentrated and purified by FCC (0 to 40% EtOAc gradient in heptane) to obtain tert-butyl 4-[(2- fluoro-5-nitrophenyl)carbamoyl]piperidine-1-carboxylate (Int.99, 5.49 g, 14.794 mmol, 77%,beige solid, m/z [M+H]+: 368.4). 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.98 (dd, J = 6.7, 2.9 Hz, 1H), 8.04 (ddd, J = 9.1, 4.2, 2.9 Hz, 1H), 7.57 (dd, J = 10.2, 9.1 Hz, 1H), 4.16 – 3.86 (m, 2H), 2.88 – 2.63 (m, 3H), 1.85 – 1.76 (m, 2H), 1.50 (td, J = 12.4, 4.2 Hz, 2H), 1.41 (s, 9H). 19F NMR (376 MHz, DMSO-d6) δ -114.46 – -114.59 (m, 1F). 5-Nitro-2-(piperidin-4-yl)-1,3-benzothiazole (Int.100) To the suspension of tert-butyl 4-[(2-fluoro-5-nitrophenyl)carbamoyl]piperidine-1-carboxylate (Int.99, 6.289 g, 17.119 mmol, 1.0 eq.) in toluene (65 mL), Lawesson reagent (8.308 g, 20.541 mmol, 1.2 eq.) was Ryvu Therapeutics S.A. RVU305 157 R10945WO added. The reaction mixture was stirred under reflux for 4 h. Then, the RM was cooled down to RT, concen- trated to dryness, diluted with DCM and neutralized by a saturated solution of Na2CO3 solution to pH ~ 9. The crude product was extracted with CHCl3/i-PrOH (3:1) mixture. The combined organic layers were concentrated and diluted in DCM (100 mL), followed by an addition of a solution of HCl 6N (100 mL) and stirred for 1 h. The water layer was separatedand the organic layer was washed with 1M HCl solution. The combined water layers were washed with DCM (DCM layer discarded) one more time, and then neutralized with a solution of NaOH to pH=10 under an ice bath cooling, followed by extraction with DCM (3x). Combined organic layers were dried over Na2SO4, filtered and evaporated to obtain 5-nitro-2-(piperidin-4-yl)-1,3-benzothiazole (Int.100, 3.558 g, 13.512 mmol, 79%, beige solid, m/z [M+H]+: 264.5). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 2.2 Hz, 1H), 8.41 – 8.35 (m, 1H), 8.26 (dd, J = 8.8, 2.3 Hz, 1H), 3.30 – 3.21 (m, 1H), 3.04 (dt, J = 12.3, 3.4 Hz, 2H), 2.70 – 2.58 (m, 2H), 2.10 – 1.98 (m, 2H), 1.76 – 1.59 (m, 2H). tert-Butyl 4-(5-nitro-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.101) To a solution of 5-nitro-2-(piperidin-4-yl)-1,3-benzothiazole (Int.100, 3.558 g, 13.512 mmol, 1.0 eq.) in DCM (100 mL), Boc2O (2.949 g, 13.512 mmol, 1.0 eq.) was added. A small crystal of DMAP was added after 10 min of stirring and the reaction was stirred at RT for 2 h. Then, the reaction mixture was concentrated, then triturated with Et2O to obtain fine solid. The residue was triturated with heptane over 2 h and filtered, then washed with a small amount of heptane (2x) and dried to obtain tert-butyl 4-(5-nitro-1,3-benzothiazol-2-yl)piper- idine-1-carboxylate (Int.101, 4.39 g, 11.959 mmol, 89%, beige solid, m/z [M-H]-: 362.3). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 2.2 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.28 (dd, J = 8.8, 2.3 Hz, 1H), 4.05 (d, J = 13.1 Hz, 2H), 3.45 (tt, J = 11.4, 3.7 Hz, 1H), 2.96 (s, 2H), 2.21 – 2.04 (m, 2H), 1.79 – 1.60 (m, 2H), 1.43 (s, 9H). tert-Butyl 4-(5-amino-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.102) To a solution of tert-butyl 4-(5-nitro-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.101, 4.39 g, 11.959 mmol, 1.0 eq.) in acetone (50 mL), Zn (7.82 g, 119.608 mmol, 10.002 eq.) was added. A saturated solu- tion of NH4Cl (30.0 mL, 2.51 ml/mmol) was added slowly in a manner to not exceed 30°C. Then, the reaction mixture was stirred for 20 min. at RT and 4 h at 40°C. the RM was filtrated through Celite® and washed with EtOAc. The organic layer was washed with water, brine and dried over Na2SO4, filtered and evaporated to ob- tain tert-butyl 4-(5-amino-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.102, 3.83 g, 10.682 mmol, 89%, yellow solid, m/z [M+H]+: 334.2). 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.72 (dd, J = 8.6, 2.2 Hz, 1H), 5.23 (s, 2H), 4.03 (dd, J = 10.2, 7.1 Hz, 2H), 3.23 (tt, J = 11.4, 3.7 Hz, 1H), 2.91 (s, 2H), 2.10 – 2.01 (m, 2H), 1.68 – 1.52 (m, 2H), 1.42 (s, 9H). tert-Butyl 4-[5-(2-cyclopropylpyrimidine-5-amido)-1,3-benzothiazol-2-yl]piperidine-1-carboxylate (Int.103) To the suspension of tert-butyl 4-(5-amino-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.102, 0.5 g, 1.395 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.240 g, 1.464 mmol, 1.05 eq.) and DMAP (0.043 g, 0.349 mmol, 0.25 eq.) in toluene (15 mL), DIPEA (0.607 mL, 3.486 mmol, 2.5 eq.) was added, fol- lowed by T3P as 50% in EtOAc (1.66 mL, 2.789 mmol, 2.0 eq.). The RM was stirred at 60 °C for 4 h. Then, the reaction mixture was concentrated, diluted with a saturated solution of NaHCO3 and evaporated. The crude product was triturated with MTBE and few drops of i-PrOH, then filtered, washed with Et2O and dried to obtain Ryvu Therapeutics S.A. RVU305 158 R10945WO tert-butyl 4-[5-(2-cyclopropylpyrimidine-5-amido)-1,3-benzothiazol-2-yl]piperidine-1-carboxylate (Int.103, 0.605 g, 1.249 mmol, 90%, beige solid, m/z [M-H]-: 478.4). 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.13 (s, 2H), 8.45 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.72 (dd, J = 8.6, 2.1 Hz, 1H), 4.04 (d, J = 13.0 Hz, 2H), 3.41 – 3.34 (m, 1H), 2.95 (s, 2H), 2.33 (tt, J = 8.0, 4.8 Hz, 1H), 2.19 – 2.03 (m, 2H), 1.66 (qd, J = 12.4, 4.2 Hz, 2H), 1.43 (s, 9H), 1.21 – 1.07 (m, 4H). tert-Butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-1,3-benzo- thiazol-2-yl}piperidine-1-carboxylate (Int.104) A suspension of tert-butyl 4-[5-(2-cyclopropylpyrimidine-5-amido)-1,3-benzothiazol-2-yl]piperidine-1-car- boxylate (Int.103, 0.58 g, 1.197 mmol, 1.0 eq.), 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.384 g, 1.496 mmol, 1.25 eq.) and Cs2CO3 (0.78 g, 2.394 mmol, 2.0 eq.) in MeCN (12 mL) was stirred at 60°C overnight. The RM was cooled down, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by FCCs (first: 0 to 2% MeOH gradient in DCM; second: 0 to 60% EtOAc gradient in heptane) to obtain tert-butyl 4-{5-[N- ({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-1,3-benzothiazol-2-yl}piperi- dine-1-carboxylate (Int.104, 0.6 g, 0.835 mmol, 70%, beige solid, m/z [M+H]+: 597.4). 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 2H), 7.96 (d, J = 2.1 Hz, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 7.25 (dd, J = 8.5, 2.1 Hz, 1H), 5.51 (t, J = 3.1 Hz, 2H), 5.45 (s, 2H), 5.19 (t, J = 3.1 Hz, 2H), 4.01 (dd, J = 17.7, 10.0 Hz, 2H), 3.27 (dq, J = 11.4, 3.9 Hz, 1H), 2.87 (d, J = 21.0 Hz, 2H), 2.15 – 2.00 (m, 3H), 1.66 – 1.49 (m, 2H), 1.40 (s, 9H), 1.02 (tt, J = 7.9, 3.2 Hz, 2H), 0.92 (dt, J = 4.6, 3.0 Hz, 2H). tert-Butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclo- propylpyrimidine-5-amido}-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.105) A solution of tert-butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-am- ido]-1,3-benzothiazol-2-yl}piperidine-1-carboxylate (Int.104, 0.53 g, 0.737 mmol, 1.0 eq.) and 1-(2,4-dimethox- yphenyl)methanamine (0.739 g, 4.424 mmol, 6.0 eq.) in DMSO (10 mL) was stirred at 120°C for 24 h. The RM was concentrated, diluted with water and extracted by EtOAc (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCCs (first: 0 to 3% MeOH gradient in DCM; second: 0 to 60% EtOAc gradient in heptane) to obtain tert-butyl 4-(5-{N-[(4-{[(2,4-di- methoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido}-1,3-ben- zothiazol-2-yl)piperidine-1-carboxylate (Int.105, 0.48 g, 0.568 mmol, 77%, beige solid, m/z [M+H]+: 828.8). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 7.93 – 7.81 (m, 2H), 7.49 – 7.43 (m, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.23 – 7.15 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 6.99 (t, J = 5.7 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.41 (dd, J = 8.4, 2.4 Hz, 1H), 5.36 – 5.20 (m, 4H), 5.08 – 4.95 (m, 2H), 4.54 (d, J = 5.6 Hz, 2H), 4.09 – 3.91 (m, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 3.30 – 3.21 (m, 1H), 2.88 (s, 2H), 2.11 – 1.98 (m, 3H), 1.65 – 1.48 (m, 2H), 1.41 (s, 9H), 1.06 – 0.96 (m, 2H), 0.93 – 0.87 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]py- rimidine-5-carboxamide (Example 39) To a solution of tert-butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]2-cyclopropylpyrimidine-5-amido}-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.105, 0.48 g, 0.568 mmol, 1.0 eq.) in DCM (10 mL), TFA (2.175 mL, 28.403 mmol, 49.995 eq.) was added. The RM was Ryvu Therapeutics S.A. RVU305 159 R10945WO stirred at RT overnight. Then, the RM was concentrated and diluted by CHCl3/i-PrOH (3:1) mixture, cooled on an ice-bath and was carefully neutralized with 2M NaOH solution to pH = 10-11. The organic layer was sepa- rated, washed with water, brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC and lyophilized to obtain N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopro- pyl-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]pyrimidine-5-carboxamide (Example 39, 0.025 g, 0.046 mmol, 6%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.21%, m/z [M+H]+: 578.6). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 7.90 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.48 – 7.33 (m, 2H), 7.21 (dd, J = 8.2, 1.7 Hz, 1H), 7.17 (dd, J = 1.1 Hz, 1H), 6.45 (s, 2H), 5.31 (s, 2H), 5.28 (t, J = 3.2 Hz, 2H), 4.97 (t, J = 3.2 Hz, 2H), 3.20 (d, J = 396.2 Hz, 1H), 3.13 – 3.02 (m, 2H), 2.68 (td, J = 12.3, 11.8, 2.2 Hz, 2H), 2.12 – 2.06 (m, 1H), 2.06 – 1.97 (m, 2H), 1.67 (qd, J = 12.4, 3.8 Hz, 2H), 1.01 (dt, J = 7.7, 3.1 Hz, 2H), 0.91 (p, J = 4.0, 3.6 Hz, 2H). Example 40: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyacetyl)piperi- din-4-yl]-1,3-benzothiazol-5-yl}pyrimidine-5-carboxamide 2-(4-{5-[N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-1,3-benzothiazol- 2-yl}piperidin-1-yl)-2-oxoethyl acetate (Int.106) To a solution of N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(piperidin-4-yl)- 1,3-benzothiazol-5-yl]pyrimidine-5-carboxamide (Example 39, 0.05 g, 0.083 mmol, 1.0 eq.) and TEA (0.023 mL, 0.166 mmol, 1.998 eq.) in DCM (2 mL), 2-chloro-2-oxoethyl acetate (0.0113 g, 0.083 mmol, 1.0 eq.) was added dropwise at RT. The RM was stirred at RT for 1 h. Then, the reaction mixture was diluted with water and extracted with DCM (3x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0 to 7% MeOH gradient in DCM) to get 2-(4-{5-[N-({4- amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-1,3-benzothiazol-2-yl}piperidin- 1-yl)-2-oxoethyl acetate (Int.106, 0.035 g, 0.046 mmol, 55%, white solid, m/z [M+H]+: 679.0). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.44 – 7.38 (m, 2H), 7.24 – 7.14 (m, 2H), 6.45 (s, 2H), 5.31 (s, 2H), 5.28 (t, J = 3.4 Hz, 2H), 4.96 (t, J = 3.4 Hz, 2H), 4.80 (s, 2H), 4.33 (d, J = 13.1 Hz, 1H), 3.78 (d, J = 13.6 Hz, 1H), 3.42 – 3.37 (m, 1H), 3.23 – 3.10 (m, 1H), 2.78 (t, J = 12.4 Hz, 1H), 2.14 – 2.03 (m, 6H), 1.82 – 1.66 (m, 1H), 1.62 – 1.49 (m, 1H), 1.06 – 0.98 (m, 2H), 0.94 – 0.88 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyacetyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide (Example 40) Ryvu Therapeutics S.A. RVU305 160 R10945WO To the solution of 2-(4-{5-[N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5- amido]-1,3-benzothiazol-2-yl}piperidin-1-yl)-2-oxoethyl acetate (Int.106, 0.035 g, 0.046 mmol, 1.0 eq.) in mix- ture of MeOH (1.0 mL) and water (3.0 mL) was added, followed by an addition of a solution of NaOH 1M (0.14 mL, 0.14 mmol, 3.012 eq.) at RT. The RM was stirred for 1 h at RT . RM was quenched with water and ex- tracted by DCM (3x). Combined organic layers were washed with water, brine, and dried over Na2SO4, then filtered and evaporated. Crude was purified by FCC (0 to 5% MeOH gradient in DCM), and lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyacetyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide (DC780-124, 0.027 g, 0.041 mmol, 88%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.21%, m/z [M+H]+: 636.3). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.46 – 7.35 (m, 2H), 7.25 – 7.13 (m, 2H), 6.45 (s, 2H), 5.31 (s, 2H), 5.28 (t, J = 6.6, 3.2 Hz, 2H), 4.96 (t, J = 3.2 Hz, 2H), 4.53 (t, J = 5.5 Hz, 1H), 4.39 (d, J = 13.0 Hz, 1H), 4.18 – 4.02 (m, 2H), 3.75 (d, J = 13.6 Hz, 1H), 3.42 – 3.37 (m, 1H, s, overlapped with water signal), 3.11 (t, J = 12.0 Hz, 1H), 2.80 (t, J = 11.9 Hz, 1H), 2.08 (dt, J = 7.9, 3.5 Hz, 3H), 1.80 – 1.49 (m, 2H), 1.06 – 0.97 (m, 2H), 0.95 – 0.87 (m, 2H). Example 41: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyacetyl)piperi- din-4-yl]-1,3-benzothiazol-5-yl}pyrimidine-5-carboxamide N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-[2-(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}piperidin-4-yl)- 1,3-benzothiazol-5-yl]-2-cyclopropylpyrimidine-5-carboxamide (Int.107) To a solution of N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(piperidin-4-yl)- 1,3-benzothiazol-5-yl]pyrimidine-5-carboxamide (Example 39, 0.14 g, 0.194 mmol, 1.0 eq.) in DCM (10 mL), 2- [(tert-butyldimethylsilyl)oxy]acetaldehyde (0.050 g, 0.26 mmol, 1.34 eq.) and a three drops of acetic acid were added. The reaction mixture was stirred at RT for 4 h. STAB (0.103 g, 0.486 mmol, 2.507 eq.) was added and the reaction mixture stirred at RT overnight. Then, the reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3 and water. The organic layer was dried over Na2SO4, filtered and concentrated to obtain crude N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-[2-(1-{2-[(tert-butyldimethylsi- lyl)oxy]ethyl}piperidin-4-yl)-1,3-benzothiazol-5-yl]-2-cyclopropylpyrimidine-5-carboxamide (Int.107, 0.185 g, 0.133 mmol, 69%, beige solid, m/z [M+H]+: 736.9). N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyacetyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide (Example 41) To a solution of N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-[2-(1-{2-[(tert-butyldimethylsi- lyl)oxy]ethyl}piperidin-4-yl)-1,3-benzothiazol-5-yl]-2-cyclopropylpyrimidine-5-carboxamide (DC780-145, 0.185 g, Ryvu Therapeutics S.A. RVU305 161 R10945WO 0.133 mmol, 1.0 eq.) in DCM (10 mL), TFA (1.02 mL, 13.32 mmol, 99.987 eq.) was added and the RM was stirred at RT overnight. TFA was evaporated and then the RM was diluted by CHCl3/i-PrOH (3:1) mixture, cooled down on an ice-bath and was carefully neutralized with 2M NaOH solution to pH = 10-11. An organic layer was separated, washed with water, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC lyophilized to obtain N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclo- propyl-N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-1,3-benzothiazol-5-yl}pyrimidine-5-carboxamide (Example 41, 0.002 g, 0.003 mmol, 2%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 97.17%, m/z [M+H]+: 622.0). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.91 – 7.68 (m, 2H), 7.47 – 7.27 (m, 2H), 7.27 – 7.08 (m, 2H), 6.43 (s, 2H), 5.28 (d, J = 11.7 Hz, 4H), 4.96 (s, 2H), 4.39 (s, 1H), 3.48 (t, J = 5.7 Hz, 2H), 3.08 – 2.97 (m, 1H), 2.96 – 2.85 (m, 1H), 2.39 (t, J = 6.3 Hz, 2H), 2.15 – 1.97 (m, 5H), 1.80 – 1.63 (m, 2H), 1.06 – 0.97 (m, 2H), 0.92 – 0.86 (m, 2H). Example 42: N‐({4‐Amino‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐[6‐(6,6‐difluoro‐1,4‐diazepan‐ 1‐yl)‐2‐methylpyridin‐3‐yl]pyrimidine‐5‐carboxamide Ryvu Therapeutics S.A. RVU305 162 R10945WO tert‐Butyl 6,6‐difluoro‐4‐(6‐methyl‐5‐nitropyridin‐2‐yl)‐1,4‐diazepane‐1‐carboxylate (Int.108) To a solution of 6‐chloro‐2‐methyl‐3‐nitropyridine (0.137 g, 0.796 mmol, 1.0 eq.), tert‐butyl 6,6‐difluoro‐ 1,4‐diazepane‐1‐carboxylate (0.188 g, 0.796 mmol, 1.0 eq.) in anhydrous DMSO (4 mL), triethylamine (0.55 ml, 3.98 mmol, 5 eq.) was added. The reaction was stirred at RT for 10 min and at 120°C for 21 h. The reaction mixture was diluted with water and with saturated solution of NaHCO3 was added. The obtained mixture was extracted with ethyl acetate (3x). The combined organic phases were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 33% EtOAc gradient in hex- ane) to obtain tert‐butyl 6,6‐difluoro‐4‐(6‐methyl‐5‐nitropyridin‐2‐yl)‐1,4‐diazepane‐1‐carboxylate (Int.108, 0.164 g, 0.344 mmol, 43%). 1H NMR (400 MHz, DMSO) δ 8.25 (d, J = 9.4 Hz, 1H), 6.90 (d, J = 9.7 Hz, 1H), 4.40 – 4.23 (m, 2H), 3.94 (s, 2H), 3.90 – 3.71 (m, 2H), 3.72 – 3.55 (m, 2H), 2.68 (s, 3H), 1.36 and 1.34 (2xs, 9H). tert‐Butyl 4‐(5‐amino‐6‐methylpyridin‐2‐yl)‐6,6‐difluoro‐1,4‐diazepane‐1‐carboxylate (Int.109) Palladium (0.073 g, 0.069 mmol, 0.2 eq.) and tert‐butyl 6,6‐difluoro‐4‐(6‐methyl‐5‐nitropyridin‐2‐yl)‐1,4‐ diazepane‐1‐carboxylate (Int.108, 0.164 g, 0.344 mmol, 1.0 eq.) was taken in methanol (2 mL) and sparged with argon for 5 min. Then, the reaction mixture was stirred at RT under hydrogen balloon for 2 h. The RM was filtered through celite® and washed with methanol. The reaction mixture was concentrated to obtain tert‐butyl 4‐(5‐amino‐6‐methylpyridin‐2‐yl)‐6,6‐difluoro‐1,4‐diazepane‐1‐carboxylate (Int.109, 0.143 g, m/z [M+H]+: 343.5). 1H NMR (400 MHz, DMSO) δ 6.89 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 8.7 Hz, 1H), 4.25 (s, 2H), 3.99 (t, J = 12.6 Hz, 2H), 3.83 – 3.48 (m, 6H), 2.16 (s, 3H), 1.37 (s, 9H). 19F NMR (377 MHz, DMSO) δ -98.09 – -98.42 (m), -99.08 – -99.40 (m). tert‐Butyl 4‐[5‐(2‐cyclopropylpyrimidine‐5‐amido)‐6‐methylpyridin‐2‐yl]‐6,6‐difluoro‐1,4‐diazepane‐1‐carboxylate (Int.110) DMAP (0.002 g, 0.018 mmol, 0.05 eq.), DIPEA (0.16 ml, 0.898 mmol, 2.5 eq.), tert‐butyl 4‐(5‐amino‐6‐ methylpyridin‐2‐yl)‐6,6‐difluoro‐1,4‐diazepane ‐1‐carboxylate (Int.109, 0.142 g, 0.374 mmol, 1.04 eq.), 2‐cyclo- propylpyrimidine‐5‐carboxylic acid (0.059 g, 0.359 mmol, 1.0 eq.) were taken in toluene (1.5 mL) and T3P as 50% in EtOAc (0.43 mL, 0.72 mmol, 2 eq.) was added dropwise at 80°C. Then, the reaction mixture was stirred at 80°C. After 2h the reaction was quenched with a saturated solution of Na2CO3. The product was extracted with ethyl acetate (2x). The combined organic layers were washed with brine and dried over MgSO4, filtered and evaporated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to give tert‐butyl 4‐[5‐(2‐cyclopropylpyrimidine‐5‐amido)‐6‐methylpyridin‐2‐yl]‐6,6‐difluoro‐1,4‐diazepane‐1‐carboxylate. (Int. 110, 0.168g, 0.251 mmol, 70%, solid, m/z [M+H]+: 489.6). 1H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 9.09 (s, 2H), 7.46 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 4.16 (t, J = 12.5 Hz, 2H), 3.91 – 3.46 (m, 6H), 2.36 – 2.23 (m, 4H), 1.38 and 1.24 (2xs, 9H), 1.19 – 1.04 (m, 4H). 19F NMR (377 MHz, DMSO) δ -98.73 – -99.18 (m), -99.98 – -100.59 (m). tert‐Butyl 4‐{5‐[N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)2‐cyclopropylpyrimidine‐5‐amido]‐6‐ methylpyridin‐2‐yl}‐6,6‐difluoro‐1,4‐diazepane‐1‐carboxylate (Int.111) The mixture of tert‐butyl 4‐[5‐(2‐cyclopropylpyrimidine‐5‐amido)‐6‐methylpyridin‐2‐yl]‐6,6‐difluoro‐1,4‐ diazepane‐1‐carboxylate (Int.110, 0.165 g, 0.246 mmol), 4‐chloro‐7‐(chloromethyl)‐1H,3H‐furo[3,4‐c]quinoline (Int. C, 0.063 g, 0.247 mmol), KI (0.041 g, 0.247 mmol) and Cs2CO3 (0.096 g, 0.296 mmol) in ACN (3 ml) was Ryvu Therapeutics S.A. RVU305 163 R10945WO stirred at 70 °C for 10 h. After cooling the reaction mixture was diluted with ethyl acetate and poured into water. The layers were separated and the water layer was extracted with ethyl acetate several times. The combined organic layers were washed with brine and dried over anhydrous MgSO4. The crude mixture was purified by FCC (0% to 80% ACN gradient in DCM) followed by FCC (0% to 5% MeOH gradient in DCM) to give tert‐butyl 4‐{5‐[N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)2‐cyclopropylpyrimidine‐5‐amido]‐6‐methylpyridin‐2‐yl}‐ 6,6‐difluoro‐1,4‐diazepane‐1‐carboxylate (Int.111, 0.140 g, 0.194 mmol, 79%, solid, m/z [M+H]+: 707.1). 1H NMR (400 MHz, DMSO) δ 8.54 (s, 2H), 7.90 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.41 – 7.24 (m, 1H), 6.58 (d, J = 9.0 Hz, 1H), 5.53 (t, J = 3.1 Hz, 2H), 5.33 (d, J = 14.5 Hz, 1H), 5.21 (t, J = 3.0 Hz, 2H), 4.94 (d, J = 14.6 Hz, 1H), 4.18 – 3.91 (m, 2H), 3.84 – 3.57 (m, 4H), 3.58 – 3.43 (m, 2H), 2.11 (tt, J = 8.4, 4.7 Hz, 1H), 1.91 (s, 3H), 1.34 and 1.25 (2xs, 9H), 1.10 – 0.87 (m, 4H). 19F NMR (377 MHz, DMSO) δ -99.45, -100.82. tert‐Butyl 4‐(5‐{N‐[(4‐{[(2,4‐dimethoxyphenyl)methyl]amino}‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl)methyl]2‐cyclo- propylpyrimidine‐5‐amido}‐6‐methylpyridin‐2‐yl)‐6,6‐difluoro‐1,4‐diazepane‐1‐carboxylate (Int.112) A solution of tert‐butyl 4‐{5‐[N‐({4‐chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)2‐cyclopropylpyrimidine‐ 5‐amido]‐6‐methylpyridin‐2‐yl}‐6,6‐difluoro‐1,4‐diazepane‐1‐carboxylate (Int.111, 0.140 g, 0.194 mmol, 1.0 eq.) and 2,4-dimethoxybenzylamine (0.15 mL, 0.971 mmol, 5 eq.) in DMSO (2.5 mL) was stirred at 120°C for 10 h. After cooling down, the solution was diluted by DCM and poured into saturated solution of NaHCO3. The layers were separated and the water layer was extracted with DCM several times. The combined organic lay- ers were washed with brine and dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to obtain tert‐butyl 4‐(5‐{N‐[(4‐{[(2,4‐dimethoxyphenyl)me- thyl]amino}‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl)methyl]2‐cyclopropylpyrimidine‐5‐amido}‐6‐methylpyridin‐2‐yl)‐6,6‐ difluoro‐1,4‐diazepane‐1‐carboxylate (Int.112, 0.152 g, 0.158 mmol, 81%, solid, m/z [M+H]+: 838.40). 1H NMR (400 MHz, DMSO) δ 8.50 (s, 2H), 7.49 – 7.37 (m, 2H), 7.32 – 7.23 (m, 1H), 7.20 – 7.11 (m, 2H), 6.99 (t, J = 5.7 Hz, 1H), 6.63 – 6.51 (m, 2H), 6.42 (dd, J = 8.4, 2.3 Hz, 1H), 5.36 – 5.25 (m, 2H), 5.18 (d, J = 14.2 Hz, 1H), 5.10 – 4.98 (m, 2H), 4.81 (d, J = 14.2 Hz, 1H), 4.55 (d, J = 5.7 Hz, 2H), 4.17 – 3.93 (m, 2H), 3.81 (s, 3H), 3.79 – 3.56 (m, 4H), 3.71 (s, 3H), 3.57 – 3.43 (m, 2H), 2.10 (tt, J = 8.1, 4.7 Hz, 1H), 1.88 (s, 3H), 1.07 – 0.87 (m, 4H). 19F NMR (377 MHz, DMSO) δ -99.26, -100.67. N‐({4‐amino‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐[6‐(6,6‐difluoro‐1,4‐diazepan‐1‐yl)‐2‐ methylpyridin‐3‐yl]pyrimidine‐5‐carboxamide (Example 42) A solution of tert‐Butyl 4‐(5‐{N‐[(4‐{[(2,4‐dimethoxyphenyl)methyl]amino}‐1H,3H‐furo[3,4‐c]quinolin‐7‐ yl)methyl-2‐cyclopropylpyrimidine‐5‐amido}‐6‐methylpyridin‐2‐yl)‐6,6‐difluoro‐1,4‐diazepane‐1‐carboxylate (Int. 112, 0.145 g, 0.150 mmol, 1.0 eq.) in DCM (1.5 mL), TFA (0.58 mL, 7.53 mmol, 50 eq.) was added. Then, the RM was stirred at RT overnight. The reaction mixture was diluted with DCM and poured into water, then alka- lized with 0.5 M NaOH. The organic layer was separated. The water phase was extracted with DCM (3x). The combined organic layers were washed with saturated solution of NaHCO3, brine and dried over MgSO4, filtered and evaporated. The product was isolated by preparative HPLC to obtain N‐({4‐amino‐1H,3H‐furo[3,4‐c]quino- lin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐[6‐(6,6‐difluoro‐1,4‐diazepan‐1‐yl)‐2‐methylpyridin‐3‐yl]pyrimidine‐5‐carbox- amide after lyophilization (Example 42, 0.017 g, 0.029 mmol, 19%, white solid, m/z [M+H]+: 587.2692). 1H NMR (400 MHz, DMSO) δ 8.49 (s, 2H), 7.47 – 7.37 (m, 2H), 7.28 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 8.1, 1.7 Hz, 1H), 6.52 (d, J = 9.0 Hz, 1H), 6.47 (s, 2H), 5.29 (t, J = 3.4 Hz, 2H), 5.15 (d, J = 14.2 Hz, 1H), 4.98 (t, J = 3.4 Ryvu Therapeutics S.A. RVU305 164 R10945WO Hz, 2H), 4.88 (d, J = 14.2 Hz, 1H), 4.17 – 3.92 (m, 2H), 3.73 – 3.47 (m, 2H), 3.01 – 2.58 (m, 5H), 2.11 (tt, J = 8.8, 4.9 Hz, 1H), 1.83 (s, 3H), 1.17 – 0.80 (m, 4H). 19F NMR (377 MHz, DMSO) δ -96.61 – -96.89 (m). Example 43: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-6-{1-[(methyla- mino)methyl]cyclopropoxy}pyridin-3-yl)pyrimidine-5-carboxamide tert-Butyl N-methyl-N-({1-[(6-methyl-5-nitropyridin-2-yl)oxy]cyclopropyl}methyl)carbamate (Int.113) To a mixture of 6-chloro-2-methyl-3-nitropyridine (0.345 g, 1.999 mmol, 1.0 eq.) and tert-butyl N-[(1-hy- droxycyclopropyl)methyl]-N-methylcarbamate (0.484 g, 2.406 mmol, 1.204 eq.) in toluene (7 mL), Pd(dba)2 (0.057 g, 0.1 mmol, 0.05 eq.), Cs2CO3 (0.977 g, 2.999 mmol, 1.5 eq.) and BINAP (0.249 g, 0.4 mmol, 0.2 eq.) were added in one portion at RT under nitrogen. The mixture was stirred to 110° C for 4 h. The mixture was cooled down to RT and the residue was poured into water. The aqueous phase was extracted with ethyl ace- tate (3x). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and con- centrated. The residue was purified by FCC (0 to 40% EtOAc gradient in heptane) to obtain tert-butyl N-methyl- N-({1-[(6-methyl-5-nitropyridin-2-yl)oxy]cyclopropyl}methyl)carbamate (Int.113, 0.562 g, 1.616 mmol, 81%, yel- lowish oil). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 15.2, 9.1 Hz, 1H), 6.89 (dd, J = 29.0, 9.0 Hz, 1H), 3.73 (d, J = 21.5 Hz, 2H), 2.87 (s, 3H), 2.72 (s, 3H), 1.17 (d, J = 95.6 Hz, 9H), 1.01 – 0.91 (m, 4H). tert-Butyl N-({1-[(5-amino-6-methylpyridin-2-yl)oxy]cyclopropyl}methyl)-N-methylcarbamate (Int.114) A mixture of iron (0.601 g, 10.767 mmol, 7.0 eq.), ammonium chloride (0.987 g, 18.452 mmol, 11.996 eq.), tert-butyl N-methyl-N-({1-[(6-methyl-5-nitropyridin-2-yl)oxy]cyclopropyl}methyl)carbamate (Int.113, 0.535 g, 1.538 mmol, 1.0 eq.) in ethanol (15 mL) and water (5 mL) was stirred under reflux for 1 h. The hot reaction mixture was filtered through a Celit ® pad and washed with hot EtOH. The filtrate was concentrated and the Ryvu Therapeutics S.A. RVU305 165 R10945WO crude product was diluted with water and extracted by EtOAc(3x). The combined organic layers were washed with water and brine, then dried over Na2SO4, filtered and evaporated to obtain tert-butyl N-({1-[(5-amino-6- methylpyridin-2-yl)oxy]cyclopropyl}methyl)-N-methylcarbamate (Int.114, 0.373 g, 1.092 mmol, 71%, yellow solid, m/z [M+H]+: 308.3). tert-Butyl N-[(1-{[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]oxy}cyclopropyl)methyl]-N-methyl- carbamate (Int.115) To the solution of tert-butyl N-({1-[(5-amino-6-methylpyridin-2-yl)oxy]cyclopropyl}methyl)-N-methylcarba- mate (Int.114, 0.323 g, 0.946 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.186 g, 1.135 mmol, 1.2 eq.) and DMAP (0.0116 g, 0.095 mmol, 0.1 eq.) in toluene (6.0 mL), DIPEA (0.412 mL, 2.365 mmol, 2.501 eq.) was added, followed by T3P as 50% in EtOAc (0.563 mL, 1.892 mmol, 2.00 eq.). The RM was stirred at 90°C for 2 h. Then the RM was cooled down, quenched with a saturated solution of NaHCO3 and extracted with EtOAc (3x). The organic layers were washed with water, brine and dried over Na2SO4, filtered and evapo- rated. The crude product was purified by FCC (0 to 60% EtOAc gradient in heptane) to obtain tert-butyl N-[(1- {[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]oxy}cyclopropyl)methyl]-N-methylcarbamate (Int. 115, 0.335 g, 0.702 mmol, 74%, beige solid, m/z [M+H]+: 454.6). 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.11 (s, 2H), 7.64 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H), 3.73 (d, J = 18.1 Hz, 2H), 2.86 (s, 3H), 2.34 (s, 3H), 2.33 – 2.27 (m, 1H), 1.41 – 1.06 (m, 13H), 0.96 – 0.84 (m, 4H). tert-Butyl N-{[1-({5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6- methylpyridin-2-yl}oxy)cyclopropyl]methyl}-N-methylcarbamate (Int.116) A suspension of tert-butyl N-[(1-{[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]oxy}cyclopro- pyl)methyl]-N-methylcarbamate (Int.115, 0.312 g, 0.654 mmol, 1.0 eq.), 4-chloro-7-(chloromethyl)-1H,3H- furo[3,4-c]quinoline (Int. C, 0.192 g, 0.752 mmol, 1.15 eq.) and Cs2CO3 (0.426 g, 1.307 mmol, 2.001 eq.) in MeCN (6 mL) was stirred at 70°C for 2 h. The RM was cooled down, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evapo- rated. The residue was purified by FCC (0 to 100% EtOAc gradient in heptane) to obtain tert-butyl N-{[1-({5-[N- ({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6-methylpyridin-2-yl}oxy)cy- clopropyl]methyl}-N-methylcarbamate (Int.116, 0.376 g, 0.515 mmol, 79%, beige solid, m/z [M+H]+: 672.1). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 9.5 Hz, 2H), 7.85 (d, J = 7.4 Hz, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 11.5 Hz, 1H), 6.61 (d, J = 8.7 Hz, 1H), 5.54 (s, 2H), 5.35 (d, J = 14.6 Hz, 1H), 5.22 (t, J = 3.1 Hz, 2H), 5.08 – 4.92 (m, 1H), 3.61 (dd, J = 35.9, 15.8 Hz, 2H), 2.66 (d, J = 41.4 Hz, 3H), 2.12 (s, 1H), 1.97 (s, 3H), 1.31 (s, 3H), 1.09 – 0.61 (m, 14H). tert-Butyl N-({1-[(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclo- propylpyrimidine-5-amido}-6-methylpyridin-2-yl)oxy]cyclopropyl}methyl)-N-methylcarbamate (Int.117) A solution of tert-butyl N-{[1-({5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5- amido]-6-methylpyridin-2-yl}oxy)cyclopropyl]methyl}-N-methylcarbamate (Int.116, 0.356 g, 0.488 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.49 g, 2.93 mmol, 6.006 eq.) in DMSO (7 mL) was stirred at 120°C overnight. The RM was evaporated, then diluted with water and extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was puri- fied by FCCs (first: 0 to 5% MeOH gradient in DCM; second: 0 to 50% EtOAc gradient in heptane; third: 0 to Ryvu Therapeutics S.A. RVU305 166 R10945WO 50% EtOAc gradient in DCM) to obtain tert-butyl N-({1-[(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H- furo[3,4-c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido}-6-methylpyridin-2-yl)oxy]cyclopropyl}methyl)- N-methylcarbamate (Int.117, 0.222 g, 0.249 mmol, 51%, yellow solid, m/z [M+H]+: 803.0). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 2H), 7.51 – 7.35 (m, 3H), 7.24 – 7.16 (m, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.00 (t, J = 5.7 Hz, 1H), 6.63 – 6.54 (m, 2H), 6.42 (dd, J = 8.4, 2.4 Hz, 1H), 5.31 (s, 2H), 5.23 – 5.13 (m, 1H), 5.04 (s, 2H), 4.89 (dd, J = 33.4, 14.1 Hz, 1H), 4.61 – 4.49 (m, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 3.70 – 3.47 (m, 2H), 2.65 (d, J = 51.5 Hz, 3H), 2.11 (s, 1H), 1.92 (d, J = 3.7 Hz, 3H), 1.31 (s, 2H), 1.08 – 1.01 (m, 2H), 0.99 (s, 7H), 0.93 – 0.71 (m, 6H). 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2-methyl- 6-{1-[(methylamino)methyl]cyclopropoxy}pyridin-3-yl)pyrimidine-5-carboxamide (Int.118) To a solution of tert-butyl N-({1-[(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quino- lin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido}-6-methylpyridin-2-yl)oxy]cyclopropyl}methyl)-N-methylcarba- mate (Int.117, 0.219 g, 0.246 mmol, 1.0 eq.) in DCM (5 mL), TFA (0.47 mL, 6.138 mmol, 24.974 eq.) was added. The RM was stirred at RT for 3 h. Then, the RM was diluted with DCM, cooled down on an ice-bath, carefully neutralized with 2M NaOH solution to pH = 10-11 and stirred at RT for 20 min. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (0 to 10% MeOH gradient in DCM) to give 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}- 1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2-methyl-6-{1-[(methylamino)methyl]cyclopropoxy}pyridin-3-yl)pyrimi- dine-5-carboxamide (Int.118, 0.12 g, 0.116 mmol, 47%, m/z [M+H]+: 702.8). 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 2H), 7.47 – 7.42 (m, 2H), 7.20 – 7.13 (m, 2H), 7.01 (t, J = 5.6 Hz, 1H), 6.61 (d, J = 8.6 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 5.30 (d, J = 3.7 Hz, 2H), 5.20 (dd, J = 13.8, 7.0 Hz, 1H), 5.04 (s, 2H), 4.91 (d, J = 14.2 Hz, 1H), 4.55 (d, J = 5.7 Hz, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 2.78 (d, J = 2.8 Hz, 2H), 2.21 (d, J = 3.9 Hz, 3H), 2.15 – 2.08 (m, 1H), 1.89 (d, J = 7.9 Hz, 2H), 1.03 (dd, J = 8.1, 3.3 Hz, 2H), 0.95 – 0.81 (m, 4H), 0.79 – 0.64 (m, 5H). N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-6-{1-[(methylamino)methyl]cyclo- propoxy}pyridin-3-yl)pyrimidine-5-carboxamide (Example 43) To a solution of 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-(2-methyl-6-{1-[(methylamino)methyl]cyclopropoxy}pyridin-3-yl)pyrimidine-5-carboxamide (Int. 118, 0.12 g, 0.116 mmol, 1.0 eq.) in DCM (5 mL), TFA (0.445 mL, 5.811 mmol, 49.979 eq.) was added and the RM was stirred at RT overnight. Then, the RM was diluted by CHCl3/i-PrOH (3:1) mixture, cooled down on an ice-bath, carefully neutralized with 2M NaOH solution to pH = 10-11 and stirred for 10 min. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered, and concentrated. A crude residue was purified by FCC (0 to 100% MeOH gradient in DCM, then washed with 1N NH3 in MeOH solution) and by pre- parative HPLC and lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2- methyl-6-{1-[(methylamino)methyl]cyclopropoxy}pyridin-3-yl)pyrimidine-5-carboxamide; bis(formic acid) (Exam- ple 43, 0.026 g, 0.04 mmol, 34%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.18%, m/z [M+H]+: 552.21). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2H), 8.26 (s, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.19 (dd, J = 8.2, 1.4 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H), 6.49 (s, 2H), 5.30 (t, 2H), 5.18 (d, J = 14.2 Hz, 1H), 4.99 (t, 2H), 4.95 (d, J = 14.3 Hz, 1H), 3.02 (q, 3H), 2.34 (s, 3H), 2.12 (tt, J = 8.2, 4.8 Hz, 1H), 1.91 (s, 3H), 1.09 – 0.64 (m, 9H). Ryvu Therapeutics S.A. RVU305 167 R10945WO Example 44: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[2-(trifluorome- thyl)piperazin-1-yl]pyridin-3-yl}pyrimidine-5-carboxamide tert-Butyl 4-(6-methyl-5-nitropyridin-2-yl)-3-(trifluoromethyl)piperazine-1-carboxylate (Int.119) A mixture of 6-chloro-2-methyl-3-nitropyridine (0.244 g, 1.414 mmol, 1.198 eq.), tert-butyl 3-(trifluorome- thyl)piperazine-1-carboxylate (0.3 g, 1.18 mmol, 1.0 eq.) and cesium carbonate (1.153 g, 3.539 mmol, 2.999 eq.) in toluene (10.0 ml) was purge with Ar for 15 min. Then cataCXium A Pd G3 (0.061 g, 0.084 mmol, 0.071 eq.) was added and the resulting RM was stirred at 105°C for 16 h. then, the reaction mixture was allowed to cool down to RT, EtOAc was added and the mixture was filtered through a pad of celite®. The filtrate was con- centrated. The residue was purified by FCC (0% to 60% EtOAc gradient in Hexane) to obtain tert-butyl 4-(6- methyl-5-nitropyridin-2-yl)-3-(trifluoromethyl)piperazine-1-carboxylate (Int.119, 0.343 g, 0.835 mmol, 71%, brown solid). 1H NMR (400 MHz, DMSO) δ 8.34 (d, J = 9.3 Hz, 1H), 7.01 (d, J = 9.4 Hz, 1H), 5.69 – 5.52 (m, 1H), 4.48 – 4.23 (m, 2H), 4.14 – 3.89 (m, 1H), 3.46 – 3.30 (m, 1H), 3.27 – 2.91 (m, 2H), 2.70 (s, 3H), 1.42 (s, 9H). 19F NMR (377 MHz, DMSO) δ -68.54, -68.88. tert-Butyl 4-(5-amino-6-methylpyridin-2-yl)-3-(trifluoromethyl)piperazine-1-carboxylate (Int.120) To a solution of tert-butyl 4-(6-methyl-5-nitropyridin-2-yl)-3-(trifluoromethyl)piperazine-1-carboxylate (Int. Int.119, 0.339 g, 0.825 mmol, 1.0 eq.) in THF (28 ml) and EtOH (14 ml), zinc (0.539 g, 8.244 mmol, 9.993 eq.) followed by a saturated solution of NH4Cl (22 mL) were added and the RM was stirred at RT for 5 h. Then the reaction mixture was diluted with EtOAc, filtered through a pad of celite® and washed with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by FCC (0% to 50% EtOAc gradient in hexane) to obtain tert-butyl 4-(5-amino-6-methylpyridin-2- Ryvu Therapeutics S.A. RVU305 168 R10945WO yl)-3-(trifluoromethyl)piperazine-1-carboxylate (Int.120, 0.156 g, 0.424 mmol, 51%, brown oil, m/z [M+H]+: 361.2). 1H NMR (400 MHz, DMSO) δ 6.93 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 5.26 – 5.13 (m, 1H), 4.41 (s, 2H), 4.24 (dt, J = 14.4, 1.8 Hz, 1H), 4.06 – 3.81 (m, 1H), 3.72 (d, J = 12.6 Hz, 1H), 3.34 – 3.17 (m, 1H), 3.15 – 2.80 (m, 2H), 2.18 (s, 3H), 1.40 (s, 9H). 19F NMR (377 MHz, DMSO) δ -67.55 (d, J = 8.5 Hz), -68.17 (d, J = 8.9 Hz). tert-Butyl 4-[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]-3-(trifluoromethyl)piperazine-1-carbox- ylate (Int.121) 2-Cyclopropylpyrimidine-5-carboxylic acid (Int.120, 0.068 g, 0.414 mmol, 0.996 eq.), tert-butyl 4-(5- amino-6-methylpyridin-2-yl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.153 g, 0.416 mmol, 1.0 eq.) and DMAP (0.01 g, 0.082 mmol, 0.197 eq.) were taken in toluene (5 mL), followed by an addition of DIPEA (0.18 ml, 1.033 mmol, 2.483 eq.). Then T3P as 50% solution in EtOAc (0.5 ml, 0.84 mmol, 2.019 eq.) was added slowly and the RM was stirred at 80°C for 1 h. Then, the RM was diluted with EtOAc and neutralized with a sat- urated solution of NaHCO3. The organic phase was washed with a saturated solution of NaHCO3, brine, dried over Na2SO4, filtered and evaporated to obtain tert-butyl 4-[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyri- din-2-yl]-3-(trifluoromethyl)piperazine-1-carboxylate (Int.121, 0.23 g, 0.363 mmol, 87%, brown oil, m/z [M+H]+: 507.7). 1H NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 9.10 (s, 2H), 7.56 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.50 – 5.38 (m, 1H), 4.31 (d, J = 14.6 Hz, 1H), 4.12 – 3.88 (m, 2H), 3.32 – 2.83 (m, 3H), 2.31 (s, 3H), 1.42 (s, 9H), 1.20 – 1.13 (m, 2H), 1.12 – 1.05 (m, 2H). 19F NMR (377 MHz, DMSO) δ -68.07 (d, J = 8.6 Hz), -68.53. tert-Butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6- methylpyridin-2-yl}-3-(trifluoromethyl)piperazine-1-carboxylate (Int.122) To a solution of tert-butyl 4-[5-(2-cyclopropylpyrimidine-5-amido)-6-methylpyridin-2-yl]-3-(trifluorome- thyl)piperazine-1-carboxylate (Int.121, 0.227 g, 0.359 mmol, 1.0 eq.) in acetonitrile (30 ml) cesium carbonate (0.152 g, 0.467 mmol, 1.301 eq.) and potassium iodide (0.012 g, 0.072 mmol, 0.202 eq.) were added. The mix- ture was stirred for 10-15 min at RT, then 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.11 g, 0.429 mmol, 1.195 eq.) was added and the RM was stirred at 70°C for 4 h. The RM was cooled down, diluted with EtOAc, org phase was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to obtain tert-butyl 4-{5-[N-({4-chloro-1H,3H- furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-6-methylpyridin-2-yl}-3-(trifluoromethyl)pipera- zine-1-carboxylate (Int.122, 0.21 g, 0.249 mmol, 69%, brown solid, m/z [M+H]+: 724.8). 1/1 mixture of restricted C-N amide rotation isomers: 1H NMR (400 MHz, DMSO) δ 8.56 (s, 1H, CH, first rota- mer), 8.53 (s, 1H, CH, second rotamer), 7.94 – 7.89 (m, 1H), 7.88 – 7.81 (m, 1H), 7.75 – 7.67 (m, 1H), 7.45 – 7.38 (m, 1H), 6.68 (dd, J = 9.0, 5.4 Hz, 1H), 5.60 – 5.51 (m, 2H), 5.42 – 5.17 (m, 4H), 5.05 – 4.91 (m, 1H), 4.29 – 4.16 (m, 1H), 4.09 – 3.83 (m, 2H), 3.33 – 2.75 (m, 3H), 2.17 – 2.07 (m, 1H), 1.96 (s, 1.5H, CH3, first rota- mer), 1.90 (s, 1.5H, CH3, second rotamer), 1.39 (s, 9H), 1.09 – 0.78 (m, 4H). 19F NMR (377 MHz, DMSO) δ -67.98 – -68.38 (m), -68.55 (d, J = 40.9 Hz). tert-Butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclo- propylpyrimidine-5-amido}-6-methylpyridin-2-yl)-3-(trifluoromethyl)piperazine-1-carboxylate (Int.123) Ryvu Therapeutics S.A. RVU305 169 R10945WO A solution of tert-butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine- 5-amido]-6-methylpyridin-2-yl}-3-(trifluoromethyl)piperazine-1-carboxylate (Int.122, 0.206 g, 0.245 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.245 g, 1.465 mmol, 5.989 eq.) in DMSO (5.0 mL) was stirred at 105°C for 38 h. The RM was cooled down, diluted with EtOAc and the organic solution was washed four times with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to obtain tert-butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H- furo[3,4-c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido}-6-methylpyridin-2-yl)-3-(trifluoromethyl)pipera- zine-1-carboxylate (Int.123, 0.18 g, 0.187 mmol, 76%, yellow solid, m/z [M+H]+: 855.9). 1/1 mixture of restricted C-N amide rotation isomers: 1H NMR (400 MHz, DMSO) δ 8.53 (s, 1H, CH, first rota- mer), 8.49 (s, 1H, CH, second rotamer), 7.48 – 7.40 (m, 2H), 7.35 (dd, J = 8.9, 6.4 Hz, 1H), 7.22 – 7.11 (m, 2H), 7.03 – 6.97 (m, 1H), 6.67 (dd, J = 9.0, 5.7 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.3, 2.2 Hz, 1H), 5.38 – 5.14 (m, 4H), 5.04 (t, J = 3.4 Hz, 2H), 4.86 (dd, J = 21.4, 14.1 Hz, 1H), 4.55 (d, J = 5.7 Hz, 2H), 4.29 – 4.17 (m, 1H), 4.07 – 3.81 (m, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 3.29 – 3.12 (m, 1H), 3.08 – 2.79 (m, 2H), 2.15 – 2.05 (m, 1H), 1.91 (s, 1.5H, CH3, first rotamer), 1.87 (s, 1.5H, second rotamer), 1.39 (s, 9H), 1.07 – 0.98 (m, 2H), 0.95 – 0.82 (m, 2H). 19F NMR (377 MHz, DMSO) δ -68.19 (d, J = 25.1 Hz), -68.55 (d, J = 45.2 Hz). N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[2-(trifluoromethyl)piperazin-1- yl]pyridin-3-yl}pyrimidine-5-carboxamide (Example 44) To a solution of tert-butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]2-cyclopropylpyrimidine-5-amido}-6-methylpyridin-2-yl)-3-(trifluoromethyl)piperazine-1-carboxylate (Int.123, 0.176 g, 0.183 mmol, 1.0 eq.) in DCM (8 ml), trifluoroacetic acid (2.0 ml, 26.118 mmol, 142.551 eq.) was added and the reaction mixture was stirred for 43 h at RT. Then the RM was diluted with DCM (80 mL) and carefully basified with a saturated solution of NaHCO3. After 30 minutes of vigorous stirring, the organic layer was separated, washed carefully with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, fil- tered and concentrated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM). Fraction containing product was re-purified by preparative HPLC (basic conditions) and lyophilized to give N-({4-amino- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[2-(trifluoromethyl)piperazin-1-yl]pyridin-3- yl}pyrimidine-5-carboxamide (Example 44, 0.028 g, 0.046 mmol, 25%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.54%). 1/1 mixture of restricted C-N amide rotation isomers: 1H NMR (400 MHz, DMSO) δ 8.51 (s, 1H, CH, first rota- mer), 8.48 (s, 1H, CH, second rotamer), 7.49 – 7.24 (m, 3H), 7.18 (ddd, J = 10.0, 8.2, 1.7 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 6.47 (s, 2H), 5.30 (t, J = 3.4 Hz, 2H), 5.27 – 4.76 (m, 5H), 3.98 – 3.73 (m, 1H), 3.20 (d, J = 13.6 Hz, 1H), 3.02 – 2.89 (m, 2H), 2.83 (d, J = 13.6 Hz, 1H), 2.35 – 2.19 (m, 1H), 2.17 – 2.05 (m, 1H), 1.92 (s, 1.5H, CH3, first rotamer), 1.79 (s, 1.5H, CH3, second rotamer), 1.08 – 0.99 (m, 2H), 0.98 – 0.82 (m, 2H). 19F NMR (377 MHz, DMSO) δ -66.12 (d, J = 9.2 Hz), -66.27 (d, J = 9.2 Hz). Example 45: N-(4-methylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (DC762-045) Ryvu Therapeutics S.A. RVU305 170 R10945WO N-(4-methylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.124) To solution of 4-methylpyrimidin-5-amine (0.3 g, 2.749 mmol, 1.0 eq.), 6-(trifluoromethyl)pyridine-3-car- boxylic acid (0.525 g, 2.749 mmol, 1.0 eq.), DMAP (0.016 g, 0.137 mmol, 0.05 eq.) and DIPEA (1.2 mL, 6.889 mmol, 2.506 eq.) in toluene (5.0 mL), T3P as 50% in EtOAc (3.3 mL, 5.544 mmol, 2.017 eq.) was added. The reaction mixture was stirred at RT for 1 h. Then, the RM was diluted with water and extracted with EtOAc (3x). The combined organic extracts were washed with brine and dried over with Na2SO4, filtered and evaporated. The crude product was purified by FCC (0 to 3% MeOH gradient in EtOAc) to obtain N-(4-methylpyrimidin-5- yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.124, 0.734 g, 2.575 mmol, 94%, beige solid, m/z [M+H]+: 283.2). 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.30 (d, J = 2.1 Hz, 1H), 8.96 (s, 1H), 8.81 (s, 1H), 8.64 – 8.56 (m, 1H), 8.20 – 8.10 (m, 1H), 2.49 (s, 3H). N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-methylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide (Int.125) A suspension of cesium carbonate (1.25 g, 3.836 mmol, 1.49 eq.), potassium iodide (0.427 g, 2.572 mmol, 0.999 eq.), 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.66 g, 2.545 mmol, 0.989 eq.) and N-(4-methylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.124, 0.734 g, 2.575 mmol, 1.0 eq.) in acetonitrile (12.0 mL) was stirred at 70°C for 2 h. The RM was cooled down, diluted with water and ex- tracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0 to 80% EtOAc gradient in hexane) to obtain N-({4-chloro- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-methylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.125, 0.634 g, 1.18 mmol, 46%, yellowish solid, m/z [M+H]+: 500.3). 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.81 – 8.78 (m, 1H), 8.54 (s, 1H), 8.12 – 8.07 (m, 1H), 8.00 – 7.97 (m, 1H), 7.85 (t, J = 7.9 Hz, 2H), 7.76 – 7.70 (m, 1H), 5.59 – 5.52 (m, 3H), 5.23 – 5.18 (m, 2H), 5.07 (d, J = 14.6 Hz, 1H), 2.27 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.80 (s, 3F). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-methylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide (Example 45) Step 1: Ryvu Therapeutics S.A. RVU305 171 R10945WO A suspension of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-methylpyrimidin-5-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide (Int.125, 0.73 g, 1.344 mmol, 1.0 eq.), tert-butyl carbamate (0.31 g, 2.646 mmol, 1.97 eq.) and Cs2CO3 (1.1 g, 3.376 mmol, 2.513 eq.) in dioxane (10.0 mL) was sparged with argon for 5 min. Then, Pd2dba3 (0.25 g, 0.273 mmol, 0.203 eq.) and XantPhos (0.23 g, 0.397 mmol, 0.296 eq.) were added and reaction mixture was stirred at 70°C for 2 h. The reaction mixture was diluted with EtOAc, filtered through a pad of celite® and the filtrate was concentrated. The residue was washed with a saturated solution of Na2CO3, water, brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0 to 100% EtOAc gradient in hexane) to obtain tert-butyl N-(7-{[N-(4-methylpyrimidin-5-yl)-1-[6-(trifluoromethyl)pyri- din-3-yl]formamido]methyl}-1H,3H-furo[3,4-c]quinolin-4-yl)carbamate (0.059 g, 0.083 mmol, 6%, yellow solid, m/z [M+H]+: 581.5) Step 2: To a solution of the obtained compound was dissolved in DCM (6.0 mL), TFA (3.0 mL) was added drop- wise. The mixture was stirred at RT for 1 h. Then, the reaction mixture was basified with a saturated solution of Na2CO3 and extracted with DCM (2x). The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by FCCs (first: silica, 0 to 5% MeOH gradient in DCM; second: RP-C18, H2O-MeCN) to give product N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-methylpyrimidin- 5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 45, 0.036 g, 0.073 mmol, 5%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 97.94%, m/z [M+H]+: 481.5). 85/15 mixture of restricted C-N amide rotation isomers in DMSO-d6 at RT: Major rotamer: 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.78 – 8.73 (m, 1H), 8.51 (s, 1H), 8.09 – 8.02 (m, 1H),7.86 – 7.78 (m, 1H), 7.49 – 7.43 (m, 1H), 7.43 – 7.34 (m, 1H), 7.20 (dd, J = 8.3, 1.7 Hz, 1H), 6.49 (s, 2H), 5.39 – 5.24 (m, 3H), 5.05 – 4.91 (m, 3H), 2.16 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.80 (s, 3F). Minor rotamer: 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.92 (s, 1H), 8.71 – 8.68 (m, 1H), 8.51 (s, 1H), 8.15 – 8.11 (m, 1H), 7.43 – 7.34 (m, 1H), 7.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.03 – 6.97 (m, 1H), 6.49 (s, 2H), 5.39 – 5.24 (m, 3H), 5.05 – 4.91 (m, 3H), 2.35 – 2.30 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.57 (s, 3F). Example 46: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol- 4-yl)pyrimidine-5-carboxamide
Ryvu Therapeutics S.A. RVU305 172 R10945WO 2-Cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.126) DMAP (0.112 g, 0.917 mmol, 0.498 eq.), DIPEA (0.796 ml, 4.57 mmol, 2.484 eq.), 2-cyclopropylpyrimi- dine-5-carboxylic acid (0.302 g, 1.84 mmol, 1.0 eq.) and 1-ethyl-3-methyl-1H-pyrazol-4-amine hydrochloride (0.312 g, 1.93 mmol, 1.049 eq.) were taken in DMF (9.0 mL) and T3P as 50% in EtOAc (2.176 mL, 3.655 mmol, 1.987 eq.) was added dropwise at 0°C and the reaction mixture was stirred at 100°C for 1 h. Then, the reaction mixture was quenched with a saturated solution of Na2CO3, extracted with EtOAc (2x) and the com- bined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude prod- uct was isolated by FCC (0% to 30% ACN gradient in DCM) to obtain 2-cyclopropyl-N-(1-ethyl-3-methyl-1H- pyrazol-4-yl)pyrimidine-5-carboxamide (Int.126, 0.243 g, 0.842 mmol, 46%, yellow solid, m/z [M+H]+: 272.0). 1H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 9.05 (s, 2H), 7.95 (s, 1H), 4.04 (q, J = 7.3 Hz, 2H), 2.34 – 2.26 (m, 1H), 2.16 (s, 3H), 1.34 (t, J = 7.3 Hz, 3H), 1.20 – 1.12 (m, 2H), 1.11 – 1.03 (m, 2H). N-({4-Chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimi- dine-5-carboxamide (Int.127) To a solution of 2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.126, 0.24 g, 0.831 mmol, 1.0 eq.), 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.216 g, 0.833 mmol, 1.002 eq.) in ACN (4.5 mL) was added Cs2CO3 (0.543 g, 1.667 mmol, 2.004 eq.). The reaction mixture was stirred at 78°C for 1.5 h. The reaction mixture was cooled down to room temperature, diluted by water, extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N- (1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.127, 0.393 g, 0.683 mmol, 82%, yellow solid, m/z [M+H]+: 490.1) was used in the next step. Ryvu Therapeutics S.A. RVU305 173 R10945WO 1H NMR (400 MHz, DMSO) δ 8.59 (s, 2H), 7.90 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.70 – 7.63 (m, 2H), 5.55 (t, J = 3.1 Hz, 2H), 5.24 (t, J = 3.1 Hz, 2H), 5.11 (s, 2H), 3.88 (q, J = 7.3 Hz, 2H), 2.20 – 2.12 (m, 1H), 1.65 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H), 1.09 – 1.03 (m, 2H), 0.99 – 0.92 (m, 2H). 2-Cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(1-ethyl-3- methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.128) To a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl- 1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.127, 0.39 g, 0.678 mmol, 1.0 eq.) in DMSO (3.5 mL), 1-(2,4- dimethoxyphenyl)methanamine (1.134 g, 6.782 mmol, 10.004 eq.) was added and the reaction was stirred at 100°C overnight. Then the reaction mixture was cooled down to room temperature, diluted with water, ex- tracted with DCM (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to give 2-cyclo- propyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(1-ethyl-3-methyl- 1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.128, 0.422 g, 0.592 mmol, 87%, yellow solid, m/z [M+H]+: 620.3). 1H NMR (400 MHz, DMSO) δ 8.55 (s, 2H), 7.59 (s, 1H), 7.45 – 7.40 (m, 2H), 7.18 – 7.10 (m, 2H), 7.01 (t, J = 5.7 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 5.35 – 5.28 (m, 2H), 5.09 – 5.00 (m, 2H), 4.96 (s, 2H), 4.56 (d, J = 5.6 Hz, 2H), 3.88 (q, J = 7.3 Hz, 2H), 3.82 (s, 3H), 3.73 (s, 3H), 2.18 – 2.11 (m, 1H), 1.60 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H), 1.09 – 1.01 (m, 2H), 0.98 – 0.92 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimi- dine-5-carboxamide (Example 46) To a solution of 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.128, 0.37 g, 0.519 mmol, 1.0 eq.) in DCM (2.5 mL) trifluoroacetic acid (1.98 ml, 25.874 mmol, 49.813 eq.) was added at 0°C. The reaction was stirred at room temperature overnight. Then, the reaction mixture was diluted with DCM and with a satu- rated solution of K2CO3. The crude product was extracted and the water phases were washed by DCM and then organic phases was combined, dried over Na2SO4, filtered and evaporated. The crude product was puri- fied by FCC twice (1st: 0% to 10% MeOH gradient in DCM, 2nd: FCC C18) and lyophilized with EtOH and water to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide (Example 46, 0.055 g, 0.117 mmol, 23%, white powder, m/z [M+H]+: 470.1). 1H NMR (400 MHz, DMSO) δ 8.55 (s, 2H), 7.63 (s, 1H), 7.46 – 7.38 (m, 2H), 7.14 (dd, J = 8.2, 1.7 Hz, 1H), 6.48 (s, 2H), 5.30 (t, J = 3.4 Hz, 2H), 4.99 (t, J = 3.5 Hz, 2H), 4.97 (s, 2H), 3.89 (q, J = 7.2 Hz, 2H), 2.20 – 2.11 (m, 1H), 1.58 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H), 1.10 – 1.02 (m, 2H), 0.98 – 0.92 (m, 2H). Example 47: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 174 R10945WO N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.129) DMAP (0.096 g, 0.786 mmol, 0.499 eq.), DIPEA (0.684 ml, 3.927 mmol, 2.493 eq.), 2,4-dimethylpyrim- idin-5-amine (0.204 g, 1.656 mmol, 1.052 eq.) and 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.301 g, 1.575 mmol, 1.0 eq.) were taken in DMF (8.0 mL) and T3P as 50% solution in EtOAc (1.869 mL, 3.14 mmol, 1.994 eq.) was added dropwise at 0°C. Then, the reaction mixture was stirred at 100°C for 1 h. The reaction was quenched with a saturated solution of Na2CO3, extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. N-(2,4-dimethylpyrimidin-5-yl)-6-(tri- fluoromethyl)pyridine-3-carboxamide (Int.129, 0.465 g, 1.538 mmol, 98%, brown solid, m/z [M+H]+: 297.1) was used in the next step. 1H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 9.30 (d, J = 2.1 Hz, 1H), 8.65 (s, 1H), 8.61 (dd, J = 8.2, 2.2 Hz, 1H), 8.14 (dd, J = 8.3, 0.8 Hz, 1H), 2.61 (s, 3H), 2.43 (s, 3H). N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3- carboxamide (Int.130) To a solution of N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.129, 0.46 g, 1.522 mmol, 1.0 eq.) and 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (0.395 g, 1.523 mmol, 1.001 eq.) in ACN (8.0 mL), Cs2CO3 (0.99 g, 3.038 mmol, 1.997 eq.) was added. The reaction mixture was stirred at 78°C for 4.5 h. The reaction mixture was cooled down to room temperature, diluted with water, extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evap- orated. The crude product was purified by FCC (0% to 50% ACN gradient in DCM) to obtain N-({4-chloro- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.130, 0.265 g, 0.49 mmol, 32%, white solid, m/z [M+H]+: 514,5). 1H NMR (400 MHz, DMSO) δ 8.80 (d, J = 2.1 Hz, 1H), 8.39 (s, 1H), 8.10 (dd, J = 8.2, 2.1 Hz, 1H), 7.99 (s, 1H), 7.86 (q, 2H), 7.75 (dd, J = 8.5, 1.7 Hz, 1H), 5.58 – 5.51 (m, 3H), 5.23 (t, J = 3.1 Hz, 2H), 5.02 (d, J = 14.6 Hz, 1H), 2.43 (s, 3H), 2.22 (s, 3H). Ryvu Therapeutics S.A. RVU305 175 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3- carboxamide (Example 47) Step 1: To a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2,4-dimethylpyrimidin-5-yl)-6-(tri- fluoromethyl)pyridine-3-carboxamide (Int.130, 0.21 g, 0.388 mmol, 1.0 eq.) in DMSO (2.0 mL), 1-(2,4-di- methoxyphenyl)methanamine (0.65 g, 3.887 mmol, 10.014 eq.) was added. The reaction was stirred at 100°C overnight. The reaction mixture was cooled down to room temperature, diluted with water, extracted with DCM (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. Step 2: To a solution of the product in DCM (3.0 mL), trifluoroacetic acid (1.5 ml, 19.601 mmol, 50.492 eq.) was added at 0°C. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was diluted with DCM and quenched by a saturated solution of NaHCO3. The crude product was extracted with DCM, the water phases were washed by DCM and then organic phases was combined, dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (1st: 0% to 5% MeOH gradient in DCM, 2nd: FCC C18) and lypophilzed with EtOH and water to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N- (2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 47, 0.025 g, 0.05 mmol, 13%, white powder, m/z [M+H]+: 495,3). 1H NMR (400 MHz, DMSO) δ 8.77 (d, J = 2.1 Hz, 1H), 8.36 (s, 1H), 8.07 (dd, J = 8.2, 2.1 Hz, 1H), 7.83 (d, J = 0.9 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.21 (dd, J = 8.2, 1.7 Hz, 1H), 6.50 (s, 2H), 5.36 (d, J = 14.2 Hz, 1H), 5.33 – 5.26 (m, 2H), 5.01 – 4.98 (m, 2H), 4.95 (d, J = 14.3 Hz, 1H), 2.43 (s, 3H), 2.13 (s, 3H). 19F NMR (376 MHz, DMSO) δ -66.74. Example 48: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol- 5-yl)pyrimidine-5-carboxamide 2-Cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidine-5-carboxamide (Int.131) DMAP (0.2 g, 1.64 mmol, 0.51 eq.), DIPEA (1.39 ml, 7.98 mmol, 2.5 eq.), 1-ethyl-3-methyl-1H-pyrazol-5- amine (0.4 g, 3.20 mmol, 1.0 eq.) and 2-cyclopropylpyrimidine-5-carboxylic acid (0.52 g, 3.17 mmol, 0.99 eq.) were mixed in toluene (10.0 mL) and T3P as 50% in EtOAc (1.9 mL, 6.38 mmol, 2.0 eq.) was added dropwise at RT. Then, the reaction mixture was stirred at 55°C for 1.5 h. The reaction mixture was diluted with saturated solution of Na2CO3 and extracted with EtOAc (2x). The organic layers were washed with brine and dried over Ryvu Therapeutics S.A. RVU305 176 R10945WO Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 5% EtOH gradient in DCM) to obtain 2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidine-5-carboxamide (Int.131, 0.48 g, 1.734 mmol, 54%, beige solid, m/z [M+H]+: 272.40). 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.09 (s, 2H), 6.06 (s, 1H), 3.96 (q, J = 7.2 Hz, 2H), 2.32 (tt, J = 8.1, 4.7 Hz, 1H), 2.15 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.20 – 1.07 (m, 4H). N‐({4‐Chloro‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐(1‐ethyl‐3‐methyl‐1H‐pyrazol‐5‐yl)pyrimi- dine‐5‐carboxamide (Int.132) To 2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidine-5-carboxamide (Int.131, 0.48 g, 1.73 mmol, 1.0 eq.) in MeCN (15.0 mL), Cs2CO3 (1.13 g, 3.47 mmol, 2.0 eq.) and KI (0.34 g, 2.05 mmol, 1.18 eq.) were added. The reaction mixture was flushed with argon for 10min at RT, then 4-chloro-7-(chloromethyl)- 1H,3H-furo[3,4-c]quinoline (Int. C, 0.54 g, 2.08 mmol, 1.2 eq.) was added and the reaction mixture was stirred at 70°C for 2 h. The reaction mixture was diluted with saturated solution of Na2CO3 and extracted with DCM (2x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 40% MeCN gradient in DCM) to obtain N‐({4‐chloro‐1H,3H‐furo[3,4‐ c]quinolin‐7‐yl}methyl)‐2‐cyclopropyl‐N‐(1‐ethyl‐3‐methyl‐1H‐pyrazol‐5‐yl)pyrimidine‐5‐carboxamide (Int.132, 0.96 g, m/z [M+H]+: 490.00). 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 2H), 8.03 – 7.78 (m, 2H), 7.69 (d, J = 8.4 Hz, 1H), 6.04 (s, 1H), 5.55 (s, 2H), 5.23 (s, 3H), 5.14 – 4.98 (m, 1H), 3.52 (s, 2H), 2.18 (s, 1H), 2.03 (s, 3H), 1.15 – 0.79 (m, 7H). tert-Butyl N-(7-{[1-(2-cyclopropylpyrimidin-5-yl)-N-(1-ethyl-3-methyl-1H-pyrazol-5-l)formamido]methyl}-1H,3H- furo[3,4-c]quinolin-4-yl)carbamate (Int.133) A solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H- pyrazol-5-yl)pyrimidine-5-carboxamide (Int.132, 0.205 g, 0.40 mmol, 1.0 eq.), BocNH2 (0.094 g, 0.80 mmol, 1.99 eq.) and Cs2CO3 (0.33 g, 1.01 mmol, 2.52 eq.) in dioxane anh. (10.0 mL) was flushed with argon for 5min. Then, Pd2dba3 (0.08 g, 0.087 mmol, 0.22 eq.) and XantPhos (0.07 g, 0.12 mmol, 0.30 eq.) were added and the reaction mixture was stirred at 70°C for 3 h. Then, the reaction mixture was diluted with CHCl3/iPrOH 3/1 v/v and filtered through celite®. The filtrate was washed with saturated solution of Na2CO3, brine and dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 3% EtOH gradient in DCM) to obtain tert-butyl N-(7-{[1-(2-cyclopropylpyrimidin-5-yl)-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)formamido]methyl}-1H,3H- furo[3,4-c]quinolin-4-yl)carbamate (Int.133, 0.13 g, 0.21 mmol, 52%, yellowish powder, M/z [M+H]+: 570.40). 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.58 (s, 2H), 7.81 – 7.71 (m, 2H), 7.58 – 7.44 (m, 1H), 6.03 (s, 1H), 5.42 (t, J = 3.0 Hz, 2H), 5.19 – 5.09 (m, 4H), 3.52 – 3.41 (m, 2H), 2.17 (tt, J = 8.3, 4.6 Hz, 1H), 2.04 (s, 3H), 1.48 (s, 9H), 1.11 – 1.05 (m, 3H), 1.01 – 0.95 (m, 2H), 0.88 – 0.82 (m, 2H). N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimi- dine-5-carboxamide (Example 48) To a solution of tert-butyl N-(7-{[1-(2-cyclopropylpyrimidin-5-yl)-N-(1-ethyl-3-methyl-1H-pyrazol-5- yl)formamido]methyl}-1H,3H-furo[3,4-c]quinolin-4-yl)carbamate (Int.133, 0.13 g, 0.21 mmol, 1.0 eq.) in DCM (0.5 mL), TFA (0.24 mL) was added dropwise. The reaction mixture was stirred at RT for 5 h. The RM was poured onto saturated solution of Na2CO3/ ice and stirred for a few minutes and the crude product was ex- tracted with DCM (2x). the organic layers were combined, washed saturated solution of Na2CO3, brine and dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 4% MeOH gradient in Ryvu Therapeutics S.A. RVU305 177 R10945WO DCM) to obtain N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyra- zol-5-yl)pyrimidine-5-carboxamide (Example 48, 0.06 g, 0.127 mmol, Y=60%, white solid, UPLC long elution (polar long method, buffer type “FA”) purity 99.73%, m/z [M+H]+: 470.40). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.51 (s, 2H), 6.03 (s, 1H), 5.31 (t, J = 3.4 Hz, 2H), 5.09 – 5.01 (m, 2H), 5.00 (t, J = 3.5 Hz, 2H), 3.40 (dd, J = 14.2, 7.2 Hz, 2H), 2.17 (tt, J = 8.2, 4.5 Hz, 1H), 2.04 (s, 3H), 1.08 (dd, J = 8.1, 3.4 Hz, 2H), 1.02 – 0.93 (m, 2H), 0.80 (t, J = 6.9 Hz, 3H). Example 49: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethylpyridin-3-yl)py- rimidine-5-carboxamide 2- Phosphorus oxychloride (0.933 g, 6.09 mmol, 2.0 eq.) was added dropwise at 0 °C to a solution of 2-cyclo- propylpyrimidine-5-carboxylic acid (0.5 g, 3.05 mmol, 1.0 eq.) and 2,6-dimethylpyridin-3-amine (0.372 g, 3.05 mmol, 1.0 eq.) and DMAP (0.186 g, 1.52 mmol, 0.5 eq.) in pyridine (8 mL) under nitrogen. The RM was stirred for 120 min at RT under nitrogen. The reaction was diluted with a saturated solution of NaHCO3 and the mix- ture was extracted with DCM (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The crude product was triturated with the minimum amount of EtOAc, filtered and dried under vacuum to yield 2-cyclopropyl-N-(2,6-dimethylpyridin-3-yl)pyrimidine-5-carboxamide (Int.134, 0.542 g, 2.0 mmol, 66%, off-white solid, m/z [M+H]+: 269.0). 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.11 (s, 2H), 7.64 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.37 – 2.26 (m, 1H), 1.22 – 1.06 (m, 4H). N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethylpyridin-3-yl)pyrimidine-5-car- boxamide (Int.135) A mixture of 2-cyclopropyl-N-(2,6-dimethylpyridin-3-yl)pyrimidine-5-carboxamide (Int.134, 0.204 g, 0.63 mmol, 1.0 eq.), 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.191 g, 0.63 mmol, 1.0 eq.) and cesium carbonate (0.25 g, 0.77 mmol, 1.2 eq.) in MeCN (7.0 mL) was stirred at 70 ° C for 2 h. The RM was cooled Ryvu Therapeutics S.A. RVU305 178 R10945WO down to RT and diluted with a saturated solution of NH4Cl. The mixture was extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. N-({4-chloro-1H,3H- furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethylpyridin-3-yl)pyrimidine-5-carboxamide (Int.135, 0.302 g, 0.522 mmol, 83%, off-white solid, m/z [M+H]+: 486.9) was used in the next step without further purifi- cation. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.91 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 1.7, 8.5 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 5.54 (t, J = 3.1 Hz, 2H), 5.40 (d, J = 14.6 Hz, 1H), 5.22 (t, J = 3.1 Hz, 2H), 5.02 (d, J = 14.6 Hz, 1H), 2.33 (s, 3H), 2.17 – 2.06 (m, 1H), 2.05 (s, 3H), 1.04 (dt, J = 3.1, 7.9 Hz, 2H), 0.98 – 0.87 (m, 2H). tert-Butyl N-(7-{[1-(2-cyclopropylpyrimidin-5-yl)-N-(2,6-dimethylpyridin-3-yl)formamido]methyl}-1H,3H-furo[3,4- c]quinolin-4-yl)carbamate (Int.136) A solution of tert-butyl carbamate (0.276 g, 2.36 mmol, 2.0 eq.), Cs2CO3 (0.957 g, 2.94 mmol, 2.5 eq.) and N- ({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethylpyridin-3-yl)pyrimidine-5-carbox- amide (Int.135, 0.6 g, 1.17 mmol, 1.0 eq.) in dioxane (12 mL) and sparged with argon for 5 min. XantPhos (0.205 g, 0.35 mmol, 0.3 eq.) and Pd2(dba)3 (0.22 g, 0.24 mmol, 0.2 eq.) were added and the RM was stirred at 70 °C for 90 min. under argon. After cooled down to RT, the RM was diluted with EtOAc and filtered through a pad of Celite®. Water was added to the filtrate and the organic phase was separated. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by FCC (0 to 50% EtOAc gradient in hexane) to obtain tert-butyl N-(7-{[1-(2-cyclopropylpyrimidin-5-yl)-N-(2,6-dimethylpyridin-3-yl)formamido]methyl}-1H,3H- furo[3,4-c]quinolin-4-yl)carbamate (Int.136, 0.282 g, 0.473 mmol, 40%, yellow solid, m/z [M+H]+: 567.4). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.52 (s, 2H), 7.75 – 7.71 (m, 2H), 7.51 (dd, J = 1.6, 8.4 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 5.41 (t, J = 3.0 Hz, 2H), 5.32 (d, J = 14.3 Hz, 1H), 5.13 (t, J = 2.9 Hz, 2H), 5.04 (d, J = 14.3 Hz, 1H), 2.33 (s, 3H), 2.14 – 2.08 (m, 1H), 1.99 (s, 3H), 1.48 (s, 9H), 1.09 – 1.01 (m, 2H), 0.97 – 0.89 (m, 2H). N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethylpyridin-3-yl)pyrimidine-5-car- boxamide (Example 49) TFA (0.4 mL) was added drop wise to a solution of tert-butyl N-(7-{[1-(2-cyclopropylpyrimidin-5-yl)-N-(2,6-dime- thylpyridin-3-yl)formamido]methyl}-1H,3H-furo[3,4-c]quinolin-4-yl)carbamate (Int.136, 0.282 g, 0.47 mmol, 1.0 eq.) in DCE (2.0 mL). The RM was stirred at 60°C for 60 min. and the reaction was diluted with a saturated so- lution of Na2CO3. The mixture was extracted with DCM (3x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethylpyri- din-3-yl)pyrimidine-5-carboxamide (Example 49, 0.092 g, 0.19 mmol, 41%, off white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.09%, m/z [M+H]+: 467.4). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.16 (dd, J = 1.7, 8.2 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.48 (s, 2H), 5.30 (t, J = 3.7 Hz, 2H), 5.20 (d, J = 14.2 Hz, 1H), 5.02 – 4.97 (m, 2H), 4.96 (d, J = 13.7 Hz, 1H), 2.33 (s, 3H), 2.11 (tt, J = 4.7, 8.0 Hz, 1H), 1.96 (s, 3H), 1.08 – 1.00 (m, 2H), 0.95 – 0.90 (m, 2H). Ryvu Therapeutics S.A. RVU305 179 R10945WO Example 50: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methyl-1,2-thiazol-4-yl)-6 (trifluorome- thyl)pyridine-3-carboxamide N-(3-methyl-1,2-thiazol-4-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.137) DMAP (0.096 g, 0.786 mmol, 0.499 eq.), DIPEA (0.684 ml, 3.927 mmol, 2.493 eq.), 3-methyl-1,2-thiazol- 4-amine hydrochloride (0.249 g, 1.653 mmol, 1.05 eq.) and 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.301 g, 1.575 mmol, 1.0 eq.) were taken in DMF (8.0 mL) and T3P as 50% in EtOAc (0.934 ml, 3.138 mmol, 1.992 eq.) was added dropwise at 0°C. Then, the reaction mixture was stirred at 100°C for 2 h. The reaction mixture was diluted with a saturated solution of Na2CO3, extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product N-(3-methyl-1,2- thiazol-4-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.137, 0.436 g, 1.138 mmol, 72%, yellow solid, m/z [M+H]+: 287.9) was used in the next step. 1H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 9.24 (dd, J = 15.4, 2.1 Hz, 2H), 8.61 – 8.56 (m, 1H), 8.13 (d, J = 0.9 Hz, 1H), 2.46 (s, 3H). N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methyl-1,2-thiazol-4-yl)-6-(trifluoromethyl)pyridine-3- carboxamide (Int.138) To a solution of N-(3-methyl-1,2-thiazol-4-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.137, 0.334 g, 0.872 mmol, 1.0 eq.), 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.226 g, 0.872 mmol, 0.999 eq.) in ACN (4.5 mL), Cs2CO3 (0.568 g, 1.743 mmol, 1.999 eq.) was added. The reaction mixture was stirred at 78°C for 2 h. The reaction mixture was cooled down to RT, diluted by water, extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and concen- trated. The crude product was purified twice by FCC (1st: 0% to 3% MeOH gradient in DCM, 2nd: 0% to 50% EtOAc gradient in hexane) to obtain N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methyl-1,2-thia- zol-4-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.138, 0.172 g, 0.33 mmol, 38%, white solid, m/z [M+H]+: 505.1). 1H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.77 (s, 1H), 8.08 (dd, J = 8.4, 2.0 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.72 (dd, J = 8.5, 1.7 Hz, 1H), 5.55 (t, J = 3.1 Hz, 2H), 5.42 (s, 1H), 5.23 (t, J = 3.1 Hz, 2H), 5.10 (s, 1H), 2.09 (s, 3H). Ryvu Therapeutics S.A. RVU305 180 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methyl-1,2-thiazol-4-yl)-6-(trifluoromethyl)pyridine-3- carboxamide (Example 50) Step 1: To a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methyl-1,2-thiazol-4-yl)-6-(tri- fluoromethyl)pyridine-3-carboxamide (Int.138, 0.145 g, 0.279 mmol, 1.0 eq.) in DMSO (1.5 mL), 1-(2,4-di- methoxyphenyl)methanamine (0.467 g, 2.793 mmol, 10.026 eq.) was added. The reaction was stirred at 100°C overnight. The reaction mixture was cooled down to room temperature, diluted with water, extracted with DCM (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. Step 2: To a solution of the product dissolved in DCM (3.0 mL) in 0°C trifluoroacetic acid (1.05 ml, 13.721 mmol, 49.256 eq.) was added. The reaction was stirred at room temperature overnight. Then, the reaction mixture was diluted in MeOH and evaporated and the crude product was diluted with DCM and with a solution of K2CO3, extracted with DCM and then organic phases were combined, dried over Na2SO4. The filtrate was con- centrated and the crude product was purified by FCC (0% to 10% MeOH gradient in DCM) and lypophilzed with EtOH and water to obtain N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methyl-1,2-thiazol-4-yl)-6 (trifluoromethyl)pyridine-3-carboxamide (Example 50, 0.056 g, 0.115 mmol, 41%, white powder, m/z [M+H]+: 486.3). 1H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 8.73 (s, 1H), 8.05 (dd, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.19 (dd, J = 8.2, 1.7 Hz, 1H), 6.50 (s, 2H), 5.37 – 5.26 (m, 2H), 5.25 – 5.15 (m, 1H), 5.09 – 5.02 (m, 1H), 5.03 – 4.92 (m, 2H), 1.97 (s, 3H). 19F NMR (376 MHz, DMSO) δ -66.74. Example 51: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-ethylpyridin-3-yl)pyrimi- dine-5-carboxamide 2-Cyclopropyl-N-(2-ethylpyridin-3-yl)pyrimidine-5-carboxamide (Int.139) Phosphorus oxychloride (0.92867 g, 6.057 mmol, 2.0 eq.) was added dropwise to a solution of 2-cyclo- propylpyrimidine-5-carboxylic acid (0.49718 g, 3.029 mmol, 1.0 eq.), 2-ethylpyridin-3-amine (0.37 g, 3.029 Ryvu Therapeutics S.A. RVU305 181 R10945WO mmol, 1.0 eq.) and N,N-dimethylpyridin-4-amine (0.074 g, 0.606 mmol, 0.2 eq.) in pyridine (19.0 mL) at 0°C. The RM was stirred 5 min at 0°C and then 45 min at RT under nitrogen atmosphere. The reaction mixture was diluted with MeOH (15ml) followed by i-PrOH (150ml) and concentrated. The residue was neutralized with a saturated solution of NaHCO3 solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, then dried over anhydrous Na2SO4, filtered, and evaporated. The crude product was purified by FCC (0% to 7% MeOH gradient in DCM) to obtain 2-cyclopropyl-N-(2-ethylpyridin-3-yl)pyrimidine-5-carbox- amide (Int.139, 0.667 g, 2.461 mmol, 81%, white solid, m/z [M+H]+: 269.2). 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.12 (s, 2H), 8.44 (dd, J = 4.7, 1.6 Hz, 1H), 7.77 (dd, J = 8.0, 1.7 Hz, 1H), 7.30 (dd, J = 8.0, 4.7 Hz, 1H), 2.80 (q, J = 7.5 Hz, 2H), 2.33 (tt, J = 8.0, 4.7 Hz, 1H), 1.28 – 1.06 (m, 7H). N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-ethylpyridin-3-yl)pyrimidine-5-carbox- amide (Int.140) To a solution of 2-cyclopropyl-N-(2-ethylpyridin-3-yl)pyrimidine-5-carboxamide (Int.139, 0.659 g, 2.431 mmol, 1.0 eq.) in acetonitrile (90.0 mL), cesium carbonate (1.18833 g, 3.647 mmol, 1.5 eq.) and potassium io- dide (0.04036 g, 0.243 mmol, 0.1 eq.) were added. The mixture was stirred for 15 min at RT. Then, 4-chloro-7- (chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.81961 g, 3.161 mmol, 1.3 eq.) was added and the reaction mixture was stirred at 70°C for 3 h. The reaction mixture was cooled down, diluted with EtOAc (200 ml) and water (250 mL) and shaken vigorously. The insoluble substance was filtered off, obtaining the first portion of the desired product. The organic phase was separated, washed with brine, dried over Na2SO4, filtered and evaporated and the residue was recrystallized from EtOAc to obtain the second portion of the desired product. The two resulting portions were combined to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclo- propyl-N-(2-ethylpyridin-3-yl)pyrimidine-5-carboxamide (Int.140, 0.469 g, 0.926 mmol, 38%, white solid, m/z [M+H]+: 487.2). 1H NMR (400 MHz, DMSO) δ 8.51 (s, 2H), 8.41 (dd, J = 4.7, 1.6 Hz, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 7.23 (dd, J = 8.0, 4.7 Hz, 1H), 5.53 (t, J = 3.2 Hz, 2H), 5.34 (d, J = 14.5 Hz, 1H), 5.22 (t, J = 3.1 Hz, 2H), 5.15 (d, J = 14.6 Hz, 1H), 2.43 – 2.29 (m, 1H), 2.27 – 2.16 (m, 1H), 2.15 – 2.04 (m, 1H), 1.12 – 0.99 (m, 2H), 0.95 – 0.87 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H). 2-Cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2-ethylpyr- idin-3-yl)pyrimidine-5-carboxamide (Int.141) A solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-ethylpyridin-3-yl)py- rimidine-5-carboxamide (Int.140, 0.459 g, 0.907 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (1.06 g, 6.34 mmol, 7.0 eq.) in DMSO (6 mL) was stirred at 110°C for 20 h. The RM was cooled down, diluted with EtOAc and the organic solution was washed four times with brine, dried over Na2SO4, filtered and evapo- rated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to obtain 2-cyclopropyl-N- [(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-(2-ethylpyridin-3-yl)pyrimi- dine-5-carboxamide (Int.141, 0.473 g, 0.721 mmol, 80%, light yellow solid, m/z [M+H]+: 617.5). 1H NMR (400 MHz, DMSO) δ 8.47 (s, 2H), 8.39 (dd, J = 4.7, 1.6 Hz, 1H), 7.68 (dd, J = 8.0, 1.6 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.21 (dd, J = 8.0, 4.7 Hz, 1H), 7.14 (dd, J = 9.1, 1.8 Hz, 2H), 7.01 (t, J = 5.7 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 8.3, 2.4 Hz, 1H), 5.30 (t, J = 3.5 Hz, 2H), 5.17 (d, J = 14.2 Hz, 1H), 5.09 – 5.01 (m, 3H), 4.60 – 4.48 (m, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 2.40 – 2.26 (m, 1H), 2.23 – 2.04 (m, 2H), 1.07 – 0.98 (m, 2H), 0.94 – 0.82 (m, 2H), 0.75 (t, J = 7.4 Hz, 3H). Ryvu Therapeutics S.A. RVU305 182 R10945WO N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-ethylpyridin-3-yl)pyrimidine-5-carbox- amide (Example 51) To a solution of 2-Cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-(2-ethylpyridin-3-yl)pyrimidine-5-carboxamide (Int.141, 0.468 g, 0.713 mmol, 1.0 eq.) in DCM (24 mL), TFA (6 mL, 78.352 mmol, 110.0 eq.) was added. The RM was stirred at RT overnight. The RM was di- luted with DCM (50 mL) and carefully basified with a saturated solution of NaHCO3. After 30 minutes of vigor- ous stirring the organic layer was separated, washed carefully with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 7% MeOH gradient in DCM). Obtained fraction was co-evaporated with EtOH and lyophilized to give N-({4-amino-1H,3H-furo[3,4- c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-ethylpyridin-3-yl)pyrimidine-5-carboxamide (Example 51, 0.206 g, 0.441 mmol, 62%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.9%). 1H NMR (400 MHz, DMSO) δ 8.48 (s, 2H), 8.40 (dd, J = 4.7, 1.6 Hz, 1H), 7.71 (dd, J = 8.0, 1.6 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.23 (dd, J = 8.0, 4.6 Hz, 1H), 7.15 (dd, J = 8.2, 1.7 Hz, 1H), 6.48 (s, 2H), 5.29 (t, J = 3.3 Hz, 2H), 5.18 – 5.05 (m, 2H), 4.98 (t, J = 3.4 Hz, 2H), 2.33 – 2.21 (m, 1H), 2.21 – 2.04 (m, 2H), 1.10 – 0.97 (m, 2H), 0.95 – 0.87 (m, 2H), 0.71 (t, J = 7.4 Hz, 3H). Example 52: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-methylpyridin-3-yl)pyridine-3- carboxamide 6-Cyano-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (Int.142) To solution of 6-cyanonicotinic acid (0.351 g, 2.37 mmol, 1.0 eq.), 2-methylpyridin-3-amine (0.257 g, 2.376 mmol, 1.003 eq.), DMAP (0.145 g, 1.187 mmol, 0.501 eq.) and DIPEA (1.03 ml, 5.913 mmol, 2.495 eq.) in toluene (9.0 mL), T3P as 50% solution in EtOAc (2.8 mL, 4.739 mmol, 2.001 eq.) was added dropwise at 0°C. The reaction mixture was stirred under reflux for 1 h. The reaction mix- ture was cooled down to room temperature, diluted with a saturated solution of Na2CO3 and extracted with EtOAc (3x). The combined organic phases were washed with brine and dried over with Na2SO4. The filtrate was evaporated to obtain 6-cyano-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (Int.142, 0.56 g, 2.327 mmol, 98%, brown solid, m/z [M+H]+: 238.4). Ryvu Therapeutics S.A. RVU305 183 R10945WO 1H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 9.26 (d, J = 2.1 Hz, 1H), 8.55 (dd, J = 8.1, 2.2 Hz, 1H), 8.38 (dd, J = 4.8, 1.7 Hz, 1H), 8.27 (dd, J = 8.1, 0.9 Hz, 1H), 7.81 (dd, J = 8.0, 1.7 Hz, 1H), 7.36 – 7.26 (m, 1H), 2.47 (s, 3H). N-({4-Chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (Int.143) To a solution of 6-cyano-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (Int.142, 0.557 g, 2.315 mmol, 1.0 eq.), 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.602 g, 2.322 mmol, 1.003 eq.) in ACN (11.0 mL), Cs2CO3 (1.51 g, 4.634 mmol, 2.002 eq.) was added. The reaction mixture was stirred at 78°C for 1 h. The reaction mixture was cooled down to room temperature and diluted by water. Then, the crude product was extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was isolated by FCC (0% to 5% MeOH gradient in DCM) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-methylpyridin-3-yl)pyridine-3-carbox- amide (Int.143, 0.534 g, 0.949 mmol, 41%, yellow solid, m/z [M+H]+: 457.1). 1H NMR (400 MHz, DMSO) δ 8.72 (dd, J = 2.2, 0.9 Hz, 1H), 8.29 (dd, J = 4.7, 1.6 Hz, 1H), 8.02 (dd, J = 8.1, 2.2 Hz, 1H), 7.94 (dd, J = 8.2, 1.0 Hz, 2H), 7.85 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.16 – 7.10 (m, 1H), 5.54 (t, J = 3.1 Hz, 2H), 5.47 (d, J = 14.6 Hz, 1H), 5.22 (t, J = 3.1 Hz, 2H), 5.08 (d, J = 14.6 Hz, 1H), 2.16 (s, 3H). N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide (Example 52) Step 1: A solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-methylpyridin-3-yl)pyri- dine-3-carboxamide (Int.143, 0.48 g, 0.853 mmol, 1.0 eq.), BocNH2 (0.202 g, 1.724 mmol, 2.022 eq.), Cs2CO3 (0.7 g, 2.148 mmol, 2.519 eq.) in dry dioxane (6.0 mL) was flushed with argon for 5min. Then, Pd2dba3 (0.159 g, 0.174 mmol, 0.204 eq.) and XantPhos (0.151 g, 0.261 mmol, 0.306 eq.) were added and reaction mixture was stirred at 70°C. The reaction mixture was diluted with EtOAc and filtered through celite®. The filtrate was washed with a saturated solution of Na2CO3, water, brine and dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (0% to 5% MeOH gradient in DCM) and was used in the next step. Step 2: To a solution of Boc-protected compound in DCM (6.0 mL), TFA (0.65262 ml, 8.528 mmol, 10.0 eq.) was added at 0°C. The reaction was stirred at RT for 1 h. Then, the reaction mixture was diluted with DCM and with a solution of K2CO3. The crude product was extracted with DCM and the water phases were washed by DCM. The organic phases were combined, dried over Na2SO4. The filtrate was concentrated. The product was puri- fied by FCC (0% to 10% MeOH gradient in DCM) and finally by C18 column. The product was lyophilized with ACN and water to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-methylpyridin-3-yl)pyr- idine-3-carboxamide (Example 52, 0.038 g, 0.087 mmol, 10%, white powder, m/z [M+H]+: 437.5). 1H NMR (400 MHz, DMSO) δ 8.67 (dd, J = 2.1, 0.9 Hz, 1H), 8.28 (dd, J = 4.7, 1.6 Hz, 1H), 7.99 (dd, J = 8.1, 2.1 Hz, 1H), 7.93 (dd, J = 8.1, 0.9 Hz, 1H), 7.60 (dd, J = 8.0, 1.6 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.19 – 7.13 (m, 2H), 6.48 (s, 2H), 5.31 – 5.29 (m, 2H), 5.25 (s, 1H), 5.03 (s, 1H), 5.01 – 4.96 (m, 2H), 2.07 (s, 3H). Ryvu Therapeutics S.A. RVU305 184 R10945WO Intermediate C: 4-chloro-7-(chloromethyl)-3-methyl-1H,3H-furo[3,4-c]quinoline Methyl 2-methyl-4-oxooxolane-3-carboxylate (Int.144) To a solution of KOtBu (41.10914 g, 366.349 mmol, 1.1 eq.) in 2-MeTHF (180 mL) was cooled down to 5 ゜C, a solution of methyl glycoate (30.0 g, 333.045 mmol, 1.0 eq.) in 2Me-THF (60 mL) was added dropwise and the reaction mixture was stirred at 5゜C for 1 h. Then, a solution of methyl crotonate (70.64287 ml, 666.089 mmol, 2.0 eq.) in 2Me-THF (60 mL) was added dropwise to keep temperature constant at 6-8゜C. The RM was warmed to RT then stirred at 75゜C for 1 h. Then, the RM was cooled down to RT and stirred at RT overnight. A solution of 1M NaOH (150 mL) was added to pH 10 and the reaction mixture was extracted with EtOAc (2x) and with DCM. The aqueous layer was cooled in ice bath and a solution of 2M HCl solution was added dropwise to keep temperature below 5゜C . Once pH 2 was achieved (2M HCl solution), the crude prod- uct was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered and evapo- rated. Crude was then purified by FCC twice (0 to 20% EtOAc gradient in Hexane; 0 to 10% EtOAc gradient in Hexane then isocratic) to give methyl 2-methyl-4-oxooxolane-3-carboxylate (Int.144, 21.096 g, 126.72 mmol, 38%, yellow oil). 1H NMR (400 MHz, Chloroform-d) δ 4.59 – 4.52 (m, 1H), 4.22 (dt, J = 17.1, 0.9 Hz, 1H), 4.00 (d, J = 17.1 Hz, 1H), 3.81 (s, 3H), 3.14 (dd, J = 10.2, 1.0 Hz, 1H), 1.51 (d, J = 6.0 Hz, 3H). Methyl 2-methyl-4-(trifluoromethanesulfonyloxy)-2,5-dihydrofuran-3-carboxylate (Int.145) A solution of methyl 2-methyl-4-oxooxolane-3-carboxylate (Int.144, 21.10 g, 126.72 mmol, 1.0 eq.) and DIPEA (29.0 mL, 166.49 mmol, 1.31 eq.) in DCM (210 mL) under nitrogen was cooled down to 0°C. Trifluoro- methanesulfonic anhydride (39.80 g, 141.09 mmol, 1.11 eq.) was added dropwise, maintaining the reaction temperature between 0–5°C. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was diluted with water (210 mL) and stirred for 15 min. The mixture was Ryvu Therapeutics S.A. RVU305 185 R10945WO transferred to a separatory funnel, and the aqueous layer was discarded. The organic layer was washed se- quentially with water, a solution of 2N HCl, and a saturated solution of NaHCO₃. The organic phase was dried over Na₂SO₄, filtered and evaporated. The crude product was purified by FCC (0 to 100% DCM gradient in heptane to give methyl 2-methyl-4-(trifluoromethanesulfonyloxy)-2,5-dihydrofuran-3-carboxylate (Int.145, 32.67 g, 106.93 mmol, 84%, orange oil). 1H NMR (400 MHz, Chloroform-d) δ 5.22 – 5.13 (m, 1H), 4.78 (dd, J = 14.6, 5.9 Hz, 1H), 4.70 (dd, J = 14.6, 3.7 Hz, 1H), 3.83 (s, 3H), 1.47 (d, J = 6.3 Hz, 3H). Methyl 3-methyl-4-oxo-1H,3H,4H,5H-furo[3,4-c]quinoline-7-carboxylate (Int.146) A solution of 1,4-dioxane (490 mL) and water (100 mL) was degassed for 30 min. Then, potassium car- bonate (60.0 g, 434.14 mmol, 4.06 eq.) was then added, followed by [2-amino-4-(methoxycarbonyl)phenyl]bo- ronic acid hydrochloride (26.64 g, 113.94 mmol, 1.07 eq.), methyl 2-methyl-4-(trifluoromethanesulfonyloxy)-2,5- dihydrofuran-3-carboxylate (Int.145, 32.66 g, 106.90 mmol, 1.0 eq.), and Pd(dppf)Cl₂·DCM (2.2 g, 2.694 mmol, 0.025 eq.) under a nitrogen atmosphere. The mixture was stirred at 90°C for 2 h. The reaction mixture was cooled down to room temperature and the product was precipitated by adding water. After 60 min. of stir- ring, the mixture was filtered and the solid was washed MeCN, then with MTBE. The solid was dried to give methyl 3-methyl-4-oxo-1H,3H,4H,5H-furo[3,4-c]quinoline-7-carboxylate (Int.146, 27.55 g, 105.201 mmol, 98%, grey solid, m/z [M+H]+: 260.2). 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 8.2, 1.6 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 5.38 – 5.25 (m, 2H), 5.23 – 5.14 (m, 1H), 3.89 (s, 3H), 1.45 (d, J = 6.2 Hz, 3H). Methyl 4-chloro-3-methyl-1H,3H-furo[3,4-c]quinoline-7-carboxylate (Int.147) A mixture of and DIPEA (18.5 mL, 106.21 mmol, 1.01 eq.) in acetonitrile (220 mL) was cooled in an ice bath, and phosphorus oxychloride (24.5 g, 159.80 mmol, 1.52 eq.) was added portionwise, maintaining a tem- perature increase of 1–2°C. Next, methyl 3-methyl-4-oxo-1H,3H,4H,5H-furo[3,4-c]quinoline-7-carboxylate (Int. 146, 27.5 g, 105.01 mmol, 1.0 eq.) was added. The reaction mixture was warm to room temperature and then stirred under reflux for 3 h. The reaction mixture was cooled to 0 °C, and 2 M NaOH solution (220 mL) was added slowly, next water (280 mL) was then added, and the mixture was stirred for 30 min at 5–10 °C. The re- sulting solid was filtered off and washed sequentially with water, a 1:1 mixture of acetonitrile and water and fi- nally with heptane. The solid was dried to give methyl 4-chloro-3-methyl-1H,3H-furo[3,4-c]quinoline-7-carbox- ylate (Int.147, 26.65 g, 93.09 mmol, 89%, brown solid, m/z [M+H]+: 278.2). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 1.7, 0.6 Hz, 1H), 8.12 (dd, J = 8.6, 1.7 Hz, 1H), 7.97 (dd, J = 8.6, 0.7 Hz, 1H), 5.62 – 5.51 (m, 2H), 5.49 – 5.40 (m, 1H), 3.95 (s, 3H), 1.56 (d, J = 6.3 Hz, 3H). 4-Chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methanol (Int.148) A solution of methyl 4-chloro-3-methyl-1H,3H-furo[3,4-c]quinoline-7-carboxylate (Int.147, 26.65 g, 93.08 mmol, 1.0 eq.) in THF (270 mL) under a nitrogen atmosphere was cooled to 0 °C, and a 2 M solution of lithium aluminum hydride in THF (LAH, 28 mL, 56 mmol, 0.60 eq.) was slowly added. The reaction mixture was stirred for 1 h at 5 °C. Acetone (35 mL, 476.67 mmol, 5.12 eq.) was then added dropwise to quench the reaction, and the mixture was stirred at 5 °C. Subsequently, the mixture was carefully quenched by the dropwise addition of 2 M HCl solution (530 mL), keeping the temperature below 10 °C. The mixture was warmed to room tempera- ture and stirred for an additional 15 min. The THF was then removed via rotary evaporation, and the resulting Ryvu Therapeutics S.A. RVU305 186 R10945WO solid was filtered, washed sequentially with water and heptane and air-dried to give 4-chloro-3-methyl-1H,3H- furo[3,4-c]quinolin-7-yl}methanol (Int.148, 17.68 g, 70.1 mmol, 75%, off-white solid, m/z [M+H]+: 250.2). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (dq, J = 1.7, 1.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 8.5, 1.6 Hz, 1H), 5.61 – 5.47 (m, 3H), 5.47 – 5.38 (m, 1H), 4.80 – 4.64 (m, 2H), 1.59 – 1.52 (m, 3H). 4-chloro-7-(chloromethyl)-3-methyl-1H,3H-furo[3,4-c]quinoline (Int. G) To a solution of POCl₃ (9.5 g, 61.96 mmol, 1.30 eq.) in acetonitrile (110 mL) under a nitrogen atmos- phere, 4-chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methanol (Int.148, 12.0 g, 47.58 mmol, 1.0 eq.) was added portionwise. The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was cooled down to room temperature, and DCM was added. The mixture was then cooled to about 5 °C in an ice bath. Slowly, 2 N NaOH (60 mL) was added dropwise. Afterward, water (120 mL) was added, and the ice bath was removed. The mixture was stirred at room temperature for 30 min. The mixture was filtered off. The organic layer was separated, and the basic aqueous layer was washed with DCM then combined with the main organic phase. The organic layer was washed with brine, dried over sodium sulfate, and filtered. DCM was then evaporated and replaced with n-heptane causing the product to precipitate as an off-white solid. The solid was filtered, washed with n-heptane and air-dried to give 4-chloro-7-(chloromethyl)-3-methyl-1H,3H-furo[3,4-c]quinoline (Int. G, 11.35 g, 41.87 mmol, 88%, off-white solid, m/z [M+H]+: 269.9). 1H NMR (400 MHz, Chloroform-d) δ 8.12 – 8.03 (m, 1H), 7.70 – 7.60 (m, 2H), 5.66 – 5.51 (m, 2H), 5.48 – 5.38 (m, 1H), 4.81 – 4.72 (m, 2H), 1.69 – 1.64 (m, 3H). Example 53: Rac-N-({4-Amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl- 1H-pyrazol-4-yl)pyrimidine-5-carboxamide 2-Cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.149) To solution of 2-cyclopropylpyrimidine-5-carboxylic acid (0.886 g, 5.398 mmol, 1.0 eq.), 1,3-dimethyl-1H- pyrazol-4-amine (0.6 g, 5.398 mmol, 1.0 eq.) and DMAP (0.329 g, 2.699 mmol, 0.5 eq.) in toluene (6.0 mL) was added DIPEA (0.940 mL, 5.398 mmol, 1.0 eq.) followed by addition by T3P as 50% in EtOAc (6.42 mL, 10.796 mmol, 2.0 eq.). The reaction mixture was stirred under reflux for 1 h. the reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc (3x). The combined organic layers were washed with Ryvu Therapeutics S.A. RVU305 187 R10945WO brine and dried over Na2SO4, filtrated and evaporated. The obtained 2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol- 4-yl)pyrimidine-5-carboxamide (Int.149, 1.3 g, 3.84 mmol, 71%, beige solid, m/z [M+H]+: 258.3) was used in next step without purification. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.05 (s, 2H), 7.91 (s, 1H), 3.75 (s, 3H), 2.33 – 2.25 (m, 1H), 2.15 (s, 3H), 1.16 – 1.11 (m, 2H), 1.11 – 1.05 (m, 2H). N-({4-Chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)py- rimidine-5-carboxamide (Int.150) To solution of 2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.149, 0.4 g, 1.182 mmol, 1.0 eq.), 4-chloro-7-(chloromethyl)-3-methyl-1H,3H-furo[3,4-c]quinoline (Int. G, 0.384 g, 1.42 mmol, 1.2 eq.) and Cs2CO3 (0.577 g, 1.772 mmol, 1.5 eq.) in acetonitrile (6.0 mL), KI (0.196 g, 1.182 mmol, 1.0 eq.) was added. The reaction mixture was stirred at 70゜C for 3 h. Then, the reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc (3x). The combined organic layers were washed with brine and dried over Na2SO4, filtrated and evaporated. The crude product was purified by FCC (0 to 80% of EtOAc gradient in hexane) to obtain N-({4-chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl- N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.150, 0.514 g, 0.936 mmol, 79%, beige solid, m/z [M+H]+: 490.2). 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 2H), 7.90 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 – 7.64 (m, 2H), 5.58 – 5.51 (m, 2H), 5.43 (d, J = 13.5 Hz, 1H), 5.10 (s, 2H), 3.60 (s, 3H), 2.20 – 2.11 (m, 1H), 1.62 (s, 3H), 1.57 – 1.53 (m, 3H), 1.08 – 1.04 (m, 2H), 0.98 – 0.94 (m, 2H). N-({4-Amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)py- rimidine-5-carboxamide (Example 53) Step 1: To solution of N-({4-chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dime- thyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.150, 0.784 g, 1.395 mmol, 1.0 eq.) in DMSO (4.0 mL), DMBA (0.93 g, 5.562 mmol, 3.987 eq.) was added and the reaction mixture was stirred at 120゜C for 4 h. Then, the reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc (3x). The organic layers were combined, washed with brine and dried over with Na2SO4, filtrated and evaporate. The crude product was purified by FCC (0 to 80% of EtOAc gradient in hexane). Step 2: Obtained product was dissolved in DCM (3.0 mL), TFA (2.15 mL, 27.907 mmol, 20.006 eq.) was added at 0゜C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1M NaOH solution to obtain pH~8 and extracted with DCM (3x). the organic layers were combined, washed with brine and dried over with Na2SO4, filtrated and evaporated. The crude product was purified consecutively by FCCs (first: 0 to 10% of MeOH gradient in DCM, second: NH2 modified column, 0 to 2% of MeOH gradient in DCM). The obtained product was lyophilized with EtOH/H2O to give Rac-N-({4-amino-3-methyl-1H,3H- furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Ex- ample 53, 0.145 g, 0.307 mmol, 22%, white solid, UPLC long elution (Polar long method, buffer type “FA”) pu- rity: 99.47%, m/z [M+H]+: 470.6). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 7.60 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 8.2, 1.6 Hz, 1H), 6.38 (s, 2H), 5.44 – 5.36 (m, 1H), 5.31 (dd, J = 13.7, 3.9 Hz, 1H), 5.21 (dd, J = Ryvu Therapeutics S.A. RVU305 188 R10945WO 13.6, 1.7 Hz, 1H), 4.96 (s, 2H), 3.61 (s, 3H), 2.15 (tt, J = 8.1, 4.6 Hz, 1H), 1.56 (s, 3H), 1.39 (d, J = 6.1 Hz, 3H), 1.09 – 1.03 (m, 2H), 0.97 (dt, J = 4.5, 3.0 Hz, 2H). Example 54: Rac-N-({4-Amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-me- thyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide 2-Cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.151) To solution of 2-cyclopropylpyrimidine-5-carboxylic acid (0.6126 g, 3.732 mmol, 1.0 eq.), 1-ethyl-3-me- thyl-1H-pyrazol-4-amine (0.46711 g, 3.732 mmol, 1.0 eq.) and DMAP (0.22795 g, 1.866 mmol, 0.5 eq.) in tolu- ene (6.0 mL) was added DIPEA (0.65 g, 5.029 mmol, 1.348 eq.) followed by addition of T3P as 50% in EtOAc (4.4 mL, 7.463 mmol, 2.0 eq.) and the reaction mixture was stirred under reflux for 1 h. Then, the reaction mix- ture was diluted with NaHCO3 and extracted with EtOAc (3x). The combined organic layers were washed with brine and dried over with Na2CO3, filtrated and evaporated to obtained 2-cyclopropyl-N-(1-ethyl-3-methyl-1H- pyrazol-4-yl)pyrimidine-5-carboxamide (Int.151, 1.05 g, 3.56 mmol, 95%, green solid, m/z [M+H]+: 272.3) used in further step without purification. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.04 (d, J = 1.5 Hz, 2H), 7.94 (d, J = 1.4 Hz, 1H), 4.07 – 3.99 (m, 2H), 2.35 – 2.25 (m, 1H), 2.15 (d, J = 1.4 Hz, 3H), 1.36 – 1.30 (m, 3H), 1.17 – 1.10 (m, 2H), 1.10 – 1.04 (m, 2H). Rac-N-({4-chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide (Int.152) To solution of 2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.151, 0.4 g, 1.356 mmol, 1.0 eq.), 4-chloro-7-(chloromethyl)-3-methyl-1H,3H-furo[3,4-c]quinoline (Int. G, 0.44992 g, 1.628 mmol, 1.2 eq.) and Cs2CO3 (0.66287 g, 2.034 mmol, 1.5 eq.) in acetonitrile (4.0 mL), KI (0.22515 g, 1.356 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 70°C for 3 h. The reaction mixture was diluted with NaHCO3 and extracted with EtOAc(3x). The combined organic layers were washed with brine and dried over with Na2SO4, filtrated and evaporated. The crude product was purified by FCC (0 to 80% EtOAc in hexane gradient) to obtain rac-N-({4-chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1- ethyl-3-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.152, 0.513 g, 0.969 mmol, 71%, beige solid, m/z [M+H]+: 504.2). Ryvu Therapeutics S.A. RVU305 189 R10945WO 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 2H), 7.89 (d, J = 1.5 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 – 7.64 (m, 2H), 5.59 – 5.51 (m, 2H), 5.45 – 5.40 (m, 1H), 5.10 (s, 2H), 3.90 – 3.82 (m, 2H), 2.20 – 2.11 (m, 1H), 1.65 (s, 3H), 1.55 (d, J = 6.2 Hz, 4H), 1.17 – 1.12 (m, 4H), 1.08 – 1.02 (m, 2H), 0.98 – 0.92 (m, 2H). Rac-N-({4-Amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide (Example 54) To solution of rac-N-({4-chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl- 3-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.152, 0.713 g, 1.33 mmol, 1.0 eq.) in DMSO (5.0 mL) was added DMBA (0.89 g, 5.33 mmol, 4.0 eq.). then, the reaction mixture was stirred at 120°C overnight. The reaction mixture was diluted with NaHCO3 and extracted with EtOAc (3x). the combined organic layers were washed with brine, dried over Na2SO4, filtrated and evaporated. The crude product was purified by FCC (0 to 80% of EtOAc gradient in hexane). Product was dissolved in DCM (4.0 mL) and TFA (2.05 ml, 26.65 mmol, 20.0 eq.) was added at 0°C. The reaction mixture was stirred at room temperature overnight. The reaction mix- ture was diluted with a solution of 1M NaOH to obtain pH~8 and extratced with DCM(3x). The combined or- ganic layers were washed with brine, dried over Na2SO4, filtrated and evaporated. The crude product was puri- fied by FCC (0 to 10% of MeOH gradient in DCM). Product was lyophilized with EtOH/H2O to give Rac-N-({4- amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)py- rimidine-5-carboxamide (0.19 g, 0.393 mmol, 29%, beige solid, m/z [M+H]+: 484.6). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.61 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.41 – 7.39 (m, 1H), 7.14 (dd, J = 8.1, 1.6 Hz, 1H), 6.39 (s, 2H), 5.44 – 5.37 (m, 1H), 5.31 (dd, J = 13.7, 3.8 Hz, 1H), 5.22 (dd, J = 13.6, 1.7 Hz, 1H), 4.96 (s, 2H), 3.92 – 3.83 (m, 2H), 2.18 – 2.11 (m, 1H), 1.59 (s, 3H), 1.39 (d, J = 6.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H), 1.08 – 1.02 (m, 2H), 0.97 – 0.92 (m, 2H). Example 55: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5- yl]acetamide tert-Butyl 4-[(2-fluoro-5-nitrophenyl)carbamoyl]piperidine-1-carboxylate (Int.153) Ryvu Therapeutics S.A. RVU305 190 R10945WO To the suspension of 2-fluoro-5-nitroaniline (3.0 g, 19.216 mmol, 1.0 eq.), 1-[(tert-butoxy)carbonyl]piperi- dine-4-carboxylic acid (4.538 g, 19.793 mmol, 1.03 eq.), DIPEA (8.368 ml, 48.04 mmol, 2.5 eq.) and DMAP (0.587 g, 4.805 mmol, 0.25 eq.) in toluene (40 mL), T3P as 50% in EtOAc (17.16 mL) was added. The RM was stirred at 40°C for 2 h. The RM was evaporated to remove most of toluene. Then it was quenched with a satu- rated solution of Na2CO3 and extracted by EtOAc (500 ml). The organic layers were washed with cold 1M HCl, water, brine and dried over Na2SO4, filtered and evaporated. The crude product was triturated in an approx. 100 ml of MTBE/EtOAc 19:1 mixture, filtered and washed with MTBE, then dried. The crude product was puri- fied by FCC (0 to 40% of EtOAc gradient in Heptane), evaporated and triturated with a small amount of MTBE/EtOAc 19:1 mixture, filtered and washed with MTBE, then dried. Both fractions were combined to obtain tert-butyl 4-[(2-fluoro-5-nitrophenyl)carbamoyl]piperidine-1-carboxylate (Int.153, 5.49 g, 14.794 mmol, 77%, beige solid, m/z: [M+H]+: 368.4). 5-Nitro-2-(piperidin-4-yl)-1,3-benzothiazole (Int.154) To the suspension of tert-butyl 4-[(2-fluoro-5-nitrophenyl)carbamoyl]piperidine-1-carboxylate (Int.153, 6.289 g, 17.119 mmol, 1.0 eq.) in toluene (65 mL), Lawesson reagent (8.308 g, 20.541 mmol, 1.2 eq.) was added. The RM was stirred under reflux for 4 h. The RM was cooled down to RT and evaporated to dryness, diluted with DCM and neutralized by a saturated solution of Na2CO3 to pH ~ 9. The crude product was ex- tracted with CH3Cl/i-PrOH 3:1 mixture. The combined organic layers were evaporated and dissolved in DCM (100 mL), followed by an addition of 6N aq. HCl (100 mL) and stirred for 1 h. After stirring, water layer was col- lected. The organic layer was washed with 1M HCl, and water layer was added to the previosly collected one. The organic layer was discarded and the combined water layers were washed with DCM, and then neutralized with a solution of NaOH solution to pH=10 under in ice bath cooling, followed by extraction with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to obtain 5-nitro-2-(piperidin-4-yl)- 1,3-benzothiazole (Int.154, 3.558 g, 13.512 mmol, 79%, beige solid, m/z: [M+H]+: 264.4). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 2.2 Hz, 0H), 8.38 (dd, J = 8.8, 0.5 Hz, 1H), 8.26 (dd, J = 8.8, 2.3 Hz, 1H), 3.28 (dt, J = 11.6, 3.8 Hz, 1H), 3.04 (dt, J = 12.7, 3.6 Hz, 2H), 2.64 (td, J = 12.1, 2.5 Hz, 2H), 2.05 (ddt, J = 12.1, 4.2, 2.2 Hz, 2H), 1.75 – 1.55 (m, 2H). tert-Butyl 4-(5-nitro-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.155) To a solution of 5-nitro-2-(piperidin-4-yl)-1,3-benzothiazole (Int.154, 3.558 g, 13.512 mmol, 1.0 eq.) in DCM (100 mL), Boc2O (2.949 g, 13.512 mmol, 1.0 eq.) was added. Gas release started. A small crystal of DMAP was added after 10 min of stirring. The RM was stirred at RT for 2 h. The RM was evaporated, then trit- urated with Et2O to obtain fine solid and evaporated again. The product was triturated with heptane over 2 h and filtered, then washed with a small amount of heptane 2 times, and dried to obtain tert-butyl 4-(5-nitro-1,3- benzothiazol-2-yl)piperidine-1-carboxylate (Int.155, 4.39 g, 11.959 mmol, 89%, beige solid). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 2.2 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.28 (dd, J = 8.8, 2.3 Hz, 1H), 4.05 (d, J = 13.2 Hz, 2H), 3.45 (tt, J = 11.4, 3.7 Hz, 1H), 2.96 (s, 2H), 2.30 – 2.06 (m, 2H), 1.86 – 1.60 (m, 2H), 1.43 (s, 9H). tert-Butyl 4-(5-amino-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.156) To a solution of tert-butyl 4-(5-nitro-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.155, 4.39 g, 11.959 mmol, 1.0 eq.) in acetone (50 mL), Zn (7.82 g, 119.608 mmol, 10.002 eq.) was added. A saturated solu- tion of NH4Cl (30.0 mL) was added slowly in a manner not to exceed 30˚C and the reaction mixture was stirred Ryvu Therapeutics S.A. RVU305 191 R10945WO for 20 minutes at RT and 4 h at 40˚C. The RM was filtrated through Celite® and washed with EtOAc. The or- ganic layer was washed with water, brine, and dried over Na2SO4, filtered and evaporated to obtain tert-butyl 4- (5-amino-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.156, 3.83 g, 10.682 mmol, 89%, yellow solid, m/z: [M+H]+: 334.20). 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.72 (dd, J = 8.6, 2.2 Hz, 1H), 5.23 (s, 2H), 4.33 – 3.64 (m, 2H), 3.23 (tt, J = 11.4, 3.7 Hz, 1H), 2.91 (s, 2H), 2.14 – 1.96 (m, 2H), 1.73 – 1.53 (m, 2H), 1.42 (s, 9H). tert-Butyl 4-(5-acetamido-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.157) To a solution of tert-butyl 4-(5-amino-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.156, 0.45 g, 1.255 mmol, 1.0 eq.) in DCM (10.0 mL), triethylamine (0.44 ml, 3.174 mmol, 2.529 eq.) was added dropwise. Then, acetic anhydride (0.149 ml, 1.576 mmol, 1.256 eq.) was added and the RM was stirred at RT overnight. The reaction mixture was diluted with DCM and extracted with water. The combined organic layers were washed with brine and concentrated. The solid was triturated with hexane to obtain tert-butyl 4-(5-acetamido- 1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.157, 0.47 g, 1.214 mmol, 97%, white solid). 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.31 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.51 (dd, J = 8.7, 2.1 Hz, 1H), 4.02 (d, J = 13.1 Hz, 2H), 3.30 – 3.21 (m, 1H), 3.09 – 2.78 (m, 2H), 2.16 – 2.01 (m, 5H), 1.75 – 1.50 (m, 2H), 1.41 (s, 9H). tert-Butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)acetamido]-1,3-benzothiazol-2-yl}piperidine- 1-carboxylate (Int.158) A suspension of tert-butyl 4-(5-acetamido-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (Int.157, 0.226 g, 0.578 mmol, 1.0 eq.), 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.208 g, 0.81 mmol, 1.402 eq.) and Cs2CO3 (0.471 g, 1.446 mmol, 2.502 eq.) in Acetonitrile (5.0 mL) and DMF (1.0 mL) mixture was stirred at 80°C for 16h. The RM was cooled down and diluted with water and extracted (x2) with chloroform:iso- propanol(3:1) mixture. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by FCC (0 to 4% of MeOH gradient in DCM) to obtain tert-butyl 4-{5-[N- ({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)acetamido]-1,3-benzothiazol-2-yl}piperidine-1-carboxylate (Int. 158, 0.189 g, 0.274 mmol, 47%,light yellow solid, m/z: [M+H]+: 493.6). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.85 – 7.76 (m, 2H), 7.66 – 7.59 (m, 1H), 7.30 (dd, J = 8.5, 2.1 Hz, 1H), 5.57 – 5.48 (m, 2H), 5.26 – 5.13 (m, 2H), 4.07 – 3.94 (m, 2H), 3.30 – 3.23 (m, 1H), 2.99 – 2.81 (m, 2H), 2.11 – 1.99 (m, 2H), 1.92 (s, 3H), 1.68 – 1.53 (m, 2H), 1.40 (s, 9H). N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]acetamide (Ex- ample 55) Step 1: A solution of tert-butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)acetamido]-1,3-benzothi- azol-2-yl}piperidine-1-carboxylate (Int.158, 0.444 g, 0.666 mmol, 1.0 eq.), 1-(2,4-dimethoxyphenyl)methana- mine (0.335 g, 2.0 mmol, 3.0 eq.) in DMSO (5.0 mL) was stirred at 110˚C for 30 h. The RM was cool down to RT, diluted with Ethylacetate and extracted with water. The organic phase was collected and washed with brine, dried over Na2O4, filtered and evaporated. The crude was purified via FCC (0 to 6% of MeOH gradient in Ryvu Therapeutics S.A. RVU305 192 R10945WO DCM) to obtain tert-butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)me- thyl]acetamido}-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (0.481 g, 0.525 mmol, 79%, yellow solid, m/z: [M+H]+: 724.8). Step 2: To a solution of tert-butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]acetamido}-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (0.481 g, 0.525 mmol, 1.0 eq.) in DCM (5.0 mL), trifluoroacetic acid (1.3 mL) was added dropwise and the RM was stirred at RT for 18 h. The reaction mix- ture was diluted with a saturated solution of Na2CO3 and stirred for 30min. Then, the crude product was ex- tracted with chloroform:isopropanol mixture (3:1). The organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by using NH2-functionalized silica (0 to 5% of MeOH gradient in DCM) to obtain N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-[2-(piperidin-4-yl)-1,3- benzothiazol-5-yl]acetamide (Example 55, 0.074 g, 0.153 mmol, 29%, light yellow solid, m/z: [M+H]+: 474.4). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 8.5 Hz, 1H), 7.81 – 7.75 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.29 (s, 1H), 7.24 (dd, J = 8.6, 2.0 Hz, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 6.43 (s, 2H), 5.28 (t, J = 3.4 Hz, 2H), 5.05 (s, 2H), 4.96 (t, J = 3.4 Hz, 2H), 3.25 – 3.15 (m, 1H), 3.12 – 2.99 (m, 2H), 2.73 – 2.58 (m, 2H), 2.13 – 1.95 (m, 3H), 1.89 (s, 3H), 1.78 – 1.59 (m, 2H). Example 56: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(piperidin-4-yl)-1,3- benzothiazol-5-yl]pyridine-3-carboxamide tert-Butyl 4-[5-(6-cyclopropylpyridine-3-amido)-1,3-benzothiazol-2-yl]piperidine-1-carboxylate (Int.159) To a solution of DMAP (0.025 g, 0.21 mmol, 0.39 eq.), DIPEA (0.23 mL, 1.32 mmol, 2.5 eq.), 6-cyclopropylpyri- dine-3-carboxylic acid (0.085 g, 0.52 mmol, 1.0 eq.) and tert-butyl 4-(5-amino-1,3-benzothiazol-2-yl)piperidine- 1-carboxylate (Int.156, 0.185 g, 0.52 mmol, 1.0 eq.) in toluene (5.0 mL) and T3P as 50% in EtOAc (0.62 mL, 1.04 mmol, 2.0 eq) was added at RT. Then, the RM was stirred at 60°C for 1 h. The reaction was diluted with a saturated solution of Na2CO3 and extracted with EtOAc (2x). The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. Then, the crude product was diluted with iPrOH and little amount of Ryvu Therapeutics S.A. RVU305 193 R10945WO EtOAc and left overnight. Then yellowish solid was filtered off to obtain tert-butyl 4-[5-(6-cyclopropylpyridine-3- amido)-1,3-benzothiazol-2-yl]piperidine-1-carboxylate (Int.159, 0.22 g, 0.446 mmol, 86%, yellowish solid). 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.97 (dd, J = 2.3, 0.8 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.19 (dd, J = 8.2, 2.4 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.76 (dd, J = 8.7, 2.1 Hz, 1H), 7.48 (dd, J = 8.3, 0.8 Hz, 1H), 4.04 (d, J = 13.1 Hz, 2H), 3.32 (s, 1H overlapped with water signal), 3.04 – 2.84 (m, 2H), 2.30 – 2.19 (m, 1H), 2.17 – 2.07 (m, 2H), 1.73 – 1.59 (m, 2H), 1.43 (s, 9H), 1.11 – 0.98 (m, 4H). tert-Butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)6-cyclopropylpyridine-3-amido]-1,3-benzothi- azol-2-yl}piperidine-1-carboxylate (Int.160) A solution of tert-butyl 4-[5-(6-cyclopropylpyridine-3-amido)-1,3-benzothiazol-2-yl]piperidine-1-carboxylate (Int. 159, 0.77 g, 1.593 mmol, 1.0 eq.) and Cs2CO3 (1.24 g, 3.81 mmol, 2.4 eq.) in MeCN (10.0 mL) was flushed with argon for 10min at RT, then 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.57 g, 2.22 mmol, 1.39 eq.) and DMF (1.0 mL) were added and the RM was stirred at 70°C for 3.5 h. A saturated solution of Na2CO3 was added and the crude product was extracted with CHCl3/iPrOH 3/1 v/v (3x). the combined or- ganic phases were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to obtain tert-butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4- c]quinolin-7-yl}methyl)6-cyclopropylpyridine-3-amido]-1,3-benzothiazol-2-yl}piperidine-1-carboxylate (Int.160, 0.8 g, 1.115 mmol, 70%, whitish powder, m/z : [M+H]+ : 697.2). 1H NMR (400 MHz, DMSO-d6) δ 8.41 (dd, J = 2.2, 0.8 Hz, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.89 – 7.84 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 8.5, 1.7 Hz, 1H), 7.62 (dd, J = 8.1, 2.3 Hz, 1H), 7.18 – 7.12 (m, 2H), 5.50 (t, J = 3.1 Hz, 2H), 5.43 (s, 2H), 5.18 (t, J = 3.1 Hz, 2H), 4.02 – 3.95 (m, 2H), 3.26 (tt, J = 11.4, 3.7 Hz, 1H), 2.97 – 2.80 (m, 2H), 2.08 – 2.00 (m, 3H), 1.57 (qd, J = 12.3, 4.2 Hz, 2H), 1.40 (s, 9H), 0.94 – 0.87 (m, 2H), 0.85 – 0.80 (m, 2H). N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5- yl]pyridine-3-carboxamide (Int.161) A solution of tert-butyl 4-{5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)6-cyclopropylpyridine-3- amido]-1,3-benzothiazol-2-yl}piperidine-1-carboxylate (Int.160, 0.8 g, 1.12 mmol, 1.0 eq.), 1-(2,4-dimethoxy- phenyl)methanamine (1.11 g, 6.64 mmol, 5.96 eq.) in dry DMSO (10.0 mL) was stirred at 140°C for 3.5 h. The RM was diluted with water/Na2CO3 sat. and extracted with DCM (2x). Thecombined organic layers were washed with water, brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 70% MeCN gradient in DCM) to obtain tert-butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}- 1H,3H-furo[3,4-c]quinolin-7-yl)methyl]6-cyclopropylpyridine-3-amido}-1,3-benzothiazol-2-yl)piperidine-1-carbox- ylate (Int.161, 0.48 g, 0.511 mmol, 46%, slightly yellow solid, m/z : [M+H]+ : 828.1). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 8.2, 2.3 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.17 – 7.07 (m, 3H), 6.99 (t, J = 5.7 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.40 (dd, J = 8.4, 2.4 Hz, 1H), 5.33 – 5.24 (m, 4H), 5.02 (t, J = 3.4 Hz, 2H), 4.54 (d, J = 5.7 Hz, 2H), 3.99 (d, J = 13.0 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 3.25 (tt, J = 11.4, 3.7 Hz, 1H), 2.88 (s, 2H), 2.08 – 1.96 (m, 3H), 1.57 (qd, J = 12.3, 4.2 Hz, 2H), 1.40 (s, 9H), 0.94 – 0.87 (m, 2H), 0.86 – 0.77 (m, 2H). N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5- yl]pyridine-3-carboxamide (Example 56) Ryvu Therapeutics S.A. RVU305 194 R10945WO To a solution of tert-butyl 4-(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]6-cyclopropylpyridine-3-amido}-1,3-benzothiazol-2-yl)piperidine-1-carboxylate (0.48 g, 0.51 mmol, 1.0 eq.) in DCM (1.2 mL), TFA (0.6 mL, 7.66 mol, 15.0 eq.) was added and the RM was stirred at RT for 16 h. Then, TFA (0.3 ml, 4.09 mmol, 8.0 eq) was addded and RM was stirred at 40°C for 2 h. The RM was poured onto Na2CO3 sat. / ice and stirred for a few minutes, next brine was added and the crude product was extracted with DCM with addition of CHCl3/iPrOH 3/1 v/v mixture (3x). The organic layers was combined, washed with a solution of 1M K2CO3, brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 3.5% MeOH gradient in DCM), co-evaporated with EtOH (2x) and then lyophilized from EtOH/H2O mixture to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-ben- zothiazol-5-yl]pyridine-3-carboxamide (Example 56, 0.16 g, 0.276 mmol, 54%, white solid, m/z : [M+H]+ : 577.4). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 8.1, 2.3 Hz, 1H), 7.47 – 7.38 (m, 2H), 7.20 (dd, J = 8.2, 1.7 Hz, 1H), 7.16 – 7.06 (m, 2H), 6.45 (s, 2H), 5.30 (s, 2H), 5.28 (t, J = 3.5 Hz, 2H), 4.97 (t, J = 3.4 Hz, 2H), 3.13 (tt, J = 11.6, 3.8 Hz, 1H), 3.00 (dt, J = 12.3, 3.4 Hz, 2H), 2.59 (td, J = 12.2, 2.5 Hz, 2H), 2.06 – 1.92 (m, 3H), 1.65 – 1.53 (m, 2H), 0.94 – 0.88 (m, 2H), 0.85 – 0.78 (m, 2H). Example 57: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5- yl)pyrimidine-5-carboxamide 2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5-carboxamide (Int.162) To a solution of 2-cyclopropylpyrimidine-5-carboxylic acid (0.775 g, 4.72 mmol, 1.05 eq.), DIPEA (2.74 mL, 15.7 mmol, 2.5 eq.), N,N-dimethylpyridin-4-amine (28 mg, 0.23 mmol, 0.05 eq.) and 5-amino-1,3- dimethylpyrazole (0.50 g, 4.5 mmol, 1.0 eq.) in toluene (22.5 mL), T3P as 50% in EtOAc (3.35 mL, 5.6 mmol, 1.25 eq.) was added dropwise at 0˚C and the reaction mixture was stirred at 90˚C for 17 h. Then the reaction mixture was concentrated, diluted with EtOAc and washed with a solution of Na2CO3 (3x). The organic layer was dried over Na2SO4, filtered and evaporated to obtain a yellow solid. The crude was dissolved in a mixture Ryvu Therapeutics S.A. RVU305 195 R10945WO of DCM and hexane and then DCM was evaporated, leading to a precipitation which was filtered off. The re- covered solid was dried in vacuo to give 2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5-carbox- amide (Int.162, 792 mg, 66 % yield, pale beige solid, m/z : [M+H]+ : 258.3). 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 2H), 8.33 (s, 1H), 6.12 (s, 1H), 3.73 (s, 3H), 2.35 (tt, J = 7.9, 4.8 Hz, 1H), 2.26 (s, 3H), 1.31 – 1.24 (m, 2H), 1.24 – 1.16 (m, 2H). N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5- carboxamide (Int.163) Under nitrogen atmosphere, to a solution of 2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5-carbox- amide (Int.162, 692 mg, 2.58 mmol, 1.0 eq.) in dry DMF (8.0 mL), a solution of NaH 60% in mineral oil (124 mg, 3.09 mmol, 1.2 eq) in DMF (5 mL) was added dropwise at 0°C. The reaction mixture was stirred 15 min at 0°C, then a solution of 4‐chloro‐7‐(chloromethyl)‐1H,3H‐furo[3,4‐c]quinoline (Int. C, 1.00 g, 3,87 mmol, 1.5 eq) in DMF (13.5 mL) was added. The reaction mixture was stirred at 50°C for 16 h and then at 60 °C for 5h. The RM was diluted with a saturated solution of Na2CO3 and extracted with EtOAc (3x). The combined organic lay- ers were dried over Na2SO4, filtered, and evaporated. The product was purified by FCC (0% to 4% MeOH gra- dient in DCM) to obtain N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H- pyrazol-5-yl)pyrimidine-5-carboxamide (Int.163, 552mg, 71%, m/z : [M+H]+ : 475.4). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 2H), 7.95 (d, J = 3.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 1.7 Hz, 1H), 5.95 (s, 1H), 5.59 – 5.51 (m, 3H), 5.26 – 5.19 (m, 3H), 2.22 – 2.12 (m, 1H), 1.98 (s, 3H), 1.17 – 1.02 (m, 2H), 1.02 – 0.95 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5- carboxamide (Example 57) Step 1: Under nitrogen atmosphere, a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N- (1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5-carboxamide (Int.163, 552 mg, 0.825 mmol, 1 eq) and (2,4-di- methoxyphenyl)methanamine (0.62 mL, 4.126 mmol, 5 eq) in dry DMSO (8.25 mL) was stirred at 120°C for 21 h. The reaction mixture was poured into a solution of Na2CO3, leading to precipitation. The aqueous solution was extracted with EtOAc and the organic layer was washed with water and brine, dried over Na2SO4, filtered and evaporated to obtain 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin- 7-yl)methyl]-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5-carboxamide (yellow solid). Step 2: To a solution of 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)me- thyl]-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5-carboxamide in DCM (6.5 mL), TFA (1.25 mL, 20 eq) was added and the reaction mixture was stirred at room temperature for 6 h. A solution of Na2CO3 was added to the reaction mixture and stirred with intensity for 20min in RT to neutralize the excess of TFA. The reaction mixture was diluted with DCM, the layers were then separated and the organic washed with a saturated solu- tion of Na2CO3 solution (2x). The organic layer was dried over NaSO4, filtered and evaporated. The crude prod- uct was purified by FCC (2% to 10% MeOH gradient in DCM) followed by preparative HPLC to obtain N-({4- amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5-car- boxamide (Example 57, 36 mg, 9%, yellow powder, m/z :[M+H]+ 456.24). Ryvu Therapeutics S.A. RVU305 196 R10945WO 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.51 (s, 2H), 5.96 (s, 1H), 5.31 (t, J = 3.3 Hz, 2H), 5.08 – 5.01 (m, 2H), 5.00 (t, J = 3.2 Hz, 2H), 3.22 (s, 3H), 2.22 – 2.13 (m, 1H), 2.00 (s, 3H), 1.12 – 1.03 (m, 2H), 1.03 – 0.95 (m, 2H). Example 58: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-2-(1- methylpiperidin-4-yl)-1H-1,3-benzodiazol-6-yl]pyrimidine-5-carboxamide 6-Bromo-1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazole (Int.164) In a high preassure reactor, to a mixture of 5-bromo-N1-methylbenzene-1,2-diamine (1.55 g, 7.7 mmol, 1.0 eq.) and 1-methylpiperidine-4-carboxylic acid hydrochloride (1.87 g, 10.4 mmol, 1.35 eq.), POCl3 (23.0 g, 150.0 mmol, 19.5 eq.) was added. The reactor was placed in an oil bath and stirred at 120°C overnight. Then, the RM was poured portionwise into a mixture of ice and a saturated solution of NaHCO3 (100ml) placed in an ice bath. Then, a solution of 12M NaOH to pH~8-9 were added and the crude product was extracted with DCM (4x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 30% NH3/MeOH gradient in DCM) to obtain 6-bromo-1-methyl- 2-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazole (Int.164, 0.91g, 2.82 mmol, 37%, pink-brown solid m/z [M+H]+:309.2) 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 1.9 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5, 1.9 Hz, 1H), 3.77 (s, 3H), 3.00 – 2.87 (m, 2H), 2.26 (s, 3H), 2.18 – 2.06 (m, 2H), 1.93 – 1.79 (m, 4H). 2-Cyclopropyl-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazol-6-yl]pyrimidine-5-carboxamide (Int. 165) A solution of 6-bromo-1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazole (Int.164, 1.08 g, 3.33 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxamide (0.64 g, 3.68 mmol, 1.1 eq) and Cs2CO3 (2.7 g, 8.29 mmol, 2.5 eq.), in dry dioxane (30.0 mL) was flushed with argon for 10min. Then, Pd2dba3 (0.6 g, 0.65 mmol, 0.2 eq.) and XantPhos (0.57 g, 0.98 mmol, 0.3 eq.) were added and the RM was stirred at 100°C for 2 h. Then, the RM was diluted with a solution of Na2CO3 and CHCl3/iPrOH 3/1 v/v. After separation of layers, to the aqueous layer, brine was added and the crude product was extracted with CHCl3/iPrOH 3/1 (2x). the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 35% MeCN gradient in water) to obtain 2-cyclopropyl-N-[1-methyl-2-(1-methylpiperidin- Ryvu Therapeutics S.A. RVU305 197 R10945WO 4-yl)-1H-1,3-benzodiazol-6-yl]pyrimidine-5-carboxamide (Int.165, 0.95 g, 2.36 mmol, 71%, white solid, , m/z [M+H]+:391.4) 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.13 (s, 2H), 8.05 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 8.6, 2.0 Hz, 1H), 3.74 (s, 3H), 2.99 – 2.84 (m, 3H), 2.32 (tt, J = 8.0, 4.8 Hz, 1H), 2.22 (s, 3H), 2.04 (td, J = 11.3, 3.3 Hz, 2H), 1.93 – 1.80 (m, 4H), 1.20 – 1.06 (m, 4H). N-({4-Chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H- 1,3-benzodiazol-6-yl]pyrimidine-5-carboxamide (Int.166) To a solution of 2-cyclopropyl-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazol-6-yl]pyrimidine- 5-carboxamide (0.5 g, 1.242 mmol, 1.0 eq.) in dry DMF (20.0 mL), NaH (60% in oil, 0.14 g, 3.65 mmol, 2.94 eq.) was added under argon atmosphere at 0°C and the RM was stirred at 0°C for 20 min, followed by the addi- tion of 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.56 g, 1.519 mmol, 1.223 eq.) suspended in dry DMF (10.0 ml) over 20 min. The reaction mixture was stirred at 0°C for 1 h and the RM was diluted with ice and saturated solution of NaHCO3 and the crude product was extracted with CHCl3/iPrOH 3/1 v/v (2x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 20% MeCN gradient in DCM) to obtain N-({4-chloro-1H,3H-furo[3,4-c]quin- olin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazol-6-yl]pyrimidine-5-car- boxamide (Int.166, 0.25 g, 0.378 mmol, 30%, yellowish solid, m/z [M+H]+:608.8) 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 7.92 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.5, 1.7 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 6.77 (dd, J = 8.6, 1.9 Hz, 1H), 5.51 (t, J = 3.1 Hz, 2H), 5.41 (s, 2H), 5.19 (t, J = 3.1 Hz, 2H), 3.69 (s, 3H), 2.92 – 2.82 (m, 3H), 2.19 (s, 3H), 2.08 – 1.94 (m, 3H), 1.89 – 1.73 (m, 4H), 1.05 – 0.97 (m, 2H), 0.92 – 0.87 (m, 2H). 2-Cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-[1-methyl- 2-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazol-6-yl]pyrimidine-5-carboxamide (Int.167) A solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-2-(1- methylpiperidin-4-yl)-1H-1,3-benzodiazol-6-yl]pyrimidine-5-carboxamide (, Int.166, 0.235 g, 0.36 mmol, 1.0 eq.), 1-(2,4-dimethoxyphenyl)methanamine (0.35 g, 2.09 mmol, 5.89 eq.) in dry DMSO (5.0 mL) was stirred at 140°C for 4.5 h. Then, the RM was diluted with a solution of Na2CO3 and the crude product was extracted with DCM with addition of CHCl3/iPrOH 3/1 v/v (3x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 50% MeCN gradi- ent in H2O) to obtain 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazol-6-yl]pyrimidine-5-carboxamide (Int.167, 0.1 g, 0.129 mmol, 36%, white solid, m/z [M+H]+:739.6) 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 2H), 7.56 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 8.2, 1.7 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 5.7 Hz, 1H), 6.74 – 6.68 (m, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.41 (dd, J = 8.4, 2.4 Hz, 1H), 5.31 – 5.20 (m, 4H), 5.02 (t, J = 3.4 Hz, 2H), 4.53 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 3.66 (s, 3H), 2.84 (d, J = 11.2 Hz, 3H), 2.19 (s, 3H), 2.11 – 2.04 (m, 1H), 1.99 (td, J = 11.6, 3.0 Hz, 2H), 1.87 – 1.73 (m, 4H), 1.03 – 0.96 (m, 2H), 0.93 – 0.84 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3- benzodiazol-6-yl]pyrimidine-5-carboxamide (Example 58) Ryvu Therapeutics S.A. RVU305 198 R10945WO To a solution of 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazol-6-yl]pyrimidine-5-carboxamide (Int.167, 0.1 g, 0.13 mmol, 1.0 eq.) in DCM (0.6 mL), TFA (0.5 ml, 6.53 mmol, 50.8 eq.) was added and the RM was stirred at RT overnight. Then, the RM was poured onto a mixture of Na2CO3 sat. / ice and stirred for 15 minutes and the crude product was extracted with DCM with addition of CHCl3/iPrOH 3/1 v/v mixture (3x). Organic lay- ers were combined, washed with 1M K2CO3, brine and dried over Na2SO4, filtered and evaporated. The crude mixture was purified by FCC (0% to 4% MeOH gradient in DCM) to obtain N-({4-amino-1H,3H-furo[3,4-c]quino- lin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazol-6-yl]pyrimidine-5-car- boxamide (Example 58, 0.015 g, 0.025 mmol, 19%, white solid, UPLC long elution (polar long method, buffer type “FA”) purity 99.74%, m/z [M+H]+:589.5) 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.2, 1.7 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.43 (s, 2H), 5.37 – 5.19 (m, 4H), 4.97 (t, J = 3.4 Hz, 2H), 3.68 (s, 3H), 2.91 – 2.81 (m, 3H), 2.19 (s, 3H), 2.11 – 2.04 (m, 1H), 2.03 – 1.95 (m, 2H), 1.89 – 1.73 (m, 4H), 1.04 – 0.97 (m, 2H), 0.93 – 0.86 (m, 2H). Example 59: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)- 2H-indazol-6-yl]pyridine-3-carboxamide 6-Bromo-2-(1-methylpiperidin-4-yl)-2H-indazole (Int.168) A solution of 4-bromo-2-nitrobenzaldehyde (2.5 g, 10.87 mmol, 1.0 eq.) and 1-methylpiperidin-4-amine (1.28 g, 1.40 ml, 11.21 mmol, 1.03 eq.) in iPrOH (25.0 mL) was stirred at 80°C for 2.5 h. Then, tribu- tylphosphane (8.1 mL, 32.43 mmol, 2.98 eq.) was added at RT and the RM was stirred at 80°C for 15 h. Then, the RM was diluted with water and the crude product was extracted with DCM. To the aqueous layer, a satu- rated solution of Na2CO3 and brine were added and the crude product was extracted with DCM (2x). The com- bined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude prod- uct was purified by FCC (0% to 80% DCM gradient in heptane) followed by FCC (0% to 15% MeOH gradient in DCM) to give 6-bromo-2-(1-methylpiperidin-4-yl)-2H-indazole (Int.168, 2.33 g, 7.841 mmol, 72%, white crys- tals, m/z [M+H]+:295.3) 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 1.0 Hz, 1H), 7.87 (dt, J = 1.7, 0.8 Hz, 1H), 7.68 (dd, J = 8.8, 0.7 Hz, 1H), 7.13 (dd, J = 8.8, 1.7 Hz, 1H), 4.52 – 4.35 (m, 1H), 2.96 – 2.83 (m, 2H), 2.23 (s, 3H), 2.14 – 2.04 (m, 6H). Ryvu Therapeutics S.A. RVU305 199 R10945WO 6-Cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide (Int.169) A solution of 6-bromo-2-(1-methylpiperidin-4-yl)-2H-indazole (Int.168, 1.7 g, 5.72 mmol, 1.0 eq.), 6-cy- clopropylpyridine-3-carboxamide (0.958 g, 5.68 mmol, 1.0 eq.) and Cs2CO3 (4.1 g, 12.58 mmol, 2.2 eq.) in dry dioxane (45.0 mL) was flushed with argon for 10 min. Then, Pd2dba3 (1.04 g, 1.14 mmol, 0.2 eq.) and XantPhos (0.99 g, 1.71 mmol, 0.3 eq.) were added and the RM was stirred at 100°C for 2 h. Then, the RM was diluted with a solution of Na2CO3 and the crude product was extracted with DCM with addition of CHCl3/iPrOH 3/1 v/v (3x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evapo- rated. The crude product was purified by FCC (20% to 80% MeOH gradient in DCM) to obtain 6-cyclopropyl-N- [2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide (Int.169, 1.8 g, 4.602 mmol, 80%, yellow solid, m/z [M+H]+:374.4) 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.96 (dd, J = 2.4, 0.8 Hz, 1H), 8.37 (d, J = 1.0 Hz, 1H), 8.21 – 8.14 (m, 2H), 7.65 (dd, J = 8.9, 0.8 Hz, 1H), 7.47 (dd, J = 8.2, 0.9 Hz, 1H), 7.30 (dd, J = 9.0, 1.8 Hz, 1H), 4.48 – 4.35 (m, 1H), 2.97 – 2.85 (m, 2H), 2.25 – 2.20 (m, 4H), 2.14 – 2.05 (m, 6H), 1.08 – 0.98 (m, 4H). N-({4-Chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6- yl]pyridine-3-carboxamide (Int.170) To a solution of 6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide (Int. 169, 0.6 g, 1.53 mmol, 1.0 eq.) in dry DMF (10.0 mL), NaH (60% in oil, 0.18 g, 4.70 mmol, 3.06 eq.) was added under argon atmosphere at 0°C and the RM was stirred at 0°C for 30min, followed by the addition of 7-(bromo- methyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.59 g, 1.75 mmol, 1.13 eq.) suspended in dry DMF (10.0 ml) over 30 min. The reaction mixture was stirred at 0°C for 2 h. Then, the RM was diluted with ice and a satu- rated solution of NaHCO3 and the crude product was extracted with CHCl3/iPrOH 3/1 v/v (3x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 20% MeOH gradient in DCM) to obtain N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}me- thyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide (Int.170, 0.37 g, 0.593 mmol, 39%, yellowish solid, m/z [M+H]+:593.3) 1H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, J = 2.3, 0.8 Hz, 1H), 8.34 (d, J = 0.9 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 8.5, 1.7 Hz, 1H), 7.64 (dd, J = 8.2, 2.3 Hz, 1H), 7.54 (dd, J = 8.8, 0.8 Hz, 1H), 7.39 (dd, J = 2.0, 1.0 Hz, 1H), 7.14 (dd, J = 8.2, 0.9 Hz, 1H), 6.84 (dd, J = 8.8, 1.8 Hz, 1H), 5.52 (t, J = 3.1 Hz, 2H), 5.39 (s, 2H), 5.19 (t, J = 3.1 Hz, 2H), 4.40 – 4.32 (m, 1H), 2.91 – 2.82 (m, 2H), 2.20 (s, 3H), 2.06 – 1.95 (m, 7H), 0.93 – 0.84 (m, 4H). tert-Butyl N-(7-{[1-(6-cyclopropylpyridin-3-yl)-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]formamido]methyl}- 1H,3H-furo[3,4-c]quinolin-4-yl)carbamate (Int.171) A solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4- yl)-2H-indazol-6-yl]pyridine-3-carboxamide (Int.170, 0.36 g, 0.58 mmol, 1.0 eq.), BocNH2 (0.14 g, 1.19 mmol, 2.07 eq.) and Cs2CO3 (0.47 g, 1.44 mmol, 2.50 eq.) in dry dioxane (15.0 ml, 26.0 ml/mmol) was flushed with argon for 10 min. Then, Pd2dba3 (0.1 g, 0.11 mmol, 0.19 eq.) and XantPhos (0.1 g, 0.17 mmol, 0.3 eq.) were added and the RM was stirred at 70°C for 1.5 h. Then, the RM was diluted with CHCl3/iPrOH 3/1 v/v and fil- tered through celite®. The filtrate was washed with a solution of Na2CO3, brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 20% MeOH gradient in DCM) to obtain tert- Ryvu Therapeutics S.A. RVU305 200 R10945WO butyl N-(7-{[1-(6-cyclopropylpyridin-3-yl)-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]formamido]methyl}- 1H,3H-furo[3,4-c]quinolin-4-yl)carbamate (Int.171, 0.23 g, 0.137 mmol, 24%, yellow solid, m/z [M+H]+:674.7) N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6- yl]pyridine-3-carboxamide (Example 59) To a solution of tert-butyl N-(7-{[1-(6-cyclopropylpyridin-3-yl)-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6- yl]formamido]methyl}-1H,3H-furo[3,4-c]quinolin-4-yl)carbamate (Int.171, 0.23 g, 0.137 mmol, 1.0 eq.) in DCM (1.5 ml, 11.0 ml/mmol), TFA (0.31 ml, 4.09 mmol, 30.0 eq.) was added and the RM was stirred at RT overnight. Then, TFA (0.31 ml, 4.09 mmol, 30.0 eq.) was added after 3h at RM the RM was poured onto a mixture of Na2CO3 sat. / ice and stirred for a few minutes. The crude product was extracted with DCM with addition of CHCl3/iPrOH 3/1 v/v mixture (3x). The organic layers were combined, washed with a solution of 1M K2CO3, brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 35% MeOH gradient in DCM) followed by preparative HPLC and lyophilization to obtain N-({4-amino-1H,3H-furo[3,4- c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide (Ex- ample 59, 0.02 g, 0.035 mmol, 26%, white powder, UPLC long elution (polar long method, buffer type “FA”) purity 100%, m/z [M+H]+:574.6) 1H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, J = 16.5, 1.7 Hz, 2H), 7.60 (dd, J = 8.1, 2.3 Hz, 1H), 7.53 (dd, J = 8.8, 0.8 Hz, 1H), 7.47 – 7.38 (m, 2H), 7.32 – 7.28 (m, 1H), 7.20 (dd, J = 8.2, 1.7 Hz, 1H), 7.13 (dd, J = 8.2, 0.9 Hz, 1H), 6.80 (dd, J = 8.8, 1.8 Hz, 1H), 6.45 (s, 2H), 5.28 (t, J = 3.4 Hz, 2H), 5.26 (s, 2H), 4.97 (t, J = 3.4 Hz, 2H), 4.44 – 4.27 (m, 1H), 2.90 – 2.77 (m, 2H), 2.20 (s, 3H), 2.10 – 1.94 (m, 7H), 0.89 (dt, J = 7.9, 2.9 Hz, 2H), 0.82 (dt, J = 4.7, 2.9 Hz, 2H). Example 60: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)- 1,3-benzothiazol-6-yl]pyrimidine-5-carboxamide 2-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-1,3-benzothiazole(Int.172) A solution of 2-bromo-6-nitro-1,3-benzothiazole (1.0 g, 3.86 mmol, 1.0 eq.), 1-methyl-4-(4,4,5,5-tetrame- thyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.95 g, 4.26 mmol, 1.10 eq.) and K2CO3 (1.6 g, 11.58 mmol, 3.00 eq.) in dioxane / water 5/1 v/v (10.0 ml / 2.0 ml) was flushed with argon for 10min. Then, Pd(PPh3)4 Ryvu Therapeutics S.A. RVU305 201 R10945WO (0.66 g, 0.57 mmol, 0.15 eq.) was added and the RM was stirred in MW at 100°C for 1 h. The RM was diluted with water and the crude product was extracted with DCM (3x). The combined organic fractions were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 6% MeOH gradient in DCM) to obtain 2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-1,3-benzothiazole (Int. 172, 0.06 g, 0.196 mmol, 5%, orange-brown solid, m/z [M+H]+:27.5) 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 9.0, 2.4 Hz, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.02 – 6.89 (m, 1H), 3.21 – 3.13 (m, 2H), 2.75 – 2.67 (m, 2H), 2.62 (t, J = 5.6 Hz, 2H), 2.32 (s, 3H). 2-(1-Methylpiperidin-4-yl)-1,3-benzothiazol-6-amine (Int.173) To the solution of 2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-1,3-benzothiazole (Int.172, 0.06 g, 0.196 mmol, 1.0 eq.) in a mixture of MeOH (5.0 mL) and EtOAc (3.0 mL), palladium on carbon (10%, 50% wet, 0.1 g) was added. Air was removed from the flask and hydrogen was introduced from the baloon. The RM was stirred at RT overnight and catalyst was removed on celite®, washed with MeOH and DCM. Filtrate after con- centrated to obtain 2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-6-amine (Int.173, 0.04 g, 0.144 mmol, 73%, brown solid, m/z [M+H]+:248.4) 2-Cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-6-yl]pyrimidine-5-carboxamide (Int.174) DMAP (0.07 g, 0.57 mmol, 0.40 eq.), DIPEA (0.62 ml, 3.56 mmol, 2.50 eq.), 2-(1-methylpiperidin-4-yl)- 1,3-benzothiazol-6-amine (0.37 g, 1.42 mmol, 1.0 eq.) and 2-cyclopropylpyrimidine-5-carboxylic acid (0.24 g, 1.46 mmol, 1.0 eq.) were taken in a mixture of toluene (7.0 mL) and DMF (3.0 mL) and tT3P as 50% in EtOAc (1.7 ml, 2.86 mmol, 2.01 eq.) was added at RT and the RM was stirred at 100°C for 1.5 h. The reaction mixture was diluted with a saturated solution of Na2CO3 and extracted with EtOAc. Then, brine was added to the aque- ous layer and the crude product was extracted with EtOAc (2x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The residues was flooded with heptane and beige solid was filtered off to obtain 2-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-6-yl]pyrimidine-5- carboxamide (Int.174, 0.36 g, 0.887 mmol, 62%, beige solid, m/z [M+H]+: 394.7) 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.12 (s, 2H), 8.55 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.73 (dd, J = 8.8, 2.2 Hz, 1H), 3.11 – 3.00 (m, 1H), 2.92 – 2.80 (m, 2H), 2.38 – 2.29 (m, 1H), 2.20 (s, 3H), 2.13 – 2.01 (m, 4H), 1.81 (qd, J = 12.3, 3.6 Hz, 2H), 1.19 – 1.07 (m, 4H). 2-Cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-6-yl]pyrimidine-5-carboxamide (Int.175) To a solution of 2-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-6-yl]pyrimidine-5-carbox- amide (Int.174, 0.345 g, 0.85 mmol, 1.0 eq.) in dry DMF (8.0 mL), NaH (60% in oil, 0.1 g, 2.61 mmol, 3.07 eq.) was added under argon atmosphere at 0°C and the RM was stirred at 0°C for 30min, followed by the addition of 7-(bromomethyl)-4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.29 g, 0.93 mmol, 1.1 eq.) suspended in dry DMF (4.0 mL) over 20min. The reaction mixture was stirred at 0°C for 30min. New portion of 7-(bromomethyl)- 4-chloro-1H,3H-furo[3,4-c]quinoline (Int. B, 0.29 g, 0.93 mmol, 1.1 eq.) suspended in dry DMF (4.0 ml) over 20min was added and the reaction mixture was stirred for 30min. Then, the RM was diluted with ice and a satu- rated solution of NaHCO3 and the crude product was extracted with CHCl3/iPrOH 3/1 v/v (3x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 20% MeOH gradient in DCM) to obtain N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}me- thyl)-2-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-6-yl]pyrimidine-5-carboxamide (Int.175, 0.05 g, 0.059 mmol, 7%, beige solid, m/z [M+H]+: 611.6) Ryvu Therapeutics S.A. RVU305 202 R10945WO 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 8.09 (d, J = 2.2 Hz, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.80 (dd, J = 11.6, 8.5 Hz, 2H), 7.70 (dd, J = 8.5, 1.7 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 5.52 (t, J = 3.2 Hz, 2H), 5.42 (s, 2H), 5.20 (t, J = 3.1 Hz, 2H), 3.16 – 2.90 (m, 4H), 2.53 (s, 3H overlapped with DMSO signal), 2.15 – 2.05 (m, 3H), 1.88 – 1.75 (m, 1H), 1.38 – 1.27 (m, 2H), 1.06 – 1.00 (m, 2H), 0.94 – 0.88 (m, 2H). 2-Cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N-[2-(1- methylpiperidin-4-yl)-1,3-benzothiazol-6-yl]pyrimidine-5-carboxamide (Int.176) A solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(1-methylpiperidin-4- yl)-1,3-benzothiazol-6-yl]pyrimidine-5-carboxamide (Int.175, 0.05 g, 0.059 mmol, 1.0 eq.), 1-(2,4-dimethoxy- phenyl)methanamine (0.059 g, 0.35 mmol, 6.0 eq.) in DMSO (2.0 mL) was stirred at 140°C overnight. Then, a new portion of 1-(2,4-dimethoxyphenyl)methanamine (0.03 g, 0.18 mmol, 3.0 eq.) was added and the RM was stirred at 140°C for 2 h. Then, the RM was diluted with a solution of Na2CO3 and the crude product was ex- tracted with DCM with addition of CHCl3/iPrOH 3/1 v/v (3x). the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 15% MeOH gradient in DCM) to obtain 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4- c]quinolin-7-yl)methyl]-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-6-yl]pyrimidine-5-carboxamide (Int.176, 0.027 g, 0.018 mmol, 31%, beige solid, m/z [M+H]+: 742.8) N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-6-yl]pyrimidine-5-carboxamide (Example 60) To a solution of 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-6-yl]pyrimidine-5-carboxamide (Int.176, 0.027 g, 0.018 mmol, 1.0 eq.) in DCM (0.8 mL), TFA (0.07 mL) was added and the RM was stirred at RT overnight. Then, a new portion of TFA (0.21 mL was added and the reaction mixture was stirred for 4 h. Then, the RM was poured onto Na2CO3 sat. / ice and stirred for a few minutes and the crude product was extracted with DCM with addition of CHCl3/iPrOH 3/1 v/v mixture (3x). The organic layers were combined, washed with a solution of 1M K2CO3, brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by prepar- ative HPLC and lyophilization to obtain N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2- (1-methylpiperidin-4-yl)-1,3-benzothiazol-6-yl]pyrimidine-5-carboxamide (Example 60, 0.002 g, 0.003 mmol, 26%, white solid, UPLC long elution (polar long method, buffer type “FA”) purity 98.74%, m/z [M+H]+: 592.8) 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 2H), 8.00 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.47 – 7.33 (m, 2H), 7.26 – 7.12 (m, 2H), 6.44 (s, 2H), 5.31 – 5.23 (m, 4H), 4.97 (t, J = 3.4 Hz, 2H), 3.07 – 2.96 (m, 1H), 2.88 – 2.78 (m, 2H), 2.18 (s, 3H), 2.09 (dq, J = 8.1, 4.1 Hz, 1H), 2.06 – 1.95 (m, 4H), 1.86 – 1.69 (m, 2H), 1.01 (dt, J = 7.9, 3.2 Hz, 2H), 0.94 – 0.87 (m, 2H). Example 61: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(piperidin-4-yl)methyl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide Ryvu Therapeutics S.A. RVU305 203 R10945WO 2-Amino-4-bromobenzene-1-thiol (Int.177) In a high pressure reactor, to a solution of KOH (9.8 g, 174.7 mmol, 20.0 eq.) in water (24.0 ml, 2.75 ml/mmol), 5-bromo-1,3-benzothiazol-2-amine (2.0 g, 8.73 mmol, 1.0 eq.) was added at 0°C and the RM was stirred under reflux overnight. Then, the reactor was placed in an ice bath and the RM was diluted with water (20.0 ml) and then glacial acetic was added portionwise acid (to pH~5-6, ~12.0 ml). The Solid was filtered off and washed with water (3x). The solid was lyophilized from dioxane/water mixture to obtain 2-amino-4-bromo- benzene-1-thiol (Int.177, 1.76 g, 7.244 mmol, 83%, whitish solid, m/z [M+H]+:203.8) 1H NMR (400 MHz, DMSO-d6) δ 7.09 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.62 (dd, J = 8.2, 2.2 Hz, 1H), 5.18 (s, 2H). tert-Butyl 4-[(5-bromo-1,3-benzothiazol-2-yl)methyl]piperidine-1-carboxylate (Int.178) A solution of 2-amino-4-bromobenzene-1-thiol (Int.177, 1.74 g, 7.16 mmol, 1.0 eq.) and tert-butyl 4-(2- oxoethyl)piperidine-1-carboxylate (1.62 g, 7.13 mmol, 1.0 eq.) in DMSO (15.0 mL) was flushed with air and was stirred under reflux overnight. Then, the RM was diluted with a solution of NaHCO3 and the crude product was extracted with DCM (3x). The organic layers were combined, washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 25% EtOAc gradient in heptane) to obtain tert- butyl 4-[(5-bromo-1,3-benzothiazol-2-yl)methyl]piperidine-1-carboxylate (Int.178, 1.64 g, 3.907 mmol, 55%, beige solid, m/z [M+H]+: on ES+ visible only M-56(tBu) and M-100(Boc)) 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 1.9 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 8.6, 2.0 Hz, 1H), 3.92 (d, J = 13.2 Hz, 2H), 3.07 (d, J = 7.1 Hz, 2H), 2.82 – 2.61 (m, 2H), 2.02 (dqd, J = 11.0, 7.3, 3.5 Hz, 1H), 1.67 (d, J = 11.2 Hz, 2H), 1.39 (s, 9H), 1.15 (qd, J = 12.2, 4.3 Hz, 2H). tert-butyl 4-{[5-(2-cyclopropylpyrimidine-5-amido)-1,3-benzothiazol-2-yl]methyl}piperidine-1-carboxylate (Int. 179) A solution of tert-butyl 4-[(5-bromo-1,3-benzothiazol-2-yl)methyl]piperidine-1-carboxylate (Int.178, 1.62 g, 3.86 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxamide (0.64 g, 3.87 mmol, 1.0 eq.) and Cs2CO3 (2.76 g, 8.47 mmol, 2.20 eq.) in dry dioxane (15.0 mL) was flushed with argon for 10min. Then, XPhos Pd G3 (0.45 g, 0.54 mmol, 0.14 eq.) was added and the RM was stirred at 100°C for 2 h. Then, a new portion of XPhos Pd Ryvu Therapeutics S.A. RVU305 204 R10945WO G3 (0.2 g.0.23 mmol, 0.06 eq.) was added and the RM was stirred at 100°C overnight. Then, the RM was di- luted with a solution of Na2CO3 and the crude product was extracted with DCM with addition of CHCl3/iPrOH 3/1 v/v (2x). The combined organic layers were washed with brine and dried over Na2SO4, filtered and evapo- rated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to obtain tert-butyl 4-{[5-(2- cyclopropylpyrimidine-5-amido)-1,3-benzothiazol-2-yl]methyl}piperidine-1-carboxylate (Int.179, 0.48 g, 0.924 mmol, 24%, orange solid, m/z [M+H]+:on ES+visible only M-Boc/100) 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.13 (s, 2H), 8.43 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.72 (dd, J = 8.7, 2.1 Hz, 1H), 3.93 (d, J = 13.0 Hz, 2H), 3.06 (d, J = 7.1 Hz, 2H), 2.83 – 2.65 (m, 2H), 2.37 – 2.27 (m, 1H), 2.09 – 1.96 (m, 1H), 1.69 (d, J = 13.0 Hz, 2H), 1.39 (s, 9H), 1.20 – 1.08 (m, 6H). tert-Butyl 4-({5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-1,3-benzo- thiazol-2-yl}methyl)piperidine-1-carboxylate (Int.180) A solution of tert-butyl 4-{[5-(2-cyclopropylpyrimidine-5-amido)-1,3-benzothiazol-2-yl]methyl}piperidine-1- carboxylate (Int.179, 0.61 g, 1.17 mmol, 1.0 eq.), Cs2CO3 (1.15 g, 3.52 mmol, 3.0 eq.) in a mixture of MeCN (15.0 mL) and DMF (5.0 mL) was flushed with argon for 10min at RT and 4-chloro-7-(chloromethyl)-1H,3H- furo[3,4-c]quinoline (Int. C, 0.42 g, 1.64 mmol, 1.4 eq.) was added and the RM was stirred at 75°Cfor 1 h. A new portions of Cs2CO3 (0.35 g, 1.06 mmol, 0.9 eq.) and 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (0.15 g, 0.59 mmol, 0.5 eq.) were added the RM was stirred at 75°C for 1 h. Then, the RM was poured into a solution of Na2CO3 and the crude product was extracted with DCM with addition of CHCl3/iPrOH 3/1 v/v (2x). the combined organic phases were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 80% MeCN gradient in DCM) to obtain tert-butyl 4-({5-[N-({4-chloro- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine-5-amido]-1,3-benzothiazol-2-yl}methyl)piperi- dine-1-carboxylate (Int.180, 0.4 g, 0.484 mmol, 41%, whitish solid, m/z [M+H]+:712.3) 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 2H), 7.96 (d, J = 1.7 Hz, 1H), 7.93 – 7.87 (m, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 7.26 (dd, J = 8.5, 2.1 Hz, 1H), 5.51 (t, J = 3.1 Hz, 2H), 5.45 (s, 2H), 5.20 (t, J = 3.1 Hz, 2H), 3.89 (d, J = 13.2 Hz, 2H), 2.99 (d, J = 7.0 Hz, 2H), 2.72 – 2.62 (m, 2H), 2.12 – 2.08 (m, 1H), 2.02 – 1.91 (m, 1H), 1.62 (d, J = 12.8 Hz, 2H), 1.38 (s, 9H), 1.18 – 1.07 (m, 2H), 1.06 – 0.99 (m, 2H), 0.95 – 0.87 (m, 2H). tert-Butyl 4-[(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclo- propylpyrimidine-5-amido}-1,3-benzothiazol-2-yl)methyl]piperidine-1-carboxylate (Int.181) A solution of tert-butyl 4-({5-[N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)2-cyclopropylpyrimidine- 5-amido]-1,3-benzothiazol-2-yl}methyl)piperidine-1-carboxylate (Int.180, 0.4 g, 0.48 mmol, 1.0 eq.), 1-(2,4-di- methoxyphenyl)methanamine (0.485 g, 2.90 mmol, 6.0 eq.) in dry DMSO (10.0 mL) was stirred at 140°C for 5.5 h. then, the RM was diluted with a solution of Na2CO3 and the crude product was extraced with DCM (2x). The combined organic layers were washed with water, brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 40% MeCN gradient in DCM) to give tert-butyl 4-[(5-{N-[(4-{[(2,4- dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]2-cyclopropylpyrimidine-5-amido}-1,3- benzothiazol-2-yl)methyl]piperidine-1-carboxylate (Int.181, 0.34 g, 0.311 mmol, 64%, yellow solid, m/z [M+H]+:840.6) 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.88 (d, J = 8.8 Hz, 1H), 7.84 – 7.79 (m, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.26 – 7.17 (m, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.99 (t, J = 5.7 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.41 (dd, J = 8.3, 2.4 Hz, 1H), 5.30 (s, 2H), 5.28 (t, J = 3.8 Hz, 2H), 5.02 (t, J = 3.5 Hz, 2H), 4.54 Ryvu Therapeutics S.A. RVU305 205 R10945WO (d, J = 5.6 Hz, 2H), 3.88 (d, J = 11.9 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 2.98 (d, J = 7.1 Hz, 2H), 2.17 – 2.03 (m, 1H), 2.02 – 1.89 (m, 1H), 1.62 (d, J = 12.9 Hz, 2H), 1.38 (s, 9H), 1.28 – 1.22 (m, 2H), 1.15 – 1.07 (m, 2H), 1.04 – 0.98 (m, 2H), 0.93 – 0.87 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(piperidin-4-yl)methyl]-1,3-benzothiazol- 5-yl}pyrimidine-5-carboxamide (Example 61) To a solution of tert-butyl 4-[(5-{N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1H,3H-furo[3,4-c]quinolin-7- yl)methyl]2-cyclopropylpyrimidine-5-amido}-1,3-benzothiazol-2-yl)methyl]piperidine-1-carboxylate (Int.180, 0.34 g, 0.31 mmol, 1.0 eq.) in DCM (2.0 ml, 6.4 ml/mmol), TFA (0.71 mL) was added and the RM was stirred at RT overnight. Then, a new portion of TFA (0.35 mL) was added and the reaction mixture was stirred at RT for 2 h. then, the RM was poured onto Na2CO3 sat. / ice and stirred for a few minutes, next brine was added and product was extracted with DCM with addition of CHCl3/iPrOH 3/1 v/v mixture (3x). the organic layers were combined, washed with a solution of 1M K2CO3, brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 10% MeOH gradient in DCM) and by preparative HPLC and lyophi- lization to obtain N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(piperidin-4-yl)methyl]- 1,3-benzothiazol-5-yl}pyrimidine-5-carboxamide (Example 61, 0.02 g, 0.033 mmol, white solid, UPLC long elu- tion (polar long method, buffer type “FA”) purity 98.71%, m/z [M+H]+:592.5) 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.37 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.44 – 7.40 (m, 2H), 7.24 – 7.18 (m, 2H), 6.45 (s, 2H), 5.31 (s, 2H), 5.28 (t, J = 3.3 Hz, 2H), 4.97 (t, J = 3.4 Hz, 2H), 3.08 (d, J = 12.4 Hz, 2H), 2.99 (d, J = 7.0 Hz, 2H), 2.71 – 2.63 (m, 2H), 2.09 (tt, J = 8.3, 4.7 Hz, 1H), 2.03 – 1.94 (m, 1H), 1.71 (d, J = 13.2 Hz, 2H), 1.29 (q, J = 12.0 Hz, 2H), 1.01 (dt, J = 8.0, 3.2 Hz, 2H), 0.91 (dt, J = 4.6, 3.1 Hz, 2H). Example 62: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(1-methylpiperidin-4- yl)methyl]-1,3-benzothiazol-5-yl}pyrimidine-5-carboxamide N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(1-methylpiperidin-4-yl)methyl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide (Example 62) Formaldehyde solution, 37 wt. % in H2O, contains methanol as stabilizer (0.007 ml, 0.094 mmol, 1.47 eq.) and acetic acid (0.008 ml, 0.14 mmol, 2.19 eq.) were added to a stirred solution of N-({4-amino-1H,3H- furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(piperidin-4-yl)methyl]-1,3-benzothiazol-5-yl}pyrimidine-5- carboxamide (Example 61, 0.0425 g, 0.064 mmol, 1.0 eq.) in MeOH (1.5 ml, 23.5 ml/mmol). The resulting mixture was stirred at RT for 1h, then NaBH3CN (0.005 g, 0.084 mmol, 1.31 eq.) was added in one portion. After 1h RM was quenched with water and diluted with Na2CO3 sat. aq., then extraction with DCM with addition of CHCl3/iPrOH 3/1 v/v (3x) was done. The combined organic fractions was washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC and and lyophilization to obtain N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(1- Ryvu Therapeutics S.A. RVU305 206 R10945WO methylpiperidin-4-yl)methyl]-1,3-benzothiazol-5-yl}pyrimidine-5-carboxamide (Example 62, 0.02 g, 0.033 mmol, 52%, white solid, UPLC long elution (polar long method, buffer type “FA”) purity 99.73%, m/z [M+H]+:606.6 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.88 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.21 (dd, J = 8.1, 1.7 Hz, 1H), 7.17 (dd, J = 8.6, 2.1 Hz, 1H), 6.45 (s, 2H), 5.31 (s, 2H), 5.28 (t, J = 3.4 Hz, 2H), 4.97 (t, J = 3.3 Hz, 2H), 2.96 (d, J = 7.1 Hz, 2H), 2.74 – 2.66 (m, 2H), 2.11 (s, 3H), 2.10 – 2.05 (m, 1H), 1.79 (td, J = 11.6, 2.4 Hz, 2H), 1.75 – 1.66 (m, 1H), 1.60 (d, J = 12.1 Hz, 2H), 1.25 (qd, J = 11.9, 3.8 Hz, 2H), 1.01 (dt, J = 8.0, 3.2 Hz, 2H), 0.90 (dt, J = 4.5, 3.1 Hz, 2H). Example 63: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[3-methyl-2-(1- methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide; bis(formic acid) 6-Bromo-3-methyl-2-(1-methylpiperidin-4-yl)-2H-indazole (Int.181) A solution of 1-methylpiperidin-4-amine (0.235 g, 2.058 mmol, 0.998 eq.), titanium(4+) tetraethanolate (0.95 g, 4.165 mmol, 2.021 eq.) and 1-(4-bromo-2-nitrophenyl)ethan-1-one (0.503 g, 2.061 mmol, 1.0 eq.) in toluene (10.0 mL) was stirred at 80°C overnight. Toluene was evaporated under vacuum and the residue was diluted in iPrOH (8.0 mL), tributylphosphane (1.6 ml, 6.406 mmol, 3.108 eq.) was added and the reaction mix- ture was stirred at 80°C overnight. The reaction mixture was diluted with water and a solution of NaOH was added to pH = 10 and the crude product was extracted from the water phase with CHCl3:i-PrOH 3:1. The or- ganic layer were dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to obtain 6-bromo-3-methyl-2-(1-methylpiperidin-4-yl)-2H-indazole (Int.181, 0.228 g, 0.658 mmol, 32%, yellow oil, m/z [M+H]+: 309.3). 1H NMR (400 MHz, DMSO) δ 7.79 (dd, J = 1.7, 0.7 Hz, 1H), 7.67 (dd, J = 8.8, 0.7 Hz, 1H), 7.06 (dd, J = 8.8, 1.7 Hz, 1H), 4.49 – 4.38 (m, 1H), 2.93 (d, J = 8.9 Hz, 2H), 2.64 (s, 3H), 2.25 (s, 3H), 2.22 – 2.10 (m, 4H), 1.93 – 1.86 (m, 2H). 6-Cyclopropyl-N-[3-methyl-2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide (Int.182) A solution of 6-cyclopropylpyridine-3-carboxamide (0.095 g, 0.521 mmol, 1.003 eq.), 6-bromo-3-methyl- 2-(1-methylpiperidin-4-yl)-2H-indazole (Int.181, 0.18 g, 0.52 mmol, 1.0 eq.) and Cs2CO3 (0.373 g, 1.145 mmol, 2.203 eq.) in dry dioxane (3.0 mL) was flushed with argon for 10 minutes. Then, Pd2(dba)3 (0.095 g, 0.104 mmol, 0.2 eq.) and Xantphos Ryvu Therapeutics S.A. RVU305 207 R10945WO (0.09 g, 0.156 mmol, 0.299 eq.) were added and reaction mixture was stirred at 100°C for 2 h and at 140°C for 3h. The reaction was diluted with a saturated solution of Na2CO3, the crude product was extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 2% MeOH gradient in DCM) to give 6-cyclopropyl-N-[3-methyl- 2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide (Int.182, 0.125 g, 0.266 mmol, 51%, orange solid, m/z [M+H]+: 390.6). 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.95 (d, 1H), 8.17 (dd, J = 8.2, 2.4 Hz, 1H), 8.08 (d, J = 0.8 Hz, 1H), 7.67 – 7.60 (m, 1H), 7.46 (dd, J = 8.2, 0.8 Hz, 1H), 7.23 (dd, J = 9.0, 1.7 Hz, 1H), 4.45 – 4.33 (m, 1H), 2.95 – 2.89 (m, 2H), 2.61 (s, 3H), 2.37 – 2.32 (m, 1H), 2.24 (s, 3H), 2.18 – 2.09 (m, 4H), 1.93 – 1.85 (m, 2H), 1.07 – 1.05 (m, 2H), 1.02 – 0.98 (m, 2H). N-({4-Chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[3-methyl-2-(1-methylpiperidin-4-yl)-2H- indazol-6-yl]pyridine-3-carboxamide (Int.183) To a solution of 6-cyclopropyl-N-[3-methyl-2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carbox- amide (Int.182, 0.1 g, 0.213 mmol, 1.0 eq.) and 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.066 g, 0.257 mmol, 1.207 eq.) in ACN (1.0 mL), Cs2CO3 (0.14 g, 0.43 mmol, 2.016 eq.) was added and the reaction mixture was stirred at 78°C for 3.5 h. The reaction mixture was cooled down to room temperature and then diluted with water. The crude product was extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 10% MeOH gradient in DCM) to give N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclo- propyl-N-[3-methyl-2-(1-methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide (Int.183, 0.027 g, 0.034 mmol, 16%, white solid, m/z [M+H]+: 607.8). 1H NMR (400 MHz, DMSO) δ 8.42 (d, J = 2.2 Hz, 1H), 7.89 (d, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.72 (d, 1H), 7.65 (dd, J = 8.1, 2.2 Hz, 1H), 7.51 (dd, J = 8.7, 0.8 Hz, 1H), 7.33 (d, J = 0.8 Hz, 1H), 7.14 (dd, J = 8.2, 0.9 Hz, 1H), 6.74 (dd, J = 8.8, 1.8 Hz, 1H), 5.52 (t, J = 3.1 Hz, 2H), 5.38 (s, 2H), 5.19 (t, J = 3.1 Hz, 2H), 4.38 – 4.25 (m, 1H), 2.90 – 2.83 (m, 2H), 2.70 – 2.66 (m, 1H), 2.20 (s, 3H), 2.10 – 1.99 (m, 4H), 1.85 – 1.79 (m, 2H), 1.26 (s, 3H), 0.91 – 0.86 (m, 2H), 0.85 – 0.81 (m, 2H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[3-methyl-2-(1-methylpiperidin-4-yl)-2H- indazol-6-yl]pyridine-3-carboxamide; bis formic acid (Example 63) Step 1: To a solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[3-methyl-2-(1- methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide (Int.183, 0.025 g, 0.032 mmol, 1.0 eq.) in DMSO (1.0 mL), 1-(2,4-dimethoxyphenyl)methanamine (0.055 g, 0.329 mmol, 10.375 eq.) was added. The reaction was stirred at 100°C overnight. The reaction was cooled down to room temperature and diluted with water. Then, the crude product was extracted with EtOAc (2x) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. Step 2: To a solution of the product in DCM (1.0 mL), trifluoroacetic acid (0.125 ml, 1.633 mmol, 51.506 eq.) was added at 0°C. The reaction mixture was stirred at room temperature for 3 h. Then, the reaction mixture was di- luted in MeOH and evaporated and the crude product was dissolved DCM and quenched by K2CO3 aq. The extraction was done. Water phases were washed by DCM and then organic phases was combined, dried over Ryvu Therapeutics S.A. RVU305 208 R10945WO Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC and lypophilzed with EtOH and water to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[3-methyl-2-(1- methylpiperidin-4-yl)-2H-indazol-6-yl]pyridine-3-carboxamide; bis(formic acid) (Example 63, 0.002 g, 0.003 mmol, 9%, white powder, m/z [M+H]+: 588.6). 1H NMR (400 MHz, DMSO) δ 8.38 (d, J = 2.2 Hz, 1H), 8.30 (s, 2H), 7.61 (dd, J = 8.2, 2.3 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.40 (s, 1H), 7.26 (d, J = 1.7 Hz, 1H), 7.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.70 (dd, J = 8.8, 1.8 Hz, 1H), 6.45 (s, 2H), 5.28 (t, J = 3.4 Hz, 2H), 5.25 (s, 2H), 4.96 (t, J = 3.4 Hz, 2H), 4.38 – 4.30 (m, 1H), 2.88 – 2.84 (m, 2H), 2.53 (s, 3H), 2.21 (s, 3H), 2.10 – 2.05 (m, 4H), 2.01 – 1.96 (m, 1H), 1.85 – 1.79 (m, 2H), 0.93 – 0.86 (m, 2H), 0.85 – 0.77 (m, 2H). Example 64: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-methyl-N-{2-methyl-6-[2-(1-methylpyrrolidin- 3-yl)ethoxy]pyridin-3-yl}pyridine-3-carboxamide 2-methyl-6-[2-(1-methylpyrrolidin-3-yl)ethoxy]-3-nitropyridine (Int.184) To a solution of 2-(1-methylpyrrolidin-3-yl)ethan-1-ol (0.4 g, 3.096 mmol, 2.137 eq.) and 6-chloro-2-methyl-3- nitropyridine (0.25 g, 1.449 mmol, 1.0 eq.) in DMF (3.0 mL), K2CO3 (0.48 g, 3.47 mmol, 1.20 eq.) was added. The RM was stirred at RT for 16 h. Then, the mixture was diluted with water and extracted with EtOAc. The or- ganic layers were combined, washed with brine and dried over Na2SO4, filtrated and evaporated. The residue was purified by FCC (30% to 90% AcOEt gradient in Hexane) to obtain 2-methyl-6-[2-(1-methylpyrrolidin-3- yl)ethoxy]-3-nitropyridine (Int.184, 0.05 g, 0.188 mmol, 13%, oil, m/z [M+H]+: 266). 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 9.5 Hz, 1H), 6.63 (d, J = 9.4 Hz, 1H), 3.86 – 3.75 (m, 1H), 3.74 – 3.52 (m, 4H), 3.29 (dd, J = 8.3, 6.8 Hz, 1H), 3.11 (s, 3H), 2.67 (s, 3H), 2.14 – 2.04 (m, 1H), 2.04 – 1.99 (m, 1H), 1.67 – 1.57 (m, 2H), 1.57 – 1.46 (m, 1H). 2-methyl-6-[2-(1-methylpyrrolidin-3-yl)ethoxy]pyridin-3-amine (Int.185) To a solution of 2-methyl-6-[2-(1-methylpyrrolidin-3-yl)ethoxy]-3-nitropyridine (Int.184, 0.05 g, 0.188 mmol, 1.0 eq.) in acetone (3.0 mL) and a saturated solution of NH4Cl (1.0 mL), zinc (0.12 g, 1.835 mmol, 9.74 eq.) was added portion wise. The RM was stirred at RT for 2 h. then, the RM was filtrated through Celite® pad and the filter was washed with ethyl acetate. The filtrate was washed with sodium bicarbonate solution, brine, dried over Na2SO4, filtered and evaporated to obtain 2-methyl-6-[2-(1-methylpyrrolidin-3-yl)ethoxy]pyridin-3-amine (Int.185, 0.045 g, 0.191 mmol, 101%, brown solid, m/z [M+H]+: 236). Ryvu Therapeutics S.A. RVU305 209 R10945WO 1H NMR (400 MHz, DMSO-d6) δ 6.86 (d, J = 8.6 Hz, 1H), 6.25 (d, J = 8.6 Hz, 1H), 4.11 (s, 2H), 3.82 – 3.72 (m, 1H), 3.69 (td, J = 8.2, 4.6 Hz, 1H), 3.63 – 3.54 (m, 1H), 3.46 – 3.35 (m, 1H), 3.24 (dd, J = 8.3, 6.9 Hz, 2H), 2.82 (s, 3H), 2.15 (s, 3H), 2.12 – 1.94 (m, 2H), 1.57 – 1.43 (m, 3H). 6-methyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)ethoxy]pyridin-3-yl}pyridine-3-carboxamide (Int.186) To solution of 2-methyl-6-[2-(1-methylpyrrolidin-3-yl)ethoxy]pyridin-3-amine (Int.185, 0.045 g, 0.191 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.03 g, 0.183 mmol, 0.956 eq.) and DMAP (0.01 g, 0.082 mmol, 0.428 eq.) in DMF (2.0 mL), DIPEA (0.086 ml, 0.486 mmol, 2.542 eq) was added followed by T3P as 50% solution in EtOAc (0.24 mL, 0.388 mmol, 2.029 eq.). The reaction mixture was stirred under reflux for 1.5 h. Then, the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were com- bined, washed with brine and dried over Na2SO4, filtrated and evaporated. The residue was purified by FCC (0% to 10% MeOH gradient in DCM) to obtain 2-cyclopropyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)eth- oxy]pyridin-3-yl}pyrimidine-5-carboxamide (Int.186, 0.054 g, 0.123 mmol, 64%, brown solid, m/z [M+H]+: 382). 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.09 (s, 2H), 7.38 (d, J = 8.8 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 3.83 – 3.76 (m, 1H), 3.75 – 3.67 (m, 1H), 3.65 – 3.46 (m, 3H), 3.28 (dd, J = 8.2, 6.9 Hz, 1H), 2.97 (s, 3H), 2.36 – 2.26 (m, 1H), 2.24 (s, 3H), 2.15 – 1.94 (m, 2H), 1.65 – 1.54 (m, 2H), 1.54 – 1.45 (m, 1H), 1.18 – 1.11 (m, 2H), 1.11 – 1.05 (m, 2H). N-({4-Chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-methyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)eth- oxy]pyridin-3-yl}pyridine-3-carboxamide (Int.187). A suspension of 6-methyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)ethoxy]pyridin-3-yl}pyridine-3-carboxamide (Int.186, 0.054 g, 0.123 mmol, 1.0 eq), 4-bromo-7-(bromomethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.035 g, 0.116 mmol, 0.942 eq.). and Cs2CO3 (0.086 g, 0.264 mmol, 2.14 eq.) in dry MeCN (20.0 mL) was stirred at 70°C for 6 h. then, the RM was cooled down, diluted with water and extracted with DCM. The combined or- ganic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by FCC (0% to 10% MeOH gradient in DCM) to obtain N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-me- thyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)ethoxy]pyridin-3-yl}pyridine-3-carboxamide (Int.187, 0.065 g, 0.092 mmol, 75%, yellow solid, m/z [M+H]+: 599). 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 0.7 Hz, 2H), 7.95 – 7.62 (m, 3H), 7.24 (d, J = 8.7 Hz, 1H), 6.32 (d, J = 8.9 Hz, 1H), 5.54 (s, 2H), 5.30 (d, J = 14.6 Hz, 1H), 5.29 – 5.16 (m, 2H), 5.05 – 4.87 (m, 1H), 3.72 – 3.59 (m, 2H), 3.53 (q, J = 7.5 Hz, 1H), 3.43 (s, 2H), 3.24 – 3.15 (m, 1H), 2.87 (s, 3H), 2.18 – 2.05 (m, 1H), 2.02 – 1.87 (m, 2H), 1.84 (d, J = 1.4 Hz, 3H), 1.51 – 1.32 (m, 3H), 1.08 – 1.00 (m, 2H), 0.93 (d, J = 4.1 Hz, 2H). N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-methyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)eth- oxy]pyridin-3-yl}pyridine-3-carboxamide (Int.188) A solution of N-({4-chloro-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-methyl-N-{2-methyl-6-[2-(1-methylpyrrolidin- 3-yl)ethoxy]pyridin-3-yl}pyridine-3-carboxamide (Int.187, 0.065 g, 0.092 mmol, 1.0 eq.) and 1-(2,4-dimethoxy- phenyl)methanamine (0.14 g, 0.837 mmol, 9.079 eq.) in DMSO (2.0 mL) was stirred at 90 °C for 16 h. The re- action mixture was diluted with EtOAc and washed three times with water followed by brine, dried over anhy- drous Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 10% MeOH gradient in DCM) to give N-({4-[(2,4-dimethoxyphenyl)methyl]-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-methyl-N-{2-methyl- 6-[2-(1-methylpyrrolidin-3-yl)ethoxy]pyridin-3-yl}pyridine-3-carboxamide (Int.188, 0.07 g, 0.076 mmol, 82%, yellow oil, m/z [M+H]+: 730.60). Ryvu Therapeutics S.A. RVU305 210 R10945WO N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-methyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)eth- oxy]pyridin-3-yl}pyridine-3-carboxamide (Example 64) To a solution of N-({4-[(2,4-dimethoxyphenyl)methyl]-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-methyl-N-{2-me- thyl-6-[2-(1-methylpyrrolidin-3-yl)ethoxy]pyridin-3-yl}pyridine-3-carboxamide (Int.188, (0.07 g, 0.076 mmol, 1.0 eq.) in DCM (2.0 mL), trifluoroacetic acid (0.2 ml, 2.614 mmol, 34.501 eq.) was added and the RM was stirred at RT for 16 h. Then, the RM was diluted by DCM and then partitioned between mixture of a saturated solution of NaHCO3 and chloroform/isopropanol 3:1 mixture. The aqueous phase was extracted with chloroform/isopro- panol 3:1 mixture and the combined organic layers were washed with a solution of Na2CO3, brine, then dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM). Fractions containing the pure product were co-evaporated with EtOH and lyophilized to give N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-methyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)eth- oxy]pyridin-3-yl}pyridine-3-carboxamide (Example 64, 0.018 g, 0.031 mmol, 39%, yellow - white powder, m/z [M+H]+: 580). 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 0.8 Hz, 2H), 7.48 – 7.32 (m, 2H), 7.30 – 7.09 (m, 2H), 6.46 (s, 2H), 6.34 (d, J = 8.9 Hz, 1H), 5.35 – 5.24 (m, 2H), 5.12 (d, J = 14.1 Hz, 1H), 5.05 – 4.95 (m, 2H), 4.88 (d, J = 14.1 Hz, 1H), 3.74 – 3.61 (m, 2H), 3.60 – 3.37 (m, 3H), 3.27 – 3.13 (m, 1H), 2.87 (s, 3H), 2.22 – 2.03 (m, 1H), 2.00 – 1.82 (m, 2H), 1.78 (d, J = 1.2 Hz, 3H), 1.59 – 1.31 (m, 3H), 1.09 – 0.99 (m, 2H), 0.99 – 0.85 (m, 2H). Example 65: Rac-N-({4-Amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl- 1H-pyrazol-4-yl)pyridine-3-carboxamide 6-Cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (Int.189) T a solution of 1,3-dimethyl-1H-pyrazol-4-amine (0.409 g, 3.68 mmol, 1.0 eq.) in toluene (9.0 mL) and 6- cyclopropylpyridine-3-carboxylic acid (0.621 g, 3.806 mmol, 1.034 eq.) was added, followed by DMAP (0.022 g, 0.18 mmol, 0.05 eq.) and DIPEA (0.72 mL, 4.067 mmol, 1.105 eq.). Then, T3P as 50 wt% solution in AcOEt (1.14 mL, 3.69 mmol, 1.003 eq.) was added and the reaction mixture was stirred under reflux for 1 h. then, the reaction mixture was cooled down to RT and diluted with saturated solution of NaHCO3 in portion to pH 8-9. Then, the organic phase was separated and water phase was extracted with ethyl acetate. The organic layers Ryvu Therapeutics S.A. RVU305 211 R10945WO were combined and washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was pu- rified by FCC (5% to 10 MeOH gradient in DCM) to obtain 6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyri- dine-3-carboxamide (Int.189, 0.88 g, 3.365 mmol, 91%) DC781-090-pc, white solid, m/z [M+H]+: 257). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.89 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 8.2, 2.3 Hz, 1H), 7.88 (s, 1H), 7.42 (dd, J = 8.2, 0.8 Hz, 1H), 3.74 (s, 3H), 2.23 – 2.16 (m, 1H), 2.13 (s, 3H), 1.29 – 0.86 (m, 4H). N-({4-Chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyridine-3-carboxamide (Int.190) A suspension of 6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyridine-3-carboxamide (Int.189, 0.37 g, 1.177 mmol, 1.07 eq.), 4-chloro-7-(chloromethyl)-3-methyl-1H,3H-furo[3,4-c]quinoline (Int. G, 0.3 g, 1.147 mmol, 1.0 eq.) and Cs2CO3 (0.8 g, 2.46 mmol, 2.14 eq.) in dry MeCN (4.0 mL) was stirred at 70°C for 3h. Then, the RM was cooleddown, diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (0% to 10% MeOH gradient in DCM) to obtain N-({4-chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl- N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (Int.190, 0.7 g, 1.22 mmol, 106%, yellow oil, m/z [M+H]+: 489.20). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.92 – 7.78 (m, 2H), 7.70 – 7.54 (m, 3H), 7.20 (d, J = 8.1 Hz, 1H), 5.61 – 5.48 (m, 2H), 5.43 (d, J = 13.1 Hz, 1H), 5.08 (s, 2H), 3.59 (s, 3H), 2.12 – 1.99 (m, 1H), 1.59 (s, 3H), 1.55 (d, J = 6.2 Hz, 3H), 1.00 – 0.91 (m, 2H), 0.91 – 0.79 (m, 2H) 6-Cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N- (1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (Int.191) A solution of N-({4-chloro-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl- 1H-pyrazol-4-yl)pyridine-3-carboxamide (Int.190, 0.7 g, 1.22 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)meth- anamine (1.2 g, 7.177 mmol, 5.89 eq.) in DMSO (3.0 mL) was stirred at 90 °C for 16 h. The reaction mixture was diluted with EtOAc and washed three times with water followed by brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM) to give 6- cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl)methyl]-N- (1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (Int.191). Rac-N-({4-Amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyridine-3-carboxamide (Example 65) To a solution of 6-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-methyl-1H,3H-furo[3,4- c]quinolin-7-yl)methyl]-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (Int.191) in DCM (4.0 mL), tri- fluoroacetic acid (1.0 ml, 12.29 mmol, 10.1 eq.) was added and the RM was stirred at RT for 16 h. Then, the RM was diluted by DCM and then partitioned between mixture of a saturated solution of NaHCO3 and chloro- form/isopropanol 3:1 mixture. The aqueous phase was extracted with chloroform/isopropanol 3:1 mixture and the combined organic layers were washed with aq. Na2CO3 solution, brine, then dried over anhydrous Na2SO4, filtered and evaporated. The crude material was purified by FCC (0% to 5% MeOH gradient in DCM). Fractions containing the pure product were co-evaporated with EtOH and lyophilized to give N-({4-amino-3-methyl- 1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (Example 65, 0.317 g, 0.672 mmol, 55%, white powder, m/z [M+H]+: 468.40). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), 7.17 (dd, J = 17.3, 8.2 Hz, 2H), 6.39 (s, 2H), 5.39 (d, J = 5.7 Hz, 1H), 5.37 – 5.18 (m, 2H), 4.95 (s, Ryvu Therapeutics S.A. RVU305 212 R10945WO 2H), 3.59 (s, 3H), 2.05 (td, J = 8.1, 4.1 Hz, 1H), 1.55 (s, 3H), 1.39 (d, J = 6.2 Hz, 3H), 1.01 – 0.90 (m, 2H), 0.90 – 0.82 (m, 2H). Example 66: N-{[(3S)-4-Amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1-ethyl-3- methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide Rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H- pyrazol-4-yl)pyrimidine-5-carboxamide (Example 54, 0.09 g, 0.186 mmol, 1.0 eq.) was submitted for chiral preparative purification (column: CHIRAL IF; mobile phase: isocratic hexane/i-PrOH:MeOH 75:25; elution time: 82 min.) to give N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1-ethyl-3- methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Example 66, 0.018 g, 0.037 mmol, 20%, white solid, UPLC long elution purity: 98.39%, chiral purity: 99.15%, white solid, m/z [M+H]+: 484.25). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.61 (s, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.16 – 7.12 (m, 1H), 6.38 (s, 2H), 5.44 – 5.37 (m, 1H), 5.31 (dd, J = 13.7, 3.8 Hz, 1H), 5.21 (dd, J = 13.6, 1.7 Hz, 1H), 4.96 (s, 2H), 3.91 – 3.84 (m, 2H), 2.19 – 2.11 (m, 1H), 1.59 (s, 3H), 1.39 (d, J = 6.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H), 1.07 – 1.02 (m, 2H), 0.97 – 0.92 (m, 2H). Example 67: N-{[(3R)-4-Amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1-ethyl-3- methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide Rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H- pyrazol-4-yl)pyrimidine-5-carboxamide (Example 54, 0.09 g, 0.186 mmol, 1.0 eq.) was submitted for chiral preparative purification (column: CHIRAL IF; mobile phase: isocratic hexane/i-PrOH:MeOH 75:25; elution time: 82 min.) to give N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1-ethyl-3- methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Example 67, 0.033 g, 0.066 mmol, 35%, white solid, UPLC long elution purity: 96.1%, chiral purity: 89.1%, [M+H]+: 484.25). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.61 (s, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.16 – 7.10 (m, 1H), 6.38 (s, 2H), 5.43 – 5.36 (m, 1H), 5.31 (dd, J = 13.7, 3.8 Hz, 1H), 5.21 (dd, J = 13.6, 1.7 Hz, 1H), 4.96 (s, 2H), 3.94 Ryvu Therapeutics S.A. RVU305 213 R10945WO – 3.82 (m, 2H), 2.20 – 2.09 (m, 1H), 1.59 (s, 3H), 1.39 (d, J = 6.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H), 1.08 – 1.02 (m, 2H), 0.97 – 0.91 (m, 2H). Example 68: N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl- 1H-pyrazol-4-yl)pyrimidine-5-carboxamide and Example 69: N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4- c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide Rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide (DC773-107) by HPLC chiral separation (column: ADH; mobile phase: isocratic hexanes/(i-PrOH/MeOH 1/1 v/v) = 60%/(25%); flow rate: 20 mL/min.; elution time: 75 min.). R and S configura- tions were attributed arbitrarily. N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide(Example 68, 28 mg, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 96.55%, chiral purity: 98.20%, m/z [M+H]+: 470.26). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 7.60 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 8.2, 1.7 Hz, 1H), 6.38 (s, 2H), 5.44 – 5.36 (m, 1H), 5.31 (dd, J = 13.6, 3.9 Hz, 1H), 5.22 (dd, J = 13.7, 1.7 Hz, 1H), 4.96 (s, 2H), 3.61 (s, 3H), 2.19 – 2.10 (m, 1H), 1.56 (s, 3H), 1.39 (d, J = 6.2 Hz, 3H), 1.08 – 1.03 (m, 2H), 0.99 – 0.93 (m, 2H). N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide (Example 69, 40 mg, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 95.76%, chiral purity: 89.35%, m/z [M+H]+: 470.27). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 7.60 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H), 7.15 (dd, J = 8.2, 1.6 Hz, 1H), 6.38 (s, 2H), 5.44 – 5.36 (m, 1H), 5.31 (dd, J = 13.7, 3.8 Hz, 1H), 5.22 (dd, J = 13.6, 1.7 Hz, 1H), 4.96 (s, 2H), 3.61 (s, 3H), 2.19 – 2.11 (m, 1H), 1.56 (s, 3H), 1.39 (d, J = 6.2 Hz, 3H), 1.09 – 1.03 (m, 2H), 0.99 – 0.94 (m, 2H). 4-Oxo-2-(trifluoromethyl)oxolane-3-carbonitrile (Int.192) Ryvu Therapeutics S.A. RVU305 214 R10945WO To a solution of methyl 2-hydroxyacetate (1.965 g, 21.814 mmol, 1.0 eq.) in THF (4.0 mL), a suspension of sodium hydride (60% in mineral oil, 0.314 g, 7.854 mmol, 0.36 eq.) in THF (20.0 mL) was added dropwise at 0°C. After bubbles stopped forming, the resulting mixture was heated at 65°C. Once reflux started, a solution of (2E)-4,4,4-trifluorobut-2-enenitrile (2.641 g, 21.815 mmol, 1.0 eq.) in THF (1.0 mL) was added dropwise, and the resulting mixture was stirred at 65°C for 3 h. The reaction mixture was cooled down to RT, quenched with water and extracted twice with EtOAc. The obtained aqueous layer was acidified with conc. HCl to adjust the pH to ~1 and extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and distil- lated under vacuum at 24 mbar and 36-38°C to obtain 4-oxo-2-(trifluoromethyl)oxolane-3-carbonitrile (Int.192, 1.053 g, 5.292 mmol, 24%, light yellow crystals). This product was used in the next step without further purifica- tion. 1H NMR (400 MHz, DMSO) δ 5.50 – 5.41 (m, 1H), 4.65 (dd, J = 14.3, 4.0 Hz, 1H), 4.59 (dd, J = 14.3, 1.8 Hz, 1H). 19F NMR (377 MHz, DMSO) δ -78.60 (d, J = 6.1 Hz). 4-Cyano-5-(trifluoromethyl)-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Int. H) To a solution of 4-oxo-2-(trifluoromethyl)oxolane-3-carbonitrile (Int.192, 0.786 g, 3.95 mmol, 1.0 eq.) in DCM (14.0 mL), DIPEA (1.93 ml, 11.08 mmol, 2.805 eq.) was added and reaction mixture was cooled to -70°C. Then, trifluoromethanesulfonic anhydride (2.117 g, 7.504 mmol, 1.9 eq.) was added dropwise at -70°C and re- action mixture was stirred for 15 min at that same temperature. The reaction mixture was then stirred at RT for 2 h. After that time, the reaction mixture purified by FCC (0-20% EtOAc gradient in Hexane). The fraction con- taining the desired product was evaporated in vacuo at 100 mbar and a temperature below 36 degrees to ob- tain 4-cyano-5-(trifluoromethyl)-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Int. H, 0.635 g, 2.041 mmol, 52%, light yellow oil). 1H NMR (400 MHz, CDCl3) δ 5.23 (pd, J = 5.5, 2.6 Hz, 1H), 5.09 (dd, J = 15.6, 5.6 Hz, 1H), 4.99 (ddd, J = 15.6, 2.6, 0.8 Hz, 1H). 19F NMR (377 MHz, CDCl3) δ -71.97, -78.32 (d, J = 4.8 Hz). Example 70: Rac-N-{[4-Amino-3-(trifluoromethyl)-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3- dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide 2-Cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.193) Ryvu Therapeutics S.A. RVU305 215 R10945WO To a solution of 2-cyclopropylpyrimidine-5-carboxylic acid (0.886 g, 5.398 mmol, 1.0 eq.), 1,3-dimethyl- 1H-pyrazol-4-amine (0.6 g, 5.398 mmol, 1.0 eq.) and DMAP (0.329 g, 2.699 mmol, 0.5 eq.) in toluene (6.0 mL), DIPEA (0.9403 ml, 5.398 mmol, 1.0 eq.) was added. Then, T3P as 50% solution in EtOAc (6.42 ml, 10.796 mmol, 2.0 eq.) was added slowly and the RM was stirred at 110°C for 1 h. Then the RM was diluted with EtOAc and neutralized with sat. aq. NaHCO3 solution. The organic phase was washed with a saturated solution of Na- HCO3, brine, dried over Na2SO4, filtered and evaporated to obtain 2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide (Int.193, 1.3 g, 3.84 mmol, 71%, beige solid, m/z [M+H]+: 258.3). This product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.05 (s, 2H), 7.91 (s, 1H), 3.75 (s, 3H), 2.33 – 2.25 (m, 1H), 2.15 (s, 3H), 1.16 – 1.11 (m, 2H), 1.11 – 1.05 (m, 2H). N-[(4-Bromo-3-nitrophenyl)methyl]-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.194) To 2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.193, 0.35 g, 1.034 mmol, 1.0 eq.) in acetonitrile (30.0 mL), cesium carbonate (0.505 g, 1.55 mmol, 1.499 eq.) was added. The mixture was stirred for 15 min at RT. Then, 4-chloro-7-(chloromethyl)-1H,3H-furo[3,4-c]quinoline (Int. C, 0.411 g, 1.394 mmol, 1.348 eq.) was added and the reaction mixture was stirred at 70°C for 4 h. The reaction mixture was cooled down, diluted with EtOAc and water and shaken vigorously. The organic phase was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The crude was purified by FCC (0% to 100% EtOAc gradient in Hexane) to give N-[(4-bromo-3-nitrophenyl)methyl]-2-cyclopropyl-N-(1,3-dimethyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide (Int.194, 0.307 g, 0.619 mmol, 60%, light yellow oil, m/z [M+H]+: 472.3). 1H NMR (400 MHz, DMSO) δ 8.58 (s, 2H), 7.95 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.56 (dd, J = 8.3, 2.1 Hz, 1H), 4.93 (s, 2H), 3.63 (s, 3H), 2.22 – 2.11 (m, 1H), 1.73 (s, 3H), 1.12 – 1.01 (m, 2H), 1.01 – 0.89 (m, 2H). N-[(3-Amino-4-bromophenyl)methyl]-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.195) A solution of N-[(4-bromo-3-nitrophenyl)methyl]-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimi- dine-5-carboxamide (Int.194, 0.304 g, 0.613 mmol, 1.0 eq.), SnCl2 dihydrate (0.76 g, 3.368 mmol, 5.497 eq.) in EtOAc (60.0 ml) was stirred under refluxed for 3h. The reaction mixture was then cooled down and cold 25% aqueous NH3 (150 ml) was added. The resulting mixture was transferred to a separating funnel, shaken thor- oughly and filtered through a pad of celite®. The organic layer was separated, washed twice with brine, dried over Na2SO4, filtered and evaporated to obtain N-[(3-amino-4-bromophenyl)methyl]-2-cyclopropyl-N-(1,3-dime- thyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int.195, 0.295 g, 0.588 mmol, 96%, yellow viscous oil, m/z [M+H]+: 442.5). This product was used in the next step without further purification. 1H NMR (400 MHz, DMSO) δ 8.56 (s, 2H), 7.60 (s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 2.1 Hz, 1H), 6.39 (dd, J = 8.2, 2.1 Hz, 1H), 5.32 (s, 2H), 4.70 (s, 2H), 3.64 (s, 3H), 2.21 – 2.10 (m, 1H), 1.67 (s, 3H), 1.11 – 1.02 (m, 2H), 1.02 – 0.92 (m, 2H). N-{[3-Amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H- pyrazol-4-yl)pyrimidine-5-carboxamide (Int.196) A mixture of N-[(3-amino-4-bromophenyl)methyl]-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimi- dine-5-carboxamide (Int.195, 0.183 g, 0.365 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- Ryvu Therapeutics S.A. RVU305 216 R10945WO dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.185 g, 0.729 mmol, 1.997 eq.) and potassium acetate (0.107 g, 1.09 mmol, 2.988 eq.) in 1,4-dioxane (5.5 mL) was purge with Ar for 15 min. Then, 1,1'-bis(diphenylphosphino)ferro- cene dichloropalladium (II) (0.027 g, 0.037 mmol, 0.101 eq.) was added and the RM was stirred at 100°C for 3.5 h. then, the reaction mixture was cooled down to RT, EtOAc was added and the mixture was filtered through a pad of celite®. Water was added to the filtrate and layers were separated. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by FCC (0% to 10% MeOH gradient in DCM) to give N-{[3- amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol- 4-yl)pyrimidine-5-carboxamide (Int.196, 0.109 g, 0.112 mmol, 31%, dark brown oil). This product was used in the next step without further purification. 1H NMR (400 MHz, DMSO) δ 8.56 (s, 2H), 7.59 (s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 1.6 Hz, 1H), 6.40 (d, J = 7.7 Hz, 1H), 5.53 (s, 2H), 4.72 (s, 2H), 3.63 (s, 3H), 2.22 – 2.10 (m, 1H), 1.69 (s, 3H), 1.28 (s, 12H), 1.08 – 1.03 (m, 2H), 1.00 – 0.94 (m, 2H). N-{[4-Amino-3-(trifluoromethyl)-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide (Example 70) In a microwave reactor, 4-cyano-5-(trifluoromethyl)-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Int. DC785-076, 0.081 g, 0.26 mmol, 2.399 eq.), N-{[3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe- nyl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide (Int. H, 0.106 g, 0.109 mmol, 1.0 eq.) and dipotassium carbonate (0.046 g, 0.333 mmol, 3.067 eq.) followed by 1,4-dioxane (3.0 mL) and water (0.3 mL) were charged under argon. The reaction mixture was bubbled with argon for 10 min and tetrakis(triphenylphosphane) palladium (0.013 g, 0.011 mmol, 0.104 eq.) was added. The RM was stirred at 120°C for 1 h 30 min in microwave, then an excess of 4-cyano-5-(trifluoromethyl)-2,5-dihydrofuran-3-yl trifluoro- methanesulfonate (Int. H, 0.081 g, 0.26 mmol, 2.399 eq.) and dipotassium carbonate (0.046 g, 0.333 mmol, 3.067 eq.) were added and the RM was again stirred at 120°C for 2h 30min in microwave. Then, the RM was diluted with ethyl acetate and water. Aqueous phase was extracted with ethyl acetate (2x). the combined or- ganic layers were washed with brine, then dried over Na2SO4, filtered and evaporated. The crude product was purified by FCC (0% to 5% MeOH gradient in DCM). Fraction containing product was re-purified by preparative HPLC and lyophilized to give N-{[4-amino-3-(trifluoromethyl)-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopro- pyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide(Example 70, 0.007 g, 0.013 mmol, 12%, white solid, UPLC long elution (Polar long method, buffer type “FA”) purity: 99.63%, m/z [M+H]+: 524.22). 1H NMR (400 MHz, DMSO) δ 8.58 (s, 2H), 7.63 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.20 (dd, J = 8.3, 1.7 Hz, 1H), 6.59 (s, 2H), 6.02 – 5.95 (m, 1H), 5.46 (d, J = 2.2 Hz, 2H), 4.99 (d, J = 2.7 Hz, 2H), 3.62 (s, 3H), 2.21 – 2.11 (m, 1H), 1.60 (s, 3H), 1.10 – 1.02 (m, 2H), 1.02 – 0.90 (m, 2H). 19F NMR (377 MHz, DMSO) δ -75.44 (d, J = 6.3 Hz). Biological assays and data As stated above, the compounds of the present invention are PRMT5 modulators and are useful in treating dis- eases by PRMT5 activity regulation. The biological activity of the compounds of the present invention can be determined by any appropriate test to determine the activity of the compound as PRMT5 modulator, as well as cell lines and in vivo models, in particular in presence or absence of MTA as exemplified below. Biochemical assay for recombinant PRMT5/MEP50 complex in presence or absence of MTA Ryvu Therapeutics S.A. RVU305 217 R10945WO Four mixes were prepared on ice: Mix 1 – containing 3x concentrated PRMT5/MEP50 enzyme (in-house production) in 1x buffer (50 mM TRIS pH 8.0, 50 mM KCl, 15 mM MgCl2, 1 mM EDTA) including 3x carrier protein (BSA, final conc.0.005%) and reduc- ing agent (DTT, final conc.1 mM) Mix 2 - 1x buffer including 3x carrier protein and reducing agent Mix 3 – containing 3x concentrated Histone H4 (N-terminal Peptide, Biotinylated; EpiCypher, #12-0029) in 1x buffer; Mix 4 – containing 3x concentrated SAM in 1x buffer. Briefly, 5 µL of Mix 4 were added on a plate with 1% of DMSO or MTA at 0.8 µM (dispensed with Tecan D300e or Echo acoustic dispenser). Then using a MultiFlo FX dispenser, 5 µL of Mix 1 and Mix 2 were added to the appropriate wells and the plate was pre-incubated for 20 minutes at RT. After that, the tested compounds at 10 concentrations, each one in duplicate, were added and normalized to 3% of DMSO (using a Tecan D300e or an Echo acoustic dispenser) and incubated again for 20 minutes at RT. Then, 5 µL of Mix 3 were added to all the wells except the low control wells (buffer 1x was added instead to the low control wells). The plate was incubated at RT for 60 min. After 60 min, 5 µL of TFA were added to all wells using DragonFly Discovery liquid dispenser and the plate was incubated at RT for 5 minutes. After 5 minutes, 5 µL of MTase-Glo Reagent (Promega #V7601 or #V7602) 1X was added using a MultiFlo FX dispenser and the plate was incubated at RT for 30 min. Next, 15 µL of MTaseGlo Detection Solution was added to all wells and the plate was incubated at RT for 30 min. Afterwards, the luminescence signal was rec- orded using plate reader. The data were analyzed in GraphPad Prism®. IC50, Hill slope and efficacy parameters were determined by fit- ting a variable slope sigmoidal function. HCT116 MTAP Knockout model The HCT116 cell line was purchased from PHE ECACC (Acc No: 91091005). The HCT116 MTAP KO cell line was generated using a CRISPR/Cas9 system and sgRNA targeting the MTAP gene. HCT116 cell line was co- transfected with MTAP CRISPR/Cas9 KO and MTAP HDR plasmids (Santa Cruz Biotechnology, sc-406223, and sc-406223-HDR, respectively), followed by puromycin selection. Knockout of the MTAP gene after clonal selection was validated using western blotting (Antibody Cell Sig., 4158). HCT116 WT and HCT116 MTAP knockout cells were propagated in RPMI 1640 medium supplemented with 10% FBS and 1 mM sodium py- ruvate in a humidified 5% CO2 tissue culture incubator. SDMA ELISA assay: On Day 0, HCT116 parental and HCT116 MTAP KO cells were seeded in 96-well plate in RPMI 1640 medium containing 10% FBS and 1% sodium pyruvate and incubated overnight in a humidified, 5% CO2 tissue culture incubator. On Day 1, the cells were treated with DMSO vehicle control or a dose response of test compounds dispensed to wells at defined concentration using a Tecan D300e digital dispenser (n=2) normalized with DMSO. On Day 4, 10 µl of alamarBlue reagent (amount equal to 5% of the well volume) were added to each well and the cells were incubated at 37°C in a 5% CO2 incubator for 5 h. The fluorescence intensity was measured with a plate reader at 540 nm excitation wavelength and 590 nm emission wavelength. The culture medium was re- moved and the cells were washed with PBS. Then the PBS was completely removed.50 µL of Lysis Buffer Ryvu Therapeutics S.A. RVU305 219 R10945WO SDMA ELISA, SDMA ELISA, Example No. MTase-Glo MTase-Glo + MTA HCT116-WT HCT116-KO Example 17 B A - A Example 18 A A - A Example 19 A A - A Example 20 B A - A Example 21 B A - A Example 22 A A A A Example 23 B A B A Example 24 C A C A Example 25 C A C A Example 26 B A B A Example 27 C A C A Example 28 B A - A Example 29 A A A A Example 30 C B - B Example 31 A A A A Example 32 A A A A Example 33 A A A A Example 34 A A B B Example 35 A A A A Example 36 A A A A Example 37 A B A C Example 38 A A A A Example 39 A A A B Example 40 A A A B Example 41 - - A B Example 42 A A A A Example 43 A A A A Example 44 - - A A Example 45 B C A C Example 46 A A A A Example 47 B C A C Example 48 A B A A Example 49 A A A A Example 50 A B A B Example 51 A B A B Example 52 A B A C Example 53 B B A A Example 54 A B A A Example 55 C B A C Ryvu Therapeutics S.A. RVU305 220 R10945WO SDMA ELISA, SDMA ELISA, Example No. MTase-Glo MTase-Glo + MTA HCT116-WT HCT116-KO Example 56 A A A B Example 57 A B A B Example 58 A A A B Example 59 A A A A Example 60 - - A A Example 61 A A A C Example 62 - - A B Example 63 - - A B Example 64 A A A A Example 65 A B A A Example 66 B C A C Example 67 A B A A Example 68 B C A C Example 69 A A A A Example 70 C C B C References: Blanc RS., Richard S. Arginine Methylation: The Coming of Age. Mol Cell.2017 Jan 5;65(1):8-24. doi: 10.1016/j.molcel.2016.11.003. Koh, C.M., Bezzi, M. & Guccione, E. The Where and the How of PRMT5. Curr Mol Bio Rep 1, 19–28 (2015). doi:10.1007/s40610-015-0003-5. Wu Q, Schapira M, Arrowsmith CH, Barsyte-Lovejoy D. Protein arginine methylation: from enigmatic functions to therapeutic targeting. Nat Rev Drug Discov.2021 Jul;20(7):509-530. doi: 10.1038/s41573-021-00159-8. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal.2013 Apr 2;6(269):pl1. doi: 10.1126/scisignal.2004088. Marjon K, Cameron MJ, Quang P, Clasquin MF, Mandley E, Kunii K, McVay M, Choe S, Kernytsky A, Gross S, Konteatis Z, Murtie J, Blake ML, Travins J, Dorsch M, Biller SA, Marks KM. MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. Cell Rep.2016 Apr 19;15(3):574-587. doi: 10.1016/j.celrep.2016.03.043. Firestone RS, Schramm VL. The Transition-State Structure for Human MAT2A from Isotope Effects. J Am Chem Soc.2017 Oct 4;139(39):13754-13760. doi: 10.1021/jacs.7b05803. Kryukov GV, Wilson FH, Ruth JR, Paulk J, Tsherniak A, Marlow SE, Vazquez F, Weir BA, Fitzgerald ME, Tanaka M, Bielski CM, Scott JM, Dennis C, Cowley GS, Boehm JS, Root DE, Golub TR, Clish CB, Bradner JE, Ryvu Therapeutics S.A. RVU305 221 R10945WO Hahn WC, Garraway LA. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltrans- ferase in cancer cells. Science.2016 Mar 11;351(6278):1214-8. doi: 10.1126/science.aad5214. Mavrakis KJ, McDonald ER 3rd, Schlabach MR, Billy E, Hoffman GR, deWeck A, Ruddy DA, Venkatesan K, Yu J, McAllister G, Stump M, deBeaumont R, Ho S, Yue Y, Liu Y, Yan-Neale Y, Yang G, Lin F, Yin H, Gao H, Kipp DR, Zhao S, McNamara JT, Sprague ER, Zheng B, Lin Y, Cho YS, Gu J, Crawford K, Ciccone D, Vitari AC, Lai A, Capka V, Hurov K, Porter JA, Tallarico J, Mickanin C, Lees E, Pagliarini R, Keen N, Schmelzle T, Hofmann F, Stegmeier F, Sellers WR. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science.2016 Mar 11;351(6278):1208-13. doi: 10.1126/science.aad5944. In one particular embodiment, the present invention relates to the following items: 1. A compound of formula (I) or a salt, stereoisomer, atropisomer, rotamer, tautomer, or N-oxide thereof; wherein A is the following moiety wherein the wavy line marks the connection to the N-atom of the remainder of the molecule; and wherein A1 is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA1; Y1 is CR2a, CHR2a, C(=O), N, or NR2b; Y2 is CR4a, CHR4a, O, S, N, or NR4b; wherein R2a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3; R2b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- Ryvu Therapeutics S.A. RVU305 222 R10945WO clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; R4a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3; and R4b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and wherein the dashed lines in the ring A1, as well as between E1 and E2, and between E2 and E3, denote that an additional bond may be present, so that a double bond is formed; and wherein E1 is CRE1a, CRE1aRE1b, O, S, N, or NRN1; E2 is CRE2a, CRE2aRE2b, O, S, N, or NRN2; E3 is CRE3a, CRE3aRE3b, O, S, N, or NRN3; X3 is CH, CRX3, or N; X4 is CH, CRX4, or N; X5 is CH, CRX5, or N; R1 is NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-alkyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, or heter- ocyclyloxy-C1-C2-alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; R3a is H, or D; R3b is H, or D; and wherein RA1 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, car- bobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings inde- pendently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon Ryvu Therapeutics S.A. RVU305 223 R10945WO or heteroatom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA4; or two RA1 together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned carbocyclyl or heterocyclyl is independently unsubstituted or substi- tuted with one or more, same or different substituents RA2; RA2 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently com- prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized; and wherein each substitutable atom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different sub- stituents RA3; RA3 is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, or C1-C4-haloalkyl; RA4 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently com- prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized; and wherein each substitutable atom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different sub- stituents RA3; RC1 is H, or C1-C4-alkyl; RC2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RE1a, RE1b, RE2a, RE2b, RE3a, and RE3b are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN1, RN2 and RN3 are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN4 is H, or C1-C4-alkyl; RN5 is H, or C1-C4-alkyl; RN6 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl 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; Ryvu Therapeutics S.A. RVU305 224 R10945WO and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RN7 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RS1 is C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C5-cycloalkyl, or NRN4RN5; RS2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RO is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RX3, RX4, and RX5 are independently halogen, CN, NH2, C(=O)NH2, CD3, C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, or C1-C4-hydroxyalkyl; RY is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hy- droxyalkyl, C1-C4-alkoxy-C1-C4-alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy, heterocyclyl, heterocyclyloxy, or heter- ocyclyl-C1-C2-alkyl, or 5- to 10-membered saturated carbobicyclyl or hetereobicyclyl, wherein the afore- mentioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; or two RY attached to the same atom form an oxo group; or two RY together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned het- erocyclyl 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; RZ is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or 3- to 6-membered saturated carbocyclyl, carbocyclyloxy, heterocyclyl, or heterocyclyloxy, wherein the aforementioned heterocyclyl rings com- prise 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; or two RZ attached to the same atom form an oxo group. 2. The compound according to item 1, wherein Ryvu Therapeutics S.A. RVU305 225 R10945WO E1 is CRE1a, CHRE1a, or NRN1; E2 is O or N; E3 is CRE3a, CHRE3a, or NRN3; and wherein preferably RE1a, RE3a, RN1, and RN3 are independently H, C1-C2-alkyl, or C1-C2-haloalkyl. 3. The compound according to any one of items 1 or 2, wherein the compound is a compound of formula (Ia’) ; and wherein preferably RE1a is H, CH3, or CF3; and RE3a is H. 4. The compound according to any one of items 1 to 3, wherein X3 is CH or CRX3, wherein RX3 is halogen; X4 is CH; and X5 is CH; and wherein preferably X3 is CH. 5. The compound according to any one of items 1 to 4, wherein the compound is a compound of formula , . 6. The compound according to any one of items 1 to 5, wherein A1 is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocy- clic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently unsubstituted or substituted with one or more, same or different substituents RA1; wherein Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH or N, preferably CH. and wherein preferably A1 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, or 2-oxo-1,2-dihydropyridinyl; Ryvu Therapeutics S.A. RVU305 226 R10945WO wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently un- substituted or substituted with one or more, same or different substituents RA1; wherein Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH or N, preferably CH. 7. The compound according to any one of items 1 to 6, wherein A is a moiety selected from the group consisting of ; ; wherein A2 is a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 n is 0, 1, or 2. 8. The compound according to any one of items 1 to 7, wherein R2a is H, C1-C2-alkyl, cyclopropyl, or cyclopropyloxy; and R2b is H, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; and wherein preferably R2a is H, or C1-C2-alkyl; and R2b is C1-C2-alkyl. 9. The compound according to any one of items 1 to 8, wherein RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, or cyclopropyl, Ryvu Therapeutics S.A. RVU305 227 R10945WO or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is independently unsubstituted or sub- stituted with one or more, same or different substituents RA2; RA2 is C1-C2-alkyl, NRN6RN7, a 3- to 6-membered saturated carbocyclyl or heterocyclyl, or a 5- to 7-mem- bered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned hetero- cyclyl or heterobicyclyl rings independently comprise one or more, same or different heteroatoms se- lected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein the aforementioned rings are independently unsubstituted or substituted with one or more, same or different substituents RA3; RN6 is H, or C1-C2-alkyl; RN7 is C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the afore- mentioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and RC2 is a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and wherein preferably RA3 is C1-C2-alkyl or N(CH3)2. 10. The compound according to any one of items 1 to 9, wherein RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one substituent RA2; and RA2 is a 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents RA3; and wherein preferably RA3 is C1-C2-alkyl. 11. The compound according to any one of items 1 to 10, wherein R1 is a 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- Ryvu Therapeutics S.A. RVU305 228 R10945WO and/or S-atoms are independently oxidized or non-oxidized, and wherein said carbocyclyl or heterocy- clyl is independently unsubstituted or substituted with one or more, same or different substituents RY; and wherein preferably R1 is wherein B1 is CH or N, and B2 is CH or N. 12. The compound according to any one of items 1 to 11, wherein RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; and wherein preferably RY is F, CN, CH3, CF3, or cyclopropyl. 13. The compound according to any one of items 1 to 12, wherein the compound of formula (I) is selected from the group consisting of: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-5-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyridine-3-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-cyclopropylpyridin-3-yl)pyridine-3-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)py- rimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3,6-dimethylpyrazin-2-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; Ryvu Therapeutics S.A. RVU305 229 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2-cyclopropylpyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-oxo-1,2-dihydropyridin-3-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]py- rimidine-5-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropylpyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyr- idine-3-carboxamide; and N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)py- rimidine-5-carboxamide. 14. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound ac- cording to any one of items 1 to 13 and optionally a pharmaceutically acceptable carrier, diluent or excipient. 15. A compound according to any one of items 1 to 13 or a pharmaceutical composition according to item 14 for use in medicine. 16. A compound according to any one of items 1 to 13 or a pharmaceutical composition according to item 14 for use in the treatment of a disease selected from the group consisting of cancer and pre-cancerous syn- dromes.

Claims

Ryvu Therapeutics S.A. RVU305 230 R10945WO Claims 1. A compound of formula (I) or a salt, stereoisomer, wherein A is the following moiety wherein the wavy line marks the connection to the N-atom of the remainder of the molecule; and wherein A1 is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA1; Y1 is CR2a, CHR2a, C(=O), N, or NR2b; Y2 is CR4a, CHR4a, O, S, N, or NR4b; wherein R2a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3; R2b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; R4a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3; and Ryvu Therapeutics S.A. RVU305 231 R10945WO R4b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and wherein the dashed lines in the ring A1, as well as between E1 and E2, and between E2 and E3, denote that an additional bond may be present, so that a double bond is formed; and wherein E1 is CRE1a, CRE1aRE1b, O, S, N, or NRN1; E2 is CRE2a, CRE2aRE2b, O, S, N, or NRN2; E3 is CRE3a, CRE3aRE3b, O, S, N, or NRN3; X3 is CH, CRX3, or N; X4 is CH, CRX4, or N; X5 is CH, CRX5, or N; R1 is NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-alkyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, or heter- ocyclyloxy-C1-C2-alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; R3a is H, or D; R3b is H, or D; and wherein RA1 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, or a 3- to 7-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobi- cyclyl rings independently comprise 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 sub- stitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or substi- tuted with one or more, same or different substituents RA4; or two RA1 together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned carbocyclyl or heterocyclyl is independently unsubstituted or substi- tuted with one or more, same or different substituents RA2; Ryvu Therapeutics S.A. RVU305 232 R10945WO RA2 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobi- cyclyl rings independently comprise 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 sub- stitutable atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA3; RA3 is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4- alkyl-NRN4RN5, C(=O)-C1-C4-hydroxyalkyl, or C(=O)-C1-C4-alkyl-NRN4RN5; RA4 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkyl- NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently comprise 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 atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA3; RC1 is H, or C1-C4-alkyl; RC2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3; RE1a, RE1b, RE2a, RE2b, RE3a, and RE3b are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN1, RN2 and RN3 are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN4 is H, or C1-C4-alkyl; RN5 is H, or C1-C4-alkyl; RN6 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3; RN7 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or Ryvu Therapeutics S.A. RVU305 233 R10945WO 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3; RS1 is C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C5-cycloalkyl, or NRN4RN5; RS2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3; RO is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise 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 heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or differ- ent substituents RA3; RX3, RX4, and RX5 are independently halogen, CN, NH2, C(=O)NH2, CD3, C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, or C1-C4-hydroxyalkyl; RY is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hy- droxyalkyl, C1-C4-alkoxy-C1-C4-alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy, heterocyclyl, heterocyclyloxy, or heter- ocyclyl-C1-C2-alkyl, or 5- to 10-membered saturated carbobicyclyl or hetereobicyclyl, wherein the afore- mentioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; or two RY attached to the same atom form an oxo group; or two RY together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned het- erocyclyl 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; RZ is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-hydroxyalkyl, or 3- to 6-membered saturated carbocyclyl, carbocyclyloxy, heterocyclyl, or heterocyclyloxy, wherein the aforementioned heterocyclyl rings comprise 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; or two RZ attached to the same atom form an oxo group or cyclopropyl. 2. The compound according to claim 1, wherein A is the following moiety Ryvu Therapeutics S.A. RVU305 234 R10945WO wherein the wavy line marks the connection to the N-atom of the remainder of the molecule; and wherein A1 is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA1; Y1 is CR2a, CHR2a, C(=O), N, or NR2b; Y2 is CR4a, CHR4a, O, S, N, or NR4b; wherein R2a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3; R2b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; R4a is H, OH, C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclyl or carbocyclyloxy, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or sub- stituted with one or more, same or different substituents RA3; and R4b is H, S(=O)2RS1, S(=O)(=NH)RS1, C(=O)RC1, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-hydroxyalkyl, C1-C4- alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; and wherein the dashed lines in the ring A1, as well as between E1 and E2, and between E2 and E3, denote that an additional bond may be present, so that a double bond is formed; and wherein E1 is CRE1a, CRE1aRE1b, O, S, N, or NRN1; E2 is CRE2a, CRE2aRE2b, O, S, N, or NRN2; E3 is CRE3a, CRE3aRE3b, O, S, N, or NRN3; X3 is CH, CRX3, or N; X4 is CH, CRX4, or N; X5 is CH, CRX5, or N; Ryvu Therapeutics S.A. RVU305 235 R10945WO R1 is NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocy- clyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-alkyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, or heter- ocyclyloxy-C1-C2-alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; R3a is H, or D; R3b is H, or D; and wherein RA1 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, car- bobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings inde- pendently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA4; or two RA1 together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned carbocyclyl or heterocyclyl is independently unsubstituted or substi- tuted with one or more, same or different substituents RA2; RA2 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently com- prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized; and wherein each substitutable atom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different sub- stituents RA3; RA3 is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, or C1-C4-haloalkyl; RA4 is halogen, CN, OH, S(=O)2RS2, C(=O)RC2, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, ORO, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl, C1-C4-alkoxy- C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, or a 5- to 10-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently com- prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S- Ryvu Therapeutics S.A. RVU305 236 R10945WO atoms are independently oxidized or non-oxidized; and wherein each substitutable atom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different sub- stituents RA3; RC1 is H, or C1-C4-alkyl; RC2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RE1a, RE1b, RE2a, RE2b, RE3a, and RE3b are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN1, RN2 and RN3 are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN4 is H, or C1-C4-alkyl; RN5 is H, or C1-C4-alkyl; RN6 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RN7 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RS1 is C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C5-cycloalkyl, or NRN4RN5; RS2 is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RO is H, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkyl-NRN4RN5, C1-C4-alkoxy-C1-C4-alkyl, or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RX3, RX4, and RX5 are independently halogen, CN, NH2, C(=O)NH2, CD3, C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, or C1-C4-hydroxyalkyl; RY is halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hy- droxyalkyl, C1-C4-alkoxy-C1-C4-alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, Ryvu Therapeutics S.A. RVU305 237 R10945WO or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy, heterocyclyl, heterocyclyloxy, or heter- ocyclyl-C1-C2-alkyl, or 5- to 10-membered saturated carbobicyclyl or hetereobicyclyl, wherein the afore- mentioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; or two RY attached to the same atom form an oxo group; or two RY together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heterocyclyl, wherein the aforementioned het- erocyclyl 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; RZ is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or 3- to 6-membered saturated carbocyclyl, carbocyclyloxy, heterocyclyl, or heterocyclyloxy, wherein the aforementioned heterocyclyl rings com- prise 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; or two RZ attached to the same atom form an oxo group. 3. The compound according to claim 1 or 2, wherein E1 is CRE1a, CHRE1a, or NRN1; E2 is O or N; E3 is CRE3a, CHRE3a, or NRN3; and wherein preferably RE1a, RE3a, RN1, and RN3 are independently H, C1-C2-alkyl, or C1-C2-haloalkyl. 4. The compound according to any one of claims 1 to 3, wherein the compound is a compound of formula (Ia’) ; RE3a is H. 5. The compound according to any one of claims 1 to 4, wherein X3 is CH or CRX3, wherein RX3 is halogen; X4 is CH; and X5 is CH; and wherein preferably X3 is CH. Ryvu Therapeutics S.A. RVU305 238 R10945WO 6. The compound according to any one of claims 1 to 5, wherein the compound is a compound of formula (Ia*-1*) or (Ia*-2*) . 7. The compound according to any one of claims 1 to 6, wherein A1 is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocy- clic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently unsubstituted or substituted with one or more, same or different substituents RA1; wherein Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH or N, preferably CH. and wherein preferably A1 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, or 2-oxo-1,2-dihydropyridinyl; wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently un- substituted or substituted with one or more, same or different substituents RA1; wherein Y1 is CR2a, C(=O), N, or NR2b; and Y2 is CH or N, preferably CH. 8. The compound according to any one of claims 1 to 7, wherein A is a moiety selected from the group consisting of ; preferably from the group consisting of Ryvu Therapeutics S.A. RVU305 239 R10945WO ; A2 is a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 n is 0, 1, or 2. 9. The compound according to any one of claims 1 to 8, wherein R2a is H, C1-C2-alkyl, cyclopropyl, or cyclopropyloxy; and R2b is H, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; and wherein preferably R2a is H, or C1-C2-alkyl; and R2b is C1-C2-alkyl. 10. The compound according to any one of claims 1 and 3 to 9, wherein RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6C(=O)RC2, C(=O)NRN6RN7, NRN6RN7, C(=O)RC2, ORO, cyclopropyl, or a 5- to 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is independently unsubstituted or sub- stituted with one or more, same or different substituents RA2; RA2 is C1-C2-alkyl, NRN6RN7, a 3- to 6-membered saturated carbocyclyl, heterocyclyl, or heterocyclyl-C1-C2- alkyl, or a 5- to 7-membered saturated, bridged or spiro, carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl rings independently comprise one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized; and wherein the aforementioned rings are independently unsubstituted or sub- stituted with one or more, preferably one or two, same or different substituents RA3; RA3 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RA4 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RN6 is H, or C1-C2-alkyl; RN7 is C1-C2-alkyl, C1-C2-hydroxyalkyl, C1-C4-alkyl-N(CH3)2, or a 5- or 6-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different Ryvu Therapeutics S.A. RVU305 240 R10945WO heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RA3; RC2 is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, or a 5- or 6-membered saturated carbocyclyl or heterocy- clyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroa- toms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized; and wherein each substitutable carbon or heteroatom in the aforementioned groups is inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3; and RO is H, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- or 6-membered saturated heterocy- clyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized; and wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or dif- ferent substituents RA3;and wherein preferably RA3 is C1-C2-alkyl or N(CH3)2. 11. The compound according to any one of claims 1 to 10, wherein RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, or cyclopropyl, or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one substituent RA2; and RA2 is a 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two, same or different substituents RA3; and wherein preferably RA3 is C1-C2-alkyl. 12. The compound according to any one of claims 1 and 3 to 10, wherein RA1 is C1-C4-hydroxyalkyl, ORO, or a 6- or 7-membered saturated heterocyclyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is unsubstituted or substituted with one or two substituents RA2; and RA2 is C1-C2-alkyl, a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforemen- tioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected Ryvu Therapeutics S.A. RVU305 241 R10945WO from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or two, same or different substituents RA3; RO is C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, cyclopropyl, or a 5- to 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or different heteroatoms selected from O and N, wherein said N-atoms are independently oxidized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3; RA3 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; and RA4 is halogen, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1-C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5. 13. The compound according to any one of claims 1 to 12, wherein R1 is a 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein said carbocyclyl or heterocy- clyl is independently unsubstituted or substituted with one or more, same or different substituents RY; and wherein preferably R1 is wherein B1 is CH or N, and B2 is CH or N. 14. The compound according to any one of claims 1 to 13, wherein RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; and wherein preferably RY is F, CN, CH3, CF3, or cyclopropyl. 15. The compound according to any one of claims 1, 3 to 5, 7 to 10, 13, and 14, wherein the compound is a compound of formula (Ia’) (Ia’); wherein RE1a is H, CH3, or CF3; RE3a is H; X3 is CH; Ryvu Therapeutics S.A. RVU305 242 R10945WO X4 is CH; and X5 is CH; A1 is phenyl, or a 5- or 6-membered aromatic heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned rings other than Y1 and Y2 is independently unsubstituted or substituted with one or more, same or different substituents RA1; Y1 is CR2a, C(=O), N, or NR2b; Y2 is CH or N; R2a is H, C1-C2-alkyl, cyclopropyl, or cyclopropyloxy; R2b is H, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; R1 is wherein B1 is CH or N; B2 is CH or N; and RY is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, or cyclopropyl; RA1 is halogen, CN, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, NRN6RN7, ORO, cyclo- propyl, or a 6- or 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, 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 the aforementioned heterocyclyl rings are independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RA4; or two RA1, if present, together with the atoms to which they are bonded form a fused 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl 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 the aforementioned heterocyclyl ring is independently unsubstituted or sub- stituted with one or more, same or different substituents RA2; RA2 is C1-C2-alkyl, or a 6-membered saturated heterocyclyl or heterocyclyl-C1-C2-alkyl, wherein the afore- mentioned heterocyclyl rings independently comprise one or two, same or different heteroatoms se- lected from O and N, wherein said N-atoms are oxidized or non-oxidized; and wherein the aforemen- tioned heterocyclyl rings are independently unsubstituted or substituted with one or two, same or differ- ent substituents RA3; RA3 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RA4 is halogen, C1-C2-alkyl, NRN4RN5, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, C1-C2-alkyl-NRN4RN5, C(=O)-C1- C2-hydroxyalkyl, or C(=O)-C1-C2-alkyl-NRN4RN5; RN4 is H, or C1-alkyl; RN5 is H, or C1-alkyl; RN6 is H, or C1-alkyl; RN7 is C1-C2-alkyl, or C1-C2-hydroxyalkyl; and Ryvu Therapeutics S.A. RVU305 243 R10945WO RO is C1-C2-hydroxyalkyl, cyclopropyl, or a 5- or 6-membered saturated heterocyclyl or heterocyclyl-C1-C2- alkyl, wherein the aforementioned heterocyclyl rings independently comprise one or two, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxi- dized or non-oxidized; and wherein the aforementioned cyclopropyl or heterocyclyl rings are inde- pendently unsubstituted or substituted with one or more, same or different substituents RA3. 16. The compound according to any one of claims 1 to 11 and 13 to 15, wherein the compound of formula (I) is selected from the group consisting of: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-5-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methylpyridin-3-yl)pyridine-3-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-methoxypyridin-3-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-cyclopropylpyridin-3-yl)pyridine-3-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)py- rimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropoxypyridin-3-yl)-2-cyclopropylpyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyclopropylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3,6-dimethylpyrazin-2-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-5-yl)-2-cyclopropylpyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; Ryvu Therapeutics S.A. RVU305 244 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(6-cyclopropyl-2-methylpyridin-3-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(5-cyclopropyl-2-methylpyridin-3-yl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-oxo-1,2-dihydropyridin-3-yl)-6-(trifluoromethyl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]py- rimidine-5-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(2-methylpyridin-3-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(6-cyano-2-methylpyridin-3-yl)-2-cyclopropylpyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyr- idine-3-carboxamide; and N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)py- rimidine-5-carboxamide. 17. The compound according to any one of claims 1, 3 to 10, and 12 to 15, wherein the compound of for- mula (I) is selected from the group consisting of: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[(3,3-difluoropiperidin-4-yl)oxy]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[3-(trifluoromethyl)piperazin-1- yl]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(2-hydroxyethyl)-3-(trifluoromethyl)pi- perazin-1-yl]-2-methylpyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4- yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{6-[4-(hydroxymethyl)piperidin-1-yl]-2- methylpyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(2-hydroxyethoxy)-2-methylpyridin-3- yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-me- thyl-1H-pyrazol-4-yl}pyrimidine-5-carboxamide; rac-N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-6-{[(2R,4R)-2-(trifluorome- thyl)piperidin-4-yl]oxy}pyridin-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyridine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 245 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyacetyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-1,3- benzothiazol-5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(6,6-difluoro-1,4-diazepan-1-yl)-2- methylpyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-6-{1-[(methylamino)methyl]cyclo- propoxy}pyridin-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[2-(trifluoromethyl)piperazin-1- yl]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-methylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2,4-dimethylpyrimidin-5-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethylpyridin-3-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methyl-1,2-thiazol-4-yl)-6-(trifluoromethyl)pyridine-3- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-ethylpyridin-3-yl)pyrimidine-5-carbox- amide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(2-methylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)py- rimidine-5-carboxamide; N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]acetamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]pyr- idine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)pyrimidine-5- carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-2-(1-methylpiperidin-4-yl)-1H-1,3- benzodiazol-6-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-2H-indazol-6- yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(1-methylpiperidin-4-yl)-1,3-benzothia- zol-6-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(piperidin-4-yl)methyl]-1,3-benzothiazol- 5-yl}pyrimidine-5-carboxamide; Ryvu Therapeutics S.A. RVU305 246 R10945WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-[(1-methylpiperidin-4-yl)methyl]-1,3-ben- zothiazol-5-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-[3-methyl-2-(1-methylpiperidin-4-yl)-2H- indazol-6-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[2-(1-methylpyrrolidin-3-yl)eth- oxy]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyr- idine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyrimidine-5-carboxamide; N-{[4-amino-3-(trifluoromethyl)-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-(1,3-dimethyl-1H-pyra- zol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(piperidin-4-yl)-1,3-benzothiazol-5-yl]py- rimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)py- rimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1-methyl-1H-pyrazol-5-yl)pyridine-3-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyridine- 3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,5-dimethylpyridin-3-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-ethyl-1-methyl-1H-pyrazol-5-yl)pyrimi- dine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4- yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-methyl-1,2-thiazol-4-yl)pyrimidine-5-car- boxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-ethyl-1-methyl-1H-pyrazol-4-yl)pyrimi- dine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-{2-methyl-6-[(1-methylpiperidin-4- yl)oxy]pyridin-3-yl}pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(propan-2-yl)-1H-pyrazol-4- yl]pyrimidine-5-carboxamide; and Ryvu Therapeutics S.A. RVU305 247 R10945WO N‐({4‐amino‐1H,3H‐furo[3,4‐c]quinolin‐7‐yl}methyl)‐N‐(3‐cyano‐1‐methyl‐1H‐pyrazol‐5‐yl)‐6‐(trifluoromethyl)pyr- idine‐3‐carboxamide. 18. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound ac- cording to any one of claims 1 to 17 and optionally a pharmaceutically acceptable carrier, diluent or excipient. 19. A compound according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18 for use in medicine. 20. A compound according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18 for use in the treatment of a disease selected from the group consisting of cancer and pre-cancerous syndromes.
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