Prmt5 inhibitors

Abstract

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 compounds.

Description

[0001] Ryvu Therapeutics S.A. RVU305 1 R10391WO 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, 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. Background of the Invention Protein arginine methyltransferases are enzymes that catalyze the transfer of methyl groups from S-adenosylmethionine (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 dime- thylarginine (SDMA) (Blanc and Richard 2017). PRMT5 conjugated with WD-repeat contain- ing proteins (MEP50 / WDR77) forms methylosome, which regulates essential cellular func- tions via symmetric dimethylation of target proteins involved in regulation of gene expres- sion, RNA splicing, signal transduction, 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 represents 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 adeno- carcinoma, 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 methylthioadenosine (MTA). Data from several genome-wide shRNA drop out screens performed on wide panels of cancer cell lines have revealed a selective require- ment 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 inhibition, which in turn reduces the level of symmetric arginine dimethylation of the Ryvu Therapeutics S.A. RVU305 2 R10391WO whole proteome, and thus an increased sensitivity of cells to modulation of the methylo- some activity. PRMT5 is a well-known essential gene regulating many cellular processes including cell growth and proliferation, apoptosis and DNA damage response. Conditional PRMT5 knock- out or siRNA mediated knockdown studies indicate that significant liabilities could be asso- ciated with inhibiting PRMT5 in normal tissues. Therefore, novel approaches are required to target PRMT5 in cancerous cells while not affecting viability of normal cells (MTAP WT). MTA-cooperative PRMT5 inhibitors could provide an improved therapeutic window, by pref- erential 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 selected 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 beneficial. Objects and Summary of the Invention It is therefore an object of the present invention to provide compounds, which act as PRMT5 inhibitors, preferably with a high activity. It is another object of the present invention to provide compounds, which are suitable for use as a medicament. It is another object of the present invention to provide compounds, which are suitable for use in the treatment 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 consisting of cancer and pre-cancerous syndromes. The above objects can be achieved by the compounds of formula (I) as defined herein as well as pharmaceutical 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 defined herein act as PRMT5 inhibitors, in particular for MTA-bound PRMT5. Accordingly, the compounds of formula (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, wherein Ryvu Therapeutics S.A. RVU305 3 R10391WO A is a moiety selected from the wavy line in each case marks the connection to the N-atom of the remainder of the mol- ecule; and wherein A1is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clic or 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 sub- stitutable carbon or heteroatom in the aforementioned rings is independently unsub- stituted or substituted with one or more, same or different substituents RA1; A2is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clic or 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 sub- stitutable carbon or heteroatom in the aforementioned rings is independently unsub- stituted or substituted with one or more, same or different substituents RA2; and wherein the dashed lines in the rings A1and A2denote that an additional bond may be present, so that a double bond is formed; and wherein B is a 5- to 7-membered saturated, partially or fully unsaturated, or aromatic carbocy- clic or 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 sub- stitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB; Y is C or N; and wherein E1is CRE1a, CRE1aRE1b, O, S, N, or NRN1; E2is CRE2a, CRE2aRE2b, O, S, N, or NRN2; E3is CRE3a, CRE3aRE3b, O, S, N, or NRN3; X3is CH, CRX3, or N; X4is CH, CRX4, or N; X5is CH, CRX5, or N; R1is 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 un- saturated, or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-al- kyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, or heterocyclyloxy-C1-C2-alkyl, wherein the aforementioned heterocyclic 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-oxidized, and wherein each substitutable carbon or heteroatom in Ryvu Therapeutics S.A. RVU305 4 R10391WO the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; R2is halogen, CN, S(=O)2RS, S(=O)(=NH)RS, C(=O)RC, NHC(=O)RC, C(=O)NRN4RN5, C1- C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C6-hydroxyalkyl, or a 5- or 6-mem- bered saturated, partially or fully unsaturated, or aromatic heterocyclyl, 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-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 RA2; R3ais H, or D; R3bis H, or D; and wherein RA1is halogen, CN, OH, S(=O)2RS, C(=O)RC, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, or 3- to 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 aforemen- tioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA2; or two RA1together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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 un- substituted or substituted with one or more, same or different substituents RA2; RA2is halogen, CN, OH, C1-C4-alkyl, C1-C4-alkoxy, or C1-C4-haloalkyl; RBis halogen, CN, OH, C1-C4-alkyl, or C1-C4-haloalkyl; or two RBattached to the same atom form an oxo group; RCis H, or C1-C4-alkyl; RE1a, RE1b, RE2a, RE2b, RE3a, and RE3bare independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN1, RN2and RN3are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN4is H, or C1-C4-alkyl; RN5is H, or C1-C4-alkyl; RSis C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C5-cycloalkyl, or NRN4RN5; RX3, RX4, and RX5are 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-hydroxy- alkyl; RYis halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloal- koxy, C1-C4-hydroxyalkyl, C1-C4-alkoxy-C1-C4-alkoxy, or 3- to 10-membered satu- rated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy, heterocyclyl, heterocyclyloxy, or heterocyclyl-C1-C2-alkyl, or 5- to 10- membered saturated carbobicyclyl or hetereobicyclyl, wherein the aforementioned Ryvu Therapeutics S.A. RVU305 5 R10391WO heterocyclyl or heterobicyclyl 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-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 RYattached to the same atom form an oxo group; or two RYtogether with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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; RZis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or 3- to 6-membered satu- rated carbocyclyl, carbocyclyloxy, heterocyclyl, or heterocyclyloxy, wherein the afore- mentioned 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 RZattached to the same atom form an oxo group. In a preferred embodiment, E1is CRE1a, CHRE1a, or NRN1; E2is O or N; E3is CRE3a, CHRE3a, or NRN3; X3is CH, CRX3, or N; X4is CH; X5is CH; and wherein preferably RE1a, RE3a, RN1, and RN3are independently H or C1-C2-alkyl. In another preferred embodiment, the compound is a compound of formula (Ia*), (Ib*), or (Ic*) In a more the compound is a compound of formula (Ic*-1) Ryvu Therapeutics S.A. RVU305 6 R10391WO In another more preferred the compound is a compound of formula (Ia*-1) or (Ia*-2) X3is CH or CRX3, preferably CH. In another preferred embodiment, R2is halogen, S(=O)2RS, C1-C2-alkoxy, or C1-C2-haloalkyl; wherein preferably RSis C1-alkyl. In another preferred embodiment, R2is S(=O)2RS; wherein preferably RSis C1-alkyl. In another preferred embodiment, A1is phenyl, pyridinyl, or pyrazolyl; wherein the phenyl, pyridinyl, or pyrazolyl is independently unsubstituted or substi- tuted with one or more, same or different, substituents RA1; wherein preferably RA1is halogen, C1-C2-alkyl, or cyclopropyl; and A2is phenyl, pyridinyl, or pyrazolyl; wherein the phenyl, pyridinyl, or pyrazolyl is independently unsubstituted or substi- tuted with one or more, same or different, substituents RA2; wherein preferably the phenyl, pyridinyl, or pyrazolyl is unsubstituted. In another preferred embodiment, A1is phenyl or pyridinyl; wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, same or different, substituents RA1; wherein preferably RA1is halogen; and A2is phenyl or pyridinyl; wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, same or different, substituents RA2; wherein preferably the phenyl or pyridinyl is unsubstituted. In another preferred embodiment, A is a moiety selected from Ryvu Therapeutics S.A. RVU305 7 R10391WO partially or fully unsaturated, or aromatic, prefera- bly a saturated or partially unsaturated, heterocyclic ring, wherein the aforemen- tioned heterocyclic ring comprises 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 each substitutable carbon or heteroatom in the aforemen- tioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB1; wherein RB1is halogen, CN, OH, C1-C4-alkyl, or C1-C4-haloalkyl; and wherein preferably RB1is halogen. In another preferred embodiment, A is a moiety selected from B1partially or fully unsaturated, or aromatic heterocy- 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 carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB1; wherein RB1is halogen, CN, OH, C1-C4-alkyl, or C1-C4-haloalkyl; and wherein preferably Y is C; and RB1is halogen. In another preferred embodiment, A A1is selected from the group consisting of RA1is C1-C2-alkyl or cyclopropyl; Ryvu Therapeutics S.A. RVU305 8 R10391WO and wherein preferably RA1is CH3. In another preferred embodiment, A is a moiety selected from the group consisting of R1is 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 each substitutable carbon or heteroatom in the aforemen- tioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; and wherein preferably RYis halogen, CN, C1-C2-haloalkyl, or cyclopropyl. In a more preferred embodiment, R1is pyridinyl, or pyrimidinyl; and wherein preferably the pyridinyl or pyrimidinyl is independently unsubstituted or substi- tuted with one substituent selected from F, CN, CF3, or cyclopropyl. In an even more preferred embodiment, R1is Ryvu Therapeutics S.A. RVU305 9 R10391WO . In the compound of formula (I) is selected from the group consisting of: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide; N-({4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylphenyl)pyridine- 3-carboxamide; and N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide. In another preferred embodiment, the compound of formula (I) is selected from the group consisting of: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyano-N-(4,4-difluoro- 1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 10 R10391WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(4-fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-me- thanesulfonyl-4-methylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-2-(trifluoromethyl)pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyano-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-2-(4-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-5-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-6-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N- (4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-5-methoxypyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methanesulfonyl- 4-methylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclobutyl-N-(4-fluoro-2- methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-(3,3-difluoropyrrolidin-1- yl)-N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methanesulfonyl- 4-methylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(trifluorome- thyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro- 2-methoxyphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4,4-difluoro-1,1-di- oxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 11 R10391WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyrimidine-5-carboxamide; rac-N-({4-amino-1-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(1S)-4-amino-1-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(1R)-4-amino-1-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro-2-methoxy- phenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4,4-difluoro-1,1-di- oxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-benzothiopyran-8-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methoxypyridin-3- yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- [1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-fluoro-2-me- thanesulfonylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4- fluoro-2-methanesulfonylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(difluorome- thyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(2- methanesulfonylpyridin-3-yl)pyridine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 12 R10391WO rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,1- dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,1- dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,1- dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(4- fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-4- yl)-2-cyclopropylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-(1-cyanocyclopropyl)-N-(4-fluoro-2- methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-oxo-2,3-dihydro- 1H-isoindol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-3-oxo-2,3- dihydro-1H-isoindol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluo- romethyl)-1H-pyrazol-4-yl]pyrimidine-5-carboxamide; rac-N-({4-amino-2-methyl-2H,3H-furo[3,2-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-methoxypyridin-3- yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethoxypyri- din-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methoxypyridin-3-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-[2-(trifluoromethyl)pyridin- 3-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyano-4-fluorophenyl)-2-cyclo- propylpyrimidine-5-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(tri- fluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(2- methanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(2- methanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-cyanopyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-methoxy-1-me- thyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-4- yl)-6-cyclopropylpyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyanopyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide; Ryvu Therapeutics S.A. RVU305 13 R10391WO N-({4-amino-2H,3H-furo[3,2-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-[2-(tri- fluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-[2- (trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-5-cyano-N-[2-(trifluoromethyl)pyridin- 3-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methoxypyrazin-2-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxa- zin-3-yl}-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(difluorometh- oxy)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-[1-cyclopropyl-3-(trifluoro- methyl)-1H-pyrazol-4-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-{5H,6H,7H-pyra- zolo[3,2-b][1,3]oxazin-3-yl}pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(5-chloro-1-methyl-1H-pyrazol-4- yl)-2-cyclopropylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-4- yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-fluoro-2-methoxy- pyridin-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[3-(difluoromethyl)- 1-methyl-1H-pyrazol-4-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-cyclopropyl-3- methoxy-1H-pyrazol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(methoxyme- thyl)phenyl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-carbamoyl-1-methyl-1H-pyrazol- 4-yl)-6-cyclopropylpyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[(1R,2R)-2-hydroxy- 2,3-dihydro-1H-inden-1-yl]pyrimidine-5-carboxamide; N-({4-amino-9-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N- (4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-cyclopropyl-1H-pyrazol- 4-yl)-6-cyanopyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(4-methylpiper- azin-1-yl)-2-(trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-{5-methyl-4-oxo- 4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-3-yl}pyridine-3-carboxamide; N-({4-aminofuro[3,2-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluorome- thyl)-1H-pyrazol-4-yl]pyrimidine-5-carboxamide; Ryvu Therapeutics S.A. RVU305 14 R10391WO rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3- methoxy-1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide; and N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-chloropyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide. In a further aspect, the present invention relates to a pharmaceutical composition com- prising a pharmaceutically effective amount of the compound of formula (I) as defined herein, and optionally a pharmaceutically acceptable carrier, diluent or excipient. In yet another aspect, the present invention relates to a compound of formula (I) as de- fined herein or a pharmaceutical composition comprising the same as defined herein for use in medicine. In particular, the present invention relates to a compound of formula (I) as de- fined 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 composi- tion 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 composi- tion 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 rele- vant 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 compound of formula (I) the dashed lines an additional bond may be present, so that a double bond is formed. It is to be understood that the bond be- tween E1and E2and the bond between E2and E3cannot both be a double bond at the same time. Thus, the dashed lines between E1and E2and between E2and E3denote that either a double bond is present between E1and E2, a double bond is present between E2and E3, or no double bond is present between E1, E2and E3. The compound of formula (I) may there- fore be a compound of formula (Ia), (Ib), or (Ic), preferably a compound of formula (Ic), as shown below: Ryvu Therapeutics S.A. RVU305 15 R10391WO in each case se- lected such that suitable valences of the atoms are realized. In connection with compounds of formula (Ia), this means that E1is CRE1aRE1b, O, S, or NRN1; E2is CRE2aRE2b, O, S, or NRN2; E3is CRE3aRE3b, O, S, or NRN3; preferably that E1is CRE1aRE1b; E2is O, S, or NRN2; E3is CRE3aRE3b; more preferably that E1is CHRE1a; E2is O; E3is CHRE3a. In connection with the compounds of formula (Ib), this means that E1is CRE1aRE1b, O, S, or NRN1; E2is CRE2aor N; E3is CRE3aor N; preferably that E1is NRN1; E2is N; E3is CRE3a. In connection with the compounds of formula (Ic), this means that E1is CRE1aor N; E2is CRE2aor N; E3is CRE3aRE3b, O, S, or NRN3; preferably that E1is CRE1a; E2is N; E3is NRN3. Thus, in a preferred embodiment, in the compounds of formula (I), E1is CRE1a, CHRE1a, or NRN1; Ryvu Therapeutics S.A. RVU305 16 R10391WO E2is O or N; E3is CRE3a, CHRE3a, or NRN3. In connection with the compounds of formula (I), as well as in connection with the com- pounds of formula (Ia), (Ib), or (Ic), the following preferred embodiments regarding the re- maining substituents of the tricyclic core moiety X3, X4, and X5are relevant. As indicated above, each of X3, X4, and X5can be nitrogen (N), unsubstituted carbon (CH), or substituted carbon (CRX3, CRX4, or CRX5). If X3, X4, or X5is a substituted carbon (CRX3, CRX4, or CRX5), the substituent at the carbon atom is represented by RX3, RX4, and RX5, re- spectively. In a preferred embodiment of the compound of formula (I), none, one, or two of X3, X4, and X5are N, more preferably none or one of X3, X4, and X5are N, and even more preferably none of X3, X4, and X5is N. In another preferred embodiment of the compound of formula (I), X4is CH or CRX4, prefer- ably CH. In another preferred embodiment of the compound of formula (I), X5is CH or CRX5, preferably CH. In another preferred embodiment of the compound of formula (I), X3is CH or CRX3, preferably CH. In a more preferred embodiment of the compound of formula (I), X4is CH or CRX4and X5is CH or CRX5, even more preferably X4and X5are CH. In a particularly preferred embodiment, X4and X5are CH and X3is CH or CRX3, preferably CH. Therefore, in a preferred embodiment, in the compounds of formula (I), E1is CRE1a, CHRE1a, or NRN1; E2is O or N; E3is CRE3a, CHRE3a, or NRN3; X3is CH, CRX3, or N; X4is CH or CRX4; X5is CH or CRX5. In a more preferred embodiment, in the compounds of formula (I), E1is CRE1a, CHRE1a, or NRN1; E2is O or N; E3is CRE3a, CHRE3a, or NRN3. X3is CH, CRX3, or N; X4is CH; X5is CH. In an even more preferred embodiment, in the compounds of formula (I), E1is CRE1a, CHRE1a, or NRN1; E2is O or N; E3is CRE3a, CHRE3a, or NRN3. X3is CH or CRX3; X4is CH; X5is CH. In an even more preferred embodiment, in the compounds of formula (I), E1is CRE1a, CHRE1a, or NRN1; E2is O or N; Ryvu Therapeutics S.A. RVU305 17 R10391WO E3is CRE3a, CHRE3a, or NRN3. X3is CH; X4is CH; X5is CH. 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 (Ic’), as shown below: 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 com- pound of formula (Ic*) as shown below: H or CH3. Particularly preferably, RE1aandRE3aare H or CH3, and RN1and RN3are CH3. Thus, in connection with the compounds of formula (Ia*) it is particularly preferred that RE1a, RE3aare H or CH3, preferably RE1ais CH3and RE3ais H. In connection with the compounds of formula (Ib*) it is particularly preferred that RN1is CH3and RE3ais H. In connection with the com- pounds of formula (Ic*) it is particularly preferred that RE1ais H and RN3is CH3. Further, it is particularly preferred that X3is CH or CRX3, more preferably CH. In a particularly preferred embodiment, the compound of formula (I) is a compound of for- mula (Ic*-1) Ryvu Therapeutics S.A. RVU305 18 R10391WO even more preferably a compound of formula (Ic*-1*) In another particularly preferred embodiment, the compound of formula (I) is a compound of formula (Ia**), preferably a compound of formula (Ia**-1) More or (Ia**-1), is a compound of formula (Ia*-1) or (Ia*-2) of formula (Ia*-1), preferably a compound of formula (Ia*-1*). 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), Ryvu Therapeutics S.A. RVU305 19 R10391WO A), pref- erably a compound of formula (Ia**-1-A). In another embodiment, the compound of formula (I) is a compound of formula (Ia**-B), preferably a compound 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 2- , 2-A), pref- erably 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 compound of formula (Ia*-2*-B). 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 for- mula (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 RX5are relevant. As indicated above, in connection with the compounds of the present invention, RE1a, RE1b, RE2a, RE2b, RE3a, and RE3bare independently H, C1-C4-alkyl, or C1-C4-haloalkyl. In a preferred embodiment, RE1a, RE1b, RE2a, RE2b, RE3a, and RE3bare independently H, C1-C2-alkyl, or C1-C2-haloalkyl. In a more preferred embodiment, Ryvu Therapeutics S.A. RVU305 20 R10391WO RE1a, RE1b, RE2a, RE2b, RE3a, and RE3bare independently H or C1-C2-alkyl. In an even more preferred embodiment, RE1a, RE1b, RE2a, RE2b, RE3a, and RE3bare independently H or CH3. In an even more preferred embodiment, RE1b, RE2b, and RE3bare H; and RE1a, RE2a, and RE3aare independently H, C1-C2-alkyl, or C1-C2-haloalkyl, preferably H or C1- C2-alkyl, more preferably 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 RE3aas well as RE1b, RE2b, and RE3b, if present, are H. In a particularly preferred embodiment, RE1a, RE1b, RE2a, RE2b, RE3a, and RE3bare H. Further, in connection with the compounds of the present invention, RN1, RN2and RN3are independently H, C1-C4-alkyl, or C1-C4-haloalkyl. In a preferred embodiment, RN1, RN2and RN3are independently H, C1-C2-alkyl, or C1-C2-haloalkyl. In a more preferred embodiment, RN1, RN2and RN3are independently H or C1-C2-alkyl. In an even more preferred embodiment, RN1, RN2and RN3are independently H or CH3. In a particularly preferred embodiment, none or one of RE1a, RE2a, RE3a, RN1, RN2and RN3, if pre- sent, 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, RN2and RN3, if pre- sent, are H. In another particularly preferred embodiment, each of RE1a, RE2a, RE3a, RE1b, RE2b, RE3b, RN1, RN2and RN3, if present, is H. Further, in connection with the compounds of the present invention, RX3, RX4, and RX5are 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-hy- droxyalkyl. In a preferred embodiment, RX3, RX4, and RX5are 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-hydroxy- alkyl. In a more preferred embodiment, RX3, RX4, and RX5are 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 RX5are independently halogen, C1-C2-alkyl, C1-C2-alkoxy, or C1-C2-haloalkyl. In an even more preferred embodiment, RX3, RX4, and RX5are independently halogen. Ryvu Therapeutics S.A. RVU305 21 R10391WO In another preferred embodiment of the compounds of the present invention, none, or only one or two of RX3, RX4, and RX5are present. In a more preferred embodiment, none or only one of RX3, RX4, and RX5is present. In a particularly preferred embodiment, none of RX3, RX4, and RX5is present so that X3, X4and X5are N or CH, preferably CH. In connection with the compounds of formula (I), as well as in connection with the com- pounds 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), (Ia*-2*-B), (Ic*-1) and (Ic*-1*) the following preferred em- bodiments regarding the substituent R1are relevant. As indicated above, in connection with the compounds of the present invention, R1is 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 un- saturated, or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-al- kyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, or heterocyclyloxy-C1-C2-alkyl, wherein the aforementioned heterocyclic 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-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 RYis halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloal- koxy, C1-C4-hydroxyalkyl, C1-C4-alkoxy-C1-C4-alkoxy, or 3- to 10-membered satu- rated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy, heterocyclyl, heterocyclyloxy, or heterocyclyl-C1-C2-alkyl, or 5- to 10- membered saturated carbobicyclyl or hetereobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl 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-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 RYattached to the same atom form an oxo group; or two RYtogether with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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; RZis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or 3- to 6-membered satu- rated carbocyclyl, carbocyclyloxy, heterocyclyl, or heterocyclyloxy, wherein the afore- mentioned 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 RZattached to the same atom form an oxo group. In a preferred embodiment, Ryvu Therapeutics S.A. RVU305 22 R10391WO R1is C1-C3-alkyl, C1-C3-alkoxy, C1-C2-alkoxy-C1-C2-alkyl, C1-C3-haloalkyl, C1-C2-aminoal- kyl, or 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-alkyl, heterocyclyl, or heterocy- clyl-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 oxidized or non-oxidized, and wherein each sub- stitutable carbon or heteroatom in the aforementioned groups is independently un- substituted or substituted with one or more, same or different substituents RY; wherein RYis as defined above in connection with the compounds of formula (I), and wherein preferably RYis halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, C1-C2-hydroxyalkyl, cyclo- propyl, cyclopropyloxy, cyclobutyl, or 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 aforemen- tioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; or two RYattached to the same atom form an oxo group; or two RYtogether with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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 RZis halogen, CN, C1-alkyl, C1-haloalkyl, or C1-alkoxy; preferably halogen or C1-alkyl; or two RZattached to the same atom form an oxo group; and wherein more preferably RYis halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or cyclopropyloxy; or two RYattached to the same atom form an oxo group; or two RYtogether with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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. In a more preferred embodiment, R1is C1-C3-alkyl, C1-C3-alkoxy, C1-C2-alkoxy-C1-C2-alkyl, C1-C3-haloalkyl, C1-C2-aminoal- kyl, or 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-alkyl, heterocyclyl, or heterocy- clyl-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 oxidized or non-oxidized, and wherein each sub- stitutable carbon or heteroatom in the aforementioned groups is independently un- substituted or substituted with one or more, same or different substituents RY; and wherein preferably Ryvu Therapeutics S.A. RVU305 23 R10391WO RYis halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, cyclopropyl, cyclopropy- loxy, cyclobutyl, or 5- or 6-membered saturated, partially or fully unsaturated, or aro- matic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring com- prises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is inde- pendently unsubstituted or substituted with one or more, same or different substitu- ents RZ; or two RYattached to the same atom form an oxo group; or two RYtogether with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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; RZis halogen, CN, C1-alkyl, C1-haloalkyl, or C1-alkoxy; preferably halogen or C1-alkyl; or two RZattached to the same atom form an oxo group, and wherein more preferably RYis halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or cyclopropyloxy; or two RYattached to the same atom form an oxo group; or two RYtogether with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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. In an even more preferred embodiment, R1is C1-C3-alkyl, C1-C3-alkoxy, C1-C2-alkoxy-C1-C2-alkyl, C1-C3-haloalkyl, C1-C2-aminoal- kyl, C1-C2-aminoalkyl, 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 aforemen- tioned heterocyclyl rings 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 each substitutable carbon or heteroatom in the aforemen- tioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; wherein RYis as defined above in connection with the compounds of formula (I), and wherein preferably RYis halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, cyclopropyl, cyclopropy- loxy, cyclobutyl, pyrrolidinyl, piperidinyl, or 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or differ- ent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are inde- pendently oxidized or non-oxidized, and wherein each substitutable carbon or het- eroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; or two RYattached to the same atom form an oxo group; wherein Ryvu Therapeutics S.A. RVU305 24 R10391WO RZis halogen, CN, C1-alkyl, C1-haloalkyl, or C1-alkoxy; preferably halogen or C1-alkyl; and wherein more preferably RYis halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or cyclopropyloxy; or two RYattached to the same atom form an oxo group. In an even more preferred embodiment, R1is a 5- to 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforemen- tioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substitu- ents RY; wherein RYis as defined above in connection with the compounds of formula (I), and wherein preferably RYis halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, cyclopropyl, cyclopropy- loxy, cyclobutyl, pyrrolidinyl, piperidinyl, or 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or differ- ent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are inde- pendently oxidized or non-oxidized, and wherein each substitutable carbon or het- eroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; wherein RZis halogen, CN, C1-alkyl, C1-haloalkyl, or C1-alkoxy; preferably halogen or C1-alkyl; and wherein more preferablyRYis halogen, CN, C1-C2-haloalkyl, or cyclopropyl. In an even more preferred embodiment, R1is 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 substituents RY; wherein RYis as defined above in connection with the compounds of formula (I), and wherein preferably RYis halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, cyclopropyl, cyclopropy- loxy, cyclobutyl, pyrrolidinyl, piperidinyl, or 5-membered aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or differ- ent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are inde- pendently oxidized or non-oxidized, and wherein each substitutable carbon or het- eroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RZ; wherein RZis halogen, CN, C1-alkyl, C1-haloalkyl, or C1-alkoxy; preferably halogen or C1-alkyl; and wherein more preferably RYis halogen, CN, C1-C2-haloalkyl, or cyclopropyl. In an even more preferred embodiment, R1is pyridinyl or pyrimidinyl; wherein the pyridinyl or pyrimidinyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents RY; Ryvu Therapeutics S.A. RVU305 25 R10391WO wherein RYis as defined above in connection with the compounds of formula (I), and wherein preferably RYis halogen, CN, C1-C3-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, cyclopropyl, cyclopropy- loxy, cyclobutyl, pyrrolidinyl, or piperidinyl; and wherein more preferably RYis halogen, CN, C1-C2-haloalkyl, or cyclopropyl. In an even more preferred embodiment, R1is pyridinyl or pyrimidinyl; wherein the pyridinyl or 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 or CF3. In an even more preferred embodiment, R1is 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 cyclopro- pyl, preferably CF3. In another even more preferred embodiment, R1is 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 cy- clopropyl, preferably cyclopropyl. In a particularly preferred embodiment, R1is unsubstituted pyridinyl. In another particularly preferred embodiment, R1is pyridinyl substituted with one substituent selected from F, CN, CF3, or cyclopropyl, preferably CF3. In another particularly preferred embodiment, R1is pyrimidinyl substituted with one substituent selected from F, CN, CF3, or cyclopro- pyl, preferably cyclopropyl. Thus, in a particularly preferred embodiment, R1is selected from the group consisting of RYis halogen, CN, C1-C2-haloalkyl, or cyclopropyl, preferably RYis F, CN, CF3, or cyclopropyl, more preferably RYis cyclopropyl or CF3. Ryvu Therapeutics S.A. RVU305 26 R10391WO In one more preferred embodiment, R1is selected from the group consisting of RYis halogen, CN, C1-C2-haloalkyl, or cyclopropyl, preferably RYis F, CN, CF3, or cyclopropyl, more preferably RYis CF3. In another more preferred embodiment, R1is RYis halogen, CN, C1-C2-haloalkyl, or cyclopropyl, preferably RYis F, CN, CF3, or cyclopropyl, more preferably RYis cyclopropyl. In a particularly preferred embodiment, R1is . In connection with the compounds of formula (I), as well as in connection with the com- pounds 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), (Ia*-2*-B), (Ic*-1) and (Ic*-1*), in particular in connection with the preferred embodiments regarding R1defined above, the following preferred embodiments regarding the A moiety are relevant. As indicated above, in connection with the compounds of the present invention, A is a moiety selected from Ryvu Therapeutics S.A. RVU305 27 R10391WO The compound of formula (I) may therefore be a compound of formula (I-A1) or (I-A2) as shown below: bly, the meanings of E1, E2, E3, X3, X4, X5, RE1a, RE1b, RE2a, RE2b, RE3a, RE3b, RN1, RN2, RN3, RX3, RX4, RX5and R1correspond to the preferred embodiments defined above. In one embodiment, the compound of formula (I) is a compound of formula (I-A1). In another embodiment, the compound of formula (I) is a compound of formula (I-A2). In connection with the compounds of formula (I) and the compounds of formula (I-A1), as well as in connection with the compounds of formula (Ia), (Ib), (Ic), (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), and (Ic*), and 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), (Ia*-2*-B), (Ic*-1) and (Ic*-1*), in particular in connection with the preferred embodi- ments regarding R1defined above, the following preferences regarding A1and R2are rele- vant. As indicated above, in connection with the compounds of the present invention, A1is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clic or 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 sub- stitutable carbon or heteroatom in the aforementioned rings is independently unsub- stituted or substituted with one or more, same or different substituents RA1. In a preferred embodiment, A1is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the afore- mentioned 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 carbon or heteroatom in the afore- mentioned aromatic rings is independently unsubstituted or substituted with one or more, same or different substituents RA1. In a more preferred embodiment, A1is phenyl or a 5- or 6-membered aromatic heterocyclic ring, wherein the aforemen- tioned 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 un- substituted or substituted with one or more, same or different substituents RA1. Ryvu Therapeutics S.A. RVU305 28 R10391WO In an even more preferred embodiment, A1is phenyl, pyridinyl, pyrazolyl, or thiophenyl, wherein the phenyl, pyridinyl, pyrazolyl, or thiophenyl is independently unsubstituted or substituted with one or more, same or different substituents RA1. In an even more preferred embodiment, A1is phenyl, pyridinyl, or pyrazolyl, wherein the phenyl, pyridinyl, or pyrazolyl is inde- pendently unsubstituted or substituted with one or more, same or different substitu- ents RA1. In an even more preferred embodiment, A1is phenyl or pyridinyl, wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, same or different substituents RA1. In another even more preferred embodiment, A1is pyridinyl or pyrazolyl, wherein the pyridinyl or pyrazolyl is independently unsubsti- tuted or substituted with one or more, same or different substituents RA1. In an even more preferred embodiment, A1is phenyl or pyridinyl, wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents se- lected from halogen, preferably F. In one particularly preferred embodiment, A1is phenyl, wherein the phenyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents selected from halogen, pref- erably F. In another particularly preferred embodiment, A1is pyridinyl, wherein the pyridinyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents selected from halogen, preferably F. In another particularly preferred embodiment, A1is pyrazolyl, wherein the pyrazolyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents selected from C1-C2-al- kyl, preferably CH3. In a particularly preferred embodiment, A1is selected from the group consisting of Ryvu Therapeutics S.A. RVU305 29 R10391WO even In one more preferred embodiment, A1is selected from the group consisting of In A1is selected from the group consisting of In one particularly preferred embodiment, A1 In connection with the compounds of formula (I) and the compounds of formula (I-A1), as well as in connection with the compounds of formula (Ia), (Ib), (Ic), (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), and (Ic*), and 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*- Ryvu Therapeutics S.A. RVU305 30 R10391WO 2*-A), (Ia*-2*-B), (Ic*-1) and (Ic*-1*), in particular in connection with the preferred embodi- ments regarding R1and A1defined above, preferably, A1is unsubstituted or substituted with one, two, or three, same or different substituents RA1, more preferably A1is unsubstituted or substituted with one or two, same or different substituents RA1, even more preferably A1is unsubstituted or substituted with only one substituent RA1. It is to be understood that when ring A1or any embodiment thereof is referred to herein as being unsubstituted, this refers to said ring A1or embodiment thereof not being substituted with a substituent RA1, i.e., not having a further substituent in addition to R2. Further, in connection with the compounds of formula (I) and the compounds of formula (I-A1), as well as in connection with the compounds of formula (Ia), (Ib), (Ic), (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), and (Ic*), and 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), (Ia*-2*-B), (Ic*-1) and (Ic*-1*), in particular with the preferred embodiments regarding R1and A1as defined above, the following preferences regarding R2and, if present, RA1are relevant. As indicated above, in connection with the compounds of the present invention, R2is halogen, CN, S(=O)2RS, S(=O)(=NH)RS, C(=O)RC, NHC(=O)RC, C(=O)NRN4RN5, C1- C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C6-hydroxyalkyl, or a 5- or 6-mem- bered saturated, partially or fully unsaturated, or aromatic heterocyclyl, 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-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 RA2; wherein RCis H, or C1-C4-alkyl; RN1is H, or C1-C4-alkyl; RN2is H, or C1-C4-alkyl; RSis C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C5-cycloalkyl, or NRN4RN5. In a preferred embodiment, R2is halogen, CN, S(=O)2RS, C(=O)RC, C(=O)NRN4RN5, C1-C2-alkoxy, C1-C2-haloalkyl, C1- C2-haloalkoxy, C1-C2-alkoxy-C1-C2-alkyl, or C1-C2-hydroxyalkyl; and wherein preferably RCis H, or C1-C2-alkyl; RN1is H, or C1-C2-alkyl; RN2is H, or C1-C2-alkyl; RSis C1-C2-alkyl, C1-C2-alkoxy, C3-C5-cycloalkyl, or NRN4RN5. In a more preferred embodiment, R2is halogen, CN, S(=O)2RS, C(=O)RC, C(=O)NRN4RN5, C1-C2-alkoxy, C1-C2-haloalkyl, C1- C2-haloalkoxy, C1-C2-alkoxy-C1-C2-alkyl, or C1-C2-hydroxyalkyl; and wherein preferably RCis H, or C1-alkyl; RN1is H, or C1-alkyl; RN2is H, or C1-alkyl; Ryvu Therapeutics S.A. RVU305 31 R10391WO RSis C1-C2-alkyl, C3-C5-cycloalkyl, or NRN4RN5. In an even more preferred embodiment, R2is halogen, CN, S(=O)2RS, C(=O)NRN1RN2, C1-C2-alkoxy, C1-C2-haloalkyl, or C1-C2- haloalkoxy; and wherein RN1is H, or C1-alkyl; RN2is H, or C1-alkyl; RSis C1-C2-alkyl. In an even more preferred embodiment, R2is halogen, S(=O)2RS, C1-C2-alkoxy, or C1-C2-haloalkyl; and wherein RSis C1-alkyl. In an even more preferred embodiment, R2is Cl, F, S(=O)2RS, C1-alkoxy, CHF2, or CF3; and wherein RSis C1-alkyl. In a particularly preferred embodiment, R2is S(=O)2RS; and wherein preferably RSis C1-C2-alkyl, C1-C2-alkoxy, C3-C5-cycloalkyl, or NRN4RN5; more preferably RSis C1-C2-alkyl, C3-C5-cycloalkyl, or NRN4RN5; even more preferably RSis C1-alkyl. In another particularly preferred embodiment, R2is halogen, CN, C(=O)NRN1RN2, C1-C2-alkoxy, C1-C2-haloalkyl, or C1-C2-haloalkoxy; and wherein RN1is H, or C1-alkyl; RN2is H, or C1-alkyl. In an even more preferred embodiment, R2is halogen, C1-C2-alkoxy, or C1-C2-haloalkyl. In an even more preferred embodiment, R2is Cl, F, C1-alkoxy, CHF2, or CF3. In an even more preferred embodiment, R2is Cl, C1-alkoxy, or CF3. Thus, in a preferred embodiment of the invention, A1is selected from the group consisting of , Ryvu Therapeutics S.A. RVU305 32 R10391WO wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents RA1, preferably selected from halogen, more preferably F. In one particularly preferred embodiment, unsubstituted or substituted with one or more, prefera- bly one, same or different substituents RA1, preferably selected from halogen, more prefera- bly F. In another particularly preferred embodiment, A1; is independently unsubstituted or substituted with one or more, pref- erably one, same or different substituents RA1, preferably selected from halogen, more pref- erably F. In another preferred embodiment of the invention, A1is selected from the group consisting of with one or more, preferably one, same or different substituents RA1, preferably selected from halogen and C1- alkoxy, more preferably F. In a more preferred embodiment, A1is selected from the group consisting of Further, as indicated above, in connection with the compounds of the present invention, RA1is halogen, CN, OH, S(=O)2RS, C(=O)RC, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, or 3- to 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 aforemen- tioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA2; Ryvu Therapeutics S.A. RVU305 33 R10391WO or two RA1together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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 un- substituted or substituted with one or more, same or different substituents RA2. In a preferred embodiment, RA1is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, or 3- to 6-membered satu- rated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring com- prises one or more, same or different heteroatoms selected from O, N, or S, prefera- bly N, wherein said N- and / or S-atoms are independently oxidized or non-oxidized; and wherein each of the aforementioned rings is independently unsubstituted or substituted with one or more, preferably one, same or different substituents RA2; or two RA1together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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. In a more preferred embodiment, RA1is halogen, CN, C1-C2-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, or cyclopropyl; or two RA1together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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. In a more preferred embodiment, RA1is halogen, C1-C2-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, or cyclopropyl; or two RA1together with the atoms to which they are bonded form a fused 5- or 6- membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned hetero- cyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized. In an even more preferred embodiment, RA1is halogen, C1-C2-alkyl, C1-haloalkyl, C1-alkoxy, or cyclopropyl; or two RA1together with the atoms to which they are bonded form a fused 5-mem- bered saturated carbocyclyl. In an even more preferred embodiment, RA1is halogen, C1-C2-alkyl, or cyclopropyl. In an even more preferred embodiment, RA1is F, C1-alkyl, or cyclopropyl. It is to be understood that the preferred embodiments for RA1may vary depending on whether RA1is attached to a carbon atom or heteroatom of ring A1. For example, if RA1is at- tached to a carbon atom of ring A1, RA1is preferably halogen, C1-alkyl, or C1-alkoxy, more Ryvu Therapeutics S.A. RVU305 34 R10391WO preferably halogen, in particular F. If RA1is attached to a heteroatom of ring A1, such as N, RA1is preferably C1-C2-alkyl or cyclopropyl, more preferably CH3. Thus, in one particularly preferred embodiment, RA1is halogen; in particular F. In another particularly preferred embodiment, RA1is C1-C2-alkyl or cyclopropyl; in particular CH3. Thus, in a particularly preferred embodiment of the invention, A1is selected from the group consisting of more . In another particularly preferred embodiment of the invention, A1is selected from the group consisting of more In connection with the compounds of formula (I) and the compounds of formula (I-A2), as well as in connection with the compounds of formula (Ia), (Ib), (Ic), (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), and (Ic*), and 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), (Ia*-2*-B), (Ic*-1) and (Ic*-1*), in particular in connection with the preferred embodi- ments regarding R1defined above, the following preferences regarding Y, A2, and B are rele- vant. As indicated above, in connection with the compounds of the present invention, A2is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clic or heterocyclic ring, 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 35 R10391WO and / or S-atoms are independently oxidized or non-oxidized, and wherein each sub- stitutable carbon or heteroatom in the aforementioned rings is independently unsub- stituted or substituted with one or more, same or different substituents RA2. In a preferred embodiment, A2is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the afore- mentioned 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 carbon or heteroatom in the afore- mentioned aromatic rings is independently unsubstituted or substituted with one or more, same or different substituents RA2. In a more preferred embodiment, A2is phenyl or a 5- or 6-membered aromatic heterocyclic ring, wherein the aforemen- tioned heterocyclic ring comprises one or two N-atoms, 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 RA2. In an even more preferred embodiment, A2is phenyl, pyridinyl, or pyrazolyl; wherein the phenyl, pyridinyl, or pyrazolyl is inde- pendently unsubstituted or substituted with one or more, preferably one or two, more preferably one, same or different substituents RA2; wherein preferably the phenyl, pyridinyl, or pyrazolyl is unsubstituted. In an even more preferred embodiment, A2is phenyl or pyridinyl; wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, preferably one or two, more preferably one, same or different substituents RA2; wherein preferably the phenyl or pyridinyl is unsubstituted. In a particularly preferred embodiment, A2is phenyl; wherein the phenyl is independently unsubstituted or substituted with one or more, preferably one or two, more preferably one, same or different substituents RA2; wherein preferably the phenyl is unsubstituted. In another particularly preferred embodiment, A2is pyridinyl; wherein the pyridinyl is independently unsubstituted or substituted with one or more, preferably one or two, more preferably one, same or different substitu- ents RA2; wherein preferably the pyridinyl is unsubstituted. In another particularly preferred embodiment, A2is pyrazolyl; wherein the pyrazolyl is independently unsubstituted or substituted with one or more, preferably one or two, more preferably one, same or different substitu- ents RA2; wherein preferably the pyrazolyl is unsubstituted. In connection with the compounds of formula (I) and the compounds of formula (I-A2), as well as in connection with the compounds of formula (Ia), (Ib), (Ic), (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), and (Ic*), and 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), (Ia*-2*-B), (Ic*-1) and (Ic*-1*), in particular the preferred embodiments regarding A2defined above, preferably, A2is unsubstituted or substituted with one, two, or three, same or different substituents RA2, more preferably A2is unsubstituted or substituted with one or Ryvu Therapeutics S.A. RVU305 36 R10391WO two, same or different substituents RA2, even more preferably A2is unsubstituted or substi- tuted with only one substituent RA2. In a particularly preferred embodiment, A2is unsubsti- tuted. It is to be understood that when ring A2or any embodiment thereof is referred to herein as being unsubstituted, this refers to said ring A2or embodiment thereof not being substituted with a substituent RA2, i.e., not having a further substituent in addition to ring B. In an even more preferred embodiment, the bicyclic moiety any one of the fol- lowing groups (A2-1), (A2-2), or (A2-3), preferably (A2-1) or , (A2-1): (I), and wherein preferably ring B is defined as in any one of the preferred embodiments regarding ring B defined in the follow- ing. As indicated above, in connection with the compounds of formula (I), B is a 5- to 7-membered saturated, partially or fully unsaturated, or aromatic carbocy- clic or 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 sub- stitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB. In a preferred embodiment, B is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocy- clic 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 carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB. In a more preferred embodiment, B is a 5- or 6-membered saturated or partially unsaturated heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different het- eroatoms selected from O, N, or S, wherein said N- and / or S-atoms are inde- pendently oxidized or non-oxidized, and wherein each substitutable carbon or het- eroatom in the aforementioned cyclic rings is independently unsubstituted or substi- tuted with one or more, same or different substituents RB. In an even more preferred embodiment, B is a 5- or 6-membered saturated or partially unsaturated heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different het- eroatoms selected from O, N, or S, wherein said N- and / or S-atoms are inde- Ryvu Therapeutics S.A. RVU305 37 R10391WO pendently oxidized or non-oxidized, and wherein the heterocyclic ring is inde- pendently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RB. In a more preferred embodiment, ring B is ring B1, so that the bicyclic moiety the bicyclic moiety (B1-1): membered saturated, partially or fully unsaturated, or aromatic heterocy- a 5- or 6-membered saturated or partially unsaturated heterocy- clic ring, 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 oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB1; preferably a 5- or 6-membered saturated or partially unsaturated 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-oxidized, and wherein the heterocyclic ring is independently unsub- stituted or substituted with one or more, preferably one or two, same or different substituents RB1; Z is C(=O), C(=O)NH, C(=O)NRB, S(=O)2, S(=O)2NH, S(=O)2NRB, NH, NRB, O, N, or S; and wherein Y and A2are defined as in connection with formula (I), and wherein preferably, the meaning of A2corresponds to the preferred embodiments defined above. Preferably, B1does not comprise a heteroatom in addition to Z and Y. Since Y is preferably C, B1more preferably does not comprise a heteroatom in addition to Z. Preferably, Z is C(=O)NH, S(=O)2, S(=O)2NH, O, N, or S. More preferably, Z is C(=O)NH, S(=O)2, or O. More preferably, Z is S(=O)2. In an even more preferred embodiment, (B1-1) is a bicyclic moiety selected from the group consisting of (B1-1a), (B1-1b), (B1-1c), (B1-1d), (B1-1e), (B1-1f), (B1-1g): Ryvu Therapeutics S.A. RVU305 38 R10391WO B1is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocy- clic ring, preferably a 5- or 6-membered saturated or partially unsaturated heterocy- clic ring, 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 oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB1; preferably a 5- or 6-membered saturated or partially unsaturated 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-oxidized, and wherein the heterocyclic ring is independently unsub- stituted or substituted with one or more, preferably one or two, same or different substituents RB1; and wherein Y and A2are defined as in connection with formula (I), and wherein preferably, the meaning of A2corresponds to the preferred embodiments defined above. Preferably, B1does not comprise a heteroatom in addition to the one(s) already shown in the structures above and Y. Since Y is preferably C, B1more preferably does not comprise a heteroatom in addition to the one(s) already shown in the structures above. Particularly preferable is a bicyclic moiety selected from the group consisting of (B1-1a), (B1-1b), (B1-1d), (B1-1e), (B1-1f), (B1-1g), more preferably (B1-1a), (B1-1d), or (B1-1e), even more preferably (B1-1a). In a particularly preferred embodiment, in the bicyclic moiety the bicyclic moiety (B1-1), (B1-1a), (B1-1b), (B1-1c), (B1-1d), (B1-1e), (B1-1f), Thus, in another particularly preferred embodiment, the bicyclic moiety one of (A2-1-B1-1), (A2-2-B1-1), or (A2-3-B1-1) as shown below, preferably (A2-2- B1-1), more preferably (A2-1-B1-1): Ryvu Therapeutics S.A. RVU305 39 R10391WO B1is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocy- clic ring, preferably a 5- or 6-membered saturated or partially unsaturated heterocy- clic ring, 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 oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB1; preferably a 5- or 6-membered saturated or partially unsaturated 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-oxidized, and wherein the heterocyclic ring is independently unsub- stituted or substituted with one or more, preferably one or two, same or different substituents RB1; and wherein Z is C(=O), C(=O)NH, C(=O)NRB, S(=O)2, S(=O)2NH, S(=O)2NRB, NH, NRB, O, N, or S. Preferably, Z is C(=O)NH, S(=O)2, S(=O)2NH, O, N, or S. More preferably, Z is C(=O)NH, S(=O)2, or O. More preferably, Z is S(=O)2. Preferably, B1does not comprise a heteroatom in addition to Z and the N already shown in the structure above. In connection with the compounds of formula (I) and the compounds of formula (I-A2), as well as in connection with the compounds of formula (Ia), (Ib), (Ic), (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), and (Ic*), and 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), (Ia*-2*-B), (Ic*-1) and (Ic*-1*), in particular in connection with the preferred embodi- ments regarding R1and B defined above, preferably, B is unsubstituted or substituted with one, two, or three, same or different substituents RB, more preferably B is unsubstituted or substituted with one or two, same or different substituents RB. In connection with the compounds of formula (I) and the compounds of formula (I-A2), as well as in connection with the compounds of formula (Ia), (Ib), (Ic), (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), and (Ic*), and 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), (Ia*-2*-B), (Ic*-1) and (Ic*-1*), in particular in connection with the preferred embodi- ments regarding R1and B defined above, in particular the preferred embodiments regarding B1defined above, including (B1-1), (B1-1a), (B1-1b), (B1-1c), (B1-1d), (B1-1e), (B1-1f), (B1- Ryvu Therapeutics S.A. RVU305 40 R10391WO 1g), (A2-1-B1-1), (A2-2-B1-1), and (A2-3-B1-1), preferably, B1is unsubstituted or substituted with one, two, or three, same or different substituents RB1, more preferably B1is unsubsti- tuted or substituted with one or two, same or different substituents RB1. It is to be understood that when ring B or B1or any embodiment thereof is referred to herein as being unsubstituted, this refers to said ring B or B1or embodiment thereof not be- ing substituted with a substituent RBor RB1, respectively, i.e., not having a further substitu- ent in addition to ring A2or the moiety Z. Further, in connection with the compounds of formula (I) and the compounds of formula (I-A2), as well as in connection with the compounds of formula (Ia), (Ib), (Ic), (Ia’), (Ib’), (Ic’), (Ia*), (Ib*), and (Ic*), and 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), (Ia*-2*-B), (Ic*-1) and (Ic*-1*), in particular in connection with the preferred embodiments regarding R1, A2, R2, RA1, B and B1as defined above, the following preferences regarding RA2and RB, if present, are relevant. As indicated above, in connection with the compounds of the present invention, RA2is halogen, CN, OH, C1-C4-alkyl, or C1-C4-haloalkyl. In a preferred embodiment, RA2is halogen, CN, C1-C2-alkyl, or C1-C2-haloalkyl. In a more preferred embodiment, RA2is halogen or C1-C2-alkyl. In a particularly preferred embodiment, RA2is Cl, F, or C1-alkyl. As indicated above, in connection with the compounds of the present invention, RBis halogen, CN, OH, C1-C4-alkyl, or C1-C4-haloalkyl; or two RBattached to the same atom form an oxo group. In a preferred embodiment, RBis halogen, CN, C1-C2-alkyl, or C1-C2-haloalkyl; or two RBattached to the same atom form an oxo group. In a more preferred embodiment, RBis halogen or C1-C2-alkyl; or two RBattached to the same atom form an oxo group. In an even more preferred embodiment, RBis halogen; or two RBattached to the same atom form an oxo group. In a particularly preferred embodiment, RBis F. In connection with the compounds of the present invention, RB1is halogen, CN, OH, C1-C4-alkyl, or C1-C4-haloalkyl. In a preferred embodiment, RB1is halogen, CN, C1-C2-alkyl, or C1-C2-haloalkyl. Ryvu Therapeutics S.A. RVU305 41 R10391WO In a more preferred embodiment, RB1is halogen or C1-C2-alkyl. In an even more preferred embodiment, RB1is halogen. In a particularly preferred embodiment, RB1is F. Thus, in a particularly preferred embodiment, the bicyclic moiety is the bicyclic moiety , wherein B1 saturated, partially or fully unsaturated, or aromatic heterocy- clic ring, preferably a 5- or 6-membered saturated or partially unsaturated heterocy- clic 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 the heterocyclic ring is in- dependently unsubstituted or substituted with one or more, preferably one or two, same or different substituents RB1; preferably a 5- or 6-membered saturated or partially unsaturated 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-oxidized, and wherein the heterocyclic ring is independently unsub- stituted or substituted with one or more, preferably one or two, same or different substituents RB1; wherein RB1is halogen, CN, OH, C1-C4-alkyl, or C1-C4-haloalkyl; and wherein preferably Y is C; and RB1is halogen, preferably F. Preferably, B1does not comprise a heteroatom in addition to the S already shown in the structure above and Y. Since Y is preferably C, B1more preferably does not comprise a het- eroatom in addition to the S already shown in the structure above. In another particularly preferred embodiment, the bicyclic moiety selected from the group consisting of Ryvu Therapeutics S.A. RVU305 42 R10391WO In an even more preferred embodiment, the bicyclic moiety selected from the group consisting of In one particularly preferred embodiment, the bicyclic moiety Ryvu Therapeutics S.A. RVU305 43 R10391WO In another particularly preferred embodiment, the bicyclic moiety Overall, in a preferred embodiment, A is a moiety selected from are defined as in connection with formula (I), A1, A2, Y, Z, B1, RA1, RA2, and RB1correspond to the preferred embodiments defined above. In a more preferred embodiment, A is a moiety selected from or ; wherein R2is halogen, S(=O)2RS, CN, C1-C2-alkoxy, C1-C2-haloalkyl, or C1-C2-haloalkoxy; wherein preferably RSis C1-alkyl; and wherein A1, A2, Y, Z, B1, RA1, RA2, and RB1are defined as in connection with formula (I), and wherein preferably, the meaning of A1, A2, Y, Z, B1, RA1, RA2, and RB1correspond to the preferred embodiments defined above. In one more preferred embodiment, A is a moiety selected from R2 C1-alkyl; and wherein A1, A2, Y, B1, RA1, RA2, and RB1are defined as in connection with formula (I), and wherein preferably, the meaning of A1, A2, Y, B1, RA1, RA2, and RB1correspond to the preferred embodiments defined above. Ryvu Therapeutics S.A. RVU305 44 R10391WO In another more preferred embodiment, A is a moiety selected from wherein R2 alkoxy, C1-C2-haloalkyl, or C1-C2-haloalkoxy; preferably R2is halogen, C1-C2-alkoxy, or C1-C2-haloalkyl; more preferably R2is Cl, F, C1-alkoxy, CHF2, or CF3; and wherein A1, A2, Y, Z, B1, RA1, RA2, and RB1are defined as in connection with formula (I), and wherein preferably, the meaning of A1, A2, Y, Z, B1, RA1, RA2, and RB1correspond to the preferred embodiments defined above. In an even more preferred embodiment, A is a moiety selected from Z preferably C(=O)NH, S(=O)2, or O; more A1 wherein the phenyl, pyridinyl, or pyrazolyl is independently unsubstituted or substi- tuted with one or more, preferably one, same or different, substituents RA1; wherein preferably RA1is halogen, C1-C2-alkyl, or cyclopropyl; more preferably F or CH3; A2is phenyl, pyridinyl, or pyrazolyl; wherein the phenyl, pyridinyl, or pyrazolyl is independently unsubstituted or substi- tuted with one or more, same or different, substituents RA2; wherein preferably the phenyl, pyridinyl, or pyrazolyl is unsubstituted; B1is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocy- clic ring, preferably a saturated or partially unsaturated 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-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB1; and wherein preferably B1does not comprise a heteroatom in addition to the Z or S shown in the structures above; Y is C or N; and Ryvu Therapeutics S.A. RVU305 45 R10391WO RB1is halogen, more preferably F; and wherein R2is halogen, CN, S(=O)2RS, C1-C2-alkoxy, C1-C2-haloalkyl, or C1-C2-haloalkoxy; wherein preferably RSis C1-alkyl; and wherein preferably R2is halogen, S(=O)2RS, C1-alkoxy, or C1-haloalkyl; wherein preferably RSis C1-alkyl. In one even more preferred embodiment, A is a moiety selected from wherein A1 wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, preferably one, same or different, substituents RA1; wherein preferably RA1is halogen, more preferably F; A2is phenyl or pyridinyl; wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, same or different, substituents RA2; wherein preferably the phenyl or pyridinyl is unsubstituted; B1is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocy- clic ring, preferably a saturated or partially unsaturated 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-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB1; and wherein preferably B1does not comprise a heteroatom in addition to the S shown in the structure above; Y is C; and RB1is halogen, more preferably F; and wherein R2is halogen, CN, S(=O)2RS, C1-C2-alkoxy, C1-C2-haloalkyl, or C1-C2-haloalkoxy; wherein preferably RSis C1-alkyl; and wherein preferably R2is halogen, S(=O)2RS, C1-alkoxy, or C1-haloalkyl; wherein preferably RSis C1-alkyl; and wherein more preferably R2is S(=O)2RS; wherein preferably RSis C1-alkyl. In another even more preferred embodiment, A is a moiety selected from Ryvu Therapeutics S.A. RVU305 46 R10391WO A1 wherein the pyrazolyl is independently unsubstituted or substituted with one or more, preferably one, same or different, substituents RA1; wherein preferably RA1is C1-C2alkyl or cyclopropyl; more preferably CH3; A2is pyrazolyl; wherein the pyrazolyl is independently unsubstituted or substituted with one or more, same or different, substituents RA2; wherein preferably the pyrazolyl is unsub- stituted; B1is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocy- clic ring, preferably a saturated or partially unsaturated 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-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB1; and wherein preferably B1does not comprise a heteroatom in addition to the S or Y shown in the structure above; Y is N; and RB1is halogen, more preferably F; and wherein R2is halogen, CN, S(=O)2RS, C1-C2-alkoxy, C1-C2-haloalkyl, or C1-C2-haloalkoxy; wherein preferably RSis C1-alkyl; and wherein preferably R2is halogen, C1-alkoxy, or C1-haloalkyl; and wherein more preferably R2is Cl, F, C1-alkoxy, CHF2, or CF3. In one even more preferred embodiment, A wherein A1 or pyrazolyl; wherein the phenyl, pyridinyl, or pyrazolyl is independently unsubstituted or substi- tuted with one or more, preferably one, same or different, substituents RA1; wherein preferably RA1is halogen, C1-C2-alkyl, or cyclopropyl, more preferably F or CH3; and wherein R2is halogen, CN, S(=O)2RS, C1-C2-alkoxy, C1-C2-haloalkyl, or C1-C2-haloalkoxy; wherein preferably RSis C1-alkyl; and wherein preferably R2is halogen, S(=O)2RS, C1-alkoxy, or C1-haloalkyl; wherein preferably RSis C1-alkyl; Ryvu Therapeutics S.A. RVU305 47 R10391WO and wherein more preferably R2is Cl, F, S(=O)2RS, C1-alkoxy, CHF2, or CF3; wherein preferably RSis C1-alkyl. In one even more preferred embodiment, A wherein A1 wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, preferably one, same or different, substituents RA1; wherein preferably RA1is halogen, more preferably F; and wherein R2is S(=O)2RS; wherein preferably RSis C1-alkyl. In another even more preferred embodiment, A is ; wherein A1is pyridinyl or pyrazolyl; wherein the pyridinyl or pyrazolyl is independently unsubstituted or substituted with one or more, preferably one, same or different, substituents RA1; wherein preferably RA1is halogen, C1-C2alkyl, or cyclopropyl; more preferably F or CH3; and wherein R2is halogen, CN, C1-C2-alkoxy, C1-C2-haloalkyl, or C1-C2-haloalkoxy; and wherein preferably R2is halogen, C1-alkoxy, or C1-haloalkyl; and wherein more preferably R2is Cl, F, C1-alkoxy, CHF2, or CF3. In a particularly preferred embodiment, A is ; wherein A1is phenyl; wherein the phenyl is independently unsubstituted or substituted with one or more, preferably one, same or different, substituents RA1; wherein preferably RA1is halogen, more preferably F; and wherein R2is S(=O)2RS; wherein preferably RSis C1-alkyl. In another particularly preferred embodiment, Ryvu Therapeutics S.A. RVU305 48 R10391WO A wherein A1 wherein the pyridinyl is independently unsubstituted or substituted with one or more, preferably one, same or different, substituents RA1; wherein preferably the pyridinyl is unsubstituted; wherein R2is halogen, CN, S(=O)2RS, C1-C2-alkoxy, C1-C2-haloalkyl, or C1-C2-haloalkoxy; wherein preferably RSis C1-alkyl; and wherein preferably R2is halogen, S(=O)2RS, C1-alkoxy, or C1-haloalkyl; wherein preferably RSis C1-alkyl; and wherein more preferably R2is Cl, F, C1-alkoxy, CHF2, or CF3. In another particularly preferred embodiment, A A1 wherein the pyrazolyl is independently unsubstituted or substituted with one or more, preferably one, same or different, substituents RA1; wherein preferably RA1is C1-C2-alkyl or cyclopropyl; more preferably CH3; and wherein R2is halogen, CN, S(=O)2RS, C1-C2-alkoxy, C1-C2-haloalkyl, or C1-C2-haloalkoxy; wherein preferably RSis C1-alkyl; and wherein preferably R2is halogen, C1-alkoxy, or C1-haloalkyl; and wherein more preferably R2is Cl, F, C1-alkoxy, CHF2, or CF3; and wherein even more preferably R2is Cl, C1-alkoxy, or CF3. Overall, in preferred embodiments, A is a moiety selected from the group consisting of Ryvu Therapeutics S.A. RVU305 49 R10391WO more A is a moiety selected from the group consisting of A is a moiety selected from the group consisting of . A is a moiety selected from the group consisting of In other particularly preferred embodiments, the compound of formula (I) is a compound se- lected from the group consisting of: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide; N-({4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 50 R10391WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylphenyl)pyridine- 3-carboxamide; and N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide. In other particularly preferred embodiments, the compound of formula (I) is a compound se- lected from the group consisting of: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyano-N-(4,4-difluoro- 1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(4-fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-me- thanesulfonyl-4-methylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-2-(trifluoromethyl)pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyano-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 51 R10391WO N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-2-(4-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-5-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-6-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N- (4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-5-methoxypyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methanesulfonyl- 4-methylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclobutyl-N-(4-fluoro-2- methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-(3,3-difluoropyrrolidin-1- yl)-N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methanesulfonyl- 4-methylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(trifluorome- thyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro- 2-methoxyphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4,4-difluoro-1,1-di- oxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyrimidine-5-carboxamide; rac-N-({4-amino-1-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(1S)-4-amino-1-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 52 R10391WO N-{[(1R)-4-amino-1-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro-2-methoxy- phenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4,4-difluoro-1,1-di- oxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-benzothiopyran-8-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methoxypyridin-3- yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- [1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-fluoro-2-me- thanesulfonylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4- fluoro-2-methanesulfonylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(difluorome- thyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(2- methanesulfonylpyridin-3-yl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,1- dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,1- dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,1- dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(4- fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 53 R10391WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-4- yl)-2-cyclopropylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-(1-cyanocyclopropyl)-N-(4-fluoro-2- methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-oxo-2,3-dihydro- 1H-isoindol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-3-oxo-2,3- dihydro-1H-isoindol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluo- romethyl)-1H-pyrazol-4-yl]pyrimidine-5-carboxamide; rac-N-({4-amino-2-methyl-2H,3H-furo[3,2-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-methoxypyridin-3- yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethoxypyri- din-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methoxypyridin-3-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-[2-(trifluoromethyl)pyridin- 3-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyano-4-fluorophenyl)-2-cyclo- propylpyrimidine-5-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(tri- fluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(2- methanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(2- methanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-cyanopyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-methoxy-1-me- thyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-4- yl)-6-cyclopropylpyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyanopyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide; N-({4-amino-2H,3H-furo[3,2-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-[2-(tri- fluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-[2- (trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-5-cyano-N-[2-(trifluoromethyl)pyridin- 3-yl]pyridine-3-carboxamide; Ryvu Therapeutics S.A. RVU305 54 R10391WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methoxypyrazin-2-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxa- zin-3-yl}-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(difluorometh- oxy)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-[1-cyclopropyl-3-(trifluoro- methyl)-1H-pyrazol-4-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-{5H,6H,7H-pyra- zolo[3,2-b][1,3]oxazin-3-yl}pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(5-chloro-1-methyl-1H-pyrazol-4- yl)-2-cyclopropylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-4- yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-fluoro-2-methoxy- pyridin-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[3-(difluoromethyl)- 1-methyl-1H-pyrazol-4-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-cyclopropyl-3- methoxy-1H-pyrazol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(methoxyme- thyl)phenyl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-carbamoyl-1-methyl-1H-pyrazol- 4-yl)-6-cyclopropylpyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[(1R,2R)-2-hydroxy- 2,3-dihydro-1H-inden-1-yl]pyrimidine-5-carboxamide; N-({4-amino-9-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N- (4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-cyclopropyl-1H-pyrazol- 4-yl)-6-cyanopyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(4-methylpiper- azin-1-yl)-2-(trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-{5-methyl-4-oxo- 4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-3-yl}pyridine-3-carboxamide; N-({4-aminofuro[3,2-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluorome- thyl)-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-(3- methoxy-1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide; and N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-chloropyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide. Definitions Ryvu Therapeutics S.A. RVU305 55 R10391WO 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, rota- mer, atropisomer, tautomer or N-oxide thereof. The compounds according to the invention may be amorphous or may exist in one or more different crystalline states (polymorphs), which may have different macroscopic properties such as stability or show different biological properties such as activities. The present in- vention relates to amorphous and crystalline forms of compounds of formula (I), mixtures of different crystalline states of the compounds of formula (I), as well as amorphous or crys- talline salts thereof. Salts of the compounds according to the invention are preferably pharmaceutically ac- ceptable 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 react- ing the compound with an acid of the anion in question, if the compounds according to the invention have a basic functionality, or by reacting acidic compounds according to the in- vention with a suitable base. Suitable cationic counterions are in particular the ions of the alkali metals, preferably lith- ium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals, preferably manganese, copper, silver, zinc and iron, and also ammonium (NH4+) and substituted ammonium in which one to four of the hy- drogen 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, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, furthermore the cations of 1,4-piperazine, meglumine, benzathine and lysine. Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hex- afluorosilicate, hexafluorophosphate, 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 ac- cording 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 centres of chirality, including axial chirality providing different stereoiso- mers. The invention provides both, pure enantiomers or pure diastereomers, of the com- pounds according to the invention, and their mixtures, including racemic mixtures. For ex- ample, a chiral centre of the compounds according to the invention may be present in sub- stituent R1. Suitable compounds according to the invention also include all possible geometrical stere- oisomers (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. Ryvu Therapeutics S.A. RVU305 56 R10391WO Further, suitable compounds according to the invention also include conformational stere- oisomers (conformers), which refers to isomers that interconvert by rotations about single bonds. Rotations about single bonds involve overcoming a rotational energy barrier to inter- convert 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 indi- vidual rotamers, the rotamers are termed atropisomers. Thus, the term “atropisomers” as used herein refers to conformational stereoisomers (conformers) resulting from hindered rotation about a single bond, where the energy differences due to steric strain or other con- tributors 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 atropiso- mers. Rotational isomers (rotamers), in particular atropisomers, do not require an asymmet- ric 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 substitu- ent of highest priority on the other atom, the absolute configuration is assigned P or Δ for clockwise and M or Λ for counterclockwise. Alternatively, all four groups can be ranked by Cahn–Ingold–Prelog priority rules, with overall priority given to the substituents 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 Raand Sain analogy to the traditional R / S for a traditional tetrahedral stereocenter as exemplarily illus- trated 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. resulting, e.g., from rotation about an amide bond may also be defined as cis / trans isomers or E / Z isomers. Thus, such cis / trans iso- mers and E / Z isomers are also covered by the term rotational isomer (rotamer) or atropiso- mer. The invention provides both, pure rotational isomers (rotamers) or atropisomers of the compounds according to the invention, and their mixtures, including racemic mixtures. 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 il- lustration only, exemplary rotational isomers (rotamers) 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 1: Ryvu Therapeutics S.A. RVU305 57 R10391WO For Example 1, 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 isolate the rotational isomers (rotamers) so that no sta- ble atropisomers are observed for Example 1. However, if the barrier to rotation is high enough, the rotational isomers (rotamers) of the compounds according to the invention can be separated and isolated and can thus be termed atropisomers. In particular, depending on the substitution pattern, the barrier to ro- tation about the C-N bond between the tertiary amide nitrogen 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 po- sition 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 atropisomers. 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 isomers (rotamers) resulting from a restricted rotation about the C-N am- ide bond as shown above for Example 1. 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 atropisomers, the two at- ropisomers 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 example, 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 re- ferred 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 nitrogen and the A moiety of the compounds according to the invention, the Ryvu Therapeutics S.A. RVU305 58 R10391WO two atropisomers may be separated and isolated. Each of the separated and isolated atro- pisomers may then be present as a mixture of two rotational isomers (rotamers) resulting from the second restricted bond rotation, e.g. the rotation about the C-N amide bond. A “di- astereoisomer-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 rotation(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 compound of the present invention may thus be present as a mixture of four stereoisomers (or even 8 stereoisomers in case of two restricted bond rotations), which can be grouped into “diaster- eoisomer-like” components that are distinguishable by NMR analysis. If, e.g., the stereoiso- mers resulting from the chiral centre are separated 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 maxi- mum 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 race- mize 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 atropiso- mers of the compounds of the invention may be present, if the A moiety of the compounds of the present invention is substituted in ortho position on both sides of the carbon con- nected to the tertiary amide nitrogen of the remainder of the molecule. For class 2 atropiso- mers, it may be possible to distinguish the atropisomers in NMR or short time LC, but they may nevertheless be inseparable due to the fact that a single atropisomer would reequili- brate to a mixture within a few hours.1H NMR at 80 °C may be useful to identify stable at- ropisomers if their signals do not coalesce at this temperature. Tautomers may be formed, if a substituent is present at the compound of formula (I), which allows for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, amide-imidic acid tautomers or the like. 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 unlabeled forms as well as isotopically labeled forms of the compounds. Iso- topically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having 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, Ryvu Therapeutics S.A. RVU305 59 R10391WO such as, but not limited to2H (deuterium, D),3H (tritium),11C,13C,14C,15N,18F,31P,32P,35S,36CI and125I. For example, radioactive isotopes such as3H,13C and14C provide isotopically labelled compounds useful in metabolic studies, reaction kinetic studies, detection or imag- ing 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 ther- apeutic 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 requirements and / or an improvement in therapeutic index. See, for exam- ple, Poster, "Deuterium Isotope Effects in Studies of DrugMetabolism", Trends Pharmacol. Sei. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens 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 specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclo- sure 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 desig- nated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected. The term "substitutable", when used in reference to a designated atom, means that at- tached to the atom is a hydrogen, which can be replaced with a suitable substituent. When it is referred to certain atoms or moieties being substituted with “one or more” sub- stituents, 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 “substi- tuted” is explicitly mentioned concerning a moiety, said moiety is to be considered as un- substituted. The organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The prefixCn-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 particularfluorine, 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 atoms. 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-methyl- butyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-di- methylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dime- Ryvu Therapeutics S.A. RVU305 60 R10391WO thylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-di- methylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl- 1-methylpropyl, and 1-ethyl-2-methylpropyl. The term "haloalkyl" as used herein denotes in each case a straight-chain or branched al- kyl 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 at- oms. 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-trifluoro- ethyl, 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, preferably 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-bu- tyloxy, 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 car- bon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, to the remainder of the molecule. Thus, it refers to an alkyl group, which is bonded via oxygen to a further al- kyl group, which is then bonded to the remainder of the molecule. Examples of an alkoxy- alkyl 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 prefer- ably 1 carbon atom, wherein the hydrogen atoms of this group are partially or totally re- placed with halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties in-clude 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 branchedalkyl 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, hydroxy- ethyl, n-hydroxypropyl, 2-hydroxypropyl, n-hydroxybutyl, 2-hydroxybutyl, 2-hydroxy-2- methylpropyl, and n-hydroxypentyl. Hydroxymethyl, hydroxyethyl, hydroxypropyl, and hy- droxybutyl, are preferred, in particular hydroxymethyl and hydroxyethyl. 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 NH2group. 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 remain- der of the molecule. Examples of an aminoalkyl group are aminomethyl, aminoethyl, n-ami- Ryvu Therapeutics S.A. RVU305 61 R10391WO nopropyl, 2-aminopropyl, n-aminobutyl, 2-aminobutyl, 2-amino-2-methylpropyl, and n-ami- nopentyl. Aminomethyl, aminoethyl, aminopropyl, and aminobutyl, are preferred, in particu- lar 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, cyclo- butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopro- pyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl, cyclobutyl, cyclopentyl, and cyclo- hexyl 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-mem- bered monocyclic ring, comprising 3 to 10, preferably 4 to 8 or 3 to 6 or 5 to 7, more prefera- bly 3, 4, 5 or 6 carbon atoms. The carbocycle may be saturated, partially or fully unsatu- rated, or aromatic, wherein saturated means that only single bonds are present, and par- tially 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 covers “aromatic carbobicycles” as defined herein. The term “carbocy- clic” or “carbocyclyl”, unless otherwise indicated, may therefore cover inter alia cycloalkyl, cycloalkenyl, as well as phenyl. Preferably, the term “carbocyclic” or “carbocyclyl” covers phenyl and cycloalkyl, for example phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclo- hexyl. The term "carbobicyclic" or “carbobicyclyl” includes in general 6 to 14-membered, prefera- bly 7- to 12-membered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings comprising 6 to 14, preferably 7 to 12 or 8 to 10, more preferably 9 or 10 carbon atoms. The carbobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein satu- rated 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 ful- filled. 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 “carbobicylce” or “carbobicyclyl”, unless otherwise indicated, may therefore cover inter alia bicycloalkyl, bicycloalkenyl, as well as bicyclic aromatic groups, for example bicyclohexane (decalin), bicycloheptane (such as norbornane), bicyclooctane (such as bicyclo[2.2.2]octane, bicyclo[3.2.1]octane or bicy- clo[4.2.0]octane), bicyclononane (such as bicyclo[3.3.1]nonane or bicyclo[4.3.0]nonane ), bicyclodecane (such as bicyclo[4.4.0]decane), bicycloundecane (such as bicyclo[3.3.3]un- decane), norbornene, naphthalene and the like. Preferably, the carbobicycle is a fused car- bobicycle, 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 car- Ryvu Therapeutics S.A. RVU305 62 R10391WO bon atoms, preferably 1 carbon atom. Preferably, the term “carbocyclylalkyl” refers to phe- nylalkyl or cycloalkylalkyl, which refers to the corresponding groups being bonded to the re- mainder of the molecule via an alkyl group. Preferred examples of carbocyclylalkyl 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 carbon 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, pref- erably 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-membered, 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 satu- rated, 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 asring members, where S-atoms as ring members may be present as S, SO or SO2. Examplesof aromatic heterocycles are provided below in connection with the definition of “hetaryl”.“Hetaryls” or “heteroaryls” are covered by the term “heterocycles”. The saturated or par- tially or fully unsaturated heterocycles usually comprise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. The skilled person is aware that S, SO or SO2is to be un- derstood as follows: Further, a skilled person is 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, tetrahydrothiophene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine. Ryvu Therapeutics S.A. RVU305 63 R10391WO The term “heterobicyclic” or “heterobicyclyl” includes, unless otherwise indicated, in gen- eral 6 to 14-membered, preferably 7- to 12-membered or 8- to 10-membered, more prefera- bly 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 suita- ble 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 moieties is aromatic, while the other is non-aromatic. The heterobi- cycle typically comprises one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms se- lected 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 heterobicycles include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, ben- zoxadiazolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthy- ridyl, pteridyl, pyrido[3,2-d]pyrimidyl, pyridoimidazolyl, triethylenediamine or quinuclidine and the like. The term "hetaryl" or “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” includes monocyclic 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO2. Examples of 5- or 6-membered aromatic heterocycles include pyridyl (also referred to as pyridinyl), i.e.2-, 3-, or 4-pyridyl, pyrimidinyl, i.e.2-, 4- or 5-py- rimidinyl, pyrazinyl, pyridazinyl, i.e. 3- or 4-pyridazinyl, thienyl, i.e. 2- or 3-thienyl, furyl, i.e. 2-or 3-furyl, pyrrolyl, i.e.2- or 3-pyrrolyl, oxazolyl, i.e. 2-, 3- or 5-oxazolyl, isoxazolyl, i.e. 3-, 4- or 5-isoxazolyl, thiazolyl, i.e. 2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl, pyrazolyl, i.e.1-, 3-, 4- or 5-pyrazolyl, i.e.1-, 2-, 4- or 5-imidazolyl, oxadiazolyl, e.g.2- or 5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3-oxadiazol)yl, 3- or 5-(1,2,4-oxadiazol)yl, 2- or 5-(1,3,4- thiadiazol)yl, thiadiazolyl, e.g. 2- or 5-(1,3,4-thiadiazol)yl, 4- or 5-(1,2,3-thiadiazol)yl, 3- or 5- (1,2,4-thiadiazol)yl, triazolyl, e.g. 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 pyridinyl- methyl, pyrimidinylmethyl, pyrazolylmethyl, and piperidinylmethyl. 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 in- clude pyridinyloxy, pyrimidinyloxy, pyrazolyloxy, and piperidinyloxy. The same applies to the terms “heteroaryloxy” referring to the corresponding group, which is bonded to the remain- der 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 molecule. Examples Ryvu Therapeutics S.A. RVU305 64 R10391WO include pyridinyloxymethyl, pyrimidinyloxymethyl, pyrazolyloxymethyl, and piperidinyloxyme- thyl. The term “cyclic” moiety can refer to any cyclic groups, which are present in the com- pounds of formula (I), and which are defined above, e.g., cycloalkyl, cycloalkenyl, carbocy- clyl. The term “bicyclic” moiety can refer to any bicyclic groups, which are present in the com- pounds 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 tech- nical effect of the feature in question. The term typically indicates a deviation from the in- dicated numerical value of ±10% and preferably ±5%. It needs to be understood that the term “comprising” is not limiting. For the purposes of the present invention, the term “consisting of” is considered to be a preferred embodiment of the term “comprising of”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group which preferably consists of these embodiments only. The term “pharmaceutically acceptable excipient” as used herein refers to compounds commonly comprised in pharmaceutical compositions, which are known to the skilled per- son. Examples of suitable excipients are exemplary listed below. Typically, a pharmaceuti- cally acceptable excipient can be defined as being pharmaceutically inactive. The term “treatment” is to be understood as also including the option of “prophylaxis”. Thus, whenever reference is made herein to a “treatment” or “treating”, this is to be under- stood 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, buccal, nasal, rectal, topical, transdermal or parenteral application. Pre- ferred non-parenteral routes include mucosal (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, intrathecal, in- travesical, intramuscular, epidural or subcutaneous administration, but also intranasal and inhalative administration. Preferably administration is by subcutaneous, intra-tumoral or peri-tumoral routes, in particular in the treatment of cancer. Particularly preferred is intra- tumoral administration. In connection with the treatment of pulmonary diseases, such as asthma, chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibro- sis, 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 Ryvu Therapeutics S.A. RVU305 65 R10391WO breath-actuated and do not require the use of any propellants. Nebulizers provide the active ingredient as an aerosol created from an aqueous formulation. Metered-dose inhalers re- lease a fixed dose of medication in aerosol form, wherein a liquefied gas propellant, prefer- ably 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 formu- lation 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 interme- diate, 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 in- vention can be any substance used for the preparation of pharmaceutical dosage forms, in- cluding coating materials, film-forming materials, fillers, disintegrating agents, release-mod- ifying materials, carrier materials, diluents, binding agents, and other adjuvants. Typical pharmaceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents. The term “carrier” denotes pharmaceutically acceptable organic or inorganic carrier sub- stances with which the active ingredient is combined to facilitate the application. Suitable pharmaceutically acceptable carriers include, for instance, water, aqueous salt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbitans, poly- ethylene-polypropylene block co-polymers such as poloxamer 188 or poloxamer 407, poly- ethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amyl- ose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and triglycerides, polyoxyethylated 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, crosspovidone and the like. Preferably, the compounds of the present invention are administered in a pharmaceuti- cal composition comprising of lipids, interbilayer crosslinked multilamellar vesicles, biode- gradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanopar- ticles or microparticles, nanoporous particle-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 influ- encing 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 pharma- ceutically acceptable emulsions, solutions, suspensions and syrups containing inert diluents Ryvu Therapeutics S.A. RVU305 66 R10391WO commonly used in the art such as water. These dosage forms may contain e.g. microcrystal- line 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 solutions, as well as suspensions, emulsions, or implants. Pharmaceutical for- mulations for parenteral administration are particularly preferred and include aqueous solu- tions 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 sus- pensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Particularly preferred dosage forms are injectable preparations of a compound of formula (I). Thus, sterile injectable aqueous or oleaginous suspensions can for example be formu- lated 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 accepta- ble 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 appli- cations for injectable preparations comprising the compounds of the present invention are intravenous, intratumoral and peritumoral administration. Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g. mixing the compound with a suitable non-irritating excipient such as cocoa butter, syn- thetic triglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the compound ac- cording to formula (I) from said suppositories. For administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebu- lizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoro- methane, 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 me- tered 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, effervescent formulations, dragees and granules. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and pro- cessing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lac- tose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). 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 Ryvu Therapeutics S.A. RVU305 67 R10391WO forms may be formulated to ensure an immediate release of the compound of formula (I) or a sustained release of the compound of formula (I). A solid dosage form may comprise a film coating. 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 hydroxypropylmethylcellulose capsule, a two-piece cap- sule made of vegetable or plant-based cellulose or a two-piece capsule made of polysac- charide. The dosage form according to the invention may be formulated for topical application. Suitable pharmaceutical application forms for such an application may be a topical nasal spray, sublingual administration forms and controlled and / or sustained release skin patches. For buccal administration, the compositions may take the form of tablets or loz- enges formulated in conventional manner. The compositions may conveniently be presented in unit dosage forms and may be pre- pared 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 in- timately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. Liquid dose units are vials or ampoules. Solid dose units are tablets, capsules and suppositories. As regards human patients, the compound of formula (I) may be administered to a patient in an amount of about 0.001 mg to about 5000 mg per day, preferably of about 0.01 mg to about 1000 mg per day, more preferably 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 con- verted under physiological conditions or by solvolysis to any of the compounds of the inven- tion. A prodrug may be inactive prior to administration but may be converted to an active compound of the invention in vivo. In a preferred embodiment relating to the pharmaceutical compositions of the present in- vention, said pharmaceutical composition comprises said compound as the only pharma- ceutically active agent. Alternatively, said pharmaceutical composition comprises at least one further independent pharmaceutically active agent in addition to said compound, wherein said additional active agent is typically used for the intended indication(s) as out- lined above. In particular, when it comes to cancer, said pharmaceutical composition com- prises 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. Ryvu Therapeutics S.A. RVU305 68 R10391WO 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 comprising the same is for use in the treatment of a disease selected from the group consisting of cancer or pre-cancerous syndromes. In another embodiment, the com- pound 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 or pre-can- cerous 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 Can- cer, 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 Can- cer, Ovarian Cancer, T-Lymphoblastic Leukemia / Lymphoma, Nerve Sheath Tumor, Mature B-Cell Neoplasms, Renal Non-Clear Cell Carcinoma, Renal Cell Carcinoma, Endometrial Cancer, Mature B-cell lymphoma, High-grade glioma / astrocytoma, Renal Clear Cell Carci- noma, Prostate Adenocarcinoma, Adrenocortical Carcinoma, Salivary Gland Cancer, Invasive Breast Carcinoma, Cholangiocarcinoma, Gastrointestinal Stromal Tumor, Lung Cancer, Low- grade glioma / astrocytoma, Thymic Epithelial Tumor, Salivary Cancer, Intraductal Papillary Mucinous Neoplasm, Leukemia, Mesothelioma, Sex Cord Stromal Tumor, CNS Cancer, Em- bryonal Tumor, Skin Cancer, Cervical Cancer, Thyroid Cancer, Anal Cancer, Peripheral Nerv- ous System. In particular, said cancer is preferably selected from the group consisting of Glioblastoma Multiforme, B-Lymphoblastic Leukemia / Lymphoma, Pancreatic Adenocarcinoma, Breast In- vasive Ductal Carcinoma, Lung Squamous Cell Carcinoma, Bladder Urothelial Carcinoma, Lung Adenocarcinoma, Cutaneous Melanoma, Head and Neck Squamous Cell Carcinoma, Melanoma, Prostate Adenocarcinoma, Esophageal Adenocarcinoma, Astrocytoma, 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, Blad- der / Urinary Tract Cancer, Invasive Breast Carcinoma, Colon Adenocarcinoma, Hepatocellu- lar Adenoma, Malignant Peripheral Nerve Sheath Tumor, Papillary Renal Cell Carcinoma, Pleural Mesothelioma Biphasic Type, Bladder Squamous Cell Carcinoma, T-Lymphoblastic Leukemia / Lymphoma, Leiomyosarcoma, Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma, Sarcoma, Osteosarcoma, Renal Clear Cell Carcinoma, Intestinal Type Stomach Adenocarcinoma, Adenoid Cystic Carcinoma, Oligodendroglioma, Breast Invasive Lobular Carcinoma, Cholangiocarcinoma, Pediatric High Grade Gliomas, Acral Melanoma, Oligoastrocytoma, Breast Invasive Carcinoma, Adrenocor- tical Carcinoma, Breast Mixed Ductal and Lobular Carcinoma, Gastrointestinal Stromal Tu- mor, Thymoma, Dedifferentiated Liposarcoma, Angiosarcoma, Diffuse Type Stomach Ade- nocarcinoma, Intracholecystic Papillary Neoplasm, Pediatric Low Grade Gliomas, Intrahe- patic Cholangiocarcinoma, Ewing Sarcoma, Intraductal Papillary Mucinous Neoplasm, Ryvu Therapeutics S.A. RVU305 69 R10391WO Myxofibrosarcoma, Chordoma, Papillary Stomach Adenocarcinoma, B-Lymphoblastic Leu- kemia / Lymphoma BCR-ABL1 Like, Acute Myeloid Leukemia, Metaplastic Breast Cancer, High-Grade Serous Ovarian Cancer, Low-Grade Serous Ovarian Cancer, Liposarcoma, Ade- nocarcinoma 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 Pancreas, Rectal Adenocarcinoma, Mucinous Adenocar- cinoma of the Colon and Rectum, Chromophobe Renal Cell Carcinoma, Peritoneal Mesothe- lioma, 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 / Apo- crine Eccrine Carcinoma, Poorly differentiated Non-Small Cell Lung Cancer, Sarcomatoid Carcinoma of the Lung, Neuroblastoma, Pleural Mesothelioma, Pilocytic Astrocytoma, Sig- net Ring Cell Carcinoma of the Stomach, Ganglioglioma, Collecting Duct Renal Cell Carci- noma, Small Cell Carcinoma of the Ovary, Non-Small Cell Lung Cancer, Pancreatoblastoma, Ependymomal Tumor, Adenosquamous Carcinoma of the Stomach, Carcinoma with Osse- ous Metaplasia, Fibroblastic Osteosarcoma, Adenocarcinoma, B-Lymphoblastic Leuke- mia / 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 Cancer, B-Lymphoblastic Leukemia / Lymphoma, Pancreatic Cancer, Breast Cancer, Melanoma, Esophagogastric Cancer, Bladder Cancer, Glioma, Head and Neck Can- cer, Hepatobiliary Cancer, Prostate Cancer, Pleural Mesothelioma, Sarcoma, Ovarian Epi- thelial 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 Glio- blastoma Multiforme, B-Lymphoblastic Leukemia / Lymphoma, Pancreatic Adenocarcinoma, Breast Invasive Ductal Carcinoma, Lung Squamous Cell Carcinoma, Bladder Urothelial Car- cinoma, Lung Adenocarcinoma, Cutaneous Melanoma, Head and Neck Squamous Cell Car- cinoma, Melanoma, Prostate Adenocarcinoma, Esophageal Adenocarcinoma, Astrocytoma, Serous Ovarian Cancer, Stomach Adenocarcinoma, Esophageal Squamous Cell Carcinoma, Hepatocellular Carcinoma, Glioblastoma, Pleural Mesothelioma, Epithelioid Type Diffuse Large B-Cell Lymphoma, Tubular Stomach Adenocarcinoma, Bladder / Urinary Tract Cancer, Colon Adenocarcinoma, Hepatocellular Adenoma, Malignant Peripheral Nerve Sheath Tu- mor, Papillary Renal Cell Carcinoma, Pleural Mesothelioma Biphasic Type, T-Lymphoblastic Leukemia / Lymphoma, Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histio- cytoma / 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 com- bination 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 coadminis- tered with 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 Ryvu Therapeutics S.A. RVU305 70 R10391WO the combination of (i) a compound according to the present invention and (ii) an anti-neo- plastic 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 & Wilkins Publishers. Typical anti-neoplastic agents useful in the present invention include chemotherapeutic agents, topoisomerase II inhibitors, antimetab- olites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase inhibitors, angiogenesis inhibitors, proapoptotic agents, cell cycle signaling inhibitors, proteasome inhibitors, inhibitors of can- cer metabolism, and immunotherapeutic agents (such as STING pathway modulating com- pounds, TLR agonists and checkpoint inhibitors). Examples for chemotherapeutic agents are anti-microtubule or anti-mitotic agents (such as paclitaxel), platinum coordination com- plexes (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 in- cludes the second agent(s). The two therapies may be given in either order and may precede or follow the other treat- ment by intervals ranging from minutes to weeks. 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 pref- erably, within about 6-12 h of each other. In some situations, it may be desirable to extend the time period for treatment 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 administra- tion 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 Ryvu Therapeutics S.A. RVU305 71 R10391WO Abbreviation Meaning Atm. Atmosphere BINAP (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene Bn Benzyl (Bpin)2Bis(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]dipalla- dium(II) CDI 1,1'-Carbonyldiimidazole conc. Concentrate CRISPR / Cas9 Clustered Regularly Interspaced Short Palindromic Repeats / CRISPR-associated endonuclease 9 DAD Diode array detector DAST Diethylaminosulphur trifluoride 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 EC50Half 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 72 R10391WO Abbreviation Meaning FA Formic acid FBS Fetal bovine serum FCC Flash column chromatography h hour HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri- dinium 3-oxid hexafluorophosphate HCT116 Human colorectal carcinoma cell line 116 HOBt 1-Hydroxybenzotriazole HOAt 1-Hydroxy-7-azabenzotriazole IC50Half maximal inhibitory concentration IPA isopropyl alcohol Int. Intermediate iPrOAc isopropyl acetate KO Knock out KOAc / AcOK potassium acetate LC, HPLC High-Performance Liquid Chromatography LC MS, LCMS, High-Performance Liquid Chromatography coupled to Mass Spec- LC-MS or trometry LC / MS LiHMDS Lithium bis(trimethylsilyl)amide L-Pro-ONa Sodium (2S)-pyrrolidine-2-carboxylate M Molarity mCPBA meta-Chloroperoxybenzoic acid MEP50 Methylosome protein 50 2-MeTHF 2-Methyltetrahydrofuran Me4tBuXPhos 2-Di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopro- pyl-1,1′-biphenyl Min. Minute mm Millimeter MTA 5′-Methylthioadenosine MTAP 5′-Methylthioadenosine Phosphorylase MsCl Methanesulfonyl chloride NBS N-bromosuccinimide NCS N-chlorosuccinimide NMP 1-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance No., # Number ^W or MW Microwave PBS Phosphate Buffered Saline Pd / C Palladium on carbon Pd2dba3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Ryvu Therapeutics S.A. RVU305 73 R10391WO Abbreviation Meaning Pd(dppf)Cl2.DC [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) di- M chloromethane complex Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0) PhCH3Toluene P(n-Bu)3Tributylphosphane 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 SelectFluorTMN-Chloromethyl-N-fluorotriethylenediammonium bis(tetrafluorobo- rate) SEM Trimethylsilylethoxymethyl SM Starting material STAB Sodium triacetoxyborohydride T3P Propylphosphonic anhydride TBAB Tetrabutylammonium bromide TEA Triethylamine temp. temperature 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 Spec- trometry Ryvu Therapeutics S.A. RVU305 74 R10391WO Abbreviation Meaning WT Wild type Xantphos 4,5-bis(Diphenylphosphino)-9,9-dimethylxanthene XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XPhos Pd G3 (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-bi- phenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesul- fonate The compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exempli- fied by the following specific examples. While the present invention is described herein in conjunction with the specific examples, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. In some cases, the order of car- rying out the steps of the reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. All such alternatives, modifications and variations are in- tended to fall within the spirit and scope of the present invention. Methods and analytical data: Several methods for preparing the compounds of this invention are described in the following Schemes and Examples. Unless otherwise indicated, all variables are as previ- ously defined. All anhydrous solvents were provided by commercial suppliers, e.g., Sigma- Aldrich®, in appropriate containers, e.g., Sure / Seal™ bottles, and were used without further purification. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purifications. Unless otherwise specified, all tempera- tures are expressed in ^C and all reactions are conducted at rt. Unless otherwise specified, compounds were purified by either flash column chromatography (FCC), preparative HPLC or preparative chiral HPLC. Unless otherwise specified, silica (50 ^m average particle size) is the stationary phase used for flash column chromatography purifications. NMR1H NMR was recorded on a Bruker Ascend 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (δ = 2.50 ppm for1H NMR in DMSO- d6, δ = 3.31 ppm for1H NMR in CD3OD, δ = 7.26 ppm for1H NMR in CDCl3).1H NMR data are reported as follows: chemical shift (multiplicity, coupling constants and number of hy- drogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quar- tet), m (multiplet), dd (doublet of doublets), ddd (doublet of doublets of doublets), tt (triplet of triplets), td (triplet of doublets), dt (doublet of triplets), hept (heptuplet), dq (doublet of quartets), br s (broad singlet). NMR data were analyzed using MestReNova v10.0.2 and ul- terior (Mestrelab Research S.L., Santiago de Compostela, Spain, www.mestrelab.com). UPLC long elution Four types of eluent system were used: Ryvu Therapeutics S.A. RVU305 75 R10391WO 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”neutral” MeCN waterColumn: Waters ACQUITY UPLC® BEH C181.7 ^m, 2.1 x 100 mm 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, NH3and 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 Ryvu Therapeutics S.A. RVU305 76 R10391WO 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 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 Autopurifica- tion system (Waters 2767 – Sample Manager, Waters 2545 – Binary Gradient Module, Wa- ters SFO – System Fluidics Organizer, Waters Prep Degasser, Waters 515 – HPLC Pump, Waters UV Fraction Manager) with DAD (Waters 2998 – Photodiode Array Detector) and QDa (Waters Acquity QDa) detection, using a Phenomenex Gemini® 5µm NX-C18110 Å (00G-4454-P0-AX LC Column 250 x 21.2 mm, AX) column. Ryvu Therapeutics S.A. RVU305 77 R10391WO 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 12 95 5 14 95 5 15 10 90 Chiral HPLC purifications: The following equipment was used for Chiral HPLC purifications: HPLC Shimadzu hardware: 2x LC 20AP pumps, SPD M20A DAD detector, CBM -20A, auto sampler SIL 10AP, FRC-10A fraction collector. The chiral columns were of 4 types: Daicel CHIRALPAK® AY-H column (amylose tris(5-chloro-2-methylphenylcarbamate) coated on 5 ^m silica-gel, 250 mm x 20 mm) Daicel CHIRALPAK® AD-H column (amylose tris-(3,5-dimethylphenylcarbamate) coated on 5 ^m silica-gel, 250 mm x 20 mm) IF column Dr. Maisch (Amylose tris-(3-Chloro-4-Methylphenyl) Carbamate), (Particle Size: 5µm, 20mm x L 250mm) Daicel CHIRALPAK IE HPLC Semi-Preparative Column, (Amylose tris(3,5-dichlorophenyl- carbamate)), (particle size: 5 µm, 20 mm x L 250 mm) Method A

[0002] Ryvu Therapeutics S.A. RVU305 78 R10391WO Compounds of Formula (I) may be prepared according to Method A. Compound 3 might be product of acid 1 or acid chloride of the acid 1 with amine 2 coupling reaction. Compound 3 when treated with 4 and a base, such as Cs2CO3, provide 5. Compound 5 is subject to re- duction to compound 6 with zinc and NH4Cl. Compound 6 when subjected in step 1 for Miyaura borylation with, for example pinacolatodiboron in presence of palladium catalyst and a base form a mixture of boronic acid and boronic acid pinacol ester which in step 2 is subjected to palladium catalyzed coupling with a compound 7 to provide 8. Compound 8 when subjected to acidic conditions, like HCl generated by addition of acetyl chloride to ethanol provide desired product 9 of Formula (I). Examples Example 1: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-me- thanesulfonylphenyl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 79 R10391WO N-(2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. 001): In 100 mL flask 2-methanesulfonylaniline (0.4 g, 2.34 mmol, 1.0 eq.) and triethylamine (0.81 mL, 5.8 mmol, 2.5 eq.) were dissolved in DCM (5.0 mL) and to this pyridine-3-carbonyl chloride hydrochloride (0.499 g, 2.8 mmol, 1.2 eq.) was added. Reaction was left stirred at RT for overnight. After this time to reaction NaHCO3aq. was added slowly. Organic phase was then separated, dried over Na2SO4, filtered and concentrated. Product was isolated by FCC (0 to 2% MeOH gradient in DCM) to give N-(2-methanesulfonylphenyl)pyridine-3-car- boxamide (Int. 001, 0.39 g, 1.41 mmol, 59%, beige solid, m / z [M+H]+: 277.7).1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.12 (dd, J = 2.4, 0.9 Hz, 1H), 8.82 (dd, J = 1.6 Hz, 1H), 8.29 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 8.16 (dd, J = 8.2, 1.2 Hz, 1H), 8.00 (dd, J = 8.0, 1.5 Hz, 1H), 7.82 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 7.64 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 7.52 (ddd, J = 7.9, 7.4, 1.2 Hz, 1H), 3.33 (s, 3H). N-[(4-Bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. 002): In a pressure vessel a mixture of N-(2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. 001, 1.0 g, 3.55 mmol, 1.0 eq.), 1-bromo-4-(bromomethyl)-2-nitrobenzene (1.57 g, 5.32mmol, 1.5 eq.) and Cs2CO3 (1.4 g, 4.29 mmol, 1.21 eq.) in anhydrous acetonitrile (18 mL) wasstirred at 70°C for 1 h. After this time reaction was brought to RT and then water and Ryvu Therapeutics S.A. RVU305 80 R10391WO EtOAc were added. Organic layer was separated and dried over Na2SO4, filtered and con- centrated. From this crude mixture product was isolated by FCC (0 to 100% EtOAc gradient in hexane) to give N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylphenyl)pyri- dine-3-carboxamide (Int. 002, 0.805 g, 1.64 mmol, 45%, orange solid, m / z [M+H]+: 491.7).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 8:2) Major rotamer: δ 8.50 – 8.47 (m, 1H), 8.41 (dd, J = 4.9, 1.7 Hz, 1H), 8.07 –8.02 (m, 1H), 7.94 (dd, J = 7.9, 1.6 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.71 – 7.60 (m, 3H), 7.58 – 7.52 (m, 1H), 7.44 – 7.40 (m, 1H), 7.27 – 7.22 (m, 1H), 5.57 (d, J = 15.6 Hz, 1H), 4.61 (d, J = 15.4 Hz, 1H), 3.19 (s, 3H). Minor rotamer: δ 8.85 – 8.82 (m, 1H), 8.72 – 8.68 (m, 1H), 8.11 – 8.07 (m, 1H), 8.07 – 8.02 (m, 1H), 7.87 – 7.84 (m, 1H), 7.81 – 7.78 (m, 1H), 7.76 – 7.71 (m, 1H), 7.71 – 7.60 (m, 1H), 7.58 – 7.52 (m, 1H), 7.49 – 7.45 (m, 1H), 7.36 – 7.32 (m, 1H), 5.09 (d, J = 16.7 Hz, 1H), 4.74 (d, J = 16.5 Hz, 1H), 3.25 (s, 3H). N-[(3-Amino-4-bromophenyl)methyl]-N-(2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. 003): To a solution of N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylphenyl)pyr- idine-3-carboxamide (Int. 002, 0.8 g, 1.58 mmol, 1.0 eq.) in acetone (2.0 mL) was added zinc (1.05 g, 16.06 mmol, 10.15 eq.) followed by sat. NH4Cl aq. (4.0 mL). RM was stirred at RT for 1 h. After this time reaction was filtered through a pad of NH2modified silica layer at the top and a bottom layer of Celite®, then all was washed with DCM. Combined filtrates were washed with water. Organic layer was then separated, dried over Na2SO4, filtered and con- centrated. Solid remains were used in next step without further purification. N-[(3-amino-4- bromophenyl)methyl]-N-(2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. 003, 0.73 g, 1.59 mmol, 98%, brown solid, m / z [M+H]+: 461.7).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 1:0.5) Major rotamer: δ 8.46 (d, J = 1.7 Hz, 1H), 8.40 (dd, J = 5.0, 1.7 Hz, 1H),8.12 – 8.06 (m, 1H), 7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.74 – 7.48 (m, 3H), 7.29 – 7.17 (m, 2H), 6.85 (d, J = 2.1 Hz, 1H), 6.44 (dd, J = 8.1, 2.0 Hz, 1H), 5.51 (d, J = 15.0 Hz, 1H), 5.40 – 5.32 (m, 2H), 4.29 (d, J = 15.1 Hz, 1H), 3.18 (s, 3H). Minor rotamer: δ 8.91 – 8.87 (m, 1H, minor), 8.73 – 8.68 (m, 1H, minor), 7.74 – 7.48 (m, 4H), 7.29 – 7.17 (m, 3H), 6.72 – 6.69 (m, 1H), 6.29 – 6.24 (m, 1H), 5.40 – 5.32 (m, 2H), 4.91 (d, J = 16.5 Hz, 1H), 4.37 (d, J = 16.1 Hz, 1H), 3.24 (s, 3H). N-{[3-amino-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int. 004): Step 1. Mixture of N-[(3-amino-4-bromophenyl)methyl]-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int.003, 0.3 g, 0.64 mmol, 1.0 eq.), 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.33 g, 1.3 mmol, 2.04 eq.) and potassium acetate (0.2 g, 2.04 mmol, 3.19 eq.) in 1,4-dioxane (6.0 mL) was sparged with argon for 15 min. After this time 1,1'-bis(diphenylphosphino)ferrocene dichloropalla- dium (II) (0.0467 g, 0.064 mmol, 0.1 eq.) was added and reaction mixture was then heated at 100°C for 4 h. After this time reaction mixture was allowed to cool to RT, then DCM was added and all was filtered through a pad of Celite®. To filtrate water was added and layers were separated. Aqueous layer was extracted with DCM. Combined organic phases were Ryvu Therapeutics S.A. RVU305 81 R10391WO washed with brine, dried over MgSO4, filtered and concentrated. Solid remains were used in next step without further purification (0.685 g, dark brown solid). Step 2. Microwave reactor was charged with a crude mixture of boronic acid and pina- col boronic ester from step 1 (0.685 g), 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (0.14 g, 0.75 mmol, 1.17 eq.) and potassium carbonate (0.275 g, 1.99 mmol, 3.09 eq.). Then 1,4- dioxane (3.0 mL) and water (0.3 mL) were added. The reaction mixture was bubbled with nitrogen for 15 min and tetrakis(triphenylphosphine)palladium (0.082 g, 0.07 mmol, 0.11 eq.) was added. Reactor was closed, reaction mixture was stirred and heated at 120°C for 30 min under microwave irradiation. Then reaction was cooled to RT, mixture was diluted with DCM and water was added. Aqueous phase was extracted with DCM (x3), combined or- ganic phases were washed with brine, dried over Na2SO4, filtered and concentrated. Product was isolated by FCC (0 to 2% MeOH gradient in DCM, then isocratic) to give N-{[3-amino- 4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-N-(2-methanesulfonylphenyl)pyri- dine-3-carboxamide (Int. 004, 0.146 g, 0.264 mmol, 41%, brown solid, m / z [M+H]+: 487.4).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ratio 7:3). Major rotamer: δ 8.51 (d, J = 6.9 Hz, 1H), 8.45 – 8.39 (m, 1H), 8.10 (d, J =4.8 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.76 – 7.61 (m, 2H), 7.59 – 7.44 (m, 2H), 7.26 (m, 1H), 7.01 (dd, J = 7.9, 2.0 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.65 (dd, J = 7.8, 1.6 Hz, 1H), 5.48 (d, J = 15.9 Hz, 1H), 5.34 (d, J = 6.3 Hz, 2H), 4.55 (d, J = 15.3 Hz, 1H), 3.65 (m, 3H), 3.13 (d, J = 6.8 Hz, 3H). Minor rotamer: δ 8.89 (s, 1H), 8.73 – 8.65 (m, 1H), 8.10 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.76 – 7.61 (m, 2H), 7.59 – 7.44 (m, 2H), 7.26 (m, 1H), 6.91 (m, 1H), 6.73 (d, J = 36.0 Hz, 1H), 6.44 (dd, J = 24.7, 7.9 Hz, 1H), 5.34 (d, J = 6.3 Hz, 2H), 4.99 (d, J = 16.3 Hz, 1H), 4.48 (d, J = 16.4 Hz, 1H), 3.65 (m, 3H), 3.25 (s, 3H). N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide (Example 1): Acetyl chloride (0.06 g, 0.76 mmol, 4.18 eq.) was added to a solution of N-{[3-amino- 4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-N-(2-methanesulfonylphenyl)pyri- dine-3-carboxamide (Int. 004, 0.1 g, 0.18 mmol, 1.0 eq.) in anhydrous ethanol (2.0 mL). The mixture was heated at 100°C for 1.5 h and allowed to cool to RT. Reaction mixture was then passed through SCX column and fraction containing product was eluted using 2 M NH3in MeOH. Product was isolated from those by FCC (0 to 15% MeOH in DCM gradient) to give N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide (Example 1, 0.06 g, 0.12 mmol, 67%, white solid, UPLC long elution (Mid polar long method; buffer type “NH3”) purity 99.84%, m / z [M+H]+: 487.16).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 7:3) Major rotamer: δ 8.48 (d, J = 2.2 Hz, 1H), 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 8.26(d, J = 8.2 Hz, 1H), 8.26 (s, 1H), 7.93 (dd, J = 7.7, 1.8 Hz, 1H), 7.68 (dt, J = 8.0, 2.0 Hz, 1H), 7.58 – 7.53 (m, 2H), 7.51 (td, J = 7.8, 1.5 Hz, 1H), 7.35 (dd, J = 7.8, 1.3 Hz, 1H), 7.28 – 7.21 (m, 2H), 7.11 (br s, 2H), 5.75 (d, J = 14.9 Hz, 1H), 4.66 (d, J = 14.9 Hz, 1H), 4.39 (s, 3H), 3.16 (s, 3H). Minor rotamer: δ 8.93 (s, 1H), 8.76 – 8.70 (m, 1H), 8.23 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.17 – 8.10 (m, 1H), 8.12 – 8.07 (m, 1H), 7.66 – 7.58 (m, 3H), 7.32 (s, 1H), 7.17 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.08 (s, 2H), 5.22 (d, J = 16.1 Hz, 1H), 4.71 (d, J = 16.8 Hz, 1H), 4.35 (s, 3H), 3.26 (s, 3H). Ryvu Therapeutics S.A. RVU305 82 R10391WO Example 2: N-({4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl}methyl)-N-(2-me- thanesulfonylphenyl)pyridine-3-carboxamide Step 1. A mixture of N-[(3-amino-4-bromophenyl)methyl]-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int.003, 0.2 g, 0.41 mmol, 1.0 eq.), 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.21 g, 0.83 mmol, 2.0 eq.), potassium acetate (0.122 g, 1.24 mmol, 3.01 eq.) in 1,4-dioxane (4.0 mL) was sparged with argon for 15 min and then 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.03 g, 0.04 mmol, 0.1 eq.) was added and reaction mixture was then heated at 100°C for 4 h. After this time reaction mixture was allowed to cool to RT, then EtOAc was added and all was filtered through a pad of Celite®. To filtrate water was added and layers were sepa- rated. Aqueous layer was extracted with EtOAc (x2). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. Solid remains were used in next steps without further purification (0.598 g, brown solid). Step 2. Microwave reactor was charged with boronic acid / pinacol ester crude mixture from step 1 (0.3 g), 4-bromo-1-methyl-1H-pyrazole-5-carbonitrile (0.043 g, 0.23 mmol, 1.30 eq.) and dipotassium carbonate (0.074 g, 0.535 mmol, 3.019 eq.). Then, 1,4-dioxane (2 mL) and water (0.2 mL, 1.13 mL / mmol) were added. The reaction mixture was sparged with ni- trogen for 10 min and then tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol, 0.102 eq.) was added. Reactor was capped and left stirred and heated at 120°C for 30 min under microwave irradiation. After this time reaction was cooled to RT, diluted with EtOAc and filtered through a pad of Celite®, pad was washed with AcOEt. Filtrates were combined, concentrated and dried under vacuum for 1 h. Solid remains containing crude product (Int. 005) were used in next step without further purification. Step 3. Solid remains containing crude (Int.005) were dissolved in anhydrous ethanol (3.0 mL). Acetyl chloride (0.06 g, 0.76 mmol, 4.31 eq.) was then added at RT. Reaction was then heated at 100°C for 1 h. After this time reaction was cooled to RT and the mixture was concentrated. The residue was redissolved in water and pH was adjusted to 8 by addi- tion of 1 M NaOH aq. Then, aqueous phase was extracted with 3:1 mixture of CHCl3:i-PrOH (x3). Combined organic layers were washed with brine, dried over Na2SO4, filtered and con- centrated. From this crude mixture, the product was isolated by two consecutive FCC (each 0 to 10% MeOH gradient in DCM) to give N-({4-amino-3-methyl-3H-pyrazolo[3,4-c]quino- lin-7-yl}methyl)-N-(2-methanesulfonylphenyl)pyridine-3-carboxamide (Example 2, 0.05 g, 0.103 mmol, 58%, beige solid, UPLC long elution (Polar long method, buffer type “FA”) pu- rity 100%, m / z [M+H]+: 487.50). Ryvu Therapeutics S.A. RVU305 83 R10391WO1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 1:0.45) Major rotamer: δ 8.45 (s, 1H), 8.44 – 8.38 (m, 2H), 8.09 – 8.01 (m, 1H),7.89 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.63 – 7.56 (m, 1H), 7.55 – 7.44 (m, 2H), 7.30 (d, J = 8.2 Hz, 1H), 7.27 – 7.21 (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.79 – 6.61 (m, 2H), 5.72 (d, J = 14.8 Hz, 1H), 4.73 – 4.62 (m, 1H), 4.38 – 4.30 (m, 3H), 3.10 (s, 3H). Minor rotamer: δ 8.92 (s, 1H), 8.75 – 8.71 (m, 1H), 8.44 – 8.38 (m, 1H), 8.15 – 8.10 (m, 1H), 8.09 – 8.01 (m, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.63 – 7.56 (m, 1H), 7.55 – 7.44 (m, 2H), 7.27 – 7.21 (m, 1H), 7.14 – 7.10 (m, 1H), 7.09 – 7.05 (m, 1H), 6.79 – 6.61 (m, 2H), 5.17 (d, J = 16.2 Hz, 1H), 4.73 – 4.62 (m, 1H), 4.38 – 4.30 (m, 3H), 3.23 (s, 3H). Example 3: N-({4-Amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide 4-Cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Int. 006): To a stirred solution of 4-oxooxolane-3-carbonitrile (0.5 g, 4.5 mmol, 1.0 eq.) in di- chloromethane (5 mL) was added DIPEA (0.94 mL, 5.40 mmol, 1.2 eq.) and reaction mixture was cooled to -78°C. Then trifluoromethanesulfonic 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. 006, 0.187 g, 0.769 mmol, 17%, colorless liquid).1H NMR (400 MHz, Chloroform-d) δ 4.88 – 4.81 (m, 4H). N-{[3-amino-4-(4-cyano-2,5-dihydrofuran-3-yl)phenyl]methyl}-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int. 007): Step 1. A mixture of N-[(3-amino-4-bromophenyl)methyl]-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int.003, 0.1 g, 0.21 mmol, 1.0 eq.), 4,4,5,5-tetramethyl- Ryvu Therapeutics S.A. RVU305 84 R10391WO 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.105 g, 0.41 mmol, 2.0 eq.), potassium acetate (0.061 g, 0.62 mmol, 3.01 eq.) in 1,4-dioxane (2 mL) was sparged with argon for 15 min and then 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.0151 g, 0.021 mmol, 0.1 eq.) was added and reaction mixture was then heated at 100°C for 4 h. After this time reaction mixture was allowed to cool to RT, then EtOAc was added and all was filtered through a pad of Celite®. To filtrate water was added and layers were separated. Aqueous layer was extracted with EtOAc (x2). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. Solid remains were used in next steps without further purification (0.25 g, brown solid). Step 2. 20 mL Microwave reactor was charged with solid remains from step 1 (0.25 g), 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (0.1797 g, 0.74 mmol, 5.0 eq.) and dipotassium carbonate (0.062 g, 0.45 mmol, 3.04 eq.) followed by 1,4-dioxane (1.5 mL) and water (0.15 mL). The reaction mixture was degassed by nitrogen passing for 10 min and then tetrakis(triphenylphosphine)palladium (0.017 g, 0.015 mmol, 0.1 eq.) was added. Reac- tor was capped and left stirred and heated at 120°C for 30 min under microwave irradia- tion. After this time reaction mixture was cooled to RT and filtered through a pad of Celite®. Filtrate was concentrated, and product was isolated by FCC (0 to 10% MeOH gradient in EtOAc) to give N-{[3-amino-4-(4-cyano-2,5-dihydrofuran-3-yl)phenyl]methyl}-N-(2-me- thanesulfonylphenyl)pyridine-3-carboxamide (Int. 007, 0.042 g, 0.089 mmol, 52%, brown solid, m / z [M+H]+: 475.5).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 1:0.45) Major rotamer: δ 8.48 – 8.44 (m, 1H), 8.43 – 8.38 (m, 1H) 7.94 – 7.89 (m,1H), 7.69 – 7.63 (m, 1H), 7.63 – 7.56 (m, 2H), 7.54 – 7.44 (m, 2H), 7.29 – 7.21 (m, 2H), 7.19 – 7.11 (m, 1H), 6.64 – 6.43 (m, 2H), 5.77 – 5.71 (m, 1H), 5.34 – 5.25 (m, 2H), 5.02 – 4.96 (m, 2H), 4.61 (d, J = 14.8 Hz, 1H), 3.14 (s, 3H). Minor rotamer: δ 8.90 (s, 1H), 8.74 – 8.69 (m, 1H), 8.14 – 8.06 (m, 2H), 7.63 – 7.56 (m, 1H), 7.54 – 7.44 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H7.29 – 7.21 (m, 2H), 7.19 – 7.11 (m, 1H), 7.06 – 7.01 (m, 1H), 6.64 – 6.43 (m, 2H), 5.34 – 5.25 (m, 2H), 5.17 (d, J = 16.1 Hz, 1H), 5.02 – 4.96 (m, 2H), 4.69 (d, J = 16.5 Hz, 1H), 3.24 (s, 3H). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylphenyl)pyridine- 3-carboxamide (Example 3): In a 20 mL Biotage® microwave vial, acetyl chloride (0.023 g, 0.29 mmol, 4.0 eq.) was added to a solution of N-{[3-amino-4-(4-cyano-2,5-dihydrofuran-3-yl)phenyl]methyl}-N-(2- methanesulfonylphenyl)pyridine-3-carboxamide (Int. 007, 0.04 g, 0.07 mmol, 1.0 eq.) in an- hydrous ethanol (0.8 mL). Reaction vial was capped and reaction was stirred and heated at 100°C for 1 h. After this time reaction mixture was cooled to RT and concentrated. Re- maining residue was redissolved in water and pH was adjusted to 8 by addition of 1 M NaOH. Then, aqueous phase was extracted with CHCl3:i-PrOH (3:1) mixture (x3). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. Prod- uct was isolated by FCC (0 to 15% MeOH gradient in DCM) to give N-({4-amino-1H,3H- furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylphenyl)pyridine-3-carboxamide (Ex- ample 3, 0.018 g, 0.038 mmol, 52%, white solid, UPLC long elution (Polar long method; buffer type “NH3”) purity: 100%, m / z [M+H]+: 475.17).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 7:3). Major rotamer: δ 8.47 – 8.44 (m, 1H), 8.42 – 8.39 (m, 1H), 7.93 – 7.89 (m, Ryvu Therapeutics S.A. RVU305 85 R10391WO 1H), 7.68 – 7.64 (m, 1H), 7.63 – 7.56 (m, 1H), 7.54 – 7.45 (m, 2H), 7.44 (s, 1H), 7.28 – 7.21 (m, 2H), 7.17 – 7.11 (m, 1H), 6.47 (s, 2H), 5.74 (d, J = 14.7 Hz, 1H), 5.34 – 5.25 (m, 2H), 5.02 – 4.95 (m, 2H), 4.61 (d, J = 14.8 Hz, 1H), 3.15 (s, 3H). Minor rotamer: δ 8.92 – 8.89 (m, 1H), 8.74 – 8.70 (m, 1H), 8.13 – 8.10 (m, 1H), 8.09 – 8.05 (m, 1H), 7.63 – 7.56 (m, 1H), 7.54 – 7.45 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.28 – 7.21 (m, 1H), 7.17 – 7.11 (m, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.52 (s, 2H), 5.34 – 5.25 (m, 2H), 5.17 (d, J = 16.0 Hz, 1H), 5.02 – 4.95 (m, 2H), 4.69 (d, J = 15.5 Hz, 1H), 3.24 (s, 3H). Example 4: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2- methanesulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide N-(4-fluoro-2-methanesulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 008): To a solution of 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.606 g, 3.17 mmol, 1.0 eq.) and 4-fluoro-2-methanesulfonylaniline (0.6 g, 3.17 mmol, 1.0 eq.) in anhydrous pyridine (31 mL) was added phosphorus oxychloride (0.972 g, 6.34 mmol, 2.0 eq) dropwise, at RT. Reaction was stirred at RT for 1 h and after this time reaction mixture was diluted with DCM and water. This mixture was cooled to 0°C and then sat. NaHCO3aq. was added until pH 8. Aqueous phase was the extracted with DCM (x2), combined organic phases were Ryvu Therapeutics S.A. RVU305 86 R10391WO dried over MgSO4, filtered and concentrated. Product was isolated by FCC (0 to 50% EtOAc gradient in hexane) to give N-(4-fluoro-2-methanesulfonylphenyl)-6-(trifluoromethyl)pyri- dine-3-carboxamide (Int. 008, 0.884 g, 2.42 mmol, 76%, yellow solid, m / z [M+H]+: 363.0).1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.28 – 9.24 (m, 1H), 8.59 – 8.54 (m, 1H), 8.21– 8.16 (m, 1H), 8.01 – 7.96 (m, 1H), 7.86 – 7.82 (m, 1H), 7.78 – 7.72 (m, 1H).N-[(4-bromo-3-nitrophenyl)methyl]-N-(4-fluoro-2-methanesulfonylphenyl)-6-(trifluorome- thyl)pyridine-3-carboxamide (Int. 009): A suspension of N-(4-fluoro-2-methanesulfonylphenyl)-6-(trifluoromethyl)pyridine-3- carboxamide (Int. 008, 0.884 g, 2.42 mmol, 1.0 eq.), 1-bromo-4-(bromomethyl)-2-nitroben-zene (1.075 g, 3.65 mmol, 1.51 eq.) and Cs2CO3 (0.97 g, 2.98 mmol, 1.23 eq.) in anhydrousacetonitrile (12 mL) was stirred at 70°C for overnight in a pressure vessel. After this timereaction was left to cool to RT, then quenched with sat. NH4Cl aq. Water was then added and aqueous phase was extracted with DCM (x2). Combined organic phases were dried over Na2SO4, filtered and concentrated. From this crude material product was isolated by FCC (0 to 30% EtOAc gradient in hexane) to give N-[(4-bromo-3-nitrophenyl)methyl]-N-(4- fluoro-2-methanesulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 009, 1.109 g, 1.83 mmol, 76%, yellow solid, m / z [M+H]+: 575.8).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ratio 1:0.3). Major rotamer: δ 8.73 – 8.70 (m, 1H), 8.09 – 8.07 (m, 1H), 8.00 – 7.97 (m,1H), 7.94 – 7.91 (m, 1H), 7.91 – 7.88 (m, 1H), 7.86 – 7.83 (m, 1H), 7.69 – 7.66 (m, 1H), 7.61 – 7.57 (m, 2H), 5.58 (d, J = 15.3 Hz, 1H), 4.63 (d, J = 15.3 Hz, 1H), 3.33 (s, 3H). N-[(3-amino-4-bromophenyl)methyl]-N-(4-fluoro-2-methanesulfonylphenyl)-6-(trifluoro- methyl)pyridine-3-carboxamide (Int. 010): To a solution of N-[(4-bromo-3-nitrophenyl)methyl]-N-(4-fluoro-2-methanesul- fonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 009, 1.109 g, 1.83 mmol, 1.0 eq.) in acetone (50 mL) was added zinc (1.195 g, 18.27 mmol, 10.0 eq.) followed by sat. NH4Cl aq. (4.5 mL). Reaction mixture was stirred at RT for 30 min. After this time reaction mixture was filtered through a Celite® pad which was washed with DCM. Filtrates were combined and organic phase was washed with water (x2), then organic phase was sepa- rated, dried over Na2SO4, filtered and concentrated. From this crude material, product was isolated by FCC (0 to 30% EtOAc gradient in hexane) to give N-[(3-amino-4-bromo- phenyl)methyl]-N-(4-fluoro-2-methanesulfonylphenyl)-6-(trifluoromethyl)pyridine-3-car- boxamide (Int. 010, 1.066 g, 1.85 mmol, 101%, brown solid, m / z [M+H]+: 547.8).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 1:0.55). Major rotamer: δ 8.70 – 8.67 (m, 1H), 7.96 – 7.93 (m, 1H), 7.87 – 7.81 (m,2H), 7.60 – 7.54 (m, 1H), 7.44 – 7.39 (m, 1H), 7.33 – 7.30 (m, 1H), 6.86 – 6.83 (m, 1H), 6.49 – 6.44 (m, 1H), 5.48 (d, J = 14.9 Hz, 1H), 5.38 (s, 2H), 4.37 (d, J = 14.8 Hz, 1H), 3.31 (s, 3H). N-{[3-amino-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-N-(4-fluoro-2-me- thanesulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 011): Step 1. To a degassed solution of N-[(3-amino-4-bromophenyl)methyl]-N-(4-fluoro-2- methanesulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int.010, 0.869 g, 1.51 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- Ryvu Therapeutics S.A. RVU305 87 R10391WO dioxaborolane (0.78 g, 3.07 mmol, 2.03 eq.) in 1,4-dioxane (15 mL), potassium acetate (0.445 g, 4.53 mmol, 3.0 eq.) was added, followed by 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.115 g, 0.16 mmol, 0.10 eq.). Reaction mixture was then heated at 100°C for 3 h in a pressure vessel. The reaction mixture was then cooled to RT, diluted with DCM and filtered through a pad of Celite®. To filtrate water was added and all was ex- tracted with DCM (x2). The organic phases were combined, dried over MgSO4, filtered and concentrated. Crude mixture was further dried in vacuo for 1 hour and used in next step without further purification (1.67 g, brown solid). Step 2. 20 mL Pressure vessel was charged with crude from step 1 (1.951 g, prepared according to step 1) and 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (0.282 g, 1.52 mmol, 0.67 eq.). Then 1,4-dioxane (22.5 mL) followed by water (2.2 mL) was added. The mixture was sparged with nitrogen for 15 min. and then tetrakis(triphenylphosphine)palladium (0.27 g, 0.23 mmol, 0.10 eq.) was added followed by potassium carbonate (0.955 g, 6.91 mmol, 3.07 eq.). Reactor was sealed, and reaction mixture was stirred at 90°C for 4 h. After this time reaction was cooled to RT, water was added and aqueous phase was extracted with DCM (x2). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. From this crude material product was isolated by FCC (0 to 100% EtOAc gradient in hexane) to give N-{[3-amino-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]me- thyl}-N-(4-fluoro-2-methanesulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 011, 0.65 g, 1.02 mmol, 45%, brown solid, m / z [M+H]+: 573.0).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 1:0.55). Major rotamer: δ 8.74 – 8.70 (m, 1H), 8.10 (s, 1H), 7.99 – 7.94 (m, 1H),7.86 – 7.81 (m, 2H), 7.68 – 7.53 (m, 2H), 7.04 – 7.00 (m, 1H), 6.90 – 6.86 (m, 1H), 6.69 – 6.63 (m, 1H), 5.40 (d, J = 14.8 Hz, 1H), 5.38 – 5.30 (m, 2H), 4.63 (d, J = 15.2 Hz, 1H), 3.67 (s, 3H), 3.21 (d, J = 5.6 Hz, 3H). N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 4): Acetyl chloride (0.321 g, 4.09 mmol, 4.0 eq.) was added to a solution of N-{[3-amino- 4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-N-(4-fluoro-2-methanesul- fonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 011, 0.65 g, 1.02 mmol, 1.0 eq.) in anhydrous ethanol (10 mL). The mixture was heated at 100°C for 1.5 h. After cooling RM to RT it was quenched by addition saturated aqueous solution of NaHCO3(until pH 8), and aqueous phase was extracted with DCM (4x). Combined organic layers were dried over MgSO4, filtered and concentrated. From this material product was isolated by FCC (0 to 5% MeOH gradient in DCM then isocratic) to give N-({4-amino-1-methyl-1H-pyrazolo[4,3- c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesulfonylphenyl)-6-(trifluoromethyl)pyridine- 3-carboxamide (Example 4, 0.307 g, 0.53 mmol, 52%, white solid, UPLC long elution (Mid polar long method; buffer type “FA”) purity: 99.53%, m / z [M+H]+: 573.19).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel- ative ratio 7:3). Major rotamer: δ 8.68 (d, J = 2.1 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.96 (dd, J = 8.1, 2.1 Hz, 1H), 7.85 – 7.82 (m, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.50 (td, J = 8.2, 2.9 Hz, 1H), 7.40 (dd, J = 8.9, 5.0 Hz, 1H), 7.33 (dd, J = 8.3, 1.9 Hz, 1H), 6.96 (s, 2H), 5.70 (d, J = 14.7 Hz, 1H), 4.72 (d, J = 14.7 Hz, 1H), 4.38 (s, 3H), 3.24 (s, Ryvu Therapeutics S.A. RVU305 88 R10391WO3H). 19F NMR (376 MHz, DMSO-d6) δ -66.69 (s, 3F), -108.87 – -108.96 (m, 1F). Minor rota-mer: δ 9.08 (d, J = 2.0 Hz, 1H), 8.41 (dd, J = 8.5, 1.8 Hz, 1H), 8.22 (s, 1H), 8.16 (d, J = 8.1Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.94 (dd, J = 8.0, 3.0 Hz, 1H), 7.57 (td, J = 8.3, 3.0 Hz, 1H), 7.31 (s, 1H), 7.26 (dd, J = 8.9, 4.9 Hz, 1H), 7.12 (dd, J = 8.4, 1.5 Hz, 1H), 6.99 (s, 2H), 5.16 (d, J = 15.8 Hz, 1H), 4.73 (d, J = 16.1 Hz, 1H), 4.35 (s, 3H), 3.32 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.61 (s, 3F), -110.22 – -110.31 (m, 1F). Example 5: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl- N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide 6-Cyclopropyl-N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. 012): clopropylpyridine-3-carboxylic acid (1.25 g, 7.66 mmol, 1.08 eq.) and DMAP (0.165 g, 1.35 mmol, 0.19 eq.) in anhydrous pyridine (35 mL) was added phosphorus oxychloride (2.15 g, 14.0 mmol, 1.98 eq.) dropwise, at RT. Reaction was stirred at RT for 30 min under nitrogen. The reaction was quenched with ice / water and the mixture was neutralized with sat. aq. NaHCO3. It was extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 6-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. 012, 1.34 g, 4.008 mmol, 57%, beige solid, m / z [M+H]+: 335.4). Ryvu Therapeutics S.A. RVU305 89 R10391WO1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.93 (dd, J = 2.4, 0.8 Hz, 1H), 8.12 (dd, J = 8.2, 2.4 Hz, 1H), 8.09 (dd, J = 9.0, 5.0 Hz, 1H), 7.79 (dd, J = 8.3, 3.0 Hz, 1H), 7.70 (ddd, J = 9.0, 8.0, 3.1 Hz, 1H), 7.51 (dd, J = 8.2, 0.8 Hz, 1H), 3.35 (s, 3H), 2.26 – 2.18 (m, 1H), 1.09 – 0.98 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -113.91 (dd, J = 7.3, 6.7 Hz, 1F). N-[(4-bromo-3-nitrophenyl)methyl]-6-cyclopropyl-N-(4-fluoro-2-methanesulfonylphenyl) pyridine-3-carboxamide (Int. 013): To 6-cyclopropyl-N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. 012, 0.5 g, 1.57 mmol, 1.0 eq.) in anhydrous acetonitrile (3.0 mL) was added Cs2CO3(0.61 g, 1.87 mmol, 1.2 eq.) followed by 1-bromo-4-(bromomethyl)-2-nitrobenzene (0.6 g, 2.03 mmol, 1.3 eq.). Reaction was heated at 70°C for 1h. Reaction mixture was diluted with wa- ter and extracted with EtOAc. Organic layers were combined, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Crude product was purified by FCC (0 to 50% EtOAc gradient in hexane) to give N-[(4-bromo-3-nitrophenyl)methyl]-6-cyclopropyl-N- (4-fluoro-2-methanesulfonylphenyl) pyridine-3-carboxamide (Int. 013, 0.68 g, 1.25 mmol, 84%, brown solid, m / z [M+H]+: 549.10).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 4:1). Major rotamer: δ 8.31 (d, J = 2.3 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.93 –7.83 (m, 2H), 7.62 (dd, J = 8.2, 2.1 Hz, 1H), 7.56 (td, J = 8.2, 2.9 Hz, 1H), 7.52 – 7.42 (m, 2H), 7.15 (d, J = 8.2 Hz, 1H), 5.52 (d, J = 15.4 Hz, 1H), 4.56 (d, J = 15.3 Hz, 1H), 3.23 (s, 3H), 2.03(dd, J = 8.3, 4.6 Hz, 1H), 1.06 – 0.86 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ -109.27 (td, J= 7.9, 4.8 Hz, 1F). Minor rotamer: δ 8.64 (s, 1H), 7.93 – 7.83 (m, 3H), 7.80 (d, J = 8.3 Hz,1H), 7.62 (dd, J = 8.2, 2.1 Hz, 1H), 7.52 – 7.42 (m, 2H), 7.37 (d, J = 5.3 Hz, 1H), 5.11 (d, J = 16.3 Hz, 1H), 4.72 (d, J = 16.4 Hz, 1H), 3.30 (s, 3H), 2.17 (s, 1H), 1.06 – 0.86 (m, 4H).19F NMR (376 MHz, DMSO-d6)δ -110.27 - -110.38 (m, 1F). N-[(3-amino-4-bromophenyl)methyl]-6-cyclopropyl-N-(4-fluoro-2-methanesulfonylphenyl) pyridine-3-carboxamide (Int. 014): To a solution of N-[(4-bromo-3-nitrophenyl)methyl]-6-cyclopropyl-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide (Int. 013, 0.633 g, 1.15 mmol, 1.0 eq.) in ace- tone (3.0 mL) was added zinc (0.75 g, 11.5 mmol, 10.0 eq.) followed by sat. NH4Cl aq. (5.0 mL). Reaction mixture was stirred at RT overnight. After this time reaction mixture was fil- tered through a Celite® pad which was washed with DCM. Filtrates were combined and or- ganic phase was washed with water (x2), then organic phase was separated, dried over Na2SO4, filtered and concentrated to yield N-[(3-amino-4-bromophenyl)methyl]-6-cyclopro- pyl-N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamid (Int. 014, 0.525 g, 0.942 mmol, 82%, yellow solid, m / z [M+H]+: 517.9) which was used in the next step without fur- ther purification.1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 7:3). Major rotamer: δ 8.29 (d, J = 2.2 Hz, 1H), 7.98 – 7.79 (m, 2H), 7.68 – 7.43(m, 2H), 7.35 – 7.10 (m, 2H), 6.81 (d, J = 2.0 Hz, 1H), 6.41 (dd, J = 8.3, 2.1 Hz, 1H), 5.48 (d, J = 15.0 Hz, 1H), 5.36 (d, J = 12.5 Hz, 2H), 4.25 (d, J = 15.0 Hz, 1H), 3.23 (s, 3H), 2.03 (dd, J =8.5, 4.6 Hz, 1H), 1.07 – 0.80 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ -109.59 (q, J = 7.6 Hz,1F). Minor rotamer: δ 8.71 (s, 1H), 7.68 – 7.43 (m, 2H), 7.35 – 7.10 (m, 4H), 6.71 – 6.66 (m,1H), 6.27 (d, J = 8.1 Hz, 1H), 5.36 (d, J = 12.5 Hz, 2H), 4.94 (d, J = 16.3 Hz, 1H), 4.35 (d, J = Ryvu Therapeutics S.A. RVU305 90 R10391WO 16.2 Hz, 1H), 3.29 (s, 3H), 2.21 – 2.16 (m, 1H), 1.07 – 0.80 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -110.44 (q, J = 7.6 Hz, 1F). N-{[3-amino-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-6-cyclopropyl-N-(4- fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. 015): Step 1. To a degassed solution of N-[(3-amino-4-bromophenyl)methyl]-6-cyclopropyl- N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide (Int.014, 0.475 g, 0.85 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxabo- rolane (0.43 g, 1.69 mmol, 2.0 eq.) and potassium acetate (0.25 g, 2.55 mmol, 3.0 eq.) in 1,4-dioxane (4.0 mL) Pd(dppf)Cl2 (0.07 g, 0.096 mmol, 0.11 eq.) was added. Reaction mixturewas then heated at 100°C for 1 h in a pressure vessel. The reaction mixture was thencooled to RT, diluted with DCM and filtered through a pad of Celite®. The residue was di- luted with water and extracted with DCM and next with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give crude product which was used for next step without purification (0.412 g, dark brown solid). Step 2. A mixture of crude from step 1 (0.400 g, prepared according to step 1), 5- bromo-1-methyl-1H-pyrazole-4-carbonitrile (0.073 g, 0.392 mmol, 1.0 eq.) and K2CO3(0.165 g, 1.194 mmol, 3.0 eq.) in mixture of 1,4-dioxane (5.0 mL) and water (0.5 mL) was placed in a seal-tube. The mixture was sparged with nitrogen for 15 min. and then Pd(PPh3)4(0.045 g, 0.039 mmol, 0.1 eq.) was added. Reactor was sealed, and reaction mixture was stirred at 90°C for 2 h. After this time the reaction mixture was then cooled to RT, diluted with DCM and filtered through a pad of Celite®. The filtrate was diluted with water and aqueous phase was extracted with DCM (x2). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to give N-{[3-amino-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phe- nyl]methyl}-6-cyclopropyl-N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. 015, 0.051 g, 0.071 mmol, 18%, brown solid, m / z [M+H]+: 545.3). N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyridine-3-carboxamide (Example 5): Acetyl chloride (0.025 g, 0.318 mmol, 4.5 eq.) was added to a solution of N-{[3-amino- 4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-6-cyclopropyl-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide (Int. 015, 0.051 g, 0.071 mmol, 1.0 eq.) in anhy- drous ethanol (1.0 mL). The mixture was heated at 100°C for 1 h. After cooling reaction mixture to RT it was quenched by addition saturated aqueous solution of NaHCO3(until pH 8), and aqueous phase was extracted with DCM (4x). Combined organic layers were dried over MgSO4, filtered and concentrated. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to give N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}me- thyl)-6-cyclopropyl-N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide (Exam- ple 5, 0.018 g, 0.033 mmol, 46%, beige solid, UPLC long elution (Mid polar long method; buffer type “FA”) purity: 99.64%, m / z [M+H]+: 545.10).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 66:34). Major rotamer: δ 8.29 (d, J = 2.3 Hz, 1H), 8.22 (s, 1H), 8.23 – 8.21 (m,1H), 7.84 (dd, J = 8.3, 3.0 Hz, 1H), 7.49 (m, 2H), 7.45 (td, J = 8.3, 3.1 Hz, 1H), 7.30 (dd, J = 8.2, 1.4 Hz, 1H), 7.23 (dd, J = 8.9, 5.0 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.95 (s, 2H), 5.71 (d, J Ryvu Therapeutics S.A. RVU305 91 R10391WO = 14.9 Hz, 1H), 4.59 (d, J = 14.9 Hz, 1H), 4.37 (s, 3H), 3.20 (s, 3H), 2.02 (tt, J = 8.2, 4.7 Hz,1H), 0.94 – 0.90 (m, 2H), 0.86 – 0.80 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -109.66 (td, J= 8.2, 5.5 Hz, 1F). Minor rotamer: δ 8.77 – 8.69 (m, 1H), 8.25 (s, 1H), 8.17 (d, J = 8.3 Hz,1H), 7.98 (dd, J = 7.8, 1.8 Hz, 1H), 7.89 (dd, J = 8.2, 2.7 Hz, 1H), 7.55 – 7.42 (m, 2H), 7.32 – 7.29 (m, 1H), 7.15 – 7.11 (m, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.99 (s, 2H), 5.23 (d, J = 15.9 Hz, 1H), 4.68 (d, J = 16.0 Hz, 1H), 4.35 (s, 3H), 3.29 (s, 3H), 2.25 – 2.11 (m, 1H), 1.07 – 0.89 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -110.66 (td, J = 7.7, 4.6 Hz, 1F). Example 6: N-({4-amino-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide 5-bromo-1-(oxan-2-yl)-1H-pyrazole-4-carbonitrile (Int. 016): To a solution of 5-bromo-1H-pyrazole-4-carbonitrile (0.25 g, 1.454 mmol, 1.0 eq.) in DCM (3.0 mL) was added 3,4-dihydro-2H-pyran (0.147 g, 1.744 mmol, 1.2 eq.) and p-tol- uenesulfonic acid hydrate (0.055 g, 0.291 mmol, 0.2 eq.) at 0°C. The reaction mixture was then stirred at RT overnight. The reaction was quenched with water and extracted with EtOAc. Combined organic layers was washed with brine, dried over MgSO4and concen- trated in vacuo. Crude was purified by FCC (0 to 20% EtOAc gradient in Hexane) to give 5- bromo-1-(oxan-2-yl)-1H-pyrazole-4-carbonitrile (Int. 016, 0.367 g, 1.29 mmol, 89%, color- less oil).1H NMR (400 MHz, Chloroform-d) δ 7.99 (s, 1H), 5.42 – 5.36 (m, 1H), 4.10 – 4.04 (m, 1H), – 3.69 (m, 1H), 2.21 – 2.13 (m, 1H), 2.06 – 1.94 (m, 2H), 1.77 – 1.65 (m, 3H).

[0003] Ryvu Therapeutics S.A. RVU305 92 R10391WO N-(2-methanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 017): T3P as 50 wt% solution in AcOEt (78.0 mL, 131.04 mmol, 2.65 eq.) was added drop- wise to a solution of 6-(trifluoromethyl)pyridine-3-carboxylic acid (13.11 g, 68.62 mmol, 1.39 eq.), 2-methanesulfonylpyridin-3-amine (8.52 g, 49.46 mmol, 1.0 eq.), DIPEA (29.0 mL, 166.48 mmol, 3.3 eq.) and DMAP (0.4 g, 3.27 mmol, 0.07 eq.) in toluene (80 mL) under nitro- gen. The reaction mixture was heated at reflux under nitrogen for 3 h. Then the reaction was quenched with sat. aq. NaHCO3to pH 8. It was extracted with EtOAc (2x) and the com- bined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under re- duced pressure. The residue was dissolved in MeOH (200 mL) at reflux. Then, water (100 mL) was added dropwise and the mixture was cooled to RT. The crystallized product was filtrated off, washed with n-heptane and air-dried to give N-(2-methanesulfonylpyridin-3- yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int 017, 15.47 g, 44.365 mmol, 90%, off- white fine crystals, m / z [M+H]+: 346.5)1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.24 (d, J = 2.1 Hz, 1H), 8.64 (dd, J = 4.5, 1.5 1H), 8.56 (ddd, J = 14.3, 8.2, 1.8 Hz, 2H), 8.19 (dd, J = 8.2, 0.8 Hz, 1H), 7.86 (dd, J = 8.3, 4.5 Hz, 1H), 3.42 (s, 3H).19F NMR (376 MHz, DMSO-d6): -66.68 (s, 3F). N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide (Int. 018): To N-(2-methanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 017, 4.0 g, 11.46 mmol, 1.0 eq.) in anhydrous acetonitrile (60.0 mL) was added Cs2CO3(4.48 g, 13.76 mmol, 1.2 eq.) followed by 1-bromo-4-(bromomethyl)-2-nitrobenzene (5.07 g, 17.20 Ryvu Therapeutics S.A. RVU305 93 R10391WO mmol, 1.5 eq.). Reaction was heated at 70°C for 1h. Reaction mixture was diluted with wa- ter and extracted with EtOAc. Organic layers were combined, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Crude product was purified by FCC (0 to 40% EtOAc gradient in hexane) to give N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 018, 6.09 g, 10.34 mmol, 90%, yellow solid, m / z [M+H]+: 560.1).1H NMR (400 MHz, DMSO-d6) δ 8.76 – 8.71 (m, 1H), 8.66 – 8.61 (m, 1H), 8.05 – 7.98 (m, 3H), 7.90 – 7.87 (m, 1H), 7.85 – 7.82 (m, 1H), 7.74 – 7.68 (m, 1H), 7.64 – 7.59 (m, 1H), 5.60 (d, J = 15.3 Hz, 1H), 4.74 (d, J = 15.3 Hz, 1H), 3.35 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.76 (s, 3F). N-[(3-amino-4-bromophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-6-(trifluorome- thyl)pyridine-3-carboxamide (Int. 019): To a solution of N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3- yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 018, 6.09 g, 10.35 mmol, 1.0 eq.) in ace- tone (50 mL) was added zinc (6.76 g, 103.47 mmol, 10.0 eq.) followed by sat. NH4Cl aq. (25 mL). Reaction mixture was stirred at RT for 1 h. After this time reaction mixture was filtered through a Celite® pad which was washed with DCM. Filtrates were combined and organic phase was washed with water (2x), then organic phase was separated, dried over Na2SO4, filtered and concentrated. Crude product was purified by FCC (0 to 50% EtOAc gradient in hexane) to give N-[(3-amino-4-bromophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide (Int. 019, 5.105 g, 9.162 mmol, 89%, yellow solid, m / z [M+H]+: 530.60).1H NMR (400 MHz, DMSO-d6) δ 8.74 – 8.72 (m, 1H), 8.62 – 8.59 (m, 1H), 8.02 – 7.98 (m, 1H), 7.84 – 7.80 (m, 1H), 7.74 – 7.70 (m, 1H), 7.66 – 7.61 (m, 1H), 7.29 – 7.25 (m, 1H), 6.78 – 6.75 (m, 1H), 6.43 – 6.39 (m, 1H), 5.60 (d, J = 14.9 Hz, 1H), 5.35 (s, 2H), 4.39 (d, J = 14.9 Hz, 1H), 3.39 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.75 (s, 3F). N-({3-amino-4-[4-cyano-1-(oxan-2-yl)-1H-pyrazol-5-yl]phenyl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 020): Step 1. To a degassed solution of N-[(3-amino-4-bromophenyl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide(Int. 019, 1.52 g, 2.728 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.4 g, 5.513 mmol, 2.0 eq.), potassium acetate (0.8 g, 8.151 mmol, 3.0 eq.) in1,4-dioxane (27 mL) Pd(dppf)Cl2 (0.20 g, 0.269 mmol, 0.1 eq.) was added. Reaction mixturewas then heated at 100°C for 3 h in a pressure vessel. The reaction mixture was thencooled to RT, diluted with DCM and filtered through a pad of Celite®. The residue was di- luted with water and extracted with DCM and next with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give crude product which was used for next step without purification (3.26 g, black solid). Step 2. A mixture of crude from step 1 (0.838 g, prepared according to step 1), 5- bromo-1-(oxan-2-yl)-1H-pyrazole-4-carbonitrile (Int. 016, 0.360 g, 1.268 mmol, 1.25 eq.) and K2CO3(0.425 g, 3.075 mmol, 3.1 eq.) in mixture of 1,4-dioxane (10 mL) and water (1.0 mL) was placed in a seal-tube. The mixture was sparged with nitrogen for 15 min. and then Ryvu Therapeutics S.A. RVU305 94 R10391WOPd(PPh3)4 (0.115 g, 0.10 mmol, 0.10 eq.) was added. Reactor was sealed, and reaction mix-ture was stirred at 90°C for 2 h. After this time the reaction mixture was then cooled to RT,diluted with DCM and filtered through a pad of Celite®. The filtrate was diluted with water and aqueous phase was extracted with DCM (x2). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to give N-({3-amino-4-[4-cyano-1-(oxan-2-yl)- 1H-pyrazol-5-yl]phenyl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyri- dine-3-carboxamide (Int. 020, 0.302 g, 0.444 mmol, 44%, brown solid, m / z [M+H]+: 626.0).1H NMR (400 MHz, DMSO-d6) δ 8.90 – 8.86 (m, 1H), 8.79 – 8.76 (m, 1H), 8.63 – 8.58 (m, 1H), 8.06 – 8.01 (m, 1H), 7.85 – 7.81 (m, 2H), 7.67 – 7.62 (m, 2H), 6.83 – 6.78 (m, 1H), 6.66 – 6.60 (m, 1H), 6.25 – 6.16 (m, 2H), 5.66 (d, J = 15.1 Hz, 1H), 5.58 – 5.52 (m, 1H), 4.48 (d, J = 15.1 Hz, 1H), 3.99 – 3.93 (m, 1H), 3.72 – 3.64 (m, 1H), 3.40 (s, 3H), 2.12 – 2.01 (m, 2H), 1.97 – 1.90 (m, 1H), 1.75 – 1.63 (m, 1H), 1.59 – 1.53 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ - 66.74 (s, 3F). N-({4-amino-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide (Example 6): Acetyl chloride (0.139 g, 1.777 mmol, 4.0 eq.) was added to a solution N-({3-amino-4- [4-cyano-1-(oxan-2-yl)-1H-pyrazol-5-yl]phenyl}methyl)-N-(2-methanesulfonylpyridin-3-yl)- 6-(trifluoromethyl)pyridine-3-carboxamide (Int.020, 0.302 g, 0.444 mmol, 1.0 eq.) in anhy- drous ethanol (4.0 mL). The mixture was heated at 100°C overnight. After cooling reaction mixture to RT it was quenched by addition saturated aqueous solution of NaHCO3(until pH 8), and aqueous phase was extracted with DCM (4x). Combined organic layers were dried over MgSO4, filtered and concentrated. From this material product was isolated by FCC (NH2functionalized silica, 0 to 5% MeOH gradient in DCM then isocratic) and by preparative HPLC to yield N-({4-amino-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide as its formate salt (Example 6, 0.141 g, 0.24 mmol, 54%, white solid, UPLC long elution (Polar long method; buffer type “FA”) purity: 100%, m / z [M+H]+: 542.19).1H NMR (400 MHz, DMSO-d6): a mixture of restricted C-N amide rotation isomers at RT(relative ratio 2:8); Major rotamer: δ 8.79 – 8.71 (m, 1H), 8.58 – 8.50 (m, 1H), 8.34 – 8.24 (m,2H), 8.18 (s, 1H), 8.08 – 7.99 (m, 2H), 7.85 – 7.78 (m, 1H), 7.72 – 7.65 (m, 1H), 7.56 – 7.49 (m, 1H), 7.41 – 7.35 (m, 1H), 7.27 – 7.20 (m, 1H), 7.06 – 6.92 (m, 2H), 5.82 (d, J = 14.6 Hz, 1H),4.70 (d, J = 14.6 Hz, 1H), 3.40 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.74 (s, 3F). Minorrotamer: δ 9.10 – 9.04 (m, 1H), 8.69 – 8.64 (m, 1H), 8.43 – 8.37 (m, 1H), 8.34 – 8.24 (m, 1H),8.18 (s, 1H), 8.15 – 8.12 (m, 1H), 8.08 – 7.99 (m, 2H), 7.72 – 7.65 (m, 2H), 7.27 – 7.20 (m, 1H), 7.15 – 7.11 (m, 1H), 7.06 – 6.92 (m, 2H), 5.14 (d, J = 15.6 Hz, 1H), 4.83 (d, J = 15.4 Hz, 1H), 3.40 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.60 (s, 3F). Example 7: N-({4-amino-1-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl}methyl)-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 95 R10391WO 4-bromo-3-methyl-1-(oxan-2-yl)-1H-pyrazole-5-carbonitrile (Int. 021): To a solution of 4-bromo-5-methyl-1H-pyrazole-3-carbonitrile (0.25 g, 1.344 mmol, 1.0 eq.) in DCM (3.0 mL) was added 3,4-dihydro-2H-pyran (0.136 g, 1.613 mmol, 1.2 eq.) and p- toluenesulfonic acid hydrate (0.051 g, 0.269 mmol, 0.2 eq.) at 0°C. The reaction mixture was then stirred at RT overnight. The reaction was quenched with water and extracted with EtOAc. Combined organic layers was washed with brine, dried over MgSO4and concen- trated in vacuo. Crude was purified by FCC (0 to 20% EtOAc gradient in Hexane) to give 4- bromo-3-methyl-1-(oxan-2-yl)-1H-pyrazole-5-carbonitrile (Int. 021, 0.347 g, 1.156 mmol, 86%, colorless oil).1H NMR (400 MHz, Chloroform-d) δ 5.43 – 5.36 (m, 1H), 3.99 – 3.93 (m, 1H), 3.72 – 3.65 (m, 1H), 2.39 (s, 3H), 2.38 – 2.36 (m, 1H), 2.22 – 2.13 (m, 1H), 2.03 – 1.96 (m, 1H), 1.75 – 1.64 (m, . N-({3-amino-4-[5-cyano-3-methyl-1-(oxan-2-yl)-1H-pyrazol-4-yl]phenyl}methyl)-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 022): Step 1. To a degassed solution of N-[(3-amino-4-bromophenyl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide(Int. 019, 1.52 g, 2.728 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.4 g, 5.513 mmol, 2.021 eq.), potassium acetate (0.8 g, 8.151 mmol, 3.0 eq.)in 1,4-dioxane (27 mL) Pd(dppf)Cl2 (0.196 g, 0.269 mmol, 0.1 eq.) was added. Reaction mix-ture was then heated at 100°C for 3 h in a pressure vessel. The reaction mixture was thencooled to RT, diluted with DCM and filtered through a pad of Celite®. The residue was di- luted with water and extracted with DCM and next with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give crude product which was used for next step without purification (3.26 g, black solid). Step 2. A mixture of crude from step 1 (0.767 g, prepared according to step 1), 4- bromo-3-methyl-1-(oxan-2-yl)-1H-pyrazole-5-carbonitrile (Int. 021, 0.336 g, 1.119 mmol, 1.2 eq.)and K2CO3(0.371 g, 2.686 mmol, 3.0 eq.) in mixture of 1,4-dioxane (10 mL) and water (1.0 mL) was placed in a seal-tube. The mixture was sparged with nitrogen for 15 min. and Ryvu Therapeutics S.A. RVU305 96 R10391WOthen Pd(PPh3)4 (0.100 g, 0.087 mmol, 0.095 eq.) was added. Reactor was sealed, and reac-tion mixture was stirred at 90°C for 2 h. After this time the reaction mixture was cooled toRT, diluted with DCM and filtered through a pad of Celite®. The filtrate was diluted with wa- ter and aqueous phase was extracted with DCM (x2). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to give N-({3-amino-4-[5-cyano-3- methyl-1-(oxan-2-yl)-1H-pyrazol-4-yl]phenyl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide (Int. 022, 0.342 g, 0.374 mmol, 41%, brown solid, m / z [M+H]+: 640.40). N-({4-amino-1-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 7): Acetyl chloride (0.117 g, 1.496 mmol, 4.0 eq.) was added to a solution N-({3-amino-4- [5-cyano-3-methyl-1-(oxan-2-yl)-1H-pyrazol-4-yl]phenyl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 022, 0.342 g, 0.374 mmol, 1.0 eq.) in anhydrous ethanol (4.0 mL). The mixture was heated at 100°C for 2 h. After cooling reaction mixture to RT it was quenched by addition saturated aqueous solution of NaHCO3(until pH 8), and aqueous phase was extracted with DCM (4x). Combined organic layers were dried over MgSO4, filtered and concentrated. The crude material was purified by FCC (NH2functionalized silica, 0 to 7% MeOH gradient in DCM then isocratic) and by pre- parative HPLC to yield N-({4-amino-1-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl}methyl)-N- (2-methanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide as its formate salt (Example 7, 0.107 g, 0.178 mmol, 48%, white solid, UPLC long elution (Polar long method; buffer type “FA”) purity: 100%, m / z [M+H]+: 556.20).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ratio 2:8); Major rotamer: δ 8.77 – 8.71 (m, 1H), 8.58 – 8.52 (m, 1H), 8.18 (s, 1H), 8.04– 7.88 (m, 2H), 7.84 – 7.79 (m, 1H), 7.69 – 7.62 (m, 1H), 7.55 – 7.49 (m, 1H), 7.47 – 7.37 (m, 1H), 7.32 – 7.21 (m, 1H), 6.80 (s, 2H), 5.82 (d, J = 14.5 Hz, 1H), 4.70 (d, J = 14.5 Hz, 1H), 3.40(s, 3H), 2.77 – 2.70 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.73 (s, 3F). Minor rotamer:δ 9.10 – 9.05 (m, 1H), 8.69 – 8.65 (m, 1H), 8.43 – 8.38 (m, 1H), 8.20 – 8.13 (m, 1H), 8.04 –7.88 (m, 1H), 7.69 – 7.62 (m, 2H), 7.32 – 7.21 (m, 1H), 7.16 – 7.07 (m, 1H), 6.80 (s, 2H), 5.15 (d, J = 15.4 Hz, 1H), 4.83 (d, J = 15.5 Hz, 1H), 4.70 (d, J = 14.5 Hz, 1H), 3.40 (s, 3H), 2.77 – 2.70 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.60 (s, 3F). Example 8: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 97 R10391WO N-{[3-amino-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 023): Step 1. To a degassed solution of N-[(3-amino-4-bromophenyl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide(Int. 019, 1.52 g, 2.728 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.4 g, 5.513 mmol, 2.0 eq.), potassium acetate (0.8 g, 8.151 mmol, 3.0 eq.) in1,4-dioxane (27 mL) Pd(dppf)Cl2 (0.196 g, 0.269 mmol, 0.1 eq.) was added. Reaction mixturewas then heated at 100°C for 3 h in a pressure vessel. The reaction mixture was thencooled to RT, diluted with DCM and filtered through a pad of Celite®. The residue was di- luted with water and extracted with DCM and next with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give crude product which was used for next step without purification (3.26 g, black solid). Step 2. A mixture of crude from step 1 (1.82g, prepared according to step 1), 5-bromo- 1-methyl-1H-pyrazole-4-carbonitrile (0.4 g, 2.15 mmol, 1.0 eq.) and K2CO3(1.188 g, 8.602 mmol, 4.0 eq.) in mixture of 1,4-dioxane (10 mL) and water (1.0 mL) was placed in a seal- tube. The mixture was sparged with nitrogen for 15 min. and then Pd(dppf)Cl2.DCM (0.351 g, 0.43 mmol, 0.2 eq.) was added. Reactor was sealed, and reaction mixture was stirred at 100°C for 1 h. After this time the reaction mixture was then cooled to RT, diluted with DCM and filtered through a pad of Celite®. The filtrate was diluted with water and aqueous phase was extracted with DCM (x2). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to give N-{[3-amino-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phe- nyl]methyl}-N-(2-methanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 023, 0.296 g, 0.426 mmol, 20%, brown solid, m / z [M+H]+: 556.40).1H NMR (400 MHz, DMSO-d6) δ 8.80 – 8.75 (m, 1H), 8.64 – 8.60 (m, 1H), 8.13 – 8.07 (m, 1H), 8.06 – 8.01 (m, 1H), 7.94 – 7.88 (m, 1H), 7.86 – 7.81 (m, 1H), 7.70 – 7.65 (m, 1H), 7.03 – 6.99 (m, 1H), 6.85 – 6.80 (m, 1H), 6.66 – 6.59 (m, 1H), 5.59 (d, J = 15.1 Hz, 1H), 5.33 (d, J = 5.7 Hz, 2H), 4.57 (d, J = 15.0 Hz, 1H), 3.66 (d, J = 2.0 Hz, 3H), 3.37 – 3.35 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.75 (s, 3F). N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 8): Acetyl chloride (0.134 g, 1.706 mmol, 4.0 eq.) was added to a solution N-{[3-amino-4- (4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide (Int. 023, 0.296 g, 0.427 mmol, 1.0 eq.) in anhy- drous ethanol (4.0 mL). The mixture was heated at 100°C for 1 h. After cooling reaction mixture to RT it was quenched by addition saturated aqueous solution of NaHCO3(until pH 8), and aqueous phase was extracted with DCM (3x). Combined organic layers were dried over MgSO4, filtered and concentrated. The crude material was purified by FCC (NH2func- tionalized silica, 0 to 5% MeOH gradient in DCM then isocratic) and by preparative HPLC to yield N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide as its formate salt (Example 8, 0.111 g, 0.185 mmol, 43%, white solid, UPLC long elution (Polar long method; buffer type “FA”) purity: 100%, m / z [M+H]+: 556.20). Ryvu Therapeutics S.A. RVU305 98 R10391WO1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 2:8); Major rotamer: δ 8.78 – 8.71 (m, 1H), 8.59 – 8.53 (m, 1H), 8.25 – 8.20 (m,2H), 8.18 (s, 1H), 8.05 – 7.99 (m, 1H), 7.85 – 7.79 (m, 1H), 7.74 – 7.67 (m, 1H), 7.58 – 7.52 (m, 1H), 7.47 – 7.41 (m, 1H), 7.30 – 7.25 (m, 1H), 7.07 – 6.94 (m, 2H), 5.82 (d, J = 14.6 Hz, 1H), 4.73 (d, J = 14.6 Hz, 1H), 4.40 – 4.32 (m, 3H), 3.40 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.74 (s, 3F). Minor rotamer: δ 9.10 – 9.04 (m, 1H), 8.70 – 8.66 (m, 1H), 8.43 – 8.37 (m, 1H), 8.25 – 8.20 (m, 1H), 8.18 – 8.13 (m, 3H), 7.74 – 7.67 (m, 2H), 7.34 – 7.31 (m, 1H), 7.17 – 7.11 (m, 1H), 7.07 – 6.94 (m, 2H), 5.18 (d, J = 15.7 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 4.40 – 4.32 (m, 3H), 3.40 (s, 3H),19F NMR (376 MHz, DMSO-d6) δ -66.60 (s, 3F). Example 9: N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyr- idin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide N-{[3-amino-4-(4-cyano-2,5-dihydrofuran-3-yl)phenyl]methyl}-N-(2-methanesulfonylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 024): Step 1. To a degassed solution of N-[(3-amino-4-bromophenyl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide(Int. 019, 1.52 g, 2.728 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.4 g, 5.513 mmol, 2.0 eq.), potassium acetate (0.8 g, 8.151 mmol, 3.0 eq.) in1,4-dioxane (27 mL) Pd(dppf)Cl2 (0.196 g, 0.269 mmol, 0.1 eq.) was added. Reaction mixturewas then heated at 100°C for 3 h in a pressure vessel. The reaction mixture was thencooled to RT, diluted with DCM and filtered through a pad of Celite®. The residue was di- luted with water and extracted with DCM and next with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give crude product which was used for next step without purification (3.26 g, black solid). Step 2. A mixture of crude from step 1 (1.07g, prepared according to step 1), 4-cyano- 2,5-dihydrofuran-3-yltrifluoromethanesulfonate (Int. 006, 0.35062 g, 1.30 mmol, 1.0 eq.) and K2CO3(0.545 g, 3.943 mmol, 3.0 eq.) in mixture of 1,4-dioxane (13 mL) and water (1.2 mL) was placed in a seal-tube. The mixture was sparged with nitrogen for 15 min. and thenPd(PPh3)4 (0.167 g, 0.145 mmol, 0.1 eq.) was added. Reactor was sealed, and left stirredand heated at 120°C for 30 min under microwave irradiation. After this time the reactionmixture was then cooled to RT, diluted with DCM and filtered through a pad of Celite®. The filtrate was diluted with water and aqueous phase was extracted with DCM (x2). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (0 to 7% MeOH gradient in DCM) to give N-{[3-amino- Ryvu Therapeutics S.A. RVU305 99 R10391WO 4-(4-cyano-2,5-dihydrofuran-3-yl)phenyl]methyl}-N-(2-methanesulfonylpyridin-3-yl)-6-(tri- fluoromethyl)pyridine-3-carboxamide (Int. 024, 0.412 g, 0.72 mmol, 55%, black solid, m / z [M+H]+: 544.40).1H NMR (400 MHz, DMSO-d6) δ 8.76 – 8.72 (m, 1H), 8.57 – 8.54 (m, 1H), 8.04 – 8.00 (m, 1H), 7.83 – 7.79 (m, 1H), 7.67 – 7.64 (m, 1H), 7.55 – 7.51 (m, 1H), 7.49 – 7.46 (m, 1H), 7.41 – 7.39 (m, 1H), 7.24 – 7.20 (m, 1H), 6.52 (s, 2H), 5.82 (d, J = 14.6 Hz, 1H), 5.32 – 5.28 (m, 2H), 5.01 – 4.98 (m, 2H), 4.71 (d, J = 14.6 Hz, 1H), 3.37 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.74 (s, 3F). N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide (Example 9): Acetyl chloride (0.226 g, 2.882 mmol, 4.0 eq.) was added to a solution N-{[3-amino-4- (4-cyano-2,5-dihydrofuran-3-yl)phenyl]methyl}-N-(2-methanesulfonylpyridin-3-yl)-6-(tri- fluoromethyl)pyridine-3-carboxamide (0.412 g, 0.72 mmol, 1.0 eq.) in anhydrous ethanol (7.0 mL). The mixture was heated at 100°C for 1 h. After cooling reaction mixture to RT it was quenched by addition saturated aqueous solution of NaHCO3(until pH 8), and aqueous phase was extracted with DCM (3x). Combined organic layers were dried over MgSO4, fil- tered and concentrated. The crude material was purified by preparative HPLC to N-({4- amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6-(tri- fluoromethyl)pyridine-3-carboxamide as its formate salt (Example 9, 0.259 g, 0.434 mmol, 60%, off-white solid, UPLC long elution (Polar long method; buffer type “FA”) purity: 98,8%, m / z [M+H]+: 544.20).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 2:8); Major rotamer: δ 8.77 – 8.71 (m, 1H), 8.58 – 8.53 (m, 1H), 8.16 – 8.13 (m,1H), 8.05 – 8.00 (m, 1H), 7.84 – 7.79 (m, 1H), 7.70 – 7.63 (m, 1H), 7.56 – 7.51 (m, 1H), 7.49 – 7.45 (m, 1H), 7.43 – 7.38 (m, 1H), 7.24 – 7.19 (m, 1H), 6.61 – 6.46 (m, 2H), 5.82 (d, J = 14.6 Hz, 1H), 5.35 – 5.26 (m, 2H), 5.03 – 4.95 (m, 2H), 4.71 (d, J = 14.6 Hz, 1H), 3.40 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.74 (s, 3F). Minor rotamer: δ 9.09 – 9.04 (m, 1H), 8.69 – 8.64 (m, 1H), 8.42 – 8.37 (m, 1H), 8.16 – 8.13 (m, 2H), 7.70 – 7.63 (m, 2H), 7.43 – 7.38 (m, 1H), 7.30 – 7.26 (m, 1H), 7.13 – 7.06 (m, 1H), 6.61 – 6.46 (m, 2H), 5.35 – 5.26 (m, 2H), 5.15 (d, J = 15.6 Hz, 1H), 5.03 – 4.95 (m, 2H), 4.85 (d, J = 15.5 Hz, 1H), 3.40 (s, 3H),19F NMR (376 MHz, DMSO-d6) δ -66.61 (s, 3F). Example 10: rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide 2-methyl-4-oxooxolane-3-carbonitrile (Int. 025): 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 mix- ture was heated at 65°C. Once reflux started, a solution of trans-crotononitrile (contains Ryvu Therapeutics S.A. RVU305 100 R10391WO 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 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-me- thyl-4-oxooxolane-3-carbonitrile (Int. 025, 1.269 g, 8.113 mmol, 49%, yellow 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. 026): To a stirred solution of 2-methyl-4-oxooxolane-3-carbonitrile (Int. 025, 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 reac- tion 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 sepa- rated. 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 10% EtOAc gradient in hexane) to yield 4-cyano-5-methyl-2,5-dihydrofuran-3-yltrifluo- romethanesulfonate (Int. 026, 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). N-{[3-amino-4-(4-cyano-5-methyl-2,5-dihydrofuran-3-yl)phenyl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 027): Step 1. To a degassed solution of N-[(3-amino-4-bromophenyl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 019, 1.52 g, 2.728 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.4 g, 5.513 mmol, 2.0 eq.), potassium acetate (0.8 g, 8.151 mmol, 3.0 eq.) in1,4-dioxane (27 mL), Pd(dppf)Cl2 (0.196 g, 0.269 mmol, 0.1 eq.) was added. Reaction mix-ture was then heated at 100°C for 3 h in a pressure vessel. The reaction mixture was thencooled to RT, diluted with DCM and filtered through a pad of Celite®. The residue was di- luted with water and extracted with DCM and next with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give crude product which was used for next step without purification (3.26 g, black solid). Step 2. A mixture of crude from step 1 (1.09g, prepared according to step 1), 4-cyano- 5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (Int. 026, 0.374 g, 1.31 mmol, 1.0 Ryvu Therapeutics S.A. RVU305 101 R10391WO eq.) and K2CO3(0.535 g, 3.871 mmol, 3.0 eq.) in mixture of 1,4-dioxane (13 mL) and water (1.3 mL) was placed in a seal-tube. The mixture was sparged with nitrogen for 15 min. andthen Pd(PPh3)4 (0.151 g, 0.131 mmol, 0.1 eq.) was added. Reactor was sealed, and leftstirred and heated at 120°C for 30 min under microwave irradiation. After this time the re-action mixture was then cooled to RT, diluted with DCM and filtered through a pad of Celite®. The filtrate was diluted with water and aqueous phase was extracted with DCM (x3). Combined organic phases were washed with brine, dried over Na2SO4, filtered and con- centrated. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to give N-{[3-amino-4-(4-cyano-5-methyl-2,5-dihydrofuran-3-yl)phenyl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 027, 0.443 g, 0.715 mmol, 55%, black solid, m / z [M+H]+: 558.50).1H NMR (400 MHz, DMSO-d6) δ 8.76 – 8.72 (m, 1H), 8.58 – 8.53 (m, 1H), 8.04 – 7.99 (m, 1H), 7.84 – 7.79 (m, 1H), 7.68 – 7.62 (m, 1H), 7.57 – 7.51 (m, 1H), 7.50 – 7.45 (m, 1H), 7.43 – 7.37 (m, 1H), 7.26 – 7.18 (m, 1H), 6.45 (s, 2H), 5.83 (dd, J = 14.6, 4.9 Hz, 1H), 5.44 – 5.36 (m, 1H), 5.35 – 5.19 (m, 2H), 4.70 (dd, J = 14.6, 3.7 Hz, 1H), 3.38 (d, J = 5.5 Hz, 3H), 1.39 (d, J = 6.1 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.75 (s, 3F). rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 10): Acetyl chloride (0.224 g, 2.857 mmol, 4.0 eq.) was added to a solution N-{[3-amino-4- (4-cyano-5-methyl-2,5-dihydrofuran-3-yl)phenyl]methyl}-N-(2-methanesulfonylpyridin-3- yl)-6-(trifluoromethyl)pyridine-3-carboxamide (0.443 g, 0.714 mmol, 1.0 eq.) in anhydrous ethanol (7.0 mL). The mixture was heated at 100°C for 1 h. After cooling reaction mixture to RT it was quenched by addition saturated aqueous solution of NaHCO3(until pH 8), and aqueous phase was extracted with DCM (3x). Combined organic layers were dried over MgSO4, filtered and concentrated. The crude material was purified by preparative HPLC to rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide as its formate salt (Example 10, 0.204 g, 0.335 mmol, 47%, white solid, UPLC long elution (Polar long method; buffer type “FA”) purity: 99.2%, m / z [M+H]+: 558.23).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 2:8); Major rotamer: δ 8.80 – 8.70 (m, 1H), 8.60 – 8.53 (m, 1H), 8.17 – 8.12 (m,1H), 8.05 – 7.99 (m, 1H), 7.85 – 7.77 (m, 1H), 7.73 – 7.63 (m, 1H), 7.57 – 7.51 (m, 1H), 7.50 – 7.45 (m, 1H), 7.44 – 7.37 (m, 1H), 7.30 – 7.18 (m, 1H), 6.68 – 6.28 (m, 2H), 5.83 (d, J = 14.6 Hz, 1H), 5.44 – 5.12 (m, 3H), 4.70 (d, J = 14.7 Hz, 1H), 3.40 (s, 3H), 1.44 – 1.35 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.74 (s, 3F). Minor rotamer: δ 9.10 – 9.02 (m, 1H), 8.70 – 8.65 (m, 1H), 8.42 – 8.36 (m, 1H), 8.17 – 8.12 (m, 1H), 7.73 – 7.63 (m, 2H), 7.44 – 7.37 (m, 1H), 7.30 – 7.18 (m, 1H), 7.14 – 7.07 (m, 1H), 6.68 – 6.28 (m, 2H), 5.44 – 5.12 (m, 5H), 4.86 (d, J = 15.6 Hz, 1H), 3.40 (s, 3H), 1.44 – 1.35 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ - 66.61 (s, 3F). Example 11: N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide and Example 12: N- {[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesulfonylpyr- idin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 102 R10391WO The title compounds were obtained from rac-N-({4-amino-3-methyl-1H,3H-furo[3,4- c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3- carboxamide (Example 10) by: HPLC chiral separation (column: CHIRAL IF; mobile phase: isocratic hexane / EtOH 85:15; flow rate: 19 mL / min.; elution time: 120 min.). R and S config- urations were attributed arbitrarily. N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 11, 44 mg, white solid, UPLC long elution purity: 98.40%, chiral purity: 97.15%, m / z [M+H]+: 558.21).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 2:8); Major rotamer: δ 8.76 – 8.71 (m, 1H), 8.60 – 8.53 (m, 1H), 8.06 – 7.98 (m,1H), 7.84 – 7.78 (m, 1H), 7.72 – 7.61 (m, 1H), 7.57 – 7.50 (m, 1H), 7.50 – 7.44 (m, 1H), 7.43 – 7.36 (m, 1H), 7.29 – 7.17 (m, 1H), 6.50 – 6.32 (m, 2H), 5.83 (dd, J = 14.6, 5.0 Hz, 1H), 5.46 – 5.09 (m, 3H), 4.70 (dd, J = 14.6, 3.8 Hz, 1H), 3.40 (s, 3H), 1.44 – 1.35 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.74 (s, 3F). Minor rotamer: δ 9.10 – 9.03 (m, 1H), 8.70 – 8.64 (m, 1H), 8.42 – 8.37 (m, 1H), 8.18 – 8.11 (m, 1H), 7.72 – 7.61 (m, 2H), 7.43 – 7.36 (m, 1H), 7.29 – 7.17 (m, 1H), 7.13 – 7.06 (m, 1H), 6.50 – 6.32 (m, 2H), 5.46 – 5.09 (m, 4H), 4.85 (d, J = 15.6 Hz, 1H), 3.40 (s, 3H), 1.44 – 1.35 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.61 (s, 3F). N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example 12, 36 mg, white solid, UPLC long elution purity: 99.66%, chiral purity: 100%, m / z [M+H]+: 558.21).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 2:8); Major rotamer: δ 8.77 – 8.71 (m, 1H), 8.59 – 8.53 (m, 1H), 8.05 – 7.98 (m,1H), 7.85 – 7.78 (m, 1H), 7.72 – 7.62 (m, 1H), 7.56 – 7.50 (m, 1H), 7.49 – 7.44 (m, 1H), 7.43 – 7.36 (m, 1H), 7.28 – 7.17 (m, 1H), 6.49 – 6.36 (m, 2H), 5.83 (dd, J = 14.6, 5.0 Hz, 1H), 5.43 – 5.12 (m, 3H), 4.70 (dd, J = 14.6, 3.8 Hz, 1H), 3.40 (s, 3H), 1.46 – 1.36 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.74 (s, 3F). Minor rotamer: δ 9.09 – 9.03 (m, 1H), 8.70 – 8.65 (m, 1H), 8.39 – 8.35 (m, 1H), 8.18 – 8.12 (m, 1H), 7.72 – 7.62 (m, 2H), 7.43 – 7.36 (m, 1H), 7.28 – 7.17 (m, 1H), 7.13 – 7.07 (m, 1H), 6.49 – 6.36 (m, 2H), 5.43 – 5.12 (m, 4H), 4.85 (d, J = 15.5 Hz, 1H), 3.40 (s, 3H), 1.46 – 1.36 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.61 (s, 3F). Example 13: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3- carboxamide Ryvu Therapeutics S.A. RVU305 103 R10391WO [2-amino-4-(methoxycarbonyl)phenyl]boronic acid hydrochloride (Int. 028): A mixture of 10% Pd / C (wet, 2.37 g, 1.114 mmol, 0.01 eq.), [4-(methoxycarbonyl)-2- nitrophenyl]boronic acid (25.0 g, 111.13 mmol, 1.0 eq.) and conc. aq. HCl. (13 mL) in MeOH (240 mL) was hydrogenated in a Parr apparatus (2 bar) at RT overnight. The RM was fil- tered through a pad of Celite®and the filter cake was washed with methanol and filtrate was concentrated. The residue was suspended in acetone (125 mL) and mixed for 1h at RT. Then, precipitate was filtrated off, washed with acetone and n-Heptane to yield [2-amino- 4-(methoxycarbonyl)phenyl]boronic acid hydrochloride (Int. 028, 24.724 g, 106.82 mmol, 96%, white solid, m / z [M+H]+: 195.60).1H NMR (400 MHz, Methanol-d4) δ 8.08 (dd, J = 7.9, 1.5 Hz, 1H), 8.03 – 7.96 (m, 2H), 3.95 (s, 3H). Ethyl 5-[2-amino-4-(methoxycarbonyl)phenyl]-1-methyl-1H-pyrazole-4-carboxylate (Int. 029): A mixture of ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate (5.35 g, 22.955 mmol, 1.0 eq.), [2-amino-4-(methoxycarbonyl)phenyl]boronic acid hydrochloride (Int.028, 6.375 g, 27.546 mmol, 1.2 eq.) and K2CO3(12.69 g, 91.82 mmol, 4.0 eq.) in mixture of 1,4-dioxane (50 mL) and water (5 mL) was placed in a seal-tube. The mixture was sparged with nitrogen for 15 min. and then Pd(dppf)Cl2.DCM (3.749 g, 4.591 mmol, 0.2 eq.) was added. Reactor was sealed, and left stirred and heated at reflux for 1 h. After this time the reaction mixture was then cooled to RT, diluted with EtOAc and filtered through a pad of Celite®. The filtrate was diluted with water and aqueous phase was extracted with EtOAc (3x). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (0 to 70% EtOAc gradient in hexane) to give ethyl 5-[2-amino- 4-(methoxycarbonyl)phenyl]-1-methyl-1H-pyrazole-4-carboxylate (Int. 029, 3.1 g, 7.154 mmol, 31%, beige solid, m / z [M+H]+: 303.90). Ryvu Therapeutics S.A. RVU305 104 R10391WO1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.17 (dd, J = 7.9, 1.7 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 5.24 (s, 2H), 4.04 (qd, J = 7.1, 1.2 Hz, 2H), 3.85 (s, 3H), 3.59 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H). Methyl 1-methyl-4-oxo-1H,4H,5H-pyrazolo[4,3-c]quinoline-7-carboxylate (Int. 030): A solution of ethyl 5-[2-amino-4-(methoxycarbonyl)phenyl]-1-methyl-1H-pyrazole-4- carboxylate (Int. 029, 3.1 g, 7.154 mmol, 1.0 eq.) in acetic acid (30 mL) was heated at 100°C for 1 h. The reaction mixture was cooled to RT and evaporated to dryness. An ob- tained solid was triturated with a mixture of i-PrOH and water 5 / 1 v / v (60 mL) overnight. The suspension was filtered, washed withi-PrOH, Et2O and driedin vacuoto yield methyl 1- methyl-4-oxo-1H,4H,5H-pyrazolo[4,3-c]quinoline-7-carboxylate (Int. 030, 2.1 g, 7.02 mmol, 98%, beige solid, m / z [M+H]+: 258.00)1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.15 (s, 1H), 8.10 (d, J = 1.7 Hz, 1H), 7.82 (dd, J = 8.4, 1.7 Hz, 1H), 4.40 (s, 3H), 3.92 (s, 3H). Methyl 4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-7-carboxylate (Int. 031): A phosphorus oxychloride (5.602 g, 36.541 mmol, 5.0 eq.) was added dropwise to me- thyl 1-methyl-4-oxo-1H,4H,5H-pyrazolo[4,3-c]quinoline-7-carboxylate (Int.030, 1.88 g, 7.308 mmol, 1.0 eq.). Resulting mixture was heated at 115°C for 2 h. Reaction mixture was cooled and poured on ice, then neutralized by NaHCO3solution. An obtained suspension was stirred for 30 min. and then filtered. The residue was washed with water and dried to obtain methyl 4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-7-carboxylate (Int. 031, 2.40 g, 7.40 mmol, 101%, beige solid, m / z [M+H]+: 276.80) which was used for next step without purification.1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 8.6 Hz, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.42 (s, 1H), 8.25 (dd, J = 8.6, 1.8 Hz, 1H), 4.56 (s, 3H), 3.97 (s, 3H). {4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methanol (Int. 032): DIBAL-H (1.0 M in THF, 18.11 mL, 18.114 mmol, 2.5 eq.) was added dropwise to a so- lution of methyl 4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-7-carboxylate (Int. 031, 2.35 g, 7.245 mmol, 1.0 eq.) in DCM (400 mL) at 0°C. Reaction mixture was stirred for 1 h at 0°C. As a conversion was low, another portion of DIBAL-H (1.0 M in DCM, 48.54 mL, 48.545 mmol, 6.7 eq.) was added. Resulting mixture was stirred for 30 min. at 0°C. The re- action was quenched by careful addition of methanol and then 1 M aq. potassium sodium tartrate solution. The mixture was extracted with EtOAc (3x) and the organic layers were washed with brine, dried over Na2SO4and evaporated. Crude product was purified by FCC (0 to 5% MeOH gradient in DCM) to give to obtain {4-chloro-1-methyl-1H-pyrazolo[4,3- c]quinolin-7-yl}methanol (Int. 032, 1.89 g, 7.555 mmol, 100%, beige solid, m / z [M+H]+: 248.80).1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.74 (dd, J = 8.5, 1.8 Hz, 1H), 5.51 (t, J = 5.8 Hz, 1H), 4.76 (d, J = 5.7 Hz, 2H), 4.51 (s, 3H). 7-(bromomethyl)-4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline (Int. 033): Ryvu Therapeutics S.A. RVU305 105 R10391WO A [{4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methanol (Int.032, 1.79 g, 7.155 mmol, 1.0 eq.) was suspended in DCM (150 mL). The solution was degassed and cooled to 0°C, then triphenylphosphine (3.753 g, 14.31 mmol, 2.0 eq.) was added, followed by CBr4(3.715 g, 11.203 mmol, 1.5 eq.). The reaction was stirred at RT overnight. The sol- vent was removed and the residue was purified by FCC (0 to 100% DCM gradient in hexane) to give 7-(bromomethyl)-4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline (Int. 033, 1.693 g, 5.451 mmol, 76%, white solid, m / z [M+H]+: 309.80).1H NMR (400 MHz, DMSO-d6) δ 8.68 – 8.56 (m, 1H), 8.40 – 8.21 (m, 1H), 8.16 (dd, J = 4.2, 3-[(2-bromophenyl)sulfanyl]propanoic acid (Int. 034): A solution of 3-bromopropanoic acid (1.7 g, 11.11 mmol, 1.05 eq.), 2-bromobenzene-1- thiol (2.0 g, 10.58 mmol, 1.0 eq.) and sodium hydroxide (1.27 g, 31.75 mmol, 3.0 eq.) in water (53.0 mL) was stirred overnight at 50°C. After coming back to RT, the RM was diluted with water and acidified to pH ≈ 1 with aq.1 M HCl. The resulting precipitate was filtered off and washed with cold water and pentane. The crude material was dried under vacuum to give 3- [(2-bromophenyl)sulfanyl]propanoic acid (Int. 034, 2.48 g, 9.49 mmol, 83%, white solid, m / z [M-H]-: 259.2) which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.63 (dd, J = 7.9, 1.2 Hz, 1H), 7.45 – 7.35 (m, 2H), 7.13 (ddd, J = 7.8, 6.5, 2.4 Hz, 1H), 3.20 (t, J = 7.1 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H). 8-bromo-3,4-dihydro-2H-1-benzothiopyran-4-one (Int. 035): Step 1. A solution of 3-[(2-bromophenyl)sulfanyl]propanoic acid (Int. 034, 2.46 g, 8.76 mmol, 1.0 eq.) in thionyl chloride (6.4 mL) was refluxed for 2 h under nitrogen and concen- trated to dryness in vacuo. Step 2. The residue was diluted with chlorobenzene (100 mL) and the solution was cooled to 0°C. AlCl3(1.29 g, 9.67 mmol, 1.1 eq.) was added and the RM was stirred at 0°C for 2 h. The reaction was quenched with cold water and the layers were separated. The aqueous layer was extracted with toluene (2x) and the combined organic layers were washed with 1 M HCl, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 20% EtOAc gradient in hexane) to yield 8-bromo-3,4-dihydro-2H-1-benzothiopyran-4-one (Int. 035, 1.82 g, 7.49 mmol, 83%, yellow solid, m / z [M+H]+: 243.0). Ryvu Therapeutics S.A. RVU305 106 R10391WO1H NMR (400 MHz, DMSO-d6) δ 8.01 (dd, J = 7.9, 1.4 Hz, 1H), 7.85 (dd, J = 7.8, 1.4 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 3.41 – 3.35 (m, 2H), 2.96 – 2.88 (m, 2H). 8-bromo-4,4-difluoro-3,4-dihydro-2H-1-benzothiopyran (Int. 036): A mixture of 8-bromo-3,4-dihydro-2H-1-benzothiopyran-4-one (Int.035, 0.3 g, 1.20 mmol, 1.0 eq.) and DAST (0.812 g, 4.79 mmol, 4.0 eq.) was heated at 90°C for 2 h under ni- trogen. After coming back to RT, the RM was diluted with DCM and the solution was slowly added to stirring sat. aq. Na2CO3at 0°C. The phases were separated and the aqueous phase was extracted with DCM (2x). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by FCC (100% hexane) to yield 8-bromo-4,4-difluoro-3,4-dihydro-2H- 1-benzothiopyran (Int. 036, 0.149 g, 0.56 mmol, 47%, colorless oil, m / z [M+H]+: 265.8).1H NMR (400 MHz, DMSO-d6) δ 7.78 – 7.74 (m, 1H), 7.74 – 7.71 (m, 1H), 7.21 (t, J = 7.9 Hz, 1H), 3.27 – 3.20 (m, 2H), 2.66 – 2.51 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -82.93 (t, J = 14.0 Hz, 2F). 8-bromo-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran-1,1-dione (Int. 037): A mixture of 8-bromo-4,4-difluoro-3,4-dihydro-2H-1-benzothiopyran (Int. 036, 0.149 g, 0.56 mmol, 1.0 eq.) and mCPBA (0.252 g, 1.12 mmol, 2.0 eq.) in DCM (5.0 mL) was stirred at RT for 3 h. The RM was diluted with DCM and washed with 10% aq. Na2S2O3followed by aq. sat. NaHCO3. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hexane) to yield 8-bromo-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran-1,1-dione (Int. 037, 0.170 g, 0.54 mmol, 96%, white solid, m / z [M+2Na-H]+: 340.8).1H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, J = 8.0, 1.2 Hz, 1H), 7.90 (dd, J = 8.0, 1.2 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 3.96 – 3.85 (m, 2H), 3.06 – 2.93 (m, 2H).19F NMR (376 MHz, DMSO- d6) δ -84.67 (t, J = 13.5 Hz, 2F). 8-amino-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran-1,1-dione (Int. 038): Step 1. A pressure vessel was charged with 8-bromo-4,4-difluoro-3,4-dihydro-2H- 1λ⁶-benzothiopyran-1,1-dione (Int.037, 0.65 g, 2.2 mmol, 1.0 eq.), Cs2CO3(2.0 g, 6.14 mmol, 2.8 eq.), tert-butyl carbamate (0.18 g, 1.55 mmol, 2.2 eq.) and anhydrous dioxane (20 mL). The RM was sparged with nitrogen for 5 min. Xphos Pd G3 (0.31 g, 0.37 mmol, 0.17 eq.) was added followed by Xphos (0.19 g, 0.4 mmol, 0.18 eq.) and the vessel was sealed. The resulting RM was stirred for 1 h at 100°C. After coming back to RT, the RM was di- luted with EtOAc and filtered through a pad of Celite®. The filtrate was evaporated under re- duced pressure. Step 2. The residue was dissolved in a mixture of DCM (5.0 mL) and TFA (5.0 mL). The RM was stirred for 2 h at RT and evaporated under reduced pressure. The residue was partitioned between DCM and aq.1 M NaOH. The aqueous phase was extracted with DCM (2x) and the combined organic layers were dried over anhydrous Na2SO4, filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gra- dient in hexane) to yield 8-amino-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran-1,1-di- one (Int. 038, 0.349 g, 1.5 mmol, 68%, off-white solid, m / z [M+H]+: 234.0). Ryvu Therapeutics S.A. RVU305 107 R10391WO1H NMR (400 MHz, DMSO-d6) δ 7.42 (t, J = 8.0 Hz, 1H), 7.02 (dd, J = 8.4, 1.3 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.13 (s, 2H), 3.79 – 3.72 (m, 2H), 2.99 – 2.85 (m, 2H).19F NMR (376 MHz, DMSO- δ -83.82 J = 13.8 Hz, . N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyri- dine-3-carboxamide (Int. 039): To a solution of 8-amino-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran-1,1-dione (Int. 038, 0.26 g, 1.104 mmol, 1.0 eq.) 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.245 g, 1.282 mmol, 1.162 eq.) and DMAP (0.03 g, 0.246 mmol, 0.2 eq.) in anhydrous pyridine (5.5 mL) was added phosphorus oxychloride (0.49 g, 3.196 mmol, 3.0 eq.) dropwise, at RT. Reac- tion was stirred at RT for 1 h under nitrogen. The reaction was quenched with ice / water and the mixture was neutralized with sat. aq. NaHCO3 / 1 M NaOH mixture. It was extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (0 to 60% EtOAc gradient in hexane) to yield N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothi- opyran-8-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 039, 0.405 g, 0.897 mmol, 81%, beige solid, m / z [M+H]+: 407.20).1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.24 (d, J = 2.1 Hz, 1H), 8.54 (dd, J = 8.2, 2.1 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.97 – 7.91 (m, 2H), 7.87 (dd, J = 6.7, 2.6 Hz, 1H), 3.95 – 3.88 (m, 2H), 3.11 – 2.96 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -66.65 (s, 3F), -84.63 (t, J = 13.6 Hz, 2F). N-({4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 040): To N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide (Int. 039, 0.18 g, 0.399 mmol, 1.0 eq.) in anhydrous acetoni- trile (4.0 mL) was added Cs2CO3(0.2 g, 0.614 mmol, 1.5 eq.) followed by 7-(bromomethyl)- 4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline (Int. 033, 0.143 g, 0.46 mmol, 1.15 eq.). Re- Ryvu Therapeutics S.A. RVU305 108 R10391WO action was heated at 65°C for 40 min. Reaction mixture was diluted with water and ex- tracted with DCM. Organic layers were combined, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Crude product was purified by FCC (0 to 100% EtOAc gradient in hexane) to give N-({4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)- N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyri- dine-3-carboxamide (Int. 040, 0.315 g, 0.466 mmol, 90%, white solid, m / z [M+H]+: 636.10).1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.35 (s, 1H), 8.10 (dd, J = 8.2, 2.1 Hz, 1H), 8.02 – 8.00 (m, 1H), 7.84 – 7.78 (m, 3H), 7.59 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 6.01 (d, J = 15.1 Hz, 1H), 4.80 (d, J = 15.1 Hz, 1H), 4.55 – 4.45 (m, 3H), 4.10 – 3.99 (m, 2H), 3.06 (d, J = 24.2 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -66.74 (s, 3F), -80.04 – -82.14 (m, 1F), -84.17 – -86.12 (m, 1F). N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Ex- ample 13): Step 1. A pressure vessel was charged with N-({4-chloro-1-methyl-1H-pyrazolo[4,3- c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8- yl)-6-(trifluoromethyl)pyridine-3-carboxamide (Int. 040, 0.294 g, 0.435 mmol, 1.0 eq.), Cs2CO3(0.215 g, 0.66 mmol, 1.5 eq.), tert-butyl carbamate (0.105 g, 0.896 mmol, 2.0 eq.) and anhydrous dioxane (4.5 mL). The RM was sparged with nitrogen for 5 min. Xphos Pd G3 (0.037 g, 0.044 mmol, 0.10 eq.) was added followed by Xphos (0.033 g, 0.069 mmol, 0.16 eq.) and the vessel was sealed. The resulting RM was stirred for 1 h at 100°C. After coming back to RT the RM was poured into water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Step 2. The residue was dissolved in a mixture of DCM (2.5 mL) and TFA (1.7 mL). The RM was stirred at RT overnight and evaporated under reduced pressure. The residue was taken up 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 purified by two con- secutive FCCs (first: NH2functionalized silica, 0 to 4% EtOH gradient in DCM; second: 0 to 10% MeOH gradient in DCM). The fractions containing the pure product were pooled and freeze-dried to yield N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3- carboxamide (Example 13, 0.13 g, 0.211 mmol, 49%, white solid, UPLC long elution (Mid po- lar long method; buffer type “FA”) purity: 100%, m / z [M+H]+: 617.24).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 8:2). Major rotamer: δ 8.75 (d, J = 2.1 Hz, 1H), 8.26 – 8.20 (m, 2H), 8.07 (d, J =7.4 Hz, 1H), 7.84 – 7.76 (m, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.48 – 7.41 (m, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 6.96 (s, 2H), 5.97 (d, J = 14.7 Hz, 1H), 4.62 (d, J = 14.7 Hz, 1H), 4.37 (s, 3H), 4.10 – 3.95 (m, 2H), 3.12 – 2.95 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ - 66.74, -80.54 (ddd, J = 273.8, 22.7, 13.0 Hz), -85.01 (dt, J = 273.7, 10.9 Hz). Minor rotamer: δ 9.08 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.26 – 8.20 (m, 1H), 8.19 – 8.13 (m, 2H), 7.89 (d, J = 8.0 Hz, 1H), 7.76 – 7.68 (m, 1H), 7.25 – 7.20 (m, 1H), 7.19 – 7.13 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 7.01 – 6.96 (m, 2H), 5.22 (d, J = 15.7 Hz, 1H), 4.82 (d, J = 15.7 Hz, 1H), 4.35 (s, 3H), 4.08 Ryvu Therapeutics S.A. RVU305 109 R10391WO – 3.96 (m, 2H), 3.16 – 2.95 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -66.74 (s, 3F), -80.03 – -81.02 (m, 1F), -84.51 – -85.48 (m, 1F). Example 14: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyano-N- (4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide 6-cyano-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-car- boxamide (Int. 041): To a solution of 8-amino-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran-1,1-dione (Int. 038, 0.255 g, 1.082 mmol, 1.0 eq.), 6-cyanonicotonic acid (0.19 g, 1.283 mmol, 1.185 eq.) and DMAP (0.03 g, 0.246 mmol, 0.2 eq.) in anhydrous pyridine (5.5 mL) was added phosphorus oxychloride (0.49 g, 3.196 mmol, 3.0 eq.) dropwise, at RT. Reaction was stirred at RT for 1 h under nitrogen. The reaction was quenched with ice / water and the mixture was neutralized with sat. aq. NaHCO3 / 1 M NaOH mixture. It was extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield 6-cyano-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)pyridine-3-carboxamide (Int. 041, 0.295 g, 0.788 mmol, 73%, beige solid, m / z [M+H]+: 364.1).1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.19 (dd, J = 2.2, 0.9 Hz, 1H), 8.48 (dd, J = 2.2 Hz, 1H), 8.29 (dd, J = 8.1, 0.9 Hz, 1H), 7.97 – 7.84 (m, 3H), 3.98 – 3.87 (m, 2H), 3.10 – 2.96 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -84.65 (t, J = 13.6 Hz, 2F). N-({4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyano-N-(4,4-difluoro- 1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide (Int. 042): To 6-cyano-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyri- dine-3-carboxamide (Int. 041, 0.15 g, 0.4 mmol, 1.0 eq.) in anhydrous acetonitrile (4.0 mL) was added Cs2CO3(0.2 g, 0.614 mmol, 1.5 eq.) followed by 7-(bromomethyl)-4-chloro-1-me- thyl-1H-pyrazolo[4,3-c]quinoline (Int.033, 0.145 g, 0.467 mmol, 1.15 eq.). Reaction was heated at 65°C for 75 min. Reaction mixture was diluted with water and extracted with Ryvu Therapeutics S.A. RVU305 110 R10391WO DCM. Organic layers were combined, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Crude product was purified by FCC (0 to 3% MeOH gradient in DCM) to give N-({4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyano-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide (Int. 042, 0.214 g, 0.343 mmol, 86%, beige solid, m / z [M+H]+: 593.1).1H NMR (400 MHz, DMSO-d6) δ 8.80 – 8.73 (m, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.35 (s, 1H), 8.06 – 8.00 (m, 2H), 7.93 (d, J = 8.1 Hz, 1H), 7.80 (dd, J = 7.6, 3.0 Hz, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 5.99 (d, J = 15.0 Hz, 1H), 4.77 (d, J = 15.1 Hz, 1H), 4.51 (d, J = 3.4 Hz, 3H), 4.01 (t, J = 6.2 Hz, 2H), 3.19 – 2.88 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ - 80.34 – -81.90 (m, 1F), -83.87 – -85.94 (m, 1F). N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyano-N-(4,4-difluoro- 1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide (Example 14): Step 1. A pressure vessel was charged with N-({4-chloro-1-methyl-1H-pyrazolo[4,3- c]quinolin-7-yl}methyl)-6-cyano-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothi- opyran-8-yl)pyridine-3-carboxamide (Int.042, 0.21 g, 0.336 mmol, 1.0 eq.), Cs2CO3(0.17 g, 0.522 mmol, 1.5 eq.), tert-butyl carbamate (0.085 g, 0.726 mmol, 2.1 eq.) and anhydrous di- oxane (3.5 mL). The RM was sparged with nitrogen for 5 min XPhos Pd G3 (0.03 g, 0.035 mmol, 0.10 eq.) was added followed by XPhos (0.025 g, 0.052 mmol, 0.15 eq.) and the vessel was sealed. The resulting RM was stirred for 40 min. at 100°C. After coming back to RT the RM was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Step 2. The residue was dissolved in a mixture of DCM (2.0 mL) and TFA (1.3 mL). The RM was stirred at RT overnight and evaporated under reduced pressure. The residue was taken up 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 purified by two con- secutive FCCs (first: NH2functionalized silica, 0 to 4% EtOH gradient in DCM; second: 0 to 10% MeOH gradient in DCM). The fractions containing the pure product were pooled and freeze-dried to yield N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cy- ano-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carbox- amide (Example 14, 0.019 g, 0.033 mmol, 10%, yellowish solid, UPLC long elution (Polar long method; buffer type “FA”) purity: 99.26%, m / z [M+H]+: 574.18).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 8:2). Major rotamer: δ 8.73 (d, J = 2.1 Hz, 1H), 8.24 – 8.20 (m, 2H), 8.00 (dd, J =8.1, 2.1 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.27 (dd, J = 8.4, 1.8 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.95 (s, 2H), 5.95 (d, J = 14.8 Hz, 1H), 4.59 (d, J = 14.8 Hz, 1H), 4.37 (s, 3H), 4.01 (t, J = 6.4 Hz, 2H), 3.15 –2.91 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -80.87 (ddd, J = 273.9, 21.6, 12.6 Hz, 1F), -84.95 (ddd, J = 273.9, 11.9, 8.9 Hz, 1F). Minor rotamer: δ 9.04 (s, 1H), 8.34 (d, J = 8.1 Hz,1H), 8.27 (d, J = 8.0 Hz, 1H), 8.25 – 8.21 (m, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.91 – 7.85 (m, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.99 (s, 2H), 5.18 (d, J = 15.7 Hz, 1H), 4.81 (d, J = 15.8 Hz, 1H), 4.36 (s, 3H), 4.01 (t, J = 6.4 Hz, 2H), 3.04 (dt, J = 19.8, 8.9 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -82.70 (ddd, J = 271.6, 20.8, 11.5 Hz, 1F), -85.54 (ddd, J = 270.9, 15.1, 10.1 Hz, 1F). Ryvu Therapeutics S.A. RVU305 111 R10391WO Example 15: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl- N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carboxamide 6-Cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Int. 043): To solution of 2-methanesulfonylpyridin-3-amine (2.0 g, 11.614 mmol, 1.0 eq.), 6-cy- clopropylpyridine-3-carboxylic acid (2.0 g, 12.195 mmol, 1.05 eq.) and DIPEA (5.05 mL, 29.036 mmol, 2.5 eq.) in toluene (10 mL) at 0°C was added T3P as 50 wt% solution in Ac- OEt (6.90 mL, 23.22 mmol, 2.0 eq.) The resulting mixture was heated at 100°C overnight. Reaction mixture was quenched with NaHCO3, extracted with EtOAc (3x). Combined organiclayers were washed with brine and dried over with Na2SO4and evaporated under reducedpressure. The residue was suspended in i-PrOH and filtrated off. Obtained precipitate was desired product 6-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Int. 043, 1.34 g, 4.138 mmol, 36%, yellow solid, m / z [M+H]+: 318.6)1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.93 (dd, J = 2.4, 0.8 Hz, 1H), 8.74 (dd, J = 1.4 Hz, 1H), 8.56 (dd, J = 4.5, 1.4 Hz, 1H), 8.11 (dd, J = 8.2, 2.4 Hz, 1H), 7.81 (dd, J = 8.5, 4.5 Hz, 1H), 7.52 (dd, J = 8.3, 0.8 Hz, 1H), 3.43 (s, 3H), 2.26 – 2.19 (m, 1H), 1.09 – 1.00 (m, 4H). N-[(4-bromo-3-nitrophenyl)methyl]-6-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyri- dine-3-carboxamide (Int. 044): To 6-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Int.043, 0.602 g, 1.85 mmol, 1.0 eq.) in anhydrous acetonitrile (9.0 mL) was added Cs2CO3(0.725 g, 2.225 mmol, 1.2 eq.) followed by 1-bromo-4-(bromomethyl)-2-nitrobenzene (0.82 g, 2.78 Ryvu Therapeutics S.A. RVU305 112 R10391WO mmol, 1.5 eq.). Reaction was heated at 70°C overnight. Reaction mixture was diluted with sat. NH4Cl aq. and extracted with DCM (3x). Organic layers were combined, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Crude product was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield N-[(4-bromo-3-nitrophenyl)methyl]-6- cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Int. 044, 0.94 g, 1.698 mmol, 91%, light yellow solid, m / z [M+H]+: 532.3).1H NMR MHz, DMSO- δ 8.61 (d, J = 4.4 Hz, 1H), 8.34 (s, 1H), 7.99 (s, 1H), 7.89 (dd, Hz, 1H), 7.71 – 7.62 (m, 1H), 7.60 – 7.49 (m, 2H), 7.14 (d, J = 8.1 Hz, 1H), 5.58 – 5.47 (m, 1H), 4.70 (d, J = 15.4 Hz, 1H), 3.30 (s, 3H), 2.06 – 1.97 (m, 1H), 1.02 – 0.76 (m, 4H). N-[(3-amino-4-bromophenyl)methyl]-6-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyri- dine-3-carboxamide (Int. 045): To a solution N-[(4-bromo-3-nitrophenyl)methyl]-6-cyclopropyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide (Int. 044, 0.94 g, 1.698 mmol, 1.0 eq.) in acetone (1.7 mL) was added zinc (1.111 g, 16.99 mmol, 10.00 eq.) followed by sat. NH4Cl aq. (4.3 mL). Reaction mixture was stirred at RT for 1 h. After this time reaction mixture was filtered through a Celite® pad which was washed with DCM. Filtrates were combined and organic phase was washed with water (2x), then organic phase was separated, dried over Na2SO4, filtered and concentrated. Crude product was purified by FCC (0 to 60% EtOAc gradient in hexane) to yield N-[(3-amino-4-bromophenyl)methyl]-6-cyclopropyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide (Int. 045, 0.7 g, 1.298 mmol, 76%, yellow solid, m / z [M+H]+: 502.2).1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, 1H), 8.34 (s, 1H), 7.67 – 7.57 (m, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.37 (d, J = 8.1 Hz, 1H), 5.58 (d, J = 15.0 Hz, 1H), 5.41 – 5.28 (m, 2H), 4.34 (d, J = 15.0 Hz, 1H), 3.36 (s, 3H), 2.05 – 2.00 (m, 1H), 0.95 – 0.88 (m, 2H), 0.86 – 0.80 (m, 2H). N-{[3-amino-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-6-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Int. 046): Step 1. To a degassed solution of N-[(3-amino-4-bromophenyl)methyl]-6-cyclopropyl- N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Int. 045, 0.68 g, 1.261 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaboro- lane (0.641 g, 2.524 mmol, 2.00 eq.), potassium acetate (0.371 g, 3.787 mmol, 3.00 eq.) in1,4-dioxane (12.5 mL) Pd(dppf)Cl2 (0.093 g, 0.126 mmol, 0.1 eq.) was added. Reaction mix-ture was then heated at 100°C for 3 h in a pressure vessel. The reaction mixture was thencooled to RT, diluted with DCM and filtered through a pad of Celite®. The residue was di- luted with water and extracted with DCM and next with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give crude product which was used for next step without purification. Step 2. A mixture of crude from step 1 (1.17 g, prepared according to step 1), 5- bromo-1-methyl-1H-pyrazole-4-carbonitrile (0.294 g, 1.583 mmol, 1.00 eq.) and K2CO3(0.656 g, 4.746 mmol, 3.00 eq.) in mixture of 1,4-dioxane (11 mL) and water (1.1 mL) was placed in a seal-tube. The mixture was sparged with nitrogen for 15 min. and then Ryvu Therapeutics S.A. RVU305 113 R10391WOPd(PPh3)4 (0.183 g, 0.158 mmol, 0.1 eq.) was added. Reactor was sealed, and reaction mix-ture was stirred at 90°C for 1 h. After this time the reaction mixture was then cooled to RT,diluted with EtOAc and filtered through a pad of Celite®. The filtrate was diluted with water and aqueous phase was extracted with EtOAc (2x). Combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (0 to 10% MeOH gradient in EtOAc) N-{[3-amino-4-(4-cyano-1-methyl-1H-pyrazol-5- yl)phenyl]methyl}-6-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Int. 046, 0.345 g, 0.477 mmol, 30%, orange oil, m / z [M+H]+: 528.6).1H NMR (400 MHz, DMSO-d6) δ 8.73 – 8.62 (m, 1H), 8.61 – 8.54 (m, 1H), 8.41 – 8.31 (m, 1H), 8.10 (s, 1H), 7.83 – 7.71 (m, 1H), 7.19 – 7.11 (m, 1H), 7.01 – 6.93 (m, 1H), 6.81 (d, J = 7.1 Hz, 1H), 6.62 – 6.48 (m, 1H), 6.47 – 6.33 (m, 1H), 5.58 (d, J = 15.1 Hz, 1H), 5.32 (s, 2H), 4.51 (d, J = 15.1 Hz, 1H), 3.65 (s, 3H), 3.45 – 3.37 (m, 3H), 2.07 – 2.00 (m, 1H), 0.96 – 0.89 (m, 2H), 0.86 – 0.79 (m, 2H). N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Example 15): Acetyl chloride (0.078 mL, 1.098 mmol, 2.60 eq.) was added to a solution N-{[3-amino- 4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl]methyl}-6-cyclopropyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide (Int. 046, 0.305 g, 0.422 mmol, 1.0 eq.) in anhy- drous ethanol (2.0 mL). The mixture was heated at 100°C for 2 h.. After cooling reaction mixture to RT it was quenched by addition saturated aqueous solution of NaHCO3(until pH 8), and aqueous phase was extracted with DCM (4x). Combined organic layers were dried over MgSO4, filtered and concentrated. From this material product was isolated by FCC (NH2functionalized silica, 0 to 2% MeOH gradient in DCM then isocratic) to yield N-({4- amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide (Example 15, 0.052 g, 0.099 mmol, 23%, white solid, UPLC long elution (Polar long method; buffer type “FA”) purity: 100%, m / z [M+H]+: 528.1).1H NMR (400 MHz, DMSO-d6): a mixture of restricted C-N amide rotation isomers at RT(relative ratio 2:8); Major rotamer: δ 8.55 (s, 1H), 8.35 (s, 1H), 8.23 – 8.16 (m, 2H), 7.57 –7.47 (m, 3H), 7.41 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.94 (s, 2H), 5.81 (d, J = 14.8 Hz, 1H), 4.67 (d, J = 14.7 Hz, 1H), 4.36 (s, 3H), 3.36 (s, 3H), 2.02 (s, 1H), 0.96 – 0.88 (m, 2H), 0.83 (s, 2H). Minor rotamer: δ 8.74 (s, 1H), 8.63 (s, 1H), 8.23 – 8.16 (m, 2H), 7.97 (s, 1H), 7.67 – 7.59 (m, 2H), 7.57 – 7.47 (m, 1H), 7.32 (s, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.94 (s, 2H), 5.29 – 5.18 (m, 1H), 4.90 – 4.76 (m, 1H), 4.36 (s, 3H), 3.36 (s, 3H), 2.19 (s, 1H), 0.99 (s, 2H), 0.96 – 0.88 (m, 2H). Example 16: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl- N-(4-fluoro-2-methanesulfonylphenyl)pyrimidine-5-carboxamide Ryvu Therapeutics S.A. RVU305 114 R10391WO 2-cyclopropyl-N-(4-fluoro-2-methanesulfonylphenyl)pyrimidine-5-carboxamide (Int. 047): To a solution of 4-fluoro-2-methanesulfonylaniline (2.0 g, 10.57 mmol, 1.0 eq.), 2-cy- clopropylpyrimidine-5-carboxylic acid (1.822 g, 11.10 mmol, 1.05 eq.), and DMAP (0.258 g, 2.114 mmol, 0.2 eq.) in anhydrous pyridine (60 mL) was added phosphorus oxychloride (3.241 g, 21.142 mmol, 2.0 eq.) dropwise, at 0°. Reaction was stirred at RT for 3 h under ni- trogen. The reaction was quenched with ice / water and the mixture was neutralized with sat. aq. NaHCO3 / 1 M NaOH mixture. It was extracted with mixture of DCM / i-PrOH v / v 3 / 1 (3x) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and evapo- rated under reduced pressure. The crude material was triturated with i-PrOH, washed with an additional portion of i-PrOH, then EtO and dried in vacuo to yield 2-cyclopropyl-N-(4- fluoro-2-methanesulfonylphenyl)pyrimidine-5-carboxamide (Int. 047, 1.837 g, 5.423 mmol, 51%, beige solid, m / z [M+H]+: 336.4).1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.08 (s, 2H), 7.97 (dd, J = 8.9, 4.9 Hz, 1H), 7.81 (dd, J = 8.3, 3.0 Hz, 1H), 7.72 (td, J = 8.4, 3.0 Hz, 1H), 3.34 (s, 3H), 2.39 – 2.27 (m, 1H), 1.22 – 1.07 (m, 4H). N-({4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyrimidine-5-carboxamide (Int. 048): To 2-cyclopropyl-N-(4-fluoro-2-methanesulfonylphenyl)pyrimidine-5-carboxamide (Int. 047, 0.20 g, 0.59 mmol, 1.0 eq.) in anhydrous acetonitrile (5.0 mL) was added Cs2CO3(0.384 g, 1.181 mmol, 2.0 eq.) followed by 7-(bromomethyl)-4-chloro-1-methyl-1H-pyra- zolo[4,3-c]quinoline (Int.033, 0.183 g, 0.59 mmol, 1.0 eq.). Reaction was heated at 60°C for 90 min. Reaction mixture was diluted with water and extracted with EtOAc. Organic layers were combined, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Crude product was purified by FCC (0 to 3% MeOH gradient in DCM) to give N-({4- chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-fluoro-2-me- thanesulfonylphenyl)pyrimidine-5-carboxamide (Int. 048, 0.228 g, 0.404 mmol, 68%, beige solid, m / z [M+H]+: 565.9). Ryvu Therapeutics S.A. RVU305 115 R10391WO1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 8.5 Hz, 1H), 8.48 (s, 1H), 8.35 (s, 1H), 8.06 (d, J = 6.2 Hz, 1H), 7.91 – 7.81 (m, 2H), 7.58 – 7.50 (m, 1H), 7.47 (dd, J = 8.9, 4.9 Hz, 1H), 5.84 – 5.71 (m, 2H), 4.80 (d, J = 15.0 Hz, 1H), 4.57 – 4.45 (m, 3H), 3.25 (s, 3H), 2.16 – 2.06 (m, 1H), 1.04 (dd, J = 7.8, 3.5 Hz, 2H), 0.94 (q, J = 3.4 Hz, 2H). 2-cyclopropyl-N-[(4-{[(3,4-dimethylphenyl)methyl]amino}-1-methyl-1H-pyrazolo[4,3- c]quinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfonylphenyl)pyrimidine-5-carboxamide (Int. 049): A solution of N-({4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclo- propyl-N-(4-fluoro-2-methanesulfonylphenyl)pyrimidine-5-carboxamide (Int.048, 0.208 g, 0.368 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.184 g, 1.104 mmol, 3.0 eq.) in 1,4-dioxane (10 mL) was heated at 110°C for 3 days. Reaction mixture was evapo- rated to dryness. The residue was purified by FCC (0 to 2.5% MeOH gradient in DCM) to ob- tain 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1-methyl-1H-pyrazolo[4,3- c]quinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfonylphenyl)pyrimidine-5-carboxamide (Int. 049, 0.236 g, 0.326 mmol, 89%, beige solid, m / z [M+H]+: 696.3). N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyrimidine-5-carboxamide (Example 16): A 2-cyclopropyl-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1-methyl-1H-pyra- zolo[4,3-c]quinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfonylphenyl)pyrimidine-5-car- boxamide (Int. 049, 0.236 g, 0.326 mmol, 1.0 eq.) was dissolved in a mixture of DCM (5.0 mL) and TFA (1.3 mL). The resulting mixture was stirred at RT overnight. Reaction mixture was quenched by addition saturated aqueous solution of NaHCO3(until pH 8), and aqueous phase was extracted with DCM (4x). Combined organic layers were dried over Na2SO4, fil- tered and concentrated. From this material product was isolated by FCC (0 to 7% MeOH gradient in DCM). Then product was triturated with EtOH, evaporated to dryness and tritu- rated with water. After lyophilization to yield N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quin- olin-7-yl}methyl)-2-cyclopropyl-N-(4-fluoro-2-methanesulfonylphenyl)pyrimidine-5-carbox- amide (Example 16, 0.1 g, 0.176 mmol, 54%, white solid, UPLC long elution (Polar long method; buffer type “FA”) purity: 95.80%, m / z [M+H]+: 546.2).1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 77:23). Major rotamer: δ 8.45 (s, 2H), 8.29 – 8.10 (m, 2H), 7.84 (dd, J = 8.2, 2.9Hz, 1H), 7.59 – 7.44 (m, 2H), 7.40 (dd, J = 8.8, 5.0 Hz, 1H), 7.35 – 7.27 (m, 1H), 6.96 (d, J = 19.3 Hz, 2H), 5.65 (d, J = 14.8 Hz, 1H), 4.68 (d, J = 14.7 Hz, 1H), 4.36 (d, J = 7.6 Hz, 3H), 3.20 (s, 3H), 2.11 (tt, J = 8.1, 4.7 Hz, 1H), 1.16 – 0.88 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ - 109.03 (td, J = 8.0, 4.9 Hz, 1F). Minor rotamer: δ 8.92 (s, 2H), 8.29 – 8.10 (m, 2H), 7.91 (dd, J = 7.9, 2.4 Hz, 1H), 7.59 – 7.44 (m, 1H), 7.35 – 7.27 (m, 1H), 7.27 – 7.20 (m, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 19.3 Hz, 2H), 5.24 (d, J = 16.0 Hz, 1H), 4.76 (d, J = 16.1 Hz, 1H), 4.36 (d, J = 7.6 Hz, 3H), 3.30 (s, 3H), 2.28 (m, 1H), 1.16 – 0.88 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -110.45 – -110.56 (m, 1F). Example 17: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl- N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 116 R10391WO 6-cyclopropyl-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine- 3-carboxamide (Int. 050): To a solution of 8-amino-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran-1,1-dione (Int. 038, 0.181 g, 0.55 mmol, 1.0 eq.), 6-cyclopropylpyridine-3-carboxylic acid (0.10 g, 0.60 mmol, 1.1 eq.), DIPEA (0.240 mL, 1.377 mmol, 2.5 eq.) and DMAP (0.014 g, 0.11 mmol, 0.2 eq.) in anhydrous pyridine (5.0 mL) was added phosphorus oxychloride (0.169 g, 1.102 mmol, 2.0 eq.) dropwise, at 0°. Reaction was stirred at RT for 3 h under nitrogen. The reac- tion was quenched with ice / water and the mixture was neutralized with sat. aq. NaHCO3. It was extracted with mixture of DCM / i-PrOH v / v 3 / 1 (3x) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (0 to 2% MeOH gradient in DCM) to yield 6-cyclopropyl- N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide (Int. 050, 0.153 g, 0.388 mmol, 70%, beige solid, m / z [M+H]+: 379.5).1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.93 (d,J= 2.3 Hz, 1H), 8.12 (dd,J= 8.2, 2.3 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.91 (t, J = 8.0 Hz, 1H), 7.80 (dd, J = 8.0, 1.2 Hz, 1H), 7.50 (dd, J = 8.2, 0.9 Hz, 1H), 3.99 – 3.85 (m, 2H), 3.10 – 2.94 (m, 2H), 2.22 (tt, J = 7.9, 4.9 Hz, 1H), 1.11 – 0.97 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -84.48 (t, J = 13.7 Hz, 2F). N-({4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide (Int. 051): To 6-cyclopropyl-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8- yl)pyridine-3-carboxamide (Int. 050, 0.131 g, 0.332 mmol, 1.0 eq.) in anhydrous acetonitrile (5.0 mL) was added Cs2CO3(0.217 g, 0.665 mmol, 2.0 eq.) followed by 7-(bromomethyl)-4- chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline (Int. 033, 0.120 g, 0.382 mmol, 1.15 eq.). Reac- tion was heated at 60°C for 30 min. Reaction mixture was diluted with water and extracted with EtOAc. Organic layers were combined, washed with brine and dried over Na2SO4, fil- Ryvu Therapeutics S.A. RVU305 117 R10391WO tered and concentrated in vacuo. Crude product was purified by FCC (0 to 2% MeOH gradi- ent in DCM) to give obtain N-({4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)- 6-cyclopropyl-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine- 3-carboxamide (Int. 051, 0.202 g, 0.332 mmol, 100%, beige solid, m / z [M+H]+: 609.1).1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 7.95 (s, 1H), 7.78 (t, J = 10.6 Hz, 2H), 7.59 (q, J = 8.6, 7.7 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 5.97 (d, J = 15.3 Hz, 1H), 4.76 (d, J = 15.2 Hz, 1H), 4.50 (d, J = 3.3 Hz, 3H), 4.00 (t, J = 6.1 Hz, 2H), 3.08 (dt, J = 21.4, 7.1 Hz, 2H), 2.03 (s, 1H), 0.89 (d, J = 36.2 Hz, 4H).19F NMR (376 MHz, DMSO-d6) δ -80.39 – -81.43 (m, 1F), -84.70 (d, J = 272.5 Hz, 1F). 6-cyclopropyl-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-N-[(4- {[(3,4-dimethylphenyl)methyl]amino}-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl)methyl]pyr- idine-3-carboxamide (Int. 052): A solution of N-({4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclo- propyl-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-car- boxamide (Int. 051, 0.208 g, 0.368 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.155 g, 0.937 mmol, 3.0 eq.) in 1,4-dioxane (10 mL) was heated at 110°C for 4 days. Re- action mixture was evaporated to dryness. The residue was purified by FCC (0 to 2.5% MeOH gradient in DCM) to yield 6-cyclopropyl-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H- 1λ⁶-benzothiopyran-8-yl)-N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1-methyl-1H-pyra- zolo[4,3-c]quinolin-7-yl)methyl]pyridine-3-carboxamide (Int. 052, 0.231 g, 0.313 mmol, 100%, beige solid, m / z [M+H]+: 739.3).1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.80 – 7.70 (m, 2H), 7.61 – 7.47 (m, 2H), 7.43 (s, 1H), 7.21 (dd, J = 8.8, 5.2 Hz, 2H), 7.12 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.3, 2.4 Hz, 1H), 5.95 (d, J = 14.9 Hz, 1H), 4.68 – 4.51 (m, 3H), 4.36 (s, 3H), 3.99 (s, 2H), 3.83 (s, 3H), 3.73 (s, 3H), 3.18 – 2.93 (m, 2H), 2.01 (d,J= 8.1 Hz, 1H), 1.08 – 0.75 (m, 4H).19F NMR (376 MHz, DMSO- d6) δ -80.14 – -81.09 (m, 1F), -84.25 – -85.33 (m, 1F). N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide (Ex- ample 17): A 6-cyclopropyl-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)- N-[(4-{[(2,4-dimethoxyphenyl)methyl]amino}-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl)me- thyl]pyridine-3-carboxamide (Int. 052, 0.231 g, 0.313 mmol, 1.0 eq.) was dissolved in a mix- ture of DCM (10 mL) and TFA (2.0 mL). The resulting mixture was stirred at RT overnight. Reaction mixture was quenched by addition saturated aqueous solution of NaHCO3(until pH 8), and aqueous phase was extracted with DCM (3x). Combined organic layers were dried over Na2SO4, filtered and concentrated. From this material product was isolated by FCC (0 to 7% MeOH gradient in DCM). Then product was triturated with EtOH, evaporated to dryness and triturated with water. After lyophilization the following were obtained N-({4- amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4,4-difluoro-1,1- dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide (Example 17, 0.14 g, 0.238 mmol, 76%, white solid, UPLC long elution (Polar long method; buffer type “FA”) purity: 100%, m / z [M+H]+: 589.2). Ryvu Therapeutics S.A. RVU305 118 R10391WO1H NMR (400 MHz, DMSO-d6) a mixture of restricted C-N amide rotation isomers at RT (rel-ative ratio 3:1). Major rotamer: δ 8.38 (s, 1H), 8.23 (d, J = 11.2 Hz, 2H), 7.90 – 7.73 (m, 1H),7.73 – 7.47 (m, 2H), 7.43 (s, 1H), 7.37 – 6.72 (m, 5H), 5.94 (d, J = 15.1 Hz, 1H), 4.59 (d, J = 15.1 Hz, 1H), 4.37 (s, 3H), 4.00 (m, 2H), 3.19 – 2.91 (m, 2H), 2.02 (m, 1H), 0.92 (m, J = 36.8,30.0 Hz, 4H). 19F NMR (376 MHz, DMSO-d6) δ -80.12 – -81.11 (m, 1F), -84.24 – -85.17 (m,1F). Minor rotamer: δ 8.76 (s, 1H), 8.23 (d, J = 11.2 Hz, 2H), 8.00 (s, 1H), 7.90 – 7.73 (m,1H), 7.73 – 7.47 (m, 2H), 7.37 – 6.72 (m, 5H), 5.29 (d, J = 14.2 Hz, 1H), 4.75 (d, J = 10.2 Hz, 1H), 4.37 (s, 3H), 4.00 (m, 2H), 3.19 – 2.91 (m, 2H), 2.19 (m, 1H), 0.92 (m, J = 36.8, 30.0 Hz, 4H).19F NMR (376 MHz, DMSO-d6) δ -83.58 (d, J = 271.3 Hz, 1F), -84.94 (d, J = 99.8 Hz, 1F). Example 18: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl- N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyrimidine-5-carbox- amide 2-cyclopropyl-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyrimi- dine-5-carboxamide (Int. 053): To a solution of 8-amino-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran-1,1-dione (Int. 038, 0.255 g, 1.071 mmol, 1.0 eq.), 2-cyclopropylpyrimidine-5-carboxylic acid (0.182 g, 1.11 mmol, 1.05 eq.) and DMAP (0.035 g, 0.286 mmol, 0.3 eq.) in anhydrous pyridine (5.5 mL) was added phosphorus oxychloride (0.325 g, 2.12 mmol, 2.0 eq.) dropwise, at RT. Reac- tion was stirred at RT for 1 h under nitrogen. The reaction was quenched with ice / water and the mixture was neutralized with sat. aq. NaHCO3 / 1 M NaOH mixture. It was extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (0 to 70% EtOAc gradient in hexane) to yield 2-cyclopropyl-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H- 1λ⁶-benzothiopyran-8-yl)pyrimidine-5-carboxamide (Int. 053, 0.3 g, 0.767 mmol, 72%, beige solid, m / z [M+H]+: 380.4).1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.07 (s, 2H), 7.94 – 7.89 (m, 2H), 7.85 (dd, J 3.3 Hz, 1H), 3.95 – 3.87 (m, 2H), 3.10 – 2.95 (m, 2H), 2.33 (tt, J = 7.9, 4.7 Hz, 1H), 1.21 Ryvu Therapeutics S.A. RVU305 119 R10391WO – 1.15 (m, 2H), 1.14 – 1.07 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -84.62 (t, J = 13.5 Hz, 2F). N-({4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyrimidine-5-carboxamide (Int. 054): To 2-cyclopropyl-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8- yl)pyrimidine-5-carboxamide (Int. 053, 0.202 g, 0.516 mmol, 1.0 eq.) in anhydrous acetoni- trile (5.0 mL) was added Cs2CO3(0.27 g, 0.829 mmol, 1.60 eq.) followed by 7-(bromome- thyl)-4-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline (Int.033, 0.168 g, 0.541 mmol, 1.05 eq.). Reaction was heated at 70°C for 1h. Reaction mixture was diluted with water and ex- tracted with DCM. Organic layers were combined, wa...

Claims

Ryvu Therapeutics S.A. RVU305 302 R10391WO Claims 1. A compound of formula (I) or a salt, stereoisomer,thereof; wherein A is a moiety selected fromthe wavy line in each case marks the connection to the N-atom of the remainder of the mol- ecule; and wherein A1is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clic or 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 sub- stitutable carbon or heteroatom in the aforementioned rings is independently unsub- stituted or substituted with one or more, same or different substituents RA1; A2is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocy- clic or 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 sub- stitutable carbon or heteroatom in the aforementioned rings is independently unsub- stituted or substituted with one or more, same or different substituents RA2; and wherein the dashed lines in the rings A1and A2, as well as between E1and E2, and be- tween E2and E3, denote that an additional bond may be present, so that a double bond is formed; and wherein B is a 5- to 7-membered saturated, partially or fully unsaturated, or aromatic carbocy- clic or 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 sub- stitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB; Y is C or N;Ryvu Therapeutics S.A. RVU305 303 R10391WO and wherein E1is CRE1a, CRE1aRE1b, O, S, N, or NRN1; E2is CRE2a, CRE2aRE2b, O, S, N, or NRN2; E3is CRE3a, CRE3aRE3b, O, S, N, or NRN3; X3is CH, CRX3, or N; X4is CH, CRX4, or N; X5is CH, CRX5, or N; R1is 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 un- saturated, or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy-C1-C2-al- kyl, heterocyclyl, heterocyclyl-C1-C2-alkyl, or heterocyclyloxy-C1-C2-alkyl, wherein the aforementioned heterocyclic 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-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; R2is halogen, CN, S(=O)2RS, S(=O)(=NH)RS, C(=O)RC, NHC(=O)RC, C(=O)NRN4RN5, C1- C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C6-hydroxyalkyl, or a 5- or 6-mem- bered saturated, partially or fully unsaturated, or aromatic heterocyclyl, 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-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 RA2; R3ais H, or D; R3bis H, or D; and wherein RA1is halogen, CN, OH, S(=O)2RS, C(=O)RC, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, or 3- to 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 aforemen- tioned rings is independently unsubstituted or substituted with one or more, same or different substituents RA2; or two RA1together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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 un- substituted or substituted with one or more, same or different substituents RA2; RA2is halogen, CN, OH, C1-C4-alkyl, C1-C4-alkoxy, or C1-C4-haloalkyl; RBis halogen, CN, OH, C1-C4-alkyl, or C1-C4-haloalkyl; or two RBattached to the same atom form an oxo group; RCis H, or C1-C4-alkyl;Ryvu Therapeutics S.A. RVU305 304 R10391WO RE1a, RE1b, RE2a, RE2b, RE3a, and RE3bare independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN1, RN2and RN3are independently H, C1-C4-alkyl, or C1-C4-haloalkyl; RN4is H, or C1-C4-alkyl; RN5is H, or C1-C4-alkyl; RSis C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C5-cycloalkyl, or NRN4RN5; RX3, RX4, and RX5are 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-hydroxy- alkyl; RYis halogen, CN, OH, NRN4RN5, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloal- koxy, C1-C4-hydroxyalkyl, C1-C4-alkoxy-C1-C4-alkoxy, or 3- to 10-membered satu- rated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C1-C2-alkyl, carbocyclyloxy, heterocyclyl, heterocyclyloxy, or heterocyclyl-C1-C2-alkyl, or 5- to 10- membered saturated carbobicyclyl or hetereobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl 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-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 RYattached to the same atom form an oxo group; or two RYtogether with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or heter- ocyclyl, 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; RZis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or 3- to 6-membered satu- rated carbocyclyl, carbocyclyloxy, heterocyclyl, or heterocyclyloxy, wherein the afore- mentioned 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 RZattached to the same atom form an oxo group.

2. The compound according to claim 1, wherein E1is CRE1a, CHRE1a, or NRN1; E2is O or N; E3is CRE3a, CHRE3a, or NRN3; X3is CH, CRX3, or N; X4is CH; X5is CH; and wherein preferably RE1a, RE3a, RN1, and RN3are independently H or C1-C2-alkyl.

3. The compound according to claim 1 or 2, wherein the compound is a compound of formula (Ia*), (Ib*), or (Ic*)Ryvu Therapeutics S.A. RVU305 305 R10391WO4. The compound according to any one of claims 1 to 3, wherein the compound is a compound of formula (Ic*-1)5. The compound according to any one of claims 1 to 3, wherein the compound is a compound of formula (Ia*-1) or (Ia*-2)6. The compound according to any one of claims 1 to 5, wherein X3is CH or CRX3, preferably CH.

7. The compound according to any one of claims 1 to 6, wherein R2is halogen, S(=O)2RS, C1-C2-alkoxy, or C1-C2-haloalkyl; and wherein preferably RSis C1-alkyl.

8. The compound according to any one of claims 1 to 7, wherein R2is S(=O) S 2R and wherein preferably RSis C1-alkyl.

9. The compound according to any one of claims 1 to 8, wherein A1is phenyl, pyridinyl, or pyrazolyl; wherein the phenyl, pyridinyl, or pyrazolyl is independently unsubstituted or substi- tuted with one or more, same or different, substituents RA1; wherein preferablyRyvu Therapeutics S.A. RVU305 306 R10391WO RA1is halogen, C1-C2-alkyl, or cyclopropyl; and A2is phenyl, pyridinyl, or pyrazolyl; wherein the phenyl, pyridinyl, or pyrazolyl is independently unsubstituted or substi- tuted with one or more, same or different, substituents RA2; wherein preferably the phenyl, pyridinyl, or pyrazolyl is unsubstituted.

10. The compound according to any one of claims 1 to 9, wherein A1is phenyl or pyridinyl; wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, same or different, substituents RA1; wherein preferably RA1is halogen; and A2is phenyl or pyridinyl; wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, same or different, substituents RA2; wherein preferably the phenyl or pyridinyl is unsubstituted.

11. The compound according to any one of claims 1 to 10, wherein A is a moiety selected from wherein Z O; B1partially or fully unsaturated, or aromatic heterocy- clic 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 carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB1; wherein RB1is halogen, CN, OH, C1-C4-alkyl, or C1-C4-haloalkyl; and wherein preferably RB1is halogen.

12. The compound according to any one of claims 1 to 11, wherein A is a moiety selected from B1partially or fully unsaturated, or aromatic heterocy-heterocyclic ring comprises one or more, sameRyvu Therapeutics S.A. RVU305 307 R10391WO 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 cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB1; wherein RB1is halogen, CN, OH, C1-C4-alkyl, or C1-C4-haloalkyl; and wherein preferably Y is C; and RB1is halogen.

13. The compound according to any one of claims 1 to 12, whereinA1is selected from the group consisting ofRA1is C1-C2-alkyl or cyclopropyl; and wherein preferably RA1is CH3.

14. The compound according to any one of claims 1 to 13, wherein A is a moiety selected from the group consisting ofRyvu Therapeutics S.A. RVU305 308 R10391WO15. The compound according to any one of claims 1 to 14, wherein R1is 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 each substitutable carbon or heteroatom in the aforemen- tioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; and wherein preferably RYis halogen, CN, C1-C2-haloalkyl, or cyclopropyl.

16. The compound according to any one of claims 1 to 15, wherein R1is pyridinyl, or pyrimidinyl; and wherein preferably the pyridinyl or pyrimidinyl is independently unsubstituted or substi- tuted with one substituent selected from F, CN, CF3, or cyclopropyl.

17. The compound according to any one of claims 1 to 16, wherein R1is .

18. The compound according to any one of claims 1 to 17, wherein the compound of for- mula (I) is selected from the group consisting of: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide; N-({4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylphenyl)pyridine- 3-carboxamide; and N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide.Ryvu Therapeutics S.A. RVU305 309 R10391WO 19. The compound according to any one of claims 1 to 17, wherein the compound of for- mula (I) is selected from the group consisting of: N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyri- din-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyano-N-(4,4-difluoro- 1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(4-fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-me- thanesulfonyl-4-methylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-2-(trifluoromethyl)pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyano-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-2-(4-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxamide;Ryvu Therapeutics S.A. RVU305 310 R10391WO N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-5-cyclopropyl-N-(4-fluoro- 2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-6-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N- (4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-5-methoxypyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methanesulfonyl- 4-methylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclobutyl-N-(4-fluoro-2- methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-(3,3-difluoropyrrolidin-1- yl)-N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methanesulfonyl- 4-methylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(trifluorome- thyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro- 2-methoxyphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4,4-difluoro-1,1-di- oxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyrimidine-5-carboxamide; rac-N-({4-amino-1-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(1S)-4-amino-1-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(1R)-4-amino-1-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide;Ryvu Therapeutics S.A. RVU305 311 R10391WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4-fluoro-2-methoxy- phenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(4,4-difluoro-1,1-di- oxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-benzothiopyran-8-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methoxypyridin-3- yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- [1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-fluoro-2-me- thanesulfonylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-N-(4-fluoro-2-methanesul- fonylphenyl)-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-N-(1,1-dioxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4- fluoro-2-methanesulfonylphenyl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(difluorome- thyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(2- methanesulfonylpyridin-3-yl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-(1,1- dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,1- dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(1,1- dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropoxy-N-(4- fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-4- yl)-2-cyclopropylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-(1-cyanocyclopropyl)-N-(4-fluoro-2- methanesulfonylphenyl)pyridine-3-carboxamide;Ryvu Therapeutics S.A. RVU305 312 R10391WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-oxo-2,3-dihydro- 1H-isoindol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2-methyl-3-oxo-2,3- dihydro-1H-isoindol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluo- romethyl)-1H-pyrazol-4-yl]pyrimidine-5-carboxamide; rac-N-({4-amino-2-methyl-2H,3H-furo[3,2-c]quinolin-7-yl}methyl)-N-(2-methanesul- fonylpyridin-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(4-methoxypyridin-3- yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(2,6-dimethoxypyri- din-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-methoxypyridin-3-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-[2-(trifluoromethyl)pyridin- 3-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyano-4-fluorophenyl)-2-cyclo- propylpyrimidine-5-carboxamide; rac-N-({4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(tri- fluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(2- methanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-6-cyclopropyl-N-(2- methanesulfonylpyridin-3-yl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(4-cyanopyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(3-methoxy-1-me- thyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-cyano-1-methyl-1H-pyrazol-4- yl)-6-cyclopropylpyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-cyanopyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide; N-({4-amino-2H,3H-furo[3,2-c]quinolin-7-yl}methyl)-N-(2-methanesulfonylpyridin-3-yl)-6- (trifluoromethyl)pyridine-3-carboxamide; N-{[(3S)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-[2-(tri- fluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-{[(3R)-4-amino-3-methyl-1H,3H-furo[3,4-c]quinolin-7-yl]methyl}-2-cyclopropyl-N-[2- (trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-5-cyano-N-[2-(trifluoromethyl)pyridin- 3-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-methoxypyrazin-2-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxa- zin-3-yl}-6-(trifluoromethyl)pyridine-3-carboxamide;Ryvu Therapeutics S.A. RVU305 313 R10391WO N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(difluorometh- oxy)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyano-N-[1-cyclopropyl-3-(trifluoro- methyl)-1H-pyrazol-4-yl]pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-{5H,6H,7H-pyra- zolo[3,2-b][1,3]oxazin-3-yl}pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(5-chloro-1-methyl-1H-pyrazol-4- yl)-2-cyclopropylpyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-methyl-1H-pyrazol-4- yl)-6-(trifluoromethyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(5-fluoro-2-methoxy- pyridin-3-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[3-(difluoromethyl)- 1-methyl-1H-pyrazol-4-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-(1-cyclopropyl-3- methoxy-1H-pyrazol-4-yl)pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[2-(methoxyme- thyl)phenyl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-carbamoyl-1-methyl-1H-pyrazol- 4-yl)-6-cyclopropylpyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[(1R,2R)-2-hydroxy- 2,3-dihydro-1H-inden-1-yl]pyrimidine-5-carboxamide; N-({4-amino-9-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-7-yl}methyl)-6-cyclopropyl-N- (4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(3-chloro-1-cyclopropyl-1H-pyrazol- 4-yl)-6-cyanopyridine-3-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[6-(4-methylpiper- azin-1-yl)-2-(trifluoromethyl)pyridin-3-yl]pyrimidine-5-carboxamide; N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-6-cyclopropyl-N-{5-methyl-4-oxo- 4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-3-yl}pyridine-3-carboxamide; N-({4-aminofuro[3,2-c]quinolin-7-yl}methyl)-2-cyclopropyl-N-[1-methyl-3-(trifluorome- thyl)-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-(3- methoxy-1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamide; and N-({4-amino-1H,3H-furo[3,4-c]quinolin-7-yl}methyl)-N-(2-chloropyridin-3-yl)-2-cyclo- propylpyrimidine-5-carboxamide.

20. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 19 and optionally a pharmaceutically ac- ceptable carrier, diluent or excipient.

21. A compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20 for use in medicine.Ryvu Therapeutics S.A. RVU305 314 R10391WO 22. A compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20 for use in the treatment of a disease selected from the group consist- ing of cancer and pre-cancerous syndromes.

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