Ryvu Therapeutics S.A. RVU305 1 R10107WO 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 R10107WO 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, tautomer, atropisomer, rotamer, or N-oxide thereof; wherein A is a moiety selected from Ryvu Therapeutics S.A. RVU305 3 R10107WO wherein the wavy line in each case marks the connection to the N-atom of the remainder of the mol- ecule; and wherein A ¹ is 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 R ^A1 ; A ² is 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 R ^A2 ; and wherein the dashed lines in the rings A ¹ and A ² 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 R ^B ; Y is C or N; and wherein X ¹ is CH, CR ^X1 , or N; X ² is CH, CR ^X2 , or N; X ³ is CH, CR ^X3 , or N; X ⁴ is CH, CR ^X4 , or N; X ⁵ is CH, CR ^X5 , or N; R ¹ is NR ^N1 R ^N2 , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ - hydroxyalkyl, C ₁ -C ₄ -aminoalkyl, or 3- to 10-membered saturated, partially or fully un- saturated, or aromatic carbocyclyl, carbocyclyl-C ₁ -C ₂ -alkyl, carbocyclyloxy-C ₁ -C ₂ -al- kyl, heterocyclyl, heterocyclyl-C ₁ -C ₂ -alkyl, or heterocyclyloxy-C ₁ -C ₂ -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 R ^Y ; Ryvu Therapeutics S.A. RVU305 4 R10107WO R ² is halogen, CN, S(=O) ₂ R ^S , C(=O)R ^C , NHC(=O)R ^C , C(=O)NR ^N1 R ^N2 , C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - haloalkyl, C ₁ -C ₄ -haloalkoxy, C ₁ -C ₆ -hydroxyalkyl, or a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non- oxidized, and wherein each substitutable carbon or heteroatom in the aforemen- tioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^A2 ; R ^3a is H, or D; R ^3b is H, or D; and wherein R ^A1 is halogen, CN, OH, S(=O) ₂ R ^S , C(=O)R ^C , C ₁ -C ₄ -alkyl, or C ₁ -C ₄ -haloalkyl; or two R ^A1 together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or 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 R ^A2 ; R ^A2 is halogen, CN, OH, C ₁ -C ₄ -alkyl, or C ₁ -C ₄ -haloalkyl; R ^B is halogen, CN, OH, C ₁ -C ₄ -alkyl, or C ₁ -C ₄ -haloalkyl; or two R ^B attached to the same atom form an oxo group; R ^C is H, or C ₁ -C ₄ -alkyl; R ^N1 is H, or C ₁ -C ₄ -alkyl; R ^N2 is H, or C ₁ -C ₄ -alkyl; R ^S is C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl, C ₃ -C ₅ -cycloalkyl, or NR ^N1 R ^N2 ; R ^X1 , R ^X2 , R ^X3 , R ^X4 , and R ^X5 are independently halogen, CN, NH ₂ , C(=O)NH ₂ , CD ₃ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -haloalkoxy, or C ₁ -C ₄ - hydroxyalkyl; R ^Y is halogen, CN, OH, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -haloalkoxy, C ₁ - C ₄ -hydroxyalkyl, or 3- to 10-membered saturated, partially or fully unsaturated, or ar- omatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different sub- stituents R ^Z ; or two R ^Y attached to the same atom form an oxo group; or two R ^Y together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or 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; R ^Z is halogen, CN, C ₁ -C ₄ -alkyl, or C ₁ -C ₄ -haloalkyl; or two R ^Z attached to the same atom form an oxo group. Ryvu Therapeutics S.A. RVU305 5 R10107WO In a preferred embodiment, the compound of formula (I) is not In a more preferred embodiment of the compounds of formula (I), the proviso applies that if X ¹ is CH or CR ^X1 ; wherein R ^X1 is Br, F, C ₁ -C ₂ -alkyl, or CF ₃ ; X ² is CH or CR ^X2 ; wherein R ^X2 is C ₁ -C ₂ -alkyl; X ³ is N; X ⁴ is CH; X ⁵ is CH; and R ¹ is C ₁ -C ₂ -alkyl; then A is not unsubstituted naphthyl or naphthyl substituted with cyano. In another preferred embodiment of the compounds of formula (I), X ¹ is CH, CR ^X1 , or N; X ² is CH, CR ^X2 , or N; X ³ is CH, CR ^X3 , or N; X ⁴ is CH; X ⁵ is CH; wherein preferably R ^X1 , R ^X2 , and R ^X3 are independently halogen, CN, NH ₂ , C(=O)NH ₂ , CD ₃ , C ₁ -C ₂ -alkyl, C ₁ -C ₂ - alkoxy, C ₁ -C ₂ -haloalkyl, or C ₁ -C ₂ -hydroxyalkyl. In a more preferred embodiment, X ¹ is CH or CR ^X1 ; X ² is CH; X ³ is CH or CR ^X3 ; X ⁴ is CH; X ⁵ is CH; or wherein X ¹ is CH or CR ^X1 ; X ² is N; X ³ is CH; X ⁴ is CH; X ⁵ is CH; or wherein X ¹ is CH or CR ^X1 ; X ² is CH; X ³ is N; X ⁴ is CH; X ⁵ is CH; and wherein preferably R ^X1 is halogen, CN, C(=O)NH ₂ , CD ₃ , C ₁ -C ₂ -alkyl, C ₁ -C ₂ -haloalkyl, or C ₁ -C ₂ -hydroxyalkyl; R ^X3 is halogen. Ryvu Therapeutics S.A. RVU305 6 R10107WO In another preferred embodiment, R ¹ is C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₂ -aminoal- kyl, or 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclyl, carbocyclyl-C ₁ -C ₂ -alkyl, carbocyclyloxy-C ₁ -C ₂ -alkyl, heterocyclyl, or heterocy- clyl-C ₁ -C ₂ -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 R ^Y ; and wherein preferably R ^Y is halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, 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 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 R ^Z ; or two R ^Y attached to the same atom form an oxo group; or two R ^Y together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or 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; R ^Z is halogen or C ₁ -alkyl; or two R ^Z attached to the same atom form an oxo group. In a more preferred embodiment, R ¹ is CH ₃ , pyridinyl, or pyrimidinyl; and wherein preferably the pyridinyl or pyrimidinyl is independently unsubstituted or substi- tuted with one or more, same or different substituents selected from halogen, CH ₃ , or CF ₃ . In another preferred embodiment, R ² is halogen, CN, S(=O) ₂ R ^S , C(=O)R ^C , C(=O)NR ^N1 R ^N2 , C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, C ₁ - C ₂ -haloalkoxy, or C ₁ -C ₂ -hydroxyalkyl; and wherein R ^C is H, or C ₁ -alkyl; R ^N1 is H, or C ₁ -alkyl; R ^N2 is H, or C ₁ -alkyl; R ^S is C ₁ -C ₂ -alkyl, C ₃ -C ₅ -cycloalkyl, or NR ^N1 R ^N2 . In a more preferred embodiment, R ² is S(=O) ₂ R ^S ; wherein preferably R ^S is C ₁ -alkyl. In another preferred embodiment, A ¹ is phenyl, pyridinyl, pyrazolyl, or thiophenyl; A ² is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl. In another preferred embodiment, Ryvu Therapeutics S.A. RVU305 7 R10107WO 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 R ^B . In a more 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 R ^B ; and R ² is S(=O) ₂ R ^S ; wherein preferably R ^S is C ₁ -alkyl. In another more 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 R ^B ; and, if present, R ^A1 is halogen, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl; or two R ^A1 together 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 another preferred embodiment, R ^A1 is halogen, CN, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl; or two R ^A1 together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or 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; R ^A2 is halogen, CN, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl; R ^B is halogen, CN, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl; or two R ^B attached to the same atom form an oxo group. In another preferred embodiment, A is a moiety selected from the group consisting of Ryvu Therapeutics S.A. RVU305 8 R10107WO In another preferred embodiment, the compound of formula (I) is selected from the group consisting of: N-[(2-aminoquinolin-7-yl)methyl]-N-(1H-indazol-7-yl)pyridine -3-carboxamide, Ryvu Therapeutics S.A. RVU305 9 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-(2-ethoxy-4-fluorophenyl) pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-2-cyclopropoxy-N-(2-methane sulfonylpyridin-3-yl)acet- amide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-{1,1-dioxo-2H,3H -1λ⁶-thieno[3,2-b]pyridin- 7-yl}acetamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfon ylphenyl)-2-methylpyrimi- dine-5-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4,4-difluoro-1,1-dioxo-3 ,4-dihydro-2H-1λ⁶-benzothi- opyran-8-yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfon ylphenyl)-6-methylpyridine- 3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfon ylphenyl)-6-methylpyri- dazine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonyl-5-meth ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(trifluoromethyl)pyrid in-3-yl]pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-N-(5-fluoro-2-methanesulfon ylpyridin-3-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-7-yl)py ridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)pyr- idine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)butanamide, N-[(2-amino-6-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-carbox- amide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)pyridine- 3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-methanesulfonylpyridin -4-yl)pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methoxyphenyl )pyridine-3-carboxamide, N-[(2-amino-4-cyanoquinolin-7-yl)methyl]-N-(2-methanesulfony lphenyl)pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-3,3-difluoro-N-(2-methanesu lfonylpyridin-3-yl)bu- tanamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-{5H,6H,7H-pyrazo lo[3,2-b][1,3]oxazin-3- yl}pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-methanesulfonyl-5-(tri fluoromethyl)pyridin-3- yl]pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)acetamide, Ryvu Therapeutics S.A. RVU305 10 R10107WO N-[(2-amino-3-methylquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide, N-[(2-amino-5-bromoquinolin-7-yl)methyl]-N-(2-methanesulfony lpyridin-3-yl)pyridine-3- carboxamide, N-{[2-amino-4-(hydroxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesulfonylphenyl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1-methyl-1H-1,3-benzodia zol-4-yl)pyridine-3-carbox- amide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4,4-difluoro-1,1-dioxo-3 ,4-dihydro-2H-1λ⁶-benzothi- opyran-8-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(quinolin-8-yl)acetamide, N-{[2-amino-3-(²H₃)methylquinolin-7-yl]methyl}-N-(2-metha nesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2,3-dihydro-1,4-benzodio xin-5-yl)pyridine-3-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-ethyl-2-methanesulfony lphenyl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-4-yl)py ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-6-(trifluoromethyl)py- ridazine-3-carboxamide, N-[(2-amino-5-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2,3-dihydro-1-benzofuran -7-yl)pyridine-3-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-[5-carbamoyl-1-(difluorom ethyl)-1H-pyrazol-4-yl]pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) imidazo[1,2-a]pyrimidine-6- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-{1,1-dioxo-2H,3H-1λ⁶-t hieno[3,2-b]pyridin-7- yl}acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1� �⁶-benzothiophen-7-yl)-2- oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-4-carboxami de, ethyl N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)carbamate, N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(2-methanesulfony lpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-cyano-2-methanesulfony lphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-methyl-1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)acetamide, N-[(2-aminoquinolin-7-yl)(²H₂)methyl]-N-(2-methanesulfony lphenyl)pyridine-3-carboxa- mide, Ryvu Therapeutics S.A. RVU305 11 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-6-methylpyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-methanesulfonyl-4-(tri fluoromethyl)phenyl]pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylquinoli n-3-yl)acetamide, N-{[2-amino-3-(hydroxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesulfonylphenyl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2,3-dihydro-1-benzofuran -7-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-4,4,4-trifluoro-N-(2-methan esulfonylpyridin-3-yl)butana- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -1,3-thiazole-5-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-(trifluoromethyl)py- rimidine-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-methylpropana- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-1λ⁶-benzoth iophen-7-yl)acetamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(3-methyl-1,1-di oxo-2H-1λ⁶,2,4-benzothia- diazin-8-yl)pyridine-3-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-{4,4-dioxo-5H,6H ,7H-4λ⁶-pyrazolo[3,2- b][1,3]thiazin-3-yl}pyridine-3-carboxamide, N-{[2-amino-3-(difluoromethyl)quinolin-7-yl]methyl}-N-(2-met hanesulfonylphenyl)pyridine- 3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) butanamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1� �⁶-benzothiophen-7-yl)-1- methyl-2-oxo-1,2-dihydropyridine-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-chloro-1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)propanamide, N-{[2-amino-5-(trifluoromethyl)quinolin-7-yl]methyl}-N-(2-me thanesulfonylpyridin-3-yl)py- ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-methoxyacetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -1-methyl-1H-pyrazole-4- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(5-fluoro-2-methanesulfon ylphenyl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(5-chloro-2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-6-(difluoromethyl)-N-(2-met hanesulfonylpyridin-3-yl)py- ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)pyridine-3-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-5-(propan-2-yl)-1,2- oxazole-4-carboxamide, Ryvu Therapeutics S.A. RVU305 12 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyrimidine-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-bromo-2-methanesulfony lphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-4-methylpyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-5-fluoro-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(ethanesulfonyl)phenyl ]pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -5-(2-oxopyrrolidin-1-yl)py- ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-5-(trifluoromethyl)py- ridine-3-carboxamide, N-[(2,4-diamino-5-fluoroquinazolin-7-yl)methyl]-N-(1,1-dioxo -2,3-dihydro-1λ⁶-benzothio- phen-7-yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -5-methoxypyridine-3-car- boxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-5-methylpyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyridine-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyridine-2-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-fluoro-2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonyl-5-meth ylphenyl)pyridine-3-car- boxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -1-methyl-2-oxo-1,2-dihy- dropyridine-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(cyclopropanesulfonyl) phenyl]pyridine-3-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -3-methyl-1,2-oxazole-4- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-6-(trifluoromethyl)py- ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyridazine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyridazine-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-5-fluoro-N-(2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -6-oxo-1,6-dihydropyridine- 2-carboxamide, Ryvu Therapeutics S.A. RVU305 13 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)pyrazolo[1,5-a]pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-3,3-difluoro-N-(2-methanesu lfonylpyridin-3-yl)cyclobu- tane-1-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-5-chloro-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, 4-{N-[(2-aminoquinolin-7-yl)methyl]-3-(pyridin-2-yl)propanam ido}-1-methyl-1H-pyrazole- 3-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1� �⁶-benzothiophen-7-yl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)oxane-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(dimethylsulfamoyl)phe nyl]pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyrimidine-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-4H,5H,6H-pyrrolo[1,2- b]pyrazole-2-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-methanesulfonyl-1-meth yl-1H-pyrazol-3-yl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) oxetane-3-carboxamide, (2R)-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylph enyl)oxolane-2-carboxa- mide, (2S)-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylph enyl)oxolane-2-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-oxo-2,3-dihydro-1H-iso indol-4-yl)pyridine-3-car- boxamide, 4-{N-[(2-aminoquinolin-7-yl)methyl]-3-(pyridin-4-yl)propanam ido}-1-methyl-1H-pyrazole- 3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-carbamoyl-1-methyl-1H- pyrazol-4-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyrazine-2-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[5-(hydroxymethyl)-1-meth yl-1H-pyrazol-4- yl]acetamide, 4-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}-1-methyl-1H-py razole-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -2-(1H-pyrazol-1- yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonyl-4-meth ylphenyl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-sulfamoylphenyl)acetam ide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1� �⁶-benzothiophen-7- yl)acetamide, N-[(2-amino-3-methylquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-methanesulfonylpyridin -3-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-{3-cyano-5H,6H,7H-cyclope nta[b]pyridin-2- yl}acetamide, Ryvu Therapeutics S.A. RVU305 14 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-{5-cyano-1H,3H,4H-pyrano[ 3,4-c]pyridin-6- yl}acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)cyclopropanecarboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -3-(1H-pyrazol-1-yl)propa- namide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphe nyl)oxolane-2-carboxa- mide, 4-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}-1-methyl-1H-py razole-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -5-methyl-1,2-oxazole-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-methanesulfonylthiophe n-2-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)acetamide, N-[(2,4-diaminoquinazolin-7-yl)methyl]-N-(2-methanesulfonylp henyl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[3-(hydroxymethyl)-1-meth yl-1H-pyrazol-4- yl]acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(1-hydroxyethyl)phenyl ]acetamide, and N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) acetamide. In another preferred embodiment, the compound of formula (I) is selected from the group consisting of: N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶,2-benzothiazol-7- yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzoxazol-4-yl)pyri dine-3-carboxamide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-(5,6,7,8-tetrahydroqu inolin-8-yl)pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-N-[4-fluoro-2-(trifluoromet hyl)phenyl]pyridine-3-carbox- amide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-[3-fluoro-1,1-dioxo-2 ,3-dihydro-1λ⁶-benzothio- phen-7-yl]acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(trifluoromethoxy)phen yl]acetamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(5-fluoro-2-meth anesulfonylphenyl)pyridine- 3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-chloro-4-fluorophenyl) pyridine-3-carboxamide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-[3-hydroxy-2,3-dihydr o-1H-inden-4-yl]pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-fluoro-2-methoxyphenyl )pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1� �⁶-benzothiophen-7-yl)pro- panamide , N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(1,1-di oxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)pyridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 15 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)propanamide , N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)propanamide , N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(1,3-benzothiazo l-4-yl)pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methoxypyridin-3-yl)py ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-2-cyclopropyl-N-(2-methanes ulfonylpyridin-3-yl)acetam- ide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)pyrimidine-5-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)propanamide , N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-(propan-2-yloxy)ac- etamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,3-benzothiazol-7-yl) pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-4,4,4-trifluorobutanamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -5-(trifluoromethyl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-chloropyridin-3-yl)pyr idine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-2- methylpyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-methylpyr- idine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[(8R)-5,6,7,8-tetrahydroq uinolin-8-yl]pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[(8S)-5,6,7,8-tetrahydroq uinolin-8-yl]pyridine-3-car- boxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)pyrimidine-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(quinoxalin-5-yl)pyridine -3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-methoxypyridin-4-yl)py ridine-3-carboxamide, N-[(2-amino-5-chloroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)- 4,4,4-trifluorobutanamide, N-[(2-aminoquinolin-7-yl)(²H₂)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)pyridine-3-carboxamide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-[5,6,7,8-tetrahydroqu inoxalin-5-yl]pyridine-3-car- boxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4-fluoro-2-meth oxyphenyl)pyridine-3-car- boxamide, Ryvu Therapeutics S.A. RVU305 16 R10107WO N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-(trifluoro- methyl)pyrimidine-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-5-cyano-N-(2-methanesulfony lpyridin-3-yl)pyridine-3- carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth oxyphenyl)pyridine-3-car- boxamide, N-[(6-amino-7-chloro-1,5-naphthyridin-3-yl)methyl]-N-(1,1-di oxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(4,4-difluoro-1,1-dioxo -3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-amino-4-methylquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(quinazolin-8-yl)pyridine -3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-4-yl)pr opanamide , N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-1-methyl-1H-pyrazole-4-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,3-benzothiazol-4-yl) pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonylpheny l)-5-methylpyridine-3-car- boxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3 -dihydro-1λ⁶-benzothio- phen-7-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-5-methylpyridine- 3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)pyridine- 3-carboxamide, N-{[2-amino-4-(trifluoromethyl)quinolin-7-yl]methyl}-N-(1,1- dioxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,3-benzothiazo l-4-yl)pyridine-3-carboxa- mide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,3-benzothiazol-7-yl) -2-(trifluoromethyl)pyrimi- dine-5-carboxamide, N-[(2-aminoquinazolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)py- ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-cyano-4-fluorophenyl)p yridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyrazolo[1,5-a]py- ridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 17 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon yl-5-methylpyridin-3-yl)-5- (trifluoromethyl)pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-5- (trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-(propan-2-yloxy)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-{1-methyl-1H-pyrazolo[4,3 -b]pyridin-3-yl}pyridine-3- carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)oxane-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[(5R)-5,6,7,8-tetrahydroq uinoxalin-5-yl]pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[(5S)-5,6,7,8-tetrahydroq uinoxalin-5-yl]pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-7-yl)-2 -(trifluoromethyl)pyrimidine- 5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-(pyridin-3-yl)-1,3- thiazole-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonylpheny l)-5-(trifluoromethyl)pyri- dine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-methylpyrimi- dine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-1-methyl-1H-py- razole-4-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(2-methanesulfon ylphenyl)-6-(trifluoro- methyl)pyridine-3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(2-methanesulfon ylphenyl)pyrazolo[1,5-a]py- ridine-3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-5-(trifluoromethyl)pyridine-3-carboxami de, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(2-methanesulfon ylphenyl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-1-cyclopropyl-N-(1 ,1-dioxo-2,3-dihydro-1λ⁶- benzothiophen-7-yl)-1H-pyrazole-4-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)pyridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 18 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesulfonylphenyl)pyri- dine-3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(2-methanesulfon yl-5-methylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyano-N-(2-metha nesulfonylphenyl)pyridine- 3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3-carboxami de, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-(trifluoromethyl)pyrimidine-5-carboxa mide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)-1,3-thiazole-4-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6- methoxypyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclopropyl-N-(4 -fluoro-2-methanesul- fonylphenyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-cyclopropyl-N-(4 -fluoro-2-methanesul- fonylphenyl)pyrimidine-5-carboxamide, N-[(6-amino-7-methyl-1,5-naphthyridin-3-yl)methyl]-N-(4,4-di fluoro-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxam ide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(2-metha nesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyclopropyl-N-(4 -fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-(4 -fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyano-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)pyridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 19 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-3-carboxamide, and N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyano-N-(2-metha nesulfonylpyridin-3-yl)pyri- dine-3-carboxamide. In another preferred embodiment, the compound of formula (I) is selected from the group consisting of: N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(difluoromethoxy)pheny l]pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonyl-5-meth ylpyridin-3-yl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonylpheny l)-2-(trifluoromethyl)py- rimidine-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(5-chloro-2-methanesulf onylphenyl)pyrazolo[1,5- a]pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-2-methylpyrimidine-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(5-chloro-2-methanesulf onylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-{1,1-dioxo-2H,3H -1λ⁶-thieno[3,2-b]pyridin- 7-yl}pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonyl-5-me thylpyridin-3-yl)-5-(trifluo- romethyl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-7-yl)-5 -(trifluoromethyl)pyridine-3- carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-5-methylpyrazine-2-carboxamide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-{2H,3H,4H-pyrano[3,2- b]pyridin-4-yl}pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-7-yl)-2 -methylpyrimidine-5-carbox- amide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(4,4-difluoro-1,1-dioxo -3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-6-methylpyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1-oxo-1,2,3,4-tetrahydro isoquinolin-8-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-{[1-(trifluorome- thyl)cyclopropyl]amino}acetamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-6-(trifluorome- thyl)pyridine-3-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(1,3-benzothia zol-7-yl)pyridine-3-carbox- amide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)pyrimidine-5-carboxamide, Ryvu Therapeutics S.A. RVU305 20 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(5-chloro-2-meth anesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-5-methylpyrazine-2-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-{imidazo[1,2-a]pyridin-8- yl}pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon yl-5-methylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(5-chloro-2-methanesulf onylphenyl)-2-methylpyrim- idine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-chloro-2-meth anesulfonylphenyl)-2- methylpyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-1-cyclohexyl-N-(1, 1-dioxo-2,3-dihydro-1λ⁶- benzothiophen-7-yl)-1H-pyrazole-4-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-methylpyridine- 4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-methylpy- rimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyrazolo[1,5-a]pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) imidazo[1,5-a]pyridine-3- carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-5-(trifluoro- methyl)pyrazine-2-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-6-(trifluorome- thyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-1-methyl-1H-pyrazole-4-carboxamide, N-{[2-amino-4-(methoxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesulfonylphenyl)pyri- dine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(5-chloro-2-meth anesulfonylphenyl)-2- methylpyrimidine-5-carboxamide, Ryvu Therapeutics S.A. RVU305 21 R10107WO N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulf onylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-2,6-dimethylpyridine-3-carboxamide, N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(2-meth anesulfonylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-5-fluoro-3-methylquinolin-7-yl)methyl]-N-(2-meth anesulfonylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-methylpyrimi- dine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-2- methylpyrimidine-5-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(5-chloro-2-meth anesulfonylphenyl)-2- methylpyrimidine-5-carboxamide, N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-4-methylpyrimi- dine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-methylpyr- idine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-5-fluoro-N-(2-meth anesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-5-chloro-N-(2-meth anesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulf onylpyridin-3-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulf onylpyridin-3-yl)-5-(trifluo- romethyl)pyridine-3-carboxamide, N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(2-meth anesulfonylpyridin-3-yl)-2- methylpyrimidine-5-carboxamide, N-[(2-amino-5-fluoro-3-methylquinolin-7-yl)methyl]-N-(2-meth anesulfonylpyridin-3-yl)-2- methylpyrimidine-5-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulf onylphenyl)-2-methylpy- rimidine-5-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(4,4-difluoro- 1,1-dioxo-3,4-dihydro-2H- 1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3-ca rboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-4-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-5-(trifluoro- methoxy)pyridine-3-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulf onylphenyl)-6-(trifluorome- thyl)pyridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 22 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2,6-dimethylpyri- dine-4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(5-chloro-2-meth anesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-5-(trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-5-cyano-N-(2-metha nesulfonylphenyl)pyridine- 3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-methylpyridine- 3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-[2-methanesulfon yl-5-(trifluoromethyl)pyri- din-3-yl]pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-1-(pro- pan-2-yl)-1H-pyrazole-4-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3 -dihydro-1λ⁶-benzothio- phen-7-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)- 5H,6H,7H,8H-imidazo[1,2-a]pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-ethyl-N-(4-fluor o-2-methanesul- fonylphenyl)pyrimidine-5-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3 -dihydro-1λ⁶-benzothio- phen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-6-methylpyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-6- (trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-5-cyano-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(propan- 2-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-ethoxy-N-(4-fluo ro-2-methanesul- fonylphenyl)pyridazine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfon ylphenyl)pyrimidine-2-car- boxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-1-(pro- pan-2-yl)-1H-pyrazole-4-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-4,6-di- methylpyridine-3-carboxamide, N-[(6-amino-7-methyl-1,5-naphthyridin-3-yl)methyl]-N-(4-fluo ro-2-methanesul- fonylphenyl)-2-methylpyrimidine-5-carboxamide, Ryvu Therapeutics S.A. RVU305 23 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-chloro-2-meth anesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-2-(pro- pan-2-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6- methylpyridazine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-cyano-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-4-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-2-(oxan- 4-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(pyrimidin- 2-yl)acetamide, N-[(2-amino-1,6-naphthyridin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-{[2-amino-3-(methoxymethyl)quinolin-7-yl]methyl}-6-cyclopr opyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(morpho- lin-4-yl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(oxan-4- yl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-cyclopropyl-N-(4 -fluoro-2-methanesul- fonylphenyl)pyridine-4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-(1 ,1-dioxo-2,3-dihydro-1λ⁶- benzothiophen-7-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-ethoxy-N-(2-meth anesulfonylpyridin-3-yl)pyr- idine-3-carboxamide, rac-N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2- methanesulfonylphenyl)-6- (oxolan-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-1-(pyridin-3- yl)-1H-pyrazole-4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-1,3-benzo- thiazole-6-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-{1,1-dioxo-2H,3H -1λ⁶-thieno[3,2-b]pyridin- 7-yl}-6-(trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(1,1-dio xo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-methyl-5- (trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(mor- pholin-4-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-[6-(trifluo- romethyl)pyridin-3-yl]-1,3-thiazole-5-carboxamide, Ryvu Therapeutics S.A. RVU305 24 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-(1-cyanocyclopro pyl)-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(ox- etan-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-(3,3-difluoropyr rolidin-1-yl)-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-5-chloro-6-cyano-N -(2-methanesulfonylpyridin- 3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclopropyl-N-{1 ,1-dioxo-2H,3H-1λ⁶- thieno[3,2-b]pyridin-7-yl}pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-ethyl-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(2-hy- droxypropan-2-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-5H,6H,7H- cyclopenta[b]pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(pyridin-3- yl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclopropyl-N-(1 ,1-dioxo-2,3-dihydro-1λ⁶- benzothiophen-7-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-{1,1-dio xo-2H,3H-1λ⁶-thieno[3,2- b]pyridin-7-yl}pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-ethyl-N-(2-metha nesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclobutyl-N-(2- methanesulfonylpyridin-3- yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclobutyl-N-(2- methanesulfonylpyridin-3- yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(pyridin-3- yl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-5-cyano-6-cyclopro pyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(2-metha nesulfonyl-4- methylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-{1 ,1-dioxo-2H,3H-1λ⁶- thieno[3,2-b]pyridin-7-yl}pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-5,6,7,8- tetrahydro-1,5-naphthyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-5-fl uoro-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesulfonyl-5- methylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-1-(pyridin-3- yl)-1H-pyrazole-4-carboxamide, Ryvu Therapeutics S.A. RVU305 25 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-(3,3-difluoroaze tidin-1-yl)-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-{[2-amino-3-(trifluoromethyl)quinolin-7-yl]methyl}-6-cyclo propyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-3-fluoro-N-(2-meth anesulfonylpyridin-3-yl)ben- zamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)- 5H,7H,8H-pyrano[4,3-b]pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-2-(mor- pholin-4-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-[1-(trifluo- romethyl)cyclopropyl]pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-5-chloro-6-cyclopr opyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyclopropyl-N-{1 ,1-dioxo-2H,3H-1λ⁶- thieno[3,2-b]pyridin-7-yl}pyridine-3-carboxamide, N-[(2-amino-3-methylquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)pyridine-3-carboxamide, N-[(2-amino-3-methylquinolin-7-yl)methyl]-6-cyano-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-5-cyclopro pyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-(3,3-difluorocyc lobutyl)-N-(2-methanesul- fonylpyridin-3-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(3-ox- opiperazin-1-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2H,3H,4H- pyrano[2,3-b]pyridine-6-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(4- methyl-3-oxopiperazin-1-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(4-fluor o-2-methanesulfonylphenyl)- 5-(morpholin-4-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(4- methylpiperazin-1-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(2-metha nesulfonylpyridin-3-yl)-5- methylpyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(1-hy- droxy-2-methylpropan-2-yl)pyridine-3-carboxamide, and N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-(1-cyanocyclopro pyl)-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide. Ryvu Therapeutics S.A. RVU305 26 R10107WO 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) each of X ¹ , X ² , X ³ , X ⁴ , and X ⁵ can be nitrogen (N), unsubstituted carbon (CH), or substituted carbon (CR ^X1 , CR ^X2 , CR ^X3 , CR ^X4 , or CR ^X5 ). If X ¹ , X ² , X ³ , X ⁴ , or X ⁵ is a substituted carbon (CR ^X1 , CR ^X2 , CR ^X3 , CR ^X4 , or CR ^X5 ), the substituent at the carbon atom is represented by R ^X1 , R ^X2 , R ^X3 , R ^X4 , and R ^X5 , respectively. In a preferred embodiment of the compound of formula (I), none, one, two, or three of X ¹ , X ² , X ³ , X ⁴ , and X ⁵ are N, more preferably none, one, or two of X ¹ , X ² , X ³ , X ⁴ , and X ⁵ are N, and even more preferably none or only one of X ¹ , X ² , X ³ , X ⁴ , and X ⁵ is N. In another preferred embodiment of the compound of formula (I), X ⁴ is CH or CR ^X4 . In an- other preferred embodiment of the compound of formula (I), X ⁵ is CH or CR ^X5 . In a more pre- ferred embodiment of the compound of formula (I), X ⁴ is CH or CR ^X4 and X ⁵ is CH or CR ^X5 , even more preferably X ⁴ and X ⁵ are CH. Therefore, in a preferred embodiment, in the compounds of formula (I), X ¹ is CH, CR ^X1 , or N; X ² is CH, CR ^X2 , or N; X ³ is CH, CR ^X3 , or N; Ryvu Therapeutics S.A. RVU305 27 R10107WO X ⁴ is CH or CR ^X4 ; X ⁵ is CH or CR ^X5 . In a more preferred embodiment, in the compounds of formula (I), X ¹ is CH, CR ^X1 , or N; X ² is CH, CR ^X2 , or N; X ³ is CH, CR ^X3 , or N; X ⁴ is CH; X ⁵ is CH. In an even more preferred embodiment, in the compounds of formula (I), X ¹ is CH, CR ^X1 , or N; X ² is CH, CR ^X2 , or N; X ³ is CH, CR ^X3 , or N; X ⁴ is CH; X ⁵ is CH; with the proviso that none or only one of X ¹ , X ² , and X ³ is N. Accordingly, in a preferred embodiment, the compound of formula (I) may be a compound of formula (I*), (Ia*), (Ib*), or (Ic*), preferably a compound of formula (I*), (Ib*), or (Ic*), as shown below: In connection with formula (I*), preferably none of X ¹ , X ² and X ³ is N or only one of X ¹ , X ² and X ³ , is N, more preferably none of X ¹ , X ² and X ³ is N or only one of X ² and X ³ is N. Thus, in one preferred embodiment, the compound of formula (I) is a compound of formula (I*), preferably wherein none of X ¹ , X ² and X ³ is N or only one of X ¹ , X ² and X ³ is N, more preferably wherein none of X ¹ , X ² and X ³ is N or only one of X ² and X ³ is N. In connection with formula (Ia*), preferably none of X ² and X ³ is N. Thus, in one preferred embodiment, the compound of formula (I) is a compound of formula (Ia*), wherein preferably none of X ² and X ³ is N. In connection with formula (Ib*), preferably none of X ¹ and X ³ is N. Thus, in one preferred embodiment, the compound of formula (I) is a compound of formula (Ib*), wherein preferably none of X ¹ and X ³ is N. In connection with formula (Ic*), preferably none of X ¹ and X ² is N. Thus, in one preferred embodiment, the compound of formula (I) is a compound of formula (Ic*), wherein preferably none of X ¹ and X ² is N. Ryvu Therapeutics S.A. RVU305 28 R10107WO Overall, the following combinations of meanings for X ¹ , X ² , X ³ , X ⁴ , and X ⁵ according to em- bodiments A-1 to A-20 according to Table A are preferred. Table A In an even more preferred embodiment, in the compound of formula (I), X ¹ , X ² , X ³ , X ⁴ , and X ⁵ are selected according to any one of embodiments A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-13, A-14, A-15, A-16, A-17, A-18, A-19, or A-20, in particular according to any one of em- bodiments A-1, A-2, A-5, A-6, A-7, A-13, A-15, A-17, or A-19. In this connection, it is partic- ularly preferred that R ^X1 , R ^X2 , and R ^X3 are independently halogen, CN, NH ₂ , C(=O)NH ₂ , CD ₃ , C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, or C ₁ -C ₂ -hydroxyalkyl. Thus, in a more preferred embodiment of the compounds of formula (I), X ¹ is CH or CR ^X1 ; X ² is CH or CR ^X2 ; X ³ is CH or CR ^X3 ; X ⁴ is CH; X ⁵ is CH; or X ¹ is CH or CR ^X1 ; X ² is N; X ³ is CH; X ⁴ is CH; X ⁵ is CH; Ryvu Therapeutics S.A. RVU305 29 R10107WO or X ¹ is CH or CR ^X1 ; X ² is CH; X ³ is N; X ⁴ is CH; X ⁵ is CH; and wherein preferably R ^X1 is halogen, CN, C(=O)NH ₂ , CD ₃ , C ₁ -C ₂ -alkyl, C ₁ -C ₂ -haloalkyl, or C ₁ -C ₂ -hydroxyalkyl; R ^X3 is halogen, preferably Cl or F. In a more preferred embodiment, the compound of formula (I) is a compound of formula (I*- 0), (I*-1), (I*-2), (I*-3), (Ia*-0), (Ia*-1), (Ib*-0), or (Ib*-1) as shown below: In a more preferred embodiment, the compound of formula (I) is a compound of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), and (Ic*-0). In an even more preferred embodiment, the compound of formula (I) is a compound of formula (I*-0), (I*-1), (I*-2), and (I*-3), in partic- ular a compound of formula (I*-0). If present, in connection with the compounds of formula (I), as well as in connection with the compounds of formula (I*), (Ia*), (Ib*), and (Ic*), and in particular in connection with the compounds of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), (Ib*-1), (Ic*-0), and (Ic*-1), the following preferred embodiments regarding the substituents R ^X1 , R ^X2 , R ^X3 , R ^X4 , and R ^X5 are relevant. As indicated above, in connection with the compounds of the present invention, R ^X1 , R ^X2 , R ^X3 , R ^X4 , and R ^X5 are independently halogen, CN, OH, NH ₂ , C(=O)NH ₂ , CD ₃ , C ₁ -C ₄ - alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -haloalkoxy, or C ₁ - C ₄ -hydroxyalkyl. In a preferred embodiment, Ryvu Therapeutics S.A. RVU305 30 R10107WO R ^X1 , R ^X2 , R ^X3 , R ^X4 , and R ^X5 are independently halogen, CN, NH ₂ , C(=O)NH ₂ , CD ₃ , C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl, C ₁ -C ₂ -haloalkyl, C ₁ -C ₂ -haloalkoxy, or C ₁ -C ₂ - hydroxyalkyl. In a more preferred embodiment, R ^X1 , R ^X2 , R ^X3 , R ^X4 , and R ^X5 are independently halogen, CN, NH ₂ , C(=O)NH ₂ , CD ₃ , C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, or C ₁ -C ₂ -hydroxyalkyl. In another preferred embodiment of the compounds of the present invention, none, or only one, two, or three, preferably none, or only one or two of R ^X1 , R ^X2 , R ^X3 , R ^X4 , and R ^X5 are pre- sent. In a more preferred embodiment, none or only one of R ^X1 , R ^X2 , R ^X3 , R ^X4 , and R ^X5 is pre- sent. In a particular preferred embodiment, R ^X5 is absent so that X ⁵ is N or CH, preferably CH. In another particular preferred embodiment, R ^X4 is absent so that X ⁴ is N or CH, prefera- bly CH. In another particular preferred embodiment, R ^X4 and R ^X5 are absent s that X ⁴ and X ⁵ are N or CH, preferably CH. Therefore, in a more preferred embodiment, none or only one or two, preferably none or only one, of R ^X1 , R ^X2 , R ^X3 are present and R ^X4 and R ^X5 are absent so that X ⁴ and X ⁵ are N or CH, preferably CH. As regards the individual substituents, further preferences are provided below. In a preferred embodiment, R ^X1 is halogen, CN, C(=O)NH ₂ , CD ₃ , C ₁ -C ₂ -alkyl, C ₁ -C ₂ -haloalkyl, or C ₁ -C ₂ -hydroxyalkyl. In a more preferred embodiment, R ^X1 is halogen, CD ₃ , C ₁ -alkyl, C ₁ -haloalkyl, or C ₁ -hydroxyalkyl. In a preferred embodiment, R ^X2 is CN, NH ₂ , C(=O)NH ₂ , C ₁ -C ₂ -alkyl, C ₁ -C ₂ -haloalkyl, or C ₁ -C ₂ -hydroxyalkyl. In a more preferred embodiment, R ^X2 is CN, NH ₂ , C(=O)NH ₂ , or C ₁ -C ₂ -hydroxyalkyl. In a particular preferred embodiment, R ^X2 is NH ₂ . In a preferred embodiment, R ^X3 is halogen, or C ₁ -C ₂ -haloalkyl. In a more preferred embodiment, R ^X3 is halogen. In an even more preferred embodiment, R ^X3 is F or Cl. In a preferred embodiment, R ^X4 is halogen or C ₁ -C ₂ -alkoxy. In a preferred embodiment, R ^X5 is C ₁ -C ₂ -alkoxy. In connection with the compounds of formula (I), as well as in connection with the com- pounds of formula (I*), (Ia*), (Ib*), and (Ic*), and in particular in connection with the com- pounds of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), (Ib*-1), (Ic*-0), and (Ic*-1), the follow- ing preferred embodiments regarding the substituent R ¹ are relevant. As indicated above, in connection with the compounds of the present invention, Ryvu Therapeutics S.A. RVU305 31 R10107WO R ¹ is NR ^N1 R ^N2 , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ - hydroxyalkyl, C ₁ -C ₄ -aminoalkyl, or 3- to 10-membered saturated, partially or fully un- saturated, or aromatic carbocyclyl, carbocyclyl-C ₁ -C ₂ -alkyl, carbocyclyloxy-C ₁ -C ₂ -al- kyl, heterocyclyl, heterocyclyl-C ₁ -C ₂ -alkyl, or heterocyclyloxy-C ₁ -C ₂ -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 R ^Y . In a preferred embodiment, R ¹ is C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₂ -aminoal- kyl, or 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclyl, carbocyclyl-C ₁ -C ₂ -alkyl, carbocyclyloxy-C ₁ -C ₂ -alkyl, heterocyclyl, or heterocy- clyl-C ₁ -C ₂ -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 R ^Y ; wherein R ^Y is as defined above in connection with the compounds of formula (I), and wherein preferably R ^Y is halogen, CN, C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, C ₁ -C ₂ -hydroxyalkyl, cyclo- propyl, or 5- or 6-membered saturated, partially or fully unsaturated, or aromatic car- bocyclyl 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 sub- stitutable carbon or heteroatom in the aforementioned groups is independently un- substituted or substituted with one or more, same or different substituents R ^Z ; or two R ^Y attached to the same atom form an oxo group; or two R ^Y together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or 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 R ^Z is halogen or C ₁ -alkyl; or two R ^Z attached to the same atom form an oxo group. and wherein more preferably R ^Y is halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxy, or C ₁ -C ₂ -haloalkyl; or two R ^Y attached to the same atom form an oxo group; or two R ^Y together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or 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, Ryvu Therapeutics S.A. RVU305 32 R10107WO R ¹ is C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₂ -aminoal- kyl, or 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclyl, carbocyclyl-C ₁ -C ₂ -alkyl, carbocyclyloxy-C ₁ -C ₂ -alkyl, heterocyclyl, or heterocy- clyl-C ₁ -C ₂ -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 R ^Y ; and wherein preferably R ^Y is halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, 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 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 R ^Z ; or two R ^Y attached to the same atom form an oxo group; or two R ^Y together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or 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; R ^Z is halogen or C ₁ -alkyl; or two R ^Z attached to the same atom form an oxo group. In another more preferred embodiment, R ¹ is C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₂ -aminoal- kyl, C ₁ -C ₂ -aminoalkyl, 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl, cyclopropyl-C ₁ -C ₂ -alkyl, cyclopropyloxy-C ₁ -C ₂ - alkyl, or 5- to 6-membered aromatic heterocyclyl-C ₁ -C ₂ -alkyl, wherein the aforemen- tioned heterocyclyl 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 groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein R ^Y is as defined above in connection with the compounds of formula (I), and wherein preferably R ^Y is halogen, CN, C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, cyclopropyl, or 5- or 6- membered aromatic 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 R ^Z ; or two R ^Y attached to the same atom form an oxo group; wherein R ^Z is halogen or C ₁ -alkyl; Ryvu Therapeutics S.A. RVU305 33 R10107WO and wherein more preferably R ^Y is halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxy, or C ₁ -C ₂ -haloalkyl; or two R ^Y attached to the same atom form an oxo group. In another more preferred embodiment, R ¹ is C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₂ -aminoal- kyl, pyridinyl, pyridonyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, pyrazolyl, thia- zolyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, cyclopropyl, cyclobu- tyl, pyridinyl-C ₁ -C ₂ -alkyl, or pyrazolyl-C ₁ -C ₂ -alkyl, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein R ^Y is as defined above in connection with the compounds of formula (I), and wherein preferably R ^Y is halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, cyclopropyl, or 5-membered ar- omatic 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 sub- stitutable carbon or heteroatom in the aforementioned groups is independently un- substituted or substituted with one or more, same or different substituents R ^Z ; wherein R ^Z is halogen or C ₁ -alkyl; and wherein more preferably R ^Y is halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxy, or C ₁ -C ₂ -haloalkyl. In an even more preferred embodiment, R ¹ is C ₁ -C ₃ -alkyl, pyrimidinyl, pyridinyl, or 2-pyridonyl; wherein each substitutable carbon or heteroatom in the aforementioned groups is inde- pendently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein R ^Y is as defined above in connection with the compounds of formula (I), and wherein preferably R ^Y is halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl. In an even more preferred embodiment, R ¹ is CH ₃ , pyrimidinyl, or pyridinyl; and wherein preferably the pyridinyl or pyrimidinyl is independently unsubstituted or substi- tuted with one or more substituents selected from halogen, CH ₃ , or CF ₃ , more preferably Cl, F, CH ₃ , or CF ₃ . In one particularly preferred embodiment, R ¹ is CH ₃ . In another particularly preferred embodiment, R ¹ is unsubstituted pyridinyl. In yet another particularly preferred embodiment, R ¹ is pyridinyl substituted with one substituent selected from Cl, F, CH ₃ , or CF ₃ . In yet another particularly preferred embodiment, R ¹ is unsubstituted pyrimidinyl. In yet another particularly preferred embodiment, R ¹ is pyrimidinyl substituted with one substituent selected from Cl, F, CH ₃ , or CF ₃ . Ryvu Therapeutics S.A. RVU305 34 R10107WO If R ¹ is a 8- to 10- membered heterobicyclyl, which is the case if R ¹ is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl or heterocyclyl substituted with one or more, same or different substituents R ^Y , wherein two R ^Y together with the atoms to which they are bonded form a fused 5- or 6-membered saturated, partially or fully un- saturated, or aromatic carbocyclyl or heterocyclyl, this heterobicyclic ring is preferably any one of the following rings: more preferably any one of the following rings: In a more preferred embodiment if R ¹ is a 8- to 10- membered heterobicyclyl, this hetero- bicyclic ring is preferably any one of the following rings: more preferably any one of the following rings: In connection with the compounds of formula (I), as well as in connection with the com- pounds of formula (I*), (Ia*), (Ib*), and (Ic*), and with the compounds of formula (I*-0), (I*- 1), (I*-2), (I*-3), (Ib*-0), (Ib*-1), (Ic*-0), and (Ic*-1), in particular in connection with the pre- ferred embodiments regarding R ¹ defined above, the following preferred embodiments re- garding the A moiety are relevant. As indicated above, in connection with the compounds of the present invention, A is a moiety selected from The compound of formula (I) may therefore be a compound of formula (I-A1) or (I-A2) as shown below: Ryvu Therapeutics S.A. RVU305 35 R10107WO wherein the substituents are defined as in connection with formula (I), and wherein prefera- bly, the meanings of X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ^X1 , R ^X2 , R ^X3 , R ^X4 , R ^X5 and R ¹ correspond to the preferred embodiments defined above. 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 (I*), (Ia*), (Ib*), and (Ic*), and with the compounds of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), (Ib*-1), (Ic*-0), and (Ic*-1), in par- ticular in connection with the preferred embodiments regarding R ¹ defined above, the fol- lowing preferences regarding A ¹ and R ² are relevant. As indicated above, in connection with the compounds of the present invention, A ¹ is 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 R ^A1 . In a preferred embodiment, A ¹ is 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 R ^A1 . In a more preferred embodiment, A ¹ is 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 R ^A1 . In an even more preferred embodiment, A ¹ is phenyl, pyridinyl, pyrazolyl, or thiophenyl. In an even more preferred embodiment, A ¹ is phenyl, pyridinyl, or pyrazolyl. In a particularly preferred embodiment, A ¹ is selected from the group consisting of Ryvu Therapeutics S.A. RVU305 36 R10107WO more preferably from the group consisting of 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 (I*), (Ia*), (Ib*), and (Ic*), and the compounds of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), (Ib*-1), (Ic*-0), and (Ic*-1), in par- ticular in connection with the preferred embodiments regarding R ¹ and A ¹ defined above, preferably, A ¹ is unsubstituted or substituted with one, two, or three, same or different sub- stituents R ^A1 , more preferably A ¹ is unsubstituted or substituted with one or two, same or different substituents R ^A1 , even more preferably A ¹ is unsubstituted or substituted with only one substituent R ^A1 . In a particularly preferred embodiment, A ¹ is unsubstituted. 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 (I*), (Ia*), (Ib*), and (Ic*), and the compounds of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), (Ib*-1), (Ic*-0), and (Ic*- 1), in particular with the preferred embodiments regarding R ¹ and A ¹ as defined above, the following preferences regarding R ² and, if present, R ^A1 are relevant. As indicated above, in connection with the compounds of the present invention, R ² is halogen, CN, S(=O) ₂ R ^S , C(=O)R ^C , NHC(=O)R ^C , C(=O)NR ^N1 R ^N2 , C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - haloalkyl, C ₁ -C ₄ -haloalkoxy, C ₁ -C ₆ -hydroxyalkyl, or a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non- Ryvu Therapeutics S.A. RVU305 37 R10107WO 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 R ^A2 ; wherein R ^C is H, or C ₁ -C ₄ -alkyl; R ^N1 is H, or C ₁ -C ₄ -alkyl; R ^N2 is H, or C ₁ -C ₄ -alkyl; R ^S is C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl, C ₃ -C ₅ -cycloalkyl, or NR ^N1 R ^N2 . In another embodiment, R ² is halogen, S(=O) ₂ R ^S , C(=O)R ^C , NHC(=O)R ^C , C(=O)NR ^N1 R ^N2 , C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - haloalkyl, C ₁ -C ₄ -haloalkoxy, C ₁ -C ₆ -hydroxyalkyl, or a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non- oxidized, and wherein each substitutable carbon or heteroatom in the aforemen- tioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^A2 ; wherein R ^C is H, or C ₁ -C ₄ -alkyl; R ^N1 is H, or C ₁ -C ₄ -alkyl; R ^N2 is H, or C ₁ -C ₄ -alkyl; R ^S is C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl, C ₃ -C ₅ -cycloalkyl, or NR ^N1 R ^N2 . In one preferred embodiment, R ² is halogen, CN, S(=O) ₂ R ^S , C(=O)R ^C , C(=O)NR ^N1 R ^N2 , C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, C ₁ - C ₂ -haloalkoxy, or C ₁ -C ₂ -hydroxyalkyl; and wherein preferably R ^C is H, or C ₁ -C ₂ -alkyl; R ^N1 is H, or C ₁ -C ₂ -alkyl; R ^N2 is H, or C ₁ -C ₂ -alkyl; R ^S is C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, C ₃ -C ₅ -cycloalkyl, or NR ^N1 R ^N2 . In another preferred embodiment, R ² is halogen, S(=O) ₂ R ^S , C(=O)R ^C , C(=O)NR ^N1 R ^N2 , C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, C ₁ -C ₂ - haloalkoxy, or C ₁ -C ₂ -hydroxyalkyl; and wherein preferably R ^C is H, or C ₁ -C ₂ -alkyl; R ^N1 is H, or C ₁ -C ₂ -alkyl; R ^N2 is H, or C ₁ -C ₂ -alkyl; R ^S is C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, C ₃ -C ₅ -cycloalkyl, or NR ^N1 R ^N2 . In one more preferred embodiment, R ² is halogen, CN, S(=O) ₂ R ^S , C(=O)R ^C , C(=O)NR ^N1 R ^N2 , C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, C ₁ - C ₂ -haloalkoxy, or C ₁ -C ₂ -hydroxyalkyl; and wherein preferably R ^C is H, or C ₁ -alkyl; R ^N1 is H, or C ₁ -alkyl; R ^N2 is H, or C ₁ -alkyl; R ^S is C ₁ -C ₂ -alkyl, C ₃ -C ₅ -cycloalkyl, or NR ^N1 R ^N2 . Ryvu Therapeutics S.A. RVU305 38 R10107WO In another more preferred embodiment, R ² is halogen, S(=O) ₂ R ^S , C(=O)R ^C , C(=O)NR ^N1 R ^N2 , C ₁ -C ₂ -alkoxy, C ₁ -C ₂ -haloalkyl, C ₁ -C ₂ - haloalkoxy, or C ₁ -C ₂ -hydroxyalkyl; and wherein preferably R ^C is H, or C ₁ -alkyl; R ^N1 is H, or C ₁ -alkyl; R ^N2 is H, or C ₁ -alkyl; R ^S is C ₁ -C ₂ -alkyl, C ₃ -C ₅ -cycloalkyl, or NR ^N1 R ^N2 . In a particularly preferred embodiment, R ² is S(=O) ₂ R ^S ; and wherein preferably R ^S is C ₁ -alkyl. Further, as indicated above, in connection with the compounds of the present invention, R ^A1 is halogen, CN, OH, S(=O) ₂ R ^S , C(=O)R ^C , C ₁ -C ₄ -alkyl, or C ₁ -C ₄ -haloalkyl; or two R ^A1 together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or 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 R ^A2 . In another embodiment, R ^A1 is halogen, CN, OH, S(=O) ₂ R ^S , C(=O)R ^C , C ₁ -C ₄ -alkyl, or C ₁ -C ₄ -haloalkyl; or two R ^A1 together with the atoms to which they are bonded form a fused 5- or 6- membered saturated or partially unsaturated carbocyclyl or 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 carbocyclyl or heterocyclyl is independently unsubstituted or substituted with one or more, same or different substituents R ^A2 . In a preferred embodiment, R ^A1 is halogen, CN, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl; or two R ^A1 together with the atoms to which they are bonded form a fused 5- or 6- membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, or 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 another preferred embodiment, R ^A1 is halogen, CN, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl; or two R ^A1 together with the atoms to which they are bonded form a fused 5- or 6- membered saturated or partially unsaturated carbocyclyl or 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.In a more preferred embodiment, Ryvu Therapeutics S.A. RVU305 39 R10107WO R ^A1 is halogen, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl; or two R ^A1 together 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, R ^A1 is halogen, C ₁ -C ₂ -alkyl, or C ₁ -haloalkyl; or two R ^A1 together with the atoms to which they are bonded form a fused 5-mem- bered saturated carbocyclyl. In an even more preferred embodiment, R ^A1 is halogen. In a particularly preferred embodiment, R ^A1 is F. Thus, in a preferred embodiment of the invention, A ¹ is selected from the group consisting of , wherein the phenyl or pyridinyl is independently unsubstituted or substituted with one or more, preferably one, same or different substituents selected from halogen, preferably F. In one particularly preferred embodiment, A ¹ ; wherein the phenyl is independently unsubstituted or substituted with one or more, prefera- bly one, same or different substituents selected from halogen, preferably F. In another particularly preferred embodiment, A ¹ ; wherein the pyridinyl is independently unsubstituted or substituted with one or more, pref- erably one, same or different substituents selected from halogen, preferably F. In a more preferred embodiment of the invention, A ¹ is selected from the group consisting of Ryvu Therapeutics S.A. RVU305 40 R10107WO 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 (I*), (Ia*), (Ib*), and (Ic*), and with the compounds of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), (Ib*-1), (Ic*-0), and (Ic*-1), in par- ticular in connection with the preferred embodiments regarding R ¹ defined above, the fol- lowing preferences regarding Y, A ² , and B are relevant. As indicated above, in connection with the compounds of the present invention, A ² is 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 R ^A2 . In a preferred embodiment, A ² is 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 R ^A2 . In a more preferred embodiment, A ² is 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 R ^A2 . In an even more preferred embodiment, A ² is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl; wherein the phenyl, pyridinyl, pyrimidi- nyl, or pyrazolyl is independently unsubstituted or substituted with one or more, pref- erably one or two, more preferably one, same or different substituents R ^A2 ; preferably A ² is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl. In a particular preferred embodiment, A ² is 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 R ^A2 ; preferably A ² is phenyl, pyridinyl, or pyrazolyl. In connection with the compounds of formula (I) and the compounds of formula (I-A2), in particular the preferred embodiments regarding A ² defined above, preferably, A ² is unsubsti- tuted or substituted with one, two, or three, same or different substituents R ^A2 , more prefer- ably A ² is unsubstituted or substituted with one or two, same or different substituents R ^A2 , Ryvu Therapeutics S.A. RVU305 41 R10107WO even more preferably A ² is unsubstituted or substituted with only one substituent R ^A2 . In a particularly preferred embodiment, A ² is unsubstituted. In an even more preferred embodiment, the bicyclic moiety any one of the fol- lowing groups (A ² -1), (A ² -2), or (A ² -3): wherein ring B is defined as in connection with formula (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 R ^B . 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 R ^B . In a more preferred embodiment, ring B is ring B ¹ , so that the bicyclic moiety the bicyclic moiety (B ¹ -1): wherein B ¹ 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 R ^B1 ; Ryvu Therapeutics S.A. RVU305 42 R10107WO Z is C(=O), C(=O)NH, C(=O)NR ^B , S(=O) ₂ , S(=O) ₂ NH, S(=O) ₂ NR ^B , NH, NR ^B , O, N, or S; and wherein Y and A ² are defined as in connection with formula (I), and wherein preferably, the meaning of A ² corresponds to the preferred embodiments defined above. Preferably, Z is C(=O)NH, S(=O) ₂ , S(=O) ₂ NH, O, N, or S. More preferably, Z is S(=O) ₂ . In an even more preferred embodiment, (B ¹ -1) is a bicyclic moiety selected from the group consisting of (B ¹ -1a), (B ¹ -1b), (B ¹ -1c), (B ¹ -1d), (B ¹ -1e), (B ¹ -1f), (B ¹ -1g): wherein Y, A ² , and B ¹ are defined as in connection with formula (I), and wherein preferably, the meaning of A ² corresponds to the preferred embodiments defined above. Particularly preferable is a bicyclic moiety selected from the group consisting of (B ¹ -1a), (B ¹ -1b), (B ¹ -1d), (B ¹ -1e), (B ¹ -1f), (B ¹ -1g), more preferably (B ¹ -1a). In another particularly preferred embodiment, the bicyclic moiety ² any one of (A - wherein B ¹ 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 R ^B1 ; and wherein Z is C(=O), C(=O)NH, C(=O)NR ^B , S(=O) ₂ , S(=O) ₂ NH, S(=O) ₂ NR ^B , NH, NR ^B , O, N, or S. Preferably, Z is C(=O)NH, S(=O) ₂ , S(=O) ₂ NH, O, N, or S. More preferably, Z is S(=O) ₂ . Ryvu Therapeutics S.A. RVU305 43 R10107WO 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 (I*), (Ia*), (Ib*), and (Ic*), and with the compounds of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), (Ib*-1), (Ic*-0), and (Ic*-1), in par- ticular in connection with the preferred embodiments regarding R ¹ and B defined above, preferably, B is unsubstituted or substituted with one, two, or three, same or different sub- stituents R ^B , more preferably B is unsubstituted or substituted with one or two, same or dif- ferent substituents R ^B , even more preferably B is unsubstituted or substituted with only one substituent R ^B . In a particularly preferred embodiment, B 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 (I*), (Ia*), (Ib*), and (Ic*), and with the compounds of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), (Ib*-1), (Ic*-0), and (Ic*-1), in par- ticular in connection with the preferred embodiments regarding R ¹ and B defined above, in particular the preferred embodiments regarding B ¹ defined above, including (B ¹ -1), (B ¹ -1a), (B ¹ -1b), (B ¹ -1c), (B ¹ -1d), (B ¹ -1e), (B ¹ -1f), (B ¹ -1g), (A ² -1-B ¹ -1), (A ² -2-B ¹ -1), and (A ² -3-B ¹ -1), preferably, B ¹ is unsubstituted or substituted with one, two, or three, same or different sub- stituents R ^B1 , more preferably B ¹ is unsubstituted or substituted with one or two, same or different substituents R ^B1 , even more preferably B ¹ is unsubstituted or substituted with only one substituent R ^B1 . In a particularly preferred embodiment, B ¹ is unsubstituted. 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 (I*), (Ia*), (Ib*), and (Ic*), and with the compounds of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), (Ib*-1), (Ic*-0), and (Ic*-1), in particular in connection with the preferred embodiments regarding R ¹ , A ² , R ² , R ^A1 , B and B ¹ as defined above, the following preferences regarding R ^A2 and R ^B , if present, are relevant. As indicated above, in connection with the compounds of the present invention, R ^A2 is halogen, CN, OH, C ₁ -C ₄ -alkyl, or C ₁ -C ₄ -haloalkyl. In a preferred embodiment, R ^A2 is halogen, CN, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl. In a more preferred embodiment, R ^A2 is halogen or C ₁ -C ₂ -alkyl. In a particularly preferred embodiment, R ^A2 is Cl, F, or C ₁ -alkyl. As indicated above, in connection with the compounds of the present invention, R ^B is halogen, CN, OH, C ₁ -C ₄ -alkyl, or C ₁ -C ₄ -haloalkyl; or two R ^B attached to the same atom form an oxo group. In a preferred embodiment, R ^B is halogen, CN, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl; or two R ^B attached to the same atom form an oxo group. In a more preferred embodiment, R ^B is halogen or C ₁ -C ₂ -alkyl; or two R ^B attached to the same atom form an oxo group. In a particularly preferred embodiment, Ryvu Therapeutics S.A. RVU305 44 R10107WO R ^B is F or C ₁ -alkyl; or two R ^B attached to the same atom form an oxo group. In connection with the compounds of the present invention, R ^B1 is halogen, CN, OH, C ₁ -C ₄ -alkyl, or C ₁ -C ₄ -haloalkyl. In a preferred embodiment, R ^B1 is halogen, CN, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl. In a more preferred embodiment, R ^B1 is halogen or C ₁ -C ₂ -alkyl. In a particularly preferred embodiment, R ^B1 is F or C ₁ -alkyl. In another particularly preferred embodiment, the bicyclic moiety selected from the group consisting of Ryvu Therapeutics S.A. RVU305 45 R10107WO In an even more preferred embodiment, the bicyclic moiety selected from the . In a particularly preferred embodiment, the bicyclic moiety selected from the group consisting of In a particularly preferred embodiment, the bicyclic moiety In another particularly preferred embodiment, the bicyclic moiety In another particularly preferred embodiment, the bicyclic moiety Ryvu Therapeutics S.A. RVU305 46 R10107WO In connection with the A moiety of the compounds of formula (I) of the present invention, it is preferred that B if present, is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each sub- stitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents R ^B ; and R ² is S(=O) ₂ R ^S ; and wherein preferably R ^S is C ₁ -alkyl. Further, in connection with the A moiety of the compounds of formula (I) of the present in- vention, it is preferred that B if present, is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each sub- stitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more, same or different substituents R ^B ; and, if present, R ^A1 is halogen, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -haloalkyl; or two R ^A1 together with the atoms to which they are bonded form a fused 5- or 6- membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized. Overall, in particularly preferred embodiments, A is a moiety selected from the group consisting of Ryvu Therapeutics S.A. RVU305 47 R10107WO In even more preferred embodiments, A is a moiety selected from the group consisting of Ryvu Therapeutics S.A. RVU305 48 R10107WO In even more preferred embodiments, A is a moiety selected from the group consisting of Ryvu Therapeutics S.A. RVU305 49 R10107WO . In even more preferred embodiments, A is a moiety selected from the group consisting of In particularly preferred embodiments, A is a moiety selected from the group consisting of . In certain preferred embodiments of the present invention, the moiety A is not unsubsti- tuted naphthyl or naphthyl substituted with cyano. This applies in particular under the pro- viso that X ¹ is CH or CR ^X1 ; wherein R ^X1 is Br, F, C ₁ -C ₂ -alkyl, or CF ₃ ; X ² is CH or CR ^X2 ; wherein R ^X2 is C ₁ -C ₂ -alkyl; X ³ is N; X ⁴ is CH; X ⁵ is CH; and R ¹ is C ₁ -C ₂ -alkyl. Particularly preferably, the compound of formula (I) according to the present invention is not: . In other particularly preferred embodiments, the compound of formula (I) is a compound se- lected from the group consisting of: N-[(2-aminoquinolin-7-yl)methyl]-N-(1H-indazol-7-yl)pyridine -3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-ethoxy-4-fluorophenyl) pyridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 50 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-2-cyclopropoxy-N-(2-methane sulfonylpyridin-3-yl)acet- amide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-{1,1-dioxo-2H,3H -1λ⁶-thieno[3,2-b]pyridin- 7-yl}acetamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfon ylphenyl)-2-methylpyrimi- dine-5-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4,4-difluoro-1,1-dioxo-3 ,4-dihydro-2H-1λ⁶-benzothi- opyran-8-yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfon ylphenyl)-6-methylpyridine- 3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfon ylphenyl)-6-methylpyri- dazine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonyl-5-meth ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(trifluoromethyl)pyrid in-3-yl]pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-N-(5-fluoro-2-methanesulfon ylpyridin-3-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-7-yl)py ridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)pyr- idine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)butanamide, N-[(2-amino-6-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-carbox- amide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)pyridine- 3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-methanesulfonylpyridin -4-yl)pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methoxyphenyl )pyridine-3-carboxamide, N-[(2-amino-4-cyanoquinolin-7-yl)methyl]-N-(2-methanesulfony lphenyl)pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-3,3-difluoro-N-(2-methanesu lfonylpyridin-3-yl)bu- tanamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-{5H,6H,7H-pyrazo lo[3,2-b][1,3]oxazin-3- yl}pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-methanesulfonyl-5-(tri fluoromethyl)pyridin-3- yl]pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)acetamide, Ryvu Therapeutics S.A. RVU305 51 R10107WO N-[(2-amino-3-methylquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide, N-[(2-amino-5-bromoquinolin-7-yl)methyl]-N-(2-methanesulfony lpyridin-3-yl)pyridine-3- carboxamide, N-{[2-amino-4-(hydroxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesulfonylphenyl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1-methyl-1H-1,3-benzodia zol-4-yl)pyridine-3-carbox- amide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4,4-difluoro-1,1-dioxo-3 ,4-dihydro-2H-1λ⁶-benzothi- opyran-8-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(quinolin-8-yl)acetamide, N-{[2-amino-3-(²H₃)methylquinolin-7-yl]methyl}-N-(2-metha nesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2,3-dihydro-1,4-benzodio xin-5-yl)pyridine-3-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-ethyl-2-methanesulfony lphenyl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-4-yl)py ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-6-(trifluoromethyl)py- ridazine-3-carboxamide, N-[(2-amino-5-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2,3-dihydro-1-benzofuran -7-yl)pyridine-3-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-[5-carbamoyl-1-(difluorom ethyl)-1H-pyrazol-4-yl]pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) imidazo[1,2-a]pyrimidine-6- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-{1,1-dioxo-2H,3H-1λ⁶-t hieno[3,2-b]pyridin-7- yl}acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1� �⁶-benzothiophen-7-yl)-2- oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-4-carboxami de, ethyl N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)carbamate, N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(2-methanesulfony lpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-cyano-2-methanesulfony lphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-methyl-1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)acetamide, N-[(2-aminoquinolin-7-yl)(²H₂)methyl]-N-(2-methanesulfony lphenyl)pyridine-3-carboxa- mide, Ryvu Therapeutics S.A. RVU305 52 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-6-methylpyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-methanesulfonyl-4-(tri fluoromethyl)phenyl]pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylquinoli n-3-yl)acetamide N-{[2-amino-3-(hydroxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesulfonylphenyl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2,3-dihydro-1-benzofuran -7-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-4,4,4-trifluoro-N-(2-methan esulfonylpyridin-3-yl)butana- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -1,3-thiazole-5-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-(trifluoromethyl)py- rimidine-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-methylpropana- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-1λ⁶-benzoth iophen-7-yl)acetamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(3-methyl-1,1-di oxo-2H-1λ⁶,2,4-benzothia- diazin-8-yl)pyridine-3-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-{4,4-dioxo-5H,6H ,7H-4λ⁶-pyrazolo[3,2- b][1,3]thiazin-3-yl}pyridine-3-carboxamide, N-{[2-amino-3-(difluoromethyl)quinolin-7-yl]methyl}-N-(2-met hanesulfonylphenyl)pyridine- 3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) butanamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1� �⁶-benzothiophen-7-yl)-1- methyl-2-oxo-1,2-dihydropyridine-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-chloro-1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)propanamide, N-{[2-amino-5-(trifluoromethyl)quinolin-7-yl]methyl}-N-(2-me thanesulfonylpyridin-3-yl)py- ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-methoxyacetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -1-methyl-1H-pyrazole-4- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(5-fluoro-2-methanesulfon ylphenyl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(5-chloro-2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-6-(difluoromethyl)-N-(2-met hanesulfonylpyridin-3-yl)py- ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)pyridine-3-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-5-(propan-2-yl)-1,2- oxazole-4-carboxamide, Ryvu Therapeutics S.A. RVU305 53 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyrimidine-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-bromo-2-methanesulfony lphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-4-methylpyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-5-fluoro-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(ethanesulfonyl)phenyl ]pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -5-(2-oxopyrrolidin-1-yl)py- ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-5-(trifluoromethyl)py- ridine-3-carboxamide, N-[(2,4-diamino-5-fluoroquinazolin-7-yl)methyl]-N-(1,1-dioxo -2,3-dihydro-1λ⁶-benzothio- phen-7-yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -5-methoxypyridine-3-car- boxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-5-methylpyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyridine-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyridine-2-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-fluoro-2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonyl-5-meth ylphenyl)pyridine-3-car- boxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -1-methyl-2-oxo-1,2-dihy- dropyridine-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(cyclopropanesulfonyl) phenyl]pyridine-3-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -3-methyl-1,2-oxazole-4- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-6-(trifluoromethyl)py- ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyridazine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyridazine-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-5-fluoro-N-(2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -6-oxo-1,6-dihydropyridine- 2-carboxamide, Ryvu Therapeutics S.A. RVU305 54 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)pyrazolo[1,5-a]pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-3,3-difluoro-N-(2-methanesu lfonylpyridin-3-yl)cyclobu- tane-1-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-5-chloro-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, 4-{N-[(2-aminoquinolin-7-yl)methyl]-3-(pyridin-2-yl)propanam ido}-1-methyl-1H-pyrazole- 3-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1� �⁶-benzothiophen-7-yl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)oxane-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(dimethylsulfamoyl)phe nyl]pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyrimidine-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-4H,5H,6H-pyrrolo[1,2- b]pyrazole-2-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-methanesulfonyl-1-meth yl-1H-pyrazol-3-yl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) oxetane-3-carboxamide, (2R)-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylph enyl)oxolane-2-carboxa- mide, (2S)-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylph enyl)oxolane-2-carboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-oxo-2,3-dihydro-1H-iso indol-4-yl)pyridine-3-car- boxamide, 4-{N-[(2-aminoquinolin-7-yl)methyl]-3-(pyridin-4-yl)propanam ido}-1-methyl-1H-pyrazole- 3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-carbamoyl-1-methyl-1H- pyrazol-4-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyrazine-2-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[5-(hydroxymethyl)-1-meth yl-1H-pyrazol-4- yl]acetamide, 4-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}-1-methyl-1H-py razole-5-carboxamide N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -2-(1H-pyrazol-1- yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonyl-4-meth ylphenyl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-sulfamoylphenyl)acetam ide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1� �⁶-benzothiophen-7- yl)acetamide, N-[(2-amino-3-methylquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-methanesulfonylpyridin -3-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-{3-cyano-5H,6H,7H-cyclope nta[b]pyridin-2- yl}acetamide, Ryvu Therapeutics S.A. RVU305 55 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-{5-cyano-1H,3H,4H-pyrano[ 3,4-c]pyridin-6- yl}acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)cyclopropanecarboxa- mide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -3-(1H-pyrazol-1-yl)propa- namide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphe nyl)oxolane-2-carboxa- mide, 4-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}-1-methyl-1H-py razole-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -5-methyl-1,2-oxazole-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-methanesulfonylthiophe n-2-yl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)acetamide, N-[(2,4-diaminoquinazolin-7-yl)methyl]-N-(2-methanesulfonylp henyl)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[3-(hydroxymethyl)-1-meth yl-1H-pyrazol-4- yl]acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(1-hydroxyethyl)phenyl ]acetamide, and N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) acetamide. In other particularly preferred embodiments, the compound of formula (I) is selected from the group consisting of: N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶,2-benzothiazol-7- yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzoxazol-4-yl)pyri dine-3-carboxamide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-[5,6,7,8-tetrahydroqu inolin-8-yl]pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-N-[4-fluoro-2-(trifluoromet hyl)phenyl]pyridine-3-carbox- amide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-[3-fluoro-1,1-dioxo-2 ,3-dihydro-1λ⁶-benzothio- phen-7-yl]acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(trifluoromethoxy)phen yl]acetamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(5-fluoro-2-meth anesulfonylphenyl)pyridine- 3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-chloro-4-fluorophenyl) pyridine-3-carboxamide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-[3-hydroxy-2,3-dihydr o-1H-inden-4-yl]pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-fluoro-2-methoxyphenyl )pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1� �⁶-benzothiophen-7-yl)pro- panamide , N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(1,1-di oxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)pyridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 56 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)propanamide , N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)propanamide , N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(1,3-benzothiazo l-4-yl)pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methoxypyridin-3-yl)py ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-2-cyclopropyl-N-(2-methanes ulfonylpyridin-3-yl)acetam- ide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)pyrimidine-5-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)propanamide , N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-(propan-2-yloxy)ac- etamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,3-benzothiazol-7-yl) pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-4,4,4-trifluorobutanamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -5-(trifluoromethyl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-chloropyridin-3-yl)pyr idine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-2- methylpyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-methylpyr- idine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[(8R)-5,6,7,8-tetrahydroq uinolin-8-yl]pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[(8S)-5,6,7,8-tetrahydroq uinolin-8-yl]pyridine-3-car- boxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)pyrimidine-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(quinoxalin-5-yl)pyridine -3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(3-methoxypyridin-4-yl)py ridine-3-carboxamide, N-[(2-amino-5-chloroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)- 4,4,4-trifluorobutanamide, N-[(2-aminoquinolin-7-yl)(²H₂)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)pyridine-3-carboxamide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-[5,6,7,8-tetrahydroqu inoxalin-5-yl]pyridine-3-car- boxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4-fluoro-2-meth oxyphenyl)pyridine-3-car- boxamide, Ryvu Therapeutics S.A. RVU305 57 R10107WO N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-(trifluoro- methyl)pyrimidine-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-5-cyano-N-(2-methanesulfony lpyridin-3-yl)pyridine-3- carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth oxyphenyl)pyridine-3-car- boxamide, N-[(6-amino-7-chloro-1,5-naphthyridin-3-yl)methyl]-N-(1,1-di oxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(4,4-difluoro-1,1-dioxo -3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-amino-4-methylquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(quinazolin-8-yl)pyridine -3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-4-yl)pr opanamide , N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-1-methyl-1H-pyrazole-4-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,3-benzothiazol-4-yl) pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonylpheny l)-5-methylpyridine-3-car- boxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3 -dihydro-1λ⁶-benzothio- phen-7-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-5-methylpyridine- 3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)pyridine- 3-carboxamide, N-{[2-amino-4-(trifluoromethyl)quinolin-7-yl]methyl}-N-(1,1- dioxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,3-benzothiazo l-4-yl)pyridine-3-carboxa- mide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,3-benzothiazol-7-yl) -2-(trifluoromethyl)pyrimi- dine-5-carboxamide, N-[(2-aminoquinazolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)py- ridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-cyano-4-fluorophenyl)p yridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyrazolo[1,5-a]py- ridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 58 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon yl-5-methylpyridin-3-yl)-5- (trifluoromethyl)pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-5- (trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-(propan-2-yloxy)acetamide, N-[(2-aminoquinolin-7-yl)methyl]-N-{1-methyl-1H-pyrazolo[4,3 -b]pyridin-3-yl}pyridine-3- carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)oxane-4-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[(5R)-5,6,7,8-tetrahydroq uinoxalin-5-yl]pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[(5S)-5,6,7,8-tetrahydroq uinoxalin-5-yl]pyridine-3-car- boxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-7-yl)-2 -(trifluoromethyl)pyrimidine- 5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-(pyridin-3-yl)-1,3- thiazole-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonylpheny l)-5-(trifluoromethyl)pyri- dine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-methylpyrimi- dine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-1-methyl-1H-py- razole-4-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(2-methanesulfon ylphenyl)-6-(trifluoro- methyl)pyridine-3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(2-methanesulfon ylphenyl)pyrazolo[1,5-a]py- ridine-3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-5-(trifluoromethyl)pyridine-3-carboxami de, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(2-methanesulfon ylphenyl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-1-cyclopropyl-N-(1 ,1-dioxo-2,3-dihydro-1λ⁶- benzothiophen-7-yl)-1H-pyrazole-4-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)pyridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 59 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesulfonylphenyl)pyri- dine-3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(2-methanesulfon yl-5-methylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyano-N-(2-metha nesulfonylphenyl)pyridine- 3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3-carboxami de, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-(trifluoromethyl)pyrimidine-5-carboxa mide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)-1,3-thiazole-4-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6- methoxypyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclopropyl-N-(4 -fluoro-2-methanesul- fonylphenyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-cyclopropyl-N-(4 -fluoro-2-methanesul- fonylphenyl)pyrimidine-5-carboxamide, N-[(6-amino-7-methyl-1,5-naphthyridin-3-yl)methyl]-N-(4,4-di fluoro-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxam ide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(2-metha nesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyclopropyl-N-(4 -fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-(4 -fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyano-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)pyridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 60 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-3-carboxamide, and N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyano-N-(2-metha nesulfonylpyridin-3-yl)pyri- dine-3-carboxamide. In other particularly preferred embodiments, the compound of formula (I) is selected from the group consisting of: N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(difluoromethoxy)pheny l]pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonyl-5-meth ylpyridin-3-yl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonylpheny l)-2-(trifluoromethyl)py- rimidine-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(5-chloro-2-methanesulf onylphenyl)pyrazolo[1,5- a]pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-2-methylpyrimidine-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(5-chloro-2-methanesulf onylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-{1,1-dioxo-2H,3H -1λ⁶-thieno[3,2-b]pyridin- 7-yl}pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonyl-5-me thylpyridin-3-yl)-5-(trifluo- romethyl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-7-yl)-5 -(trifluoromethyl)pyridine-3- carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-5-methylpyrazine-2-carboxamide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-{2H,3H,4H-pyrano[3,2- b]pyridin-4-yl}pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-7-yl)-2 -methylpyrimidine-5-carbox- amide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(4,4-difluoro-1,1-dioxo -3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-6-methylpyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1-oxo-1,2,3,4-tetrahydro isoquinolin-8-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-{[1-(trifluorome- thyl)cyclopropyl]amino}acetamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-6-(trifluorome- thyl)pyridine-3-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(1,3-benzothia zol-7-yl)pyridine-3-carbox- amide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)pyrimidine-5-carboxamide, Ryvu Therapeutics S.A. RVU305 61 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(5-chloro-2-meth anesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-5-methylpyrazine-2-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-{imidazo[1,2-a]pyridin-8- yl}pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon yl-5-methylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(5-chloro-2-methanesulf onylphenyl)-2-methylpyrim- idine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-chloro-2-meth anesulfonylphenyl)-2- methylpyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-1-cyclohexyl-N-(1, 1-dioxo-2,3-dihydro-1λ⁶- benzothiophen-7-yl)-1H-pyrazole-4-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-methylpyridine- 4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-methylpy- rimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyrazolo[1,5-a]pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) imidazo[1,5-a]pyridine-3- carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-5-(trifluoro- methyl)pyrazine-2-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-6-(trifluorome- thyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-1-methyl-1H-pyrazole-4-carboxamide, N-{[2-amino-4-(methoxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesulfonylphenyl)pyri- dine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(5-chloro-2-meth anesulfonylphenyl)-2- methylpyrimidine-5-carboxamide, Ryvu Therapeutics S.A. RVU305 62 R10107WO N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulf onylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-2,6-dimethylpyridine-3-carboxamide, N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(2-meth anesulfonylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-5-fluoro-3-methylquinolin-7-yl)methyl]-N-(2-meth anesulfonylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-methylpyrimi- dine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-2- methylpyrimidine-5-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(5-chloro-2-meth anesulfonylphenyl)-2- methylpyrimidine-5-carboxamide, N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-2-methylpyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-4-methylpyrimi- dine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-methylpyr- idine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-5-fluoro-N-(2-meth anesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-5-chloro-N-(2-meth anesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulf onylpyridin-3-yl)-6-(trifluo- romethyl)pyridine-3-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulf onylpyridin-3-yl)-5-(trifluo- romethyl)pyridine-3-carboxamide, N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(2-meth anesulfonylpyridin-3-yl)-2- methylpyrimidine-5-carboxamide, N-[(2-amino-5-fluoro-3-methylquinolin-7-yl)methyl]-N-(2-meth anesulfonylpyridin-3-yl)-2- methylpyrimidine-5-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulf onylphenyl)-2-methylpy- rimidine-5-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(4,4-difluoro- 1,1-dioxo-3,4-dihydro-2H- 1λ⁶-benzothiopyran-8-yl)-6-(trifluoromethyl)pyridine-3-ca rboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-4-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-5-(trifluoro- methoxy)pyridine-3-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulf onylphenyl)-6-(trifluorome- thyl)pyridine-3-carboxamide, Ryvu Therapeutics S.A. RVU305 63 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2,6-dimethylpyri- dine-4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(5-chloro-2-meth anesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-5-(trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-5-cyano-N-(2-metha nesulfonylphenyl)pyridine- 3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-methylpyridine- 3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-[2-methanesulfon yl-5-(trifluoromethyl)pyri- din-3-yl]pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-1-(pro- pan-2-yl)-1H-pyrazole-4-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3 -dihydro-1λ⁶-benzothio- phen-7-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)- 5H,6H,7H,8H-imidazo[1,2-a]pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-ethyl-N-(4-fluor o-2-methanesul- fonylphenyl)pyrimidine-5-carboxamide, N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3 -dihydro-1λ⁶-benzothio- phen-7-yl)-6-(trifluoromethyl)pyridine-3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)-6-methylpyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)-6- (trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-5-cyano-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(propan- 2-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-ethoxy-N-(4-fluo ro-2-methanesul- fonylphenyl)pyridazine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfon ylphenyl)pyrimidine-2-car- boxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-1-(pro- pan-2-yl)-1H-pyrazole-4-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-4,6-di- methylpyridine-3-carboxamide, N-[(6-amino-7-methyl-1,5-naphthyridin-3-yl)methyl]-N-(4-fluo ro-2-methanesul- fonylphenyl)-2-methylpyrimidine-5-carboxamide, Ryvu Therapeutics S.A. RVU305 64 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-chloro-2-meth anesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-2-(pro- pan-2-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6- methylpyridazine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-cyano-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-4-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-2-(oxan- 4-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(pyrimidin- 2-yl)acetamide, N-[(2-amino-1,6-naphthyridin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-{[2-amino-3-(methoxymethyl)quinolin-7-yl]methyl}-6-cyclopr opyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(morpho- lin-4-yl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(oxan-4- yl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-cyclopropyl-N-(4 -fluoro-2-methanesul- fonylphenyl)pyridine-4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-(1 ,1-dioxo-2,3-dihydro-1λ⁶- benzothiophen-7-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-ethoxy-N-(2-meth anesulfonylpyridin-3-yl)pyr- idine-3-carboxamide, rac-N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2- methanesulfonylphenyl)-6- (oxolan-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-1-(pyridin-3- yl)-1H-pyrazole-4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-1,3-benzo- thiazole-6-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(2-methanesulfon ylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-{1,1-dioxo-2H,3H -1λ⁶-thieno[3,2-b]pyridin- 7-yl}-6-(trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(1,1-dio xo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-methyl-5- (trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(mor- pholin-4-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-[6-(trifluo- romethyl)pyridin-3-yl]-1,3-thiazole-5-carboxamide, Ryvu Therapeutics S.A. RVU305 65 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-(1-cyanocyclopro pyl)-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(ox- etan-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-(3,3-difluoropyr rolidin-1-yl)-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-5-chloro-6-cyano-N -(2-methanesulfonylpyridin- 3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclopropyl-N-{1 ,1-dioxo-2H,3H-1λ⁶- thieno[3,2-b]pyridin-7-yl}pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-ethyl-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(2-hy- droxypropan-2-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-5H,6H,7H- cyclopenta[b]pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(pyridin-3- yl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclopropyl-N-(1 ,1-dioxo-2,3-dihydro-1λ⁶- benzothiophen-7-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-{1,1-dio xo-2H,3H-1λ⁶-thieno[3,2- b]pyridin-7-yl}pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-ethyl-N-(2-metha nesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclobutyl-N-(2- methanesulfonylpyridin-3- yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclobutyl-N-(2- methanesulfonylpyridin-3- yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(pyridin-3- yl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-5-cyano-6-cyclopro pyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(2-metha nesulfonyl-4- methylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-{1 ,1-dioxo-2H,3H-1λ⁶- thieno[3,2-b]pyridin-7-yl}pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-5,6,7,8- tetrahydro-1,5-naphthyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-5-fl uoro-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesulfonyl-5- methylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-1-(pyridin-3- yl)-1H-pyrazole-4-carboxamide, Ryvu Therapeutics S.A. RVU305 66 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-(3,3-difluoroaze tidin-1-yl)-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-{[2-amino-3-(trifluoromethyl)quinolin-7-yl]methyl}-6-cyclo propyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-3-fluoro-N-(2-meth anesulfonylpyridin-3-yl)ben- zamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)-1,3-thiazole-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)- 5H,7H,8H-pyrano[4,3-b]pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-2-(mor- pholin-4-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-[1-(trifluo- romethyl)cyclopropyl]pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-5-chloro-6-cyclopr opyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyclopropyl-N-{1 ,1-dioxo-2H,3H-1λ⁶- thieno[3,2-b]pyridin-7-yl}pyridine-3-carboxamide, N-[(2-amino-3-methylquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesulfonylpyridin-3- yl)pyridine-3-carboxamide, N-[(2-amino-3-methylquinolin-7-yl)methyl]-6-cyano-N-(4-fluor o-2-methanesul- fonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-5-cyclopro pyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-(3,3-difluorocyc lobutyl)-N-(2-methanesul- fonylpyridin-3-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(3-ox- opiperazin-1-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2H,3H,4H- pyrano[2,3-b]pyridine-6-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(4- methyl-3-oxopiperazin-1-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(4-fluor o-2-methanesulfonylphenyl)- 5-(morpholin-4-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(4- methylpiperazin-1-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(2-metha nesulfonylpyridin-3-yl)-5- methylpyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(1-hy- droxy-2-methylpropan-2-yl)pyridine-3-carboxamide, and N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-(1-cyanocyclopro pyl)-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide. Definitions Ryvu Therapeutics S.A. RVU305 67 R10107WO 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 (NH ₄ ⁺ ) and substituted ammonium in which one to four of the hy- drogen atoms are replaced by C ₁ -C ₄ -alkyl, C ₁ -C ₄ -hydroxyalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy- C ₁ -C ₄ -alkyl, hydroxy-C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, phenyl or benzyl. 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 C ₁ -C ₄ -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 R ¹ , for example at the point of attachment of R ¹ to the amide carbonyl resulting in the exemplary stereoisomers shown for Example C-003 below. Ryvu Therapeutics S.A. RVU305 68 R10107WO 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. 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 R _a and S _a in 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. or 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 Ryvu Therapeutics S.A. RVU305 69 R10107WO 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. Exem- plary rotational isomers (rotamers) of the compounds according to the invention 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 moiety of the compounds are shown below for Example C-012. If the barrier to rotation is high enough, the rotational isomers (rotamers) of the com- pounds 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 rotation about the C-N bond between the tertiary amide nitrogen and the A moiety of the com- pounds according to the invention may be high enough to form atropisomers, which can be separated and isolated. Without being bound to theory, atropisomers may, e.g., be formed if the A moiety of the compounds of the present invention is substituted in ortho position on both sides of the carbon connected to the tertiary amide nitrogen of the remainder of the molecule. On the other hand, without being bound to theory, the barrier to rotation about the C-N amide bond may typically not be high enough to form atropisomers. In view of the above, the compounds of the present invention may be present as a mixture of two rota- tional 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 amide bond. The mixture may be racemic (1 to 1 mixture) or one of the rotational isomers (rota- mers) in the mixture may be enriched over the other rotational isomer (rotamer). If the bar- rier to rotation is high enough to form atropisomers, the two atropisomers may be separated and isolated. Further, the compounds of the present invention may be present as a mixture of stereoisomers resulting from more than one restricted bond rotation. For example, if there are two restricted bond rotations, as shown above for Example C-012, 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 “dia- stereoisomer-like” mixture and the stereoisomers therein which are distinguishable by NMR analysis are referred to as “diastereoisomer-like” components. If one of the two barriers to rotation is high enough to form atropisomers, e.g. the barrier to rotation about the C-N bond between the tertiary amide nitrogen and the A moiety of the compounds according to the invention, the two atropisomers may be separated and isolated. Each of the separated and Ryvu Therapeutics S.A. RVU305 70 R10107WO isolated atropisomers may then be present as a mixture of two rotational isomers (rota- mers) resulting from the second restricted bond rotation, e.g. the rotation about the C-N amide bond. A “diastereoisomer-like” mixture with “diastereoisomer-like” distinguishable components may also result if the compounds of the present invention contain a combina- tion of one or more restricted bond rotation(s) and one or more asymmetric atom(s) (i.e., chiral centres). For example, as shown above for Example C-003, 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 stereoiso- mers, i.e. rotational isomers (rotamers). A compound of the present invention such as Ex- ample C-003 may thus be present as a mixture of four stereoisomers (or even 8 stereoiso- mers in case of two restricted bond rotations), which can be grouped into “diastereoisomer- like” components that are distinguishable by NMR analysis. If, e.g., the stereoisomers re- sulting 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 ro- tation(s), e.g. the rotation about the C-N amide bond. The skilled person is aware that the presence of further centres of chirality and/or further restricted bond rotations (chirality axes) increases the number of stereoisomers present in the mixture up to a maximum of 2 ⁿ , 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. NMR at 80 °C may be useful to identify stable at- ropisomers if their signals do not significantly coalesce at this temperature. Tautomers may be formed, if a substituent is present at the compound of formula (I), which allows for the 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 71 R10107WO such as, but not limited to ² H (deuterium, D), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ CI and ¹²⁵ I. For example, radioactive isotopes such as ³ H, ¹³ C and ¹⁴ C 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 prefix ^{Cn-Cm indicates in each case the possible number of carbon atoms in the group.} T _{he term “halogen” denotes in each case fluorine, bromine, chlorine or iodine, in particular} fluorine, chlorine, or bromine. The term "alkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably 1 to 5 or 1 to 4 carbon atoms, more preferably 1 to 3 or 1 or 2 carbon 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 72 R10107WO 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 C ₁ -C ₄ -haloalkyl, more preferably from C ₁ -C ₃ -haloalkyl or C ₁ -C ₂ -haloalkyl, in particular from C ₁ -C ₂ -fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-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.} T _{he term “hydroxyalkyl” as used herein denotes in each case a straight-chain or branched} alkyl group having usually from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms, and being further substituted with 1 to 5, preferably with 1 to 2 hydroxy groups, in particular with 1 hydroxy group, wherein a hydroxy group is a OH group. Preferably, the one hydroxy group is terminating the straight-chain or branched alkyl group so that the hydroxy group is bonded to an alkyl bridge, which is bonded to the remainder of the molecule. Examples of an hydroxyalkyl group are hydroxymethyl, 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 NH ₂ group. Preferably, the one amino group is terminating the straight-chain or branched alkyl group so that the amino group is bonded to an alkyl bridge, which is bonded to the remain- der of the molecule. Examples of an aminoalkyl group are aminomethyl, aminoethyl, n-ami- Ryvu Therapeutics S.A. RVU305 73 R10107WO 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 or bicyclic ring, preferably a 4- to 8-membered or a 3- to 6-membered or a 5- to 7-membered monocyclic or bicyclic ring, more preferably a 3-, 4-, 5- or 6-membered monocyclic ring, comprising 3 to 10, preferably 4 to 8 or 3 to 6 or 5 to 7, more preferably 3, 4, 5 or 6 carbon atoms. The carbocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are pre- sent, and partially or fully unsaturated means that one or more double bonds may be pre- sent in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aro- matic 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 “carbocyclic” or “carbocyclyl”, unless otherwise indicated, may therefore cover inter alia cycloalkyl, cycloalkenyl, as well as phenyl. Preferably, the term “carbocyclic” or “carbo- cyclyl” covers phenyl and cycloalkyl, for example phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 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 74 R10107WO 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 SO ₂ . The remaining ring members are carbon atoms. In a preferred embodiment, the heterocycle is an aromatic heterocycle, preferably a 5- or 6-membered aromatic heterocycle comprising one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ^{ring members, where S-atoms as ring members may be present as S, SO or SO2. Examples} _{of aromatic heterocycles are provided below in connection with the definition of “hetaryl”.} “Hetaryls” or “heteroaryls” are covered by the term “heterocycles”. The saturated or 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 SO ₂ . The skilled person is aware that S, SO or SO ₂ is to be un- derstood as follows: Further, a skilled person is aware resonance structures 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 75 R10107WO 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 SO ₂ . 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 SO ₂ . 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 76 R10107WO 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 77 R10107WO 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 78 R10107WO 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 79 R10107WO 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 80 R10107WO 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 81 R10107WO 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 82 R10107WO 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: Ryvu Therapeutics S.A. RVU305 83 R10107WO Ryvu Therapeutics S.A. RVU305 84 R10107WO Ryvu Therapeutics S.A. RVU305 85 R10107WO Ryvu Therapeutics S.A. RVU305 86 R10107WO 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. NMR ¹ H 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 for ¹ H NMR in DMSO- d ₆ , δ = 3.31 ppm for ¹ H NMR in CD ₃ OD, δ = 7.26 ppm for ¹ H NMR in CDCl ₃ ). ¹ H 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 Ryvu Therapeutics S.A. RVU305 87 R10107WO quartets), br s (broad singulet). 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: Column: 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 buffer type (FA, TFA, NH ₃ and neutral), flow rate 0.5 mL/min: Mid polar long method: Non polar long method: Ryvu Therapeutics S.A. RVU305 88 R10107WO UPLC Eluent composition: 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: Mid polar: Non polar: 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 Ryvu Therapeutics S.A. RVU305 89 R10107WO 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. Three types of eluent system were used: General gradient: flow rate 20 mL/min. 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 3 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) ReproSil ^® CHIRAL MIF column (amylose tris-(3-chloro-4-methylphenyl)-carbamate coated on 5 ^m silica-gel, 250 mm x 20 mm) Method A

Ryvu Therapeutics S.A. RVU305 90 R10107WO Compounds of Formula (I) may be prepared according to Method A. Halomethyl aryl 1 is treated with 2 and a base, for example NaH or Cs ₂ CO ₃ , to form 3 which is subjected to pal- ladium catalyzed coupling with tert-butyl carbamate to provide 4. The tert-butoxycarbonyl protecting group of 4 is removed in acidic conditions, for example using TFA or HCl, to fur- nish the desired product of Formula (I). Alternatively, compound 3 could be reacted with NaN ₃ to provide azide 4a which is sub- jected to reduction, for example with a phosphine in aqueous medium or zinc in the pres- ence of acid, to provide the desired product of Formula (I). Alternatively, compound 3 could be reacted with 1-(2,4-dimethoxyphenyl)methanamine to provide intermediate 4b. The 2,4-dimethoxybenzyl protecting group is cleaved in acidic con- ditions, for example using TFA or PTSA, to provide the desired product of Formula (I). Method B Ryvu Therapeutics S.A. RVU305 91 R10107WO Compounds of Formula (I) may be prepared according to Method B. Halomethyl aryl 5 is treated with 2 and a base, such as NaH or Cs ₂ CO ₃ , to form 4. The tert-butoxycarbonyl pro- tecting group of 4 is removed in acidic conditions, for example using TFA or HCl, to provide the desired product of Formula (I). Method C Compounds of Formula (I) may be prepared according to Method C. Alcohol 6 is reacted with 2 in the presence of triphenylphosphine and an azodicarboxylate, such as DIAD, to form 4. The tert-butoxycarbonyl protecting group of 4 is removed in acidic conditions, for example using TFA or HCl, to provide the desired product of Formula (I). Method D Compounds of Formula (I) may be prepared according to Method D. Alcohol 7 is reacted with 2 in the presence of triphenylphosphine and an azodicarboxylate, such as DIAD, to form 3 which is subjected to palladium catalyzed coupling with tert-butyl carbamate to pro- vide 4. The tert-butoxycarbonyl protecting group of 4 is removed in acidic conditions, for ex- ample using TFA or HCl, to provide the desired product of Formula (I). Method E Ryvu Therapeutics S.A. RVU305 92 R10107WO Compounds of Formula (I) may be prepared according to Method E. Compound 8 is treated with 2 and a base, such as NaH or Cs ₂ CO ₃ , to form 9 which is subjected to palladium cata- lyzed coupling with vinylboronic acid pinacol ester to provide 10. Product 10 is subjected to oxidation, for example with NaIO ₄ and OsO ₄ , to provide aldehyde 11. The nitro group of 11 is reduced, for example by Fe in the presence of HCl, to obtain 12 which is subjected to reac- tion with substituted diethyl cyanomethylphosphonate 13, in the presence of base such as NaH or EtONa, to provide the desired product 14 of Formula (I). Compounds of Formula (I) may be prepared according to Method F. Halide 15 is reacted with 2 in the presence of a base, such as NaH or Cs ₂ CO ₃ , to form 16. The 2,4-dimethox- ybenzyl protecting group is cleaved in acidic conditions, for example using TFA or PTSA, to provide product 17 of Formula (I). 2-Chloro quinoline and 2-chloro quinoline analogs/derivatives intermediates Ryvu Therapeutics S.A. RVU305 93 R10107WO 7-(Bromomethyl)-2-chloroquinoline (Int. A-004) Step 1: General Procedure 01 7-Methylquinoline (23.44 g, 163.7 mmol, 1.0 eq.) was dissolved in DCM (450 mL) and the solution was cooled to 0 °C. mCPBA (33.9 g, 196.44 mmol, 1.2 eq.) was added by portions and the RM was left to stir for 1 h at RT. The RM was neutralized with aq. 1 N NaOH to pH ≈ 7 and then aq. sat. NaHCO ₃ (400 mL) was added. The phases were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield crude 7-methylquinolin-1-ium-1-olate (Int. A-001, 25.07 g, 157.49 mmol, 91%, yellow solid, UPLC purity: 95%) which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (dd, J = 6.1, 1.1 Hz, 1H), 8.56 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.50 (dd, J = 8.4, 1.7 Hz, 1H), 7.27 (dd, J = 8.4, 6.0 Hz, 1H), 2.62 (s, 3H). m/z (ESI): 160.4 [M+H] ⁺ . Step 2: General Procedure 02 7-Methylquinolin-1-ium-1-olate (Int. A-001, 25.07 g, 149.61 mmol, 1.0 eq.) was dissolved in water (650 mL), and MsCl (28.5 mL, 367.32 mmol, 3.0 eq.) was added. The RM was stirred overnight at RT and filtered. The resulting white solid was washed to neutral pH with water, then dried under vacuum at 50 °C overnight to obtain 7-methyl-1,2-dihydroquinolin-2-one (Int. A-002, 18.89 g, 118.66 mmol, 76%, white solid, UPLC purity: 96%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.68 (s, 1H), 7.85 (d, J = 9.5 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.10 (s, 1H), 7.01 (dd, J = 8.0, 1.6 Hz, 1H), 6.42 (d, J = 9.5 Hz, 1H), 2.38 (s, 3H). m/z (ESI): 160.4 [M+H] ⁺ . Step 3: General Procedure 03a 7-Methyl-1,2-dihydroquinolin-2-one (Int. A-002, 18.89 g, 113.92 mmol, 1.0 eq.) was sus- pended in POCl ₃ (32.0 mL, 341.75 mmol, 3.0 eq.) and the RM was stirred for 2 hours at 100 °C under nitrogen. After coming back to RT, the RM was poured on ice, and the mixture was neutralized using 2 M aq. NaOH. The resulting precipitate was filtered, washed with water and dried under vacuum at 50 °C overnight to obtain 2-chloro-7-methylquinoline (Int. A- 003, 20.5 g, 115.41 mmol, 99%, beige solid, UPLC purity: 94%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.75 (dq, J = 1.7, 0.9 Hz, 1H), 7.51 (m, 2H), 2.53 (s, 3H). m/z (ESI): 179.1 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 94 R10107WO Step 4: General Procedure 04 To a solution of 2-chloro-7-methylquinoline (Int. A-003, 9.00 g, 49.65 mmol, 1.0 eq.) in ben- zene (180 mL), NBS (12.37 g, 69.51 mmol, 1.4 eq.) was added, followed by benzoyl peroxide (0.962 g, 3.97 mmol, 0.08 eq.). The mixture was stirred in a pressure reactor overnight at 100 °C. After coming back to RT, water was added, and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with aq. sat. Na ₂ S ₂ O ₃ , water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was dissolved in THF (108 mL) and DIPEA (25.9 mL, 148.96 mmol, 3.0 eq.) was added, followed by diethyl phosphite (19.0 mL, 148.96 mmol, 3.0 eq.). The resulting solution was stirred overnight at RT under nitrogen. The RM was then partitioned between aq. sat. Na ₂ CO ₃ and EtOAc. The organic layer was separated and sequentially washed with aq. sat. NH ₄ Cl, water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under re- duced pressure. The crude material was purified by FCC (0 to 10% EtOAc gradient in DCM) to yield 7-(bromomethyl)-2-chloroquinoline (Int. A-004, 10.58 g, 40.02 mmol, 81%, yellow solid, UPLC purity: 97%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 1.1 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 8.4, 1.5 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 4.69 (s, 2H). m/z (ESI): 257.9 [M+H] ⁺ . tert-Butyl N-[7-(hydroxymethyl)quinolin-2-yl]carbamate (Int. A-007) Step 1: A solution of 7-(bromomethyl)-2-chloroquinoline (Int. A-004, 1.0 g, 3.55 mmol, 1.0 eq.), so- dium acetate (0.37 g, 4.45 mmol, 1.25 eq.) and TBAB (0.12 g, 0.36 mmol, 0.1 eq.) in iPrOAc (8.0 mL) was refluxed with stirring under nitrogen for 20 h. After coming back to RT, the RM was partitioned between water and iPrOAc and the aqueous phase was extracted with iPrOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gra- dient in hexane) to yield (2-chloroquinolin-7-yl)methyl acetate (Int. A-005, 0.825 g, 3.50 mmol, 98%, off-white solid, UPLC purity: 97%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 8.6 Hz, 1H), 8.02 (dt, J = 1.7, 0.8 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.55 (dd, J = 8.4, 1.7 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 5.34 (d, J = 0.9 Hz, 2H), 2.19 (s, 3H). m/z (ESI): 236.8 [M+H] ⁺ . Step 2: XPhos (0.175 g, 0.37 mmol, 0.026 eq.) and Pd(OAc) ₂ (0.041 g, 0.18 mmol, 0.013 eq.) were added to a suspension of (2-chloroquinolin-7-yl)methyl acetate (Int. A-005, 3.45 g, 14.35 Ryvu Therapeutics S.A. RVU305 95 R10107WO mmol, 1.0 eq.), tert-butyl carbamate (2.53 g, 21.55 mmol, 1.50 eq.) and K ₂ CO ₃ (2.975 g, 21.53 mmol, 1.5 eq.) in anhydrous 2-MeTHF (40.0 mL). The RM was refluxed with stirring under nitrogen for 2 h. After coming back to RT, water was added with stirring and the phases were separated. The aqueous layer was extracted with EtOAc (2x) and the combined or- ganic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield (2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl acetate (Int. A-006, 4.51 g, 14.26 mmol, 97%, colorless foam, UPLC purity: 98%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J = 9.0 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.42 (dd, J = 8.3, 1.7 Hz, 1H), 5.30 (s, 2H), 2.18 (s, 3H), 1.57 (s, 9H). m/z (ESI): 339.1 [M+Na] ⁺ . Step 3: Lithium hydroxide monohydrate (0.23 g, 5.36 mmol, 1.51 eq.) was added to a solution of (2- {[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl acetate (Int. A-006, 1.15 g, 3.56 mmol, 1.0 eq.) in a mixture of THF (10.0 mL) and water (5.0 mL), and the RM was stirred at 50 °C for 4 h. After coming back to RT, it was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield tert-butyl N-[7-(hydroxymethyl)quinolin- 2-yl]carbamate (Int. A-007, 0.83 g, 3.03 mmol, 84%, off-white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 8.25 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.69 (dt, J = 1.7, 0.8 Hz, 1H), 7.39 (dd, J = 8.3, 1.6 Hz, 1H), 5.38 (t, J = 5.8 Hz, 1H), 4.67 (d, J = 5.8 Hz, 2H), 1.50 (s, 9H). _m/z (ESI): 296.7 [M+Na] ⁺ . (2-Aminoquinolin-7-yl)methanol (Int. TFA (4.1 mL) was added to a solution of tert-butyl N-[7-(hydroxymethyl)quinolin-2-yl]car- bamate (Int. A-007, 0.305 g, 1.09 mmol, 1.0 eq.) in DCM (10.0 mL). The RM was stirred at RT for 2 h and was 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 fractions containing the title compound were pooled and evapo- rated under reduced pressure to yield (2-aminoquinolin-7-yl)methanol (Int. A-008, 0.195 g, 1.07 mmol, 99%, white solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), 7.11 (dd, J = 8.1, 1.6 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.39 (s, 2H), 5.25 (t, J = 5.8 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H). m/z (ESI): 175.1 [M+H] ⁺ . tert-Butyl N-[7-(bromomethyl)quinolin-2-yl]carbamate (Int. A-010) Ryvu Therapeutics S.A. RVU305 96 R10107WO Step 1: A pressure vessel was charged with 2-chloro-7-methylquinoline (Int. A-003, 3.73 g, 20.2 mmol, 1.0 eq.), Cs ₂ CO ₃ (13.1 g, 40.3 mmol, 2.0 eq.), tert-butyl carbamate (4.7 g, 40.3 mmol, 2.0 eq.), X-Phos (0.48 g, 1.0 mmol, 0.05 eq.) and anhydrous dioxane (150 mL). The RM was sparged with nitrogen for 10 min. and XPhos Pd G3 (0.853 g, 1.0 mmol, 0.05 eq.) was added. The vessel was closed and the RM was stirred for 1.5 h at 100 °C. After coming back to RT, the RM was evaporated under reduced pressure, the residue was suspended in EtOAc and the suspension was filtered through a pad of Celite ^® . The filtrate was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 15% EtOAc gradient in hexane) to yield tert- butyl N-(7-methylquinolin-2-yl)carbamate (Int. A-009, 4.80 g, 18.58 mmol, 92%, orange foam, UPLC purity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.55 (s, 1H), 7.30 (dd, J = 8.2, 1.8 Hz, 1H), 2.50 (s, 3H), 1.51 (s, 9H). m/z (ESI): 259.1 [M+H] ⁺ . Step 2: The title compound was prepared according to General Procedure 04 using tert-butyl N-(7- methylquinolin-2-yl)carbamate (Int. A-009, 6.06 g, 21.1 mmol, 1.0 eq.), N-bromosuccinimide (9.39 g, 52.8 mmol, 2.5 eq.) and benzoyl peroxide (1.02 g, 4.2 mmol, 0.2 eq.) in carbon tetra- chloride (200 mL) at 90 °C, followed by DIPEA (10.8 mL, 63.3 mmol, 3.0 eq.) and diethyl phosphite (8.1 mL, 63.3 mmol, 3.0 eq.) in anhydrous THF (50.0 mL). The crude material was purified by FCC (0 to 100% DCM gradient in hexane). The fractions containing the product were pooled and evaporated to yield a yellow oil. This oil was rapidly stirred in hexane (30.0 mL) for 15 min. and the resulting solid was filtered off, washed with hexane and dried under vacuum at 45 °C for 20 minutes to yield tert-butyl N-[7-(bromomethyl)quinolin-2-yl]carba- mate (Int. A-010, 3.89 g, 11.5 mmol, 52%, light orange solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.50 (dd, J = 8.3, 1.8 Hz, 1H), 4.91 (s, 2H), 1.51 (s, 9H). m/z (ESI): 338.3 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 97 R10107WO Step 1: ^{A mixture of quinoline-7-carboxylic acid (1.0 g, 5.77 mmol, 1.0 eq.) and conc. H2SO4 (2.0 mL)} _{in methanol (40.0 mL) was stirred overnight at 50 °C under nitrogen. After coming back to} RT, the RM was neutralized by addition of sat. aq. NaHCO ₃ and diluted with water. It was then extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield crude methyl quinoline- 7-carboxylate (Int. A-011, 1.07 g, 5.71 mmol, 96%, orange solid, UPLC purity: 97%) which was used in the next step without further purification. ¹ H NMR (400 MHz, Chloroform-d) δ 9.04 (dd, J = 4.3, 1.7 Hz, 1H), 8.88 (d, J = 1.3 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.19 (dd, J = 8.5, 1.7 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.3, 4.2 Hz, 1H), 4.04 (s, 3H). m/z (ESI): 188.1 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 01, using mCPBA (1.91 g, 11.07 mmol, 2.0 eq.) and methyl quinoline-7-carboxylate (Int. A-011, 1.067 g, 5.53 mmol, 1.0 eq.) in DCM (11.0 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in EtOAc) to yield 7-(methoxycarbonyl)quinolin-1-ium-1-olate (Int. A-012, 0.857 g, 4.22 mmol, 75%, beige solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (d, J = 2.0 Hz, 1H), 8.70 (dd, J = 6.0, 0.9 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.19 (dd, J = 8.5, 1.7 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.63 (dd, J = 8.5, 6.1 Hz, 1H), 3.97 (s, 3H). m/z (ESI): 204.1 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 02, using MsCl (1.0 mL, 12.92 mmol, 3.1 eq.), 7-(methoxycarbonyl)quinolin-1-ium-1-olate (Int. A-012, 0.855 g, 4.12 mmol, 1.0 eq.) in water (33.0 mL). The obtained crude methyl 2-oxo-1,2-dihydroquinoline-7-carboxylate (Int. A-013, 0.803 g, 3.95 mmol, 95%, UPLC purity: 99%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.97 (s, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.72 (dd, J = 8.1, 1.6 Hz, 1H), 6.65 (dd, J = 9.6, 1.8 Hz, 1H), 3.91 (s, 3H). m/z (ESI): 204.1 [M+H] ⁺ . Step 4: General Procedure 03b A pressure vessel was charged with methyl 2-oxo-1,2-dihydroquinoline-7-carboxylate (Int. ^{A-013, 0.803 g, 3.91 mmol, 1.0 eq.) and anhydrous toluene (15.0 mL). POCl3 (1.8 g, 11.74} _{mmol, 3.0 eq.) was added under nitrogen at 0 °C, the vessel was closed and the RM was} stirred at 120 °C for 2 h. After coming back to RT, the RM was poured onto ice/water and the mixture was neutralized with aq. 2 M NaOH. The layers were separated and the aque- ous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to yield crude methyl 2-chloroquinoline-7-carboxylate (Int. A-014, 0.805 g, 3.63 mmol, 90%, UPLC purity: 97%) which was used in the next step without further purification. ¹ H NMR (400 MHz, Chloroform-d) δ 8.76 (d, J = 1.6 Hz, 1H), 8.20 (dd, J = 8.4, 1.7 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 4.03 (s, 3H). m/z (ESI): 223.7 [M+H] ⁺ . Step 5: Ryvu Therapeutics S.A. RVU305 98 R10107WO DIBAL-D (0.7 M in toluene, 10.6 mL, 7.42 mmol, 2.1 eq.) was slowly added over 5 min. to a solution of methyl 2-chloroquinoline-7-carboxylate (Int. A-014, 0.804 g, 3.52 mmol, 1.0 eq.) in anhydrous DCM (18.0 mL) at -78 °C under nitrogen. The RM was stirred at -78 °C for 30 min., an additional portion of DIBAL-D (0.7 M in toluene, 10.6 mL, 7.42 mmol, 2.1 eq.) was added and the RM was stirred for 1 h at -78 °C. The reaction was quenched at -78 °C with aq. 1 M Rochelle salt and the mixture was allowed to warm to RT over 30 min. The aqueous layer was extracted with DCM (3x) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The resulting crude aldehyde ((2-chloroquinolin-7-yl)(²H)formaldehyde) was dissolved in anhydrous DCM (18.0 mL), and the solution was cooled to -78 °C under nitrogen. DIBAL-D (0.7 M in tolu- ene, 10.6 mL, 7.42 mmol, 2.1 eq.) was slowly added over 5 min. and the RM was left with stirring at -78 °C under nitrogen for 1 h. The reaction was quenched at -78 °C with aq. 1 M Rochelle salt and the mixture was allowed to warm to RT over 30 min. The phases were separated and the aqueous layer was extracted with DCM (3x). The combined organic lay- ers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield (2-chloro- quinolin-7-yl)(²H₂)methanol (Int. A-015, 0.578 g, 2.95 mmol, 82%, light beige solid, UPLC pu- rity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.63 (dd, J = 8.4, 1.6 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 5.46 (s, 1H). m/z (ESI): 196.7 [M+H] ⁺ . 2-(Bromomethyl)-7-chloro-1,8-naphthyridine (Int. A-016) The title compound was prepared according to General Procedure 04, using 2-chloro-7-me- thyl-1,8-naphthyridine (0.2 g, 1.12 mmol, 1.0 eq.), NBS (0.239 g, 1.34 mmol, 1.2 eq.) and (BzO) ₂ (0.029 g, 0.09 mmol, 0.08 eq.) in CHCl ₃ (2.5 mL), followed by diethyl phosphite (0.122 g, 0.89 mmol, 0.8 eq.) and DIPEA (0.155 mL, 0.89 mmol, 0.8 eq.) in THF (2.0 mL). The prod- uct was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 2-(bromomethyl)-7- chloro-1,8-naphthyridine (Int. A-016, 0.137 g, 0.53 mmol, 47%, white solid, UPLC purity: 63%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (d, J = 8.3 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 4.91 (s, 2H). m/z (ESI): 258.9 [M+H] ⁺ . 7-(Bromomethyl)-2-chloroquinoxaline (Int. A-017) Ryvu Therapeutics S.A. RVU305 99 R10107WO NBS (0.499 g, 2.80 mmol, 2.5 eq.) and benzoyl peroxide (0.041 g, 0.17 mmol, 0.15 eq.) were added to a solution of 2-chloro-7-methylquinoxaline (0.2 g, 1.12 mmol, 1.0 eq.) in DMC (7.5 mL). The mixture was stirred in a sealed tube at 100 °C for 2 h. After coming back to RT, the RM was partitioned between sat. aq. Na ₂ S ₂ O ₃ and EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield 7-(bromomethyl)-2-chloroquinoxaline (Int. A-017, 0.1 g, 0.39 mmol, 34%, white solid, UPLC purity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.96 (dd, J = 8.6, 2.0 Hz, 1H), 4.97 (s, 2H). m/z (ESI): 257.0 [M+H] ⁺ . 7‐(Bromomethyl)‐2‐chloro‐5‐fluoroquinoline (Int. A-022) Step 1: General Procedure 05 Glycerol (1.4 mL, 19.18 mmol, 1.2 eq.) was added to a solution of 3-fluoro-5-methylaniline ^{(2.0 g, 15.98 mmol, 1.0 eq.) and NaI (3.2 g, 20.78 mmol, 1.3 eq.) in conc. H2SO4 (3.9 mL,} _{71.92 mmol, 4.7 eq.). The RM was stirred at 140 °C overnight, poured on ice and neutral-} ized with aq. 1 M NaOH. The mixture was extracted with DCM (3x) and the combined or- ganic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield an inseparable 3/2 mixture of 7-fluoro-5-methylquinoline Int. A-018-A and 5-fluoro-7- methylquinoline Int. A-018-B (1.6 g, 9.94 mmol, 62%, red oil, UPLC purity: 94%). ^{7-fluoro-5-methylquinoline: 1H NMR (400 MHz, DMSO-d} ₆ ^{) δ 8.93 (dd, J = 4.7, 1.7 Hz, 1H),} 8.48 (ddd, J = 8.5, 1.7, 0.9 Hz, 1H), 7.62 – 7.58 (m, 1H), 7.56 (dd, J = 8.5, 4.2 Hz, 1H), 7.43 (ddd, J = 9.7, 2.7, 1.1 Hz, 1H), 2.70 (t, J = 0.8 Hz, 3H). m/z (ESI): 162.1 [M+2H] ²⁺ . 5-fluoro-7-methylquinoline: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (dd, J = 4.4, 1.7 Hz, 1H), 8.42 (ddd, J = 8.4, 1.7, 0.9 Hz, 1H), 7.71 – 7.69 (m, 1H), 7.56 (dd, J = 8.5, 4.3 Hz, 1H), 7.33 (dd, J = 11.1, 1.5 Hz, 1H), 2.54 (s, 3H). m/z (ESI): 162.1 [M+2H] ²⁺ . Step 2: 5-Fluoro-7-methylquinolin-1-ium-1-olate (Int. A-019-A) was prepared according to General Procedure 01 using the above 3/2 mixture of 7-fluoro-5-methylquinoline Int. A-018-A and 5- fluoro-7-methylquinoline Int. A-018-B (1.5 g, 9.31 mmol, 1.0 eq.), and mCPBA (1.81 g, 10.5 mmol, 1.2 eq.) in DCM (25.0 mL). The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield: Ryvu Therapeutics S.A. RVU305 100 R10107WO 5-fluoro-7-methylquinolin-1-ium-1-olate (Int. A-019-A, 0.446 g, 2.51 mmol, 27%, white solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (dd, J = 6.0, 0.9 Hz, 1H), 8.23 – 8.18 (m, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 10.7, 1.3 Hz, 1H), 7.49 (dd, J = 8.6, 6.1 Hz, 1H), 2.57 (s, 3H). m/z (ESI): 178.0 [M+H] ⁺ . 7-fluoro-5-methylquinolin-1-ium-1-olate (Int. A-019-B, 0.806 g, 4.54 mmol, 49%, white solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (d, J = 6.0 Hz, 1H), 8.10 (dd, J = 10.3, 2.7 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.60 (dd, J = 9.4, 2.7 Hz, 1H), 7.50 (dd, J = 8.7, 6.1 Hz, 1H), 2.73 (s, 3H). m/z (ESI): 178.0 [M+H] ⁺ . Step 3: 5-Fluoro-7-methyl-1,2-dihydroquinolin-2-one (Int. A-020, 0.39 g, 2.20 mmol, 92%, white solid, UPLC purity: 93%) was prepared according to General Procedure 02 using 5-fluoro-7- methylquinolin-1-ium-1-olate (Int. A-019-A, 0.41 g, 2.22 mmol, 1.0 eq.) and MsCl (0.77 g, 6.72 mmol, 3.03 eq.) in water (10.0 mL). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.90 (s, 1H), 7.93 (d, J = 9.6 Hz, 1H), 6.94 (s, 1H), 6.89 (d, J = 11.0 Hz, 1H), 6.49 (dd, J = 9.8, 1.7 Hz, 1H), 2.39 (s, 3H). m/z (ESI): 178.4 [M+H] ⁺ . Step 4: 2-Chloro-5-fluoro-7-methylquinoline (Int. A-021, 0.39 g, 1.99 mmol, 97%, beige solid, UPLC purity: 97%) was prepared according to General Procedure 03a using 5-fluoro-7-methyl-1,2- dihydroquinolin-2-one (Int. A-020, 0.38 g, 1.99 mmol, 1.0 eq.) and POCl ₃ (0.6 mL, 6.0 mmol, 3.0 eq.). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (dd, J = 8.7, 0.8 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 10.9, 1.4 Hz, 1H), 2.55 (s, 3H). m/z (ESI): 195.9 [M+H] ⁺ . Step 5: 7-(Bromomethyl)-2-chloro-5-fluoroquinoline (Int. A-022, 0.361 g, 1.31 mmol, 62%, white solid, UPLC purity: 91%) was prepared according to General Procedure 04 using 2-chloro-5- fluoro-7-methylquinoline (Int. A-021, 0.387 g, 1.91 mmol, 1.0 eq.), NBS (0.51 g, 2.86 mmol, 1.5 eq.) and (BzO) ₂ (0.037 g, 0.15 mmol, 0.08 eq.) in DMC (8.0 mL), followed by DIPEA (0.34 mL, 1.95 mmol, 1.02 eq.) and diethyl phosphite (0.27 g, 1.97 mmol, 1.03 eq.) in THF (5.0 mL). The crude material was purified by FCC (0 to 10% EtOAc gradient in hexane). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 10.7, 1.5 Hz, 1H), 4.93 (s, 2H). m/z (ESI): 275.8 [M+H] ⁺ . tert‐Butyl N‐[7‐(bromomethyl)‐5‐chloroquinolin‐2‐yl]‐N‐ [(tert‐butoxy)car- bonyl]carbamate (Int. A-029) Ryvu Therapeutics S.A. RVU305 101 R10107WO Step 1: Step 1 was performed according to General Procedure 05, using 3-chloro-5-methylaniline (1.0 g, 7.06 mmol, 1.0 eq.), NaI (1.38 g, 9.18 mmol, 1.3 eq.) and glycerol (0.62 mL, 8.47 mmol, 1.2 eq.) in conc. H ₂ SO ₄ (1.7 mL). The crude material was purified by FCC (0 to 2% MeOH gradient in DCM) to yield an inseparable 65/35 mixture of 5-chloro-7-methylquinoline (ma- jor, Int. A-023-A) and 7-chloro-5-methylquinoline (minor, Int. A-023-B) (0.904 g, 2.54 mmol, 32%, brown oil, UPLC purity: 89%). 5-chloro-7-methylquinoline (Int. A-023-A): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (dd, J = 4.2, 1.7 Hz, 1H), 8.54 – 8.51 (m, 1H), 7.86 – 7.83 (m, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 8.5, 4.2 Hz, 1H), 2.55 (s, 3H). m/z (ESI): 178.7 [M+H] ⁺ . 7-chloro-5-methylquinoline (Int. A-023-B): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 – 8.94 (m, 1H), 8.51 – 8.48 (m, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 8.5, 4.2 Hz, 1H), 7.56 – 7.53 (m, 1H), 2.69 (s, 3H). m/z (ESI): 178.7 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 01, using the above mixture of 5- chloro-7-methylquinoline and 7-chloro-5-methylquinoline (Int. A-023-A/Int. A-023-B, 0.904 g, 4.53 mmol, 1.0 eq.) and mCPBA (0.938 g, 5.44 mmol, 1.2 eq.) in DCM (16.0 mL). The crude material was purified by FCC (silica 15 ^m, 0 to 10% MeOH gradient in EtOAc) to yield 5‐chloro‐7‐methylquinolin‐1‐ium‐1‐olate (Int. A-024-A, 0.329 g, 1.70 mmol, 36%, white solid, UPLC purity: 96%) and 7‐chloro‐5‐methylquinolin‐1‐ium ‐1‐olate (Int. A-024-B, 0.204 g, 1.05 mmol, 22%, white solid, UPLC purity: 92%). 5‐chloro‐7‐methylquinolin‐1‐ium‐1‐olate (Int. A-024-A): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.64 (dd, J = 6.1, 0.9 Hz, 1H), 8.34 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.53 (dd, J = 8.7, 6.0 Hz, 1H), 2.55 (s, 3H). _m/z (ESI): 193.9 [M+H] ⁺ . 7‐chloro‐5‐methylquinolin‐1‐ium ‐1‐olate (Int. A-024-B): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (dd, J = 6.1, 0.9 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.52 (dd, J = 8.7, 6.1 Hz, 1H), 2.68 (s, 3H). m/z (ESI): 193.9 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 02, using 5‐chloro‐7‐methylquin- olin‐1‐ium‐1‐olate (Int. A-024-A, 0.317 g, 1.57 mmol, 1.0 eq.) and MsCl (0.54 g, 4.71 mmol, 3 eq.) in water (10.0 mL). The obtained crude 5‐chloro‐7‐methyl‐1,2‐dihydro- quinolin‐2‐one (Int. A-025, 0.315 g, 1.42 mmol, 91%, white solid, UPLC purity: 92%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.95 (s, Ryvu Therapeutics S.A. RVU305 102 R10107WO 1H), 8.03 (d, J = 9.8 Hz, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.57 (dd, J = 9.8, 1.8 Hz, 1H), 2.38 (s, 3H). m/z (ESI): 193.9 [M+H] ⁺ . Step 4: Step 4 was performed according to General Procedure 03b, using 5‐chloro‐7‐methyl‐ 1,2‐dihydroquinolin‐2‐one (Int. A-025, 0.315 g, 1.42 mmol, 1.0 eq.) and POCl ₃ (0.4 mL, 4.27 mmol, 3.0 eq.) in anhydrous toluene (2.0 mL). The obtained crude 2,5‐dichloro‐7‐ methylquinoline (Int. A-026, 0.298 g, 1.41 mmol, 99%, off-white solid, UPLC purity: 93%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (dd, J = 8.8, 0.9 Hz, 1H), 7.82 – 7.77 (m, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 2.55 (s, 3H). m/z (ESI): 211.9 [M+H] ⁺ . Step 5: A mixture of 2,5‐dichloro‐7‐methylquinoline (Int. A-026, 0.319 mg, 1.41 mmol, 1.0 eq.), ^{K2CO3 (0.969 mg, 7.01 mmol, 5.0 eq.), and acetamide (1.66 g, 28 mmol, 20 eq.) was heated} _{at 200 °C with stirring for 1.5 h. After coming back to RT, water was added and the result-} ing precipitate was filtered off. The filtrate was extracted with DCM/iPrOH (3x) and the gathered organic layers were combined with the above solid, dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield 5‐chloro‐7‐methylquinolin‐2‐amine (Int. A-027, 0.215 g, 0.90 mmol, 64%, white solid, UPLC purity: 81%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (d, J = 9.0 Hz, 1H), 7.27 – 7.20 (m, 1H), 7.15 (d, J = 1.5 Hz, 1H), 6.82 (d, J = 9.1 Hz, 1H), 6.66 (s, 2H), 2.40 (s, 3H). m/z (ESI): 192.9 [M+H] ⁺ . Step 6: ^{TEA (0.35 mL, 2.54 mmol, 3 eq.) and (Boc)2O (0.277 g, 1.26 mmol, 1.5 eq.) were successively} _{added to a solution of 5‐chloro‐7‐methylquinolin‐2‐amine (Int. A-027, 0.181 g, 0.85} mmol, 1.0 eq.) and DMAP (0.020 g, 0.169 mmol, 0.2 eq.) in anhydrous THF (2.0 mL). The RM was stirred at 60 °C for 0.5 h. After coming back to RT, the RM was poured into water, then sat. aq. NaHCO ₃ was added followed by ethyl acetate. The layers were separated and the aqueous phase was extracted with DCM (2x). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (silica 15 ^m; 0 to 2% EtOAc gradient in DCM) to yield tert‐butyl N‐[(tert‐butoxy)carbonyl]‐N‐(5‐chloro‐7‐methyl quinolin‐2‐yl) carbamate (Int. A-028, 0.219 g, 0.51 mmol, 61%, yellow gummy solid, UPLC purity: 92%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 8.9 Hz, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.48 (d, J = 11.1 Hz, 1H), 2.56 (s, 3H), 1.49 (s, 18H). m/z (ESI): 238.5 [M+2MeCN+2H] ²⁺ . Step 7: A pressure vessel was charged with tert‐butyl N‐[(tert‐butoxy)carbonyl]‐N‐ (5‐ chloro‐7‐methylquinolin‐2‐yl) carbamate (Int. A-028, 0.219 g 0.51 mmol, 1.0 eq.), AIBN ^{(0.017 mg, 0.10 mmol, 0.2 eq.), NBS (0.137 g, 0.77 mmol, 1.5 eq.) and CCl4 (5.0 mL). The} _{vessel was closed and the RM was stirred at 80 °C for 5 h. After coming back to RT, the} RM was partitioned between DCM and sat. aq. NaHCO ₃ and the aqueous layer was ex- Ryvu Therapeutics S.A. RVU305 103 R10107WO tracted with DCM (2x). The combined organic layers were washed with brine, dried over an- hydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (silica 15 ^m; 0 to 17 % EtOAc gradient in hexane) to yield tert‐butyl N‐ [7‐(bromomethyl)‐5‐chloroquinolin‐2‐yl]‐N‐[(te rt‐butoxy)carbonyl]carbamate (Int. A-029, 0.179 g, 0.34 mmol, 66%, yellow gummy solid, UPLC purity: 89%). ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.70 (dd, J = 8.9, 0.9 Hz, 1H), 7.95 (d, J = 0.8 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 4.79 (s, 2H), 1.46 (s, 18H). _m/z (ESI): 533.8 [M+MeCN+Na] ⁺ . Step 1: Step 1 was performed according to General Procedure 05, using 3-bromo-5-methylaniline (3.0 g, 16.12 mmol, 1.0 eq.), NaI (3.142 g, 20.96 mmol, 1.3 eq.) and glycerol (1.43 mL, 19.35 mmol, 1.2 eq.) in conc. H ₂ SO ₄ (3.87 mL, 72.56 mmol, 4.5 eq.). The crude material was puri- fied by FCC (0 to 50% EtOAc gradient in hexane) to yield an inseparable 4/6 mixture of 5- bromo-7-methylquinoline (Int. A-030-A, minor) and 7-bromo-5-methylquinoline (Int. A-030- B, major) (2.19 g, 4.93 mmol, 26%, brown solid, UPLC purity: 85%). 5-bromo-7-methylquinoline (Int. A-030-A): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (m, 1H), 8.52 – 8.48 (m, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.67 (m, 1H), 7.63 (dd, J = 8.5, 4.2 Hz, 1H), 2.69 (s, 3H). m/z (ESI): 223.8 [M+H] ⁺ . 7-bromo-5-methylquinoline (Int. A-030-B): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (m, 1H), 8.46 (dd, J = 8.6, 1.5 Hz, 1H), 7.88 (s, 2H), 7.64 (dd, J = 8.6, 4.3 Hz, 1H), 2.55 (s, 3H). m/z (ESI): 223.8 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 01, using the above 4/6 mixture of 5- bromo-7-methylquinoline (Int. A-030-A) and 7-bromo-5-methylquinoline (Int. A-030-B) (2.19 g, 4.93 mmol, 1 eq.), and mCPBA (0.868 g, 5.03 mmol, 1.02 eq.) in DCM (20.0 mL). The crude material was purified by FCC (0 to 10% MeOH gradient in EtOAc) to give 5-bromo-7- methylquinolin-1-ium-1-olate (Int. A-031-A, 0.283 g, 1.19 mmol, 28%, off-white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (dd, J = 6.1, 0.9 Hz, 1H), 8.44 – 8.40 (m, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 8.8, 6.1 Hz, 1H), 2.56 (s, 3H). m/z (ESI): 239.8 [M+H] ⁺ . Step 3: Ryvu Therapeutics S.A. RVU305 104 R10107WO Step 3 was performed according to General Procedure 02, using 5-bromo-7-methylquinolin- 1-ium-1-olate (Int. A-031-A, 0.28 g, 1.16 mmol, 1.0 eq.) and MsCl (0.400 g, 3.49 mmol, 3.0 eq.) in water (15.0 mL). The obtained crude 5-bromo-7-methyl-1,2-dihydroquinolin-2-one (Int. A-032, 0.258 g, 1.08 mmol, 90%, off-white solid, UPLC purity: 97%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.93 (s, 1H), 7.98 (d, J = 9.8 Hz, 1H), 7.36 (d, J = 1.5 Hz, 1H), 7.12 (s, 1H), 6.56 (dd, J = 9.8, 1.7 Hz, 1H), 2.38 (s, 3H). _m/z (ESI): 239.9 [M+H] ⁺ . Step 4: Step 4 was performed according to General Procedure 03b, using 5-bromo-7-methyl-1,2- dihydroquinolin-2-one (Int. A-032, 0.256 g, 1.04 mmol, 1.0 eq.), POCl ₃ (0.480 g, 3.13 mmol, 3.0 eq.) in anhydrous toluene (10.0 mL). The obtained crude 5-bromo-2-chloro-7- methylquinoline (Int. A-033, 0.268 g, 1.04 mmol, 100%, off-white solid, UPLC purity: 100%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (dd, J = 8.8, 0.8 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.85 – 7.77 (m, 1H), 7.68 (d, J = 8.8 Hz, 1H), 2.54 (s, 3H). m/z (ESI): 257.8 [M+H] ⁺ . Step 5: Step 5 was performed according to General Procedure 04, using 5-bromo-2-chloro-7- methylquinoline (Int. A-033, 0.268 g, 1.045 mmol, 1.0 eq.), NBS (0.465 g, 2.61 mmol, 2.5 eq.) and benzoyl peroxide (0.020 g, 0.08 mmol, 0.08 eq.) in DMC (8.0 mL), followed by DIPEA (0.182 mL, 1.04 mmol, 1.0 eq.) and diethyl phosphite (0.143 g, 1.04 mmol, 1.0 eq.) in THF (8.0 mL). The crude material was purified by FCC (0 to 2% EtOAc gradient in hexane) to yield 5-bromo-7-(bromomethyl)-2-chloroquinoline (Int. A-034, 0.265 g, 0.79 mmol, 60%, yel- low solid, UPLC purity: 79%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (d, J = 8.8 Hz, 1H), 8.11 (s, 2H), 7.77 (d, J = 8.8 Hz, 1H), 4.93 (s, 2H). m/z (ESI): 335.7 [M+H] ⁺ . 7-(bromomethyl)-2-chloro-6-fluoroquinoline (Int. A-039) Step 1: Step 1 was performed according to General Procedure 05, using 4-fluoro-3-methylaniline (2.0 g, 15.98 mmol, 1.0 eq.), NaI (3.114 g, 20.78 mmol, 1.3 eq.), and glycerol (14.41 mL, 195.63 mmol, 12.2 eq.) in conc. H ₂ SO ₄ (3.8 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to give an inseparable 85/15 mixture of 6-fluoro-7- Ryvu Therapeutics S.A. RVU305 105 R10107WO methylquinoline (Int. A-035-A, major) and 6-fluoro-5-methylquinoline (Int. A-035-B, minor) (1.35 g, 3.8 mmol, 22%, black solid, UPLC purity: 94%). 6-fluoro-7-methylquinoline (Int. A-035-A): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.86 (dd, J = 4.2, 1.8 Hz, 1H), 8.32 (dd, J = 8.0, 1.3 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 10.3 Hz, 1H), 7.52 (dd, J = 8.3, 4.3 Hz, 1H), 2.47 (dd, J = 2.1, 1.1 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -117.76 (ddd, J = 10.1, 7.6, 2.3 Hz). m/z (ESI): 162.0 [M+H] ⁺ . 6-fluoro-5-methylquinoline (Int. A-035-B): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (dd, J = 4.1, 1.6 Hz, 1H), 8.52 (ddd, J = 8.6, 1.7, 0.8 Hz, 1H), 7.94 (d, J = 5.5 Hz, 1H), 7.66 (t, J = 9.3 Hz, 1H), 7.62 (dd, J = 8.6, 4.2 Hz, 1H), 2.56 (d, J = 2.4 Hz, 3H). 19F NMR (376 MHz, DMSO- d ₆ ) δ -116.40 (ddd, J = 9.1, 5.4, 2.7 Hz). _m/z (ESI): 162.2 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 01, using the above 85/15 mixture of 6-fluoro-7-methylquinoline (Int. A-035-A, major) and 6-fluoro-5-methylquinoline (Int. A- 035-B, minor) (1.33 g, 3.52 mmol, 1.0 eq.) and mCPBA (1.1 g, 6.37 mmol, 1.8 eq.) in DCM (10.0 mL). The crude material was purified by FCC (silica 15 μm, 0 to 10% MeOH gradient in EtOAc) to yield 6-fluoro-7-methylquinolin-1-ium-1-olate (Int. A-036A, 0.58 g, 3.27 mmol, 93%, grey solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (d, J = 6.0 Hz, 1H), 8.49 (d, J = 7.4 Hz, 1H), 7.89 (d, J = 10.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.5, 6.1 Hz, 1H), 2.50 – 2.48 (m, 3H).19F NMR (376 MHz, DMSO-d ₆ ) δ -114.17 – -117.22 (m). m/z (ESI): 178.2 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 02, using 6-fluoro-7-methylquinolin- 1-ium-1-olate (Int. A-036A, 0.5 g, 2.82 mmol, 1.0 eq.) and MsCl (1.939 g, 16.93 mmol, 6.0 eq.) in water (15.0 mL). The obtained crude 6-fluoro-7-methyl-1,2-dihydroquinolin-2-one (Int. A-037, 0.432 g, 2.44 mmol, 86%, white solid, UPLC purity: 100%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.75 (s, 1H), 7.85 (d, J = 9.5 Hz, 1H), 7.49 (d, J = 9.9 Hz, 1H), 7.17 (d, J = 6.7 Hz, 1H), 6.50 (d, J = 9.5 Hz, 1H), 2.32 (d, J = 1.3 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -125.48 – -125.58 (m). m/z (ESI): 178.1 [M+H] ⁺ . Step 4: Step 4 was performed according to General Procedure 03a, using 6-fluoro-7-methyl-1,2-di- hydroquinolin-2-one (Int. A-037, 0.4 g, 2.26 mmol, 1 eq.) and POCl ₃ (1.04 g, 6.77 mmol, 3 eq.). The obtained crude 2-chloro-6-fluoro-7-methylquinoline (Int. A-038, 0.412 g, 2.10 mmol, 92%, white solid, UPLC purity: 99%) was used in the next step without further purifi- cation. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 10.1 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 2.48 – 2.44 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -116.46 – -116.55 (m). m/z (ESI): 197.0 [M+H] ⁺ . Step 5: Step 5 was performed according to General Procedure 04, using 2-chloro-6-fluoro-7- methylquinoline (Int. A-038, 0.2 g, 1.01 mmol, 1.0 eq.), NBS (0.288 g, 1.62 mmol, 1.6 eq.) and benzoyl peroxide (0.020 g, 0.08 mmol, 0.08 eq.) in DMC (5.0 mL), followed by DIPEA (0.22 Ryvu Therapeutics S.A. RVU305 106 R10107WO mL, 1.26 mmol, 1.0 eq.) and diethyl phosphite (0.18 g, 1.31 mmol, 1.04 eq.) in THF (3.0 mL). The crude material was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield 7-(bro- momethyl)-2-chloro-6-fluoroquinoline (Int. A-039, 0.15 g, 0.55 mmol, 42%, white solid, UPLC purity: 78%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 7.3 Hz, 1H), 7.96 (d, J = 10.4 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 4.92 (s, 2H). m/z (ESI): 275.8 [M+H] ⁺ . Step 1: Step 1 was performed according to General Procedure 05, using 4-methoxy-3-methylaniline (2.23 g, 16.26 mmol, 1.0 eq.), NaI (3.17 g, 21.13 mmol, 1.3 eq.) and glycerol (1.44 mL, 19.51 ^{mmol, 1.2 eq.) in conc. H2SO4 (3.9 mL). The crude material was purified by FCC (0 to 40%} _{EtOAc gradient in hexane) to yield 6‐methoxy‐7‐methylquinoline (Int. A-040, 0.679 g,} 3.76 mmol, 23%, brown oil, UPLC purity: 96%) as sole isomer. _m/z (ESI): 174.1 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 01, using 6‐methoxy‐7‐ methylquinoline (Int. A-040, 0.677 g, 3.75 mmol, 1.0 eq.) and mCPBA (0.971 mg, 5.63 mmol, 1.5 eq.) in DCM (12.0 mL). The crude material was purified by FCC (0 to 10% MeOH in DCM) to afford 6‐methoxy‐7‐methylquinolin‐1‐ium‐1‐olate (Int. A-041, 0.436 g, 2.20 mmol, 59%, off-white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (dd, J = 6.1, 1.0 Hz, 1H), 8.34 (t, J = 1.1 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.38 (dd, J = 8.4, 6.0 Hz, 1H), 3.96 (s, 3H), 2.40 (s, 3H). m/z (ESI): 190.2 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 02, using 6‐methoxy‐7‐ methylquinolin‐1‐ium‐1‐olate (Int. A-041, 0.396 g, 1.99 mmol, 1.0 eq.) and MsCl (3.68 mL, 47.88 mmol, 24 eq.) in a mixture of water (12.0 mL) and dioxane (2.0 mL) for 92 h at 60 °C. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield 6‐methoxy‐7‐methyl‐1,2‐dihydroquinolin‐2‐one (Int. A-042, 0.134 g, 0.65 mmol, 34%, off-white solid, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (s, 1H), 7.84 (d, J = 9.5 Hz, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 6.43 (d, J = 9.5 Hz, 1H), 3.83 (s, 3H), 2.24 (s, 3H). m/z (ESI): 190.4 [M+H] ⁺ . Step 4: Ryvu Therapeutics S.A. RVU305 107 R10107WO Step 4 was performed according to General Procedure 03b, using 6‐methoxy‐7‐methyl‐ ^{1,2‐dihydroquinolin‐2‐one (Int. A-042, 0.233 g, 1.11 mmol, 1 eq.) and POCl3 (0.31 mL,} _{3.23 mmol, 3 eq.) in anhydrous toluene (2.0 mL). The crude 2‐chloro‐6‐methoxy‐7‐} methylquinoline (Int. A-043, 0.158 g, 0.64 mmol, 58%, off-white solid, UPLC purity: 84%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J = 8.6 Hz, 1H), 7.75 (s, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 3.95 (s, 3H), 2.38 (s, 3H). _m/z (ESI): 208.0 [M+H] ⁺ . Step 5: Step 5 was performed according to General Procedure 04, using 2‐chloro‐6‐methoxy‐ 7‐methylquinoline (Int. A-043, 0.140 g, 0.57 mmol, 1.0 eq.), NBS (0.151 g, 0.85 mmol, 1.5 eq.) and benzoyl peroxide (0.027, 0.11 mmol, 0.2 eq.) in DMC (3.5 mL). The crude material was purified by FCC (0 to 20% EtOAc gradient in hexane) to yield 7‐(bromomethyl)‐2‐ chloro‐6‐methoxyquinoline (Int. A-044, 0.053 g, 0.17 mmol, 31%, off-white solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (d, J = 8.6 Hz, 1H), 8.06 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.54 (s, 1H), 4.84 (s, 2H), 4.01 (s, 3H). m/z (ESI): 285.9 [M+H] ⁺ . Step 1: Bis(tri-tert-butylphosphine)palladium (0.08 g, 0.16 mmol, 0.05 eq.) was added to a mixture of 2-chloro-5-methylpyridin-3-amine (0.5 g, 3.51 mmol, 1.0 eq.), ethyl acrylate (0.46 mL, 4.24 mmol, 1.2 eq.) and triethylamine (2.45 mL, 17.58 mmol, 5.0 eq.), and the RM was stirred at 150 °C for 16 h in a sealed tube. The RM was cooled to RT and the volatiles were evaporated under reduced pressure. The resulting crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield 7-methyl-1,2-dihydro-1,5-naphthyridin-2-one (Int. A- ^{045, 0.26 g, 1.62 mmol, 42%, beige solid, UPLC purity: 90%). 1H NMR (400 MHz, DMSO-d6)} _{δ 11.86 (s, 1H), 8.35 (d, J = 1.9 Hz, 1H), 7.90 (d, J = 9.7 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H),} 6.68 (d, J = 9.7 Hz, 1H), 2.41 (s, 3H). _m/z (ESI): 161.2 [M+H] ⁺ . Step 2: POCl ₃ (3.2 g, 20.87 mmol, 15.0 eq.) was added to a solution of 7-methyl-1,2-dihydro-1,5- naphthyridin-2-one (Int. A-045, 0.25 g, 1.40 mmol, 1.0 eq.) in chloroform (5.0 mL) at RT. The RM was refluxed for 16 hours under nitrogen, cooled down to RT and concentrated under reduced pressure. The residue was taken up in DCM/MeOH 95:5 v/v, the solution was cooled to 0 °C and carefully basified with aq.2 M NaOH. The mixture was diluted with wa- ter, the phases were separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under Ryvu Therapeutics S.A. RVU305 108 R10107WO reduced pressure. The crude material was triturated with Et ₂ O, filtered and dried under vac- uum to yield 2-chloro-7-methyl-1,5-naphthyridine (Int. A-046, 0.241 g, 1.35 mmol, 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 2.57 (s, 3H). m/z (ESI): 178.9 [M+H] ⁺ . Step 3: 7-(Bromomethyl)-2-chloro-1,5-naphthyridine (Int. A-047, 0.110 g, 0.43 mmol, 33%, white solid, UPLC purity: 99%) was prepared according to General Procedure 04 using 2-chloro-7- methyl-1,5-naphthyridine (Int. A-046, 0.29 g, 1.30 mmol, 1.0 eq.), NBS (0.348 g, 1.96 mmol, 1.5 eq.) and (BzO) ₂ (0.025 g, 0.10 mmol, 0.08 eq.) in DMC (5.5 mL). The crude material was purified by FCC (0 to 30% EtOAc gradient in hexane). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (d, J = 2.1 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 5.01 (s, 2H). m/z (ESI): 258.9 [M+H] ⁺ . Step 1: Step 1 was carried out according to General Procedure 05, using 3-methyl-5-(trifluorome- thyl)aniline (1.0 g, 5.71 mmol, 1.0 eq.), glycerol (0.55 mL, 7.46mmol, 1.31 eq.), conc. H ₂ SO ₄ (1.37 mL, 25.70 mmol, 4.5 eq.) and NaI (1.12 g, 7.47 mmol, 1.3 eq.). The crude material was purified by FCC (0 to 35% EtOAc gradient in hexane) to yield an inseparable 1/1 mixture of 5-methyl-7-(trifluoromethyl)quinoline Int. A-048-A and 7-methyl-5-(trifluoromethyl)quino- line Int. A-048-B (0.94 g, 2.23 mmol, 74%, brown semi-solid, UPLC purity: 94%). 5-Methyl-7-(trifluoromethyl)quinoline (Int. A-048-A): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (dd, J = 4.2, 1.6 Hz, 1H), 8.61 (ddd, J = 8.6, 1.7, 0.9 Hz, 1H), 8.25 – 8.19 (m, 1H), 7.76 (dd, J = 8.6, 4.1 Hz, 1H), 7.76 (s, 1H), 2.78 (s, 3H). m/z (ESI): 212.1 [M+H] ⁺ . 7-Methyl-5-(trifluoromethyl)quinoline (Int. A-048-B): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (dd, J = 4.1, 1.6 Hz, 1H), 8.48 – 8.42 (m, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.69 (dd, J = 8.7, 4.2 Hz, 1H), 2.62 (s, 3H). m/z (ESI): 212.1 [M+H] ⁺ . Step 2: 5-Trifluoromethyl-7-methylquinolin-1-ium-1-olate (Int. A-049-B) was prepared according to General Procedure 01 using the above 1/1 mixture of 7-trifluoromethyl-5-methylquinoline Int. A-048-B and 5-trifluoromethyl-7-methylquinoline Int. A-048-A (0.925 g, 2.06 mmol, 1.0 Ryvu Therapeutics S.A. RVU305 109 R10107WO eq.), and mCPBA (0.435 g, 2.52 mmol, 1.2 eq.) in DCM (32.0 mL). The crude material was purified by FCC (0 to 10% MeOH gradient in EtOAc) to yield: 5-trifluoromethyl-7-methylquinolin-1-ium-1-olate (Int. A-049-B, 0.400 g, 1.76 mmol, 42%, yellow solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (d, J = 6.1 Hz, 1H), 8.70 (s, 1H), 8.10 (s, 1H), 7.98 – 7.88 (m, 1H), 7.61 (dd, J = 8.9, 6.1 Hz, 1H), 2.64 (s, 3H). m/z (ESI): 228.4 [M+H] ⁺ . 7-trifluoromethyl-5-methylquinolin-1-ium-1-olate (Int. A-049-A, 0.435 g, 1.92 mmol, 45%, beige solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J = 6.1 Hz, 1H), 8.71 (s, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.91 (s, 1H), 7.68 (dd, J = 8.8, 6.0 Hz, 1H), 2.78 (s, 3H). _m/z (ESI): 228.2 [M+H] ⁺ . Step 3: 5-Trifluoro-7-methyl-1,2-dihydroquinolin-2-one (Int. A-050, 0.33 g, 1.45 mmol, 77%, beige solid, UPLC purity: 88%) was prepared according to General Procedure 02 using 5-trifluoro- methyl-7-methylquinolin-1-ium-1-olate (Int. A-049-B, 0.38 g, 1.66 mmol, 1.0 eq.) and MsCl (0.6 g, 5.24 mmol, 3.2 eq.) in water (8.0 mL). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.10 (s, 1H), 7.94 (dq, J = 9.9, 2.0 Hz, 1H), 7.46 (s, 1H), 7.40 (s, 1H), 6.66 (dd, J = 9.9, 1.8 Hz, 1H), 2.46 (s, 3H). m/z (ESI): 228.1 [M+H] ⁺ . Step 4: 2-Chloro-5-trifluoromethyl-7-methylquinoline (Int. A-051, 0.330 g, 1.34 mmol, 94%, beige solid, UPLC purity: 94%) was prepared according to General Procedure 03a using 5-trifluo- romethyl-7-methyl-1,2-dihydroquinolin-2-one (Int. A-050, 0.325 g, 1.43 mmol, 1.0 eq.) and POCl ₃ (0.4 mL, 4.29 mmol, 3.0 eq.). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 – 8.42 (m, 1H), 8.07 (s, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 2.60 (s, 3H). m/z (ESI): 247.8 [M+H] ⁺ . Step 5: 7-(Bromomethyl)-2-chloro-(5-trifluoromethyl)quinoline (Int. A-052, 0.38 g, 1.17 mmol, 92%, white solid, UPLC purity: 99%) was prepared according to General Procedure 04 using 2- chloro-7-methyl-5-(trifluoromethyl)quinoline (Int. A-051, 0.33 g, 1.26 mmol, 1.0 eq.), NBS (0.34 g, 1.91 mmol, 1.5 eq.) and (BzO) ₂ (0.025 g, 0.10 mmol, 0.08 eq.). in DMC (7.0 mL), fol- lowed by DIPEA (0.22 mL, 1.26 mmol, 1.0 eq.) and diethyl phosphite (0.18 g, 1.31 mmol, 1.04 eq.) in THF (3.5 mL). The crude material was purified by FCC (0 to 10% EtOAc gradient in hexane). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 – 8.49 (m, 1H), 8.39 (s, 1H), 8.25 – 8.21 (m, 1H), 7.84 (d, J = 9.0 Hz, 1H), 5.02 (s, 2H). m/z (ESI): 324.0 [M+H] ⁺ . 7-(Bromomethyl)-2,8-dichloroquinoline (Int. A-056) Ryvu Therapeutics S.A. RVU305 110 R10107WO Step 1: General Procedure 06 NaHMDS (1 M solution in THF, 21.2 mL, 21.2 mmol, 1.5 eq.) was added over 30 min. to a solution of 2-chloro-3-methylaniline (2.0 g, 14.12 mmol, 1.0 eq.) and methyl 3,3-dimethoxy- propanoate (2.51 g, 16.94 mmol, 1.2 eq.) in anhydrous THF (28.0 mL) at 0 °C under nitro- gen. The RM was stirred at 0 °C for 10 min. and allowed to warm to RT over a period of 20 min. After stirring at RT for 16 h, 20% aq. citric acid (20.0 mL) was added at 5 °C. The THF layer was separated and the aqueous layer was extracted with DCM (50.0 mL). The THF layer was concentrated under reduced pressure. The residue was taken up in DCM (100 mL), combined with the DCM phase from the extraction and the resulting mixture was washed with water (50.0 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude N-(2-chloro-3- methylphenyl)-3,3-dimethoxypropanamide (Int. A-053, 4.5 g, 13.97 mmol, 99%, brown oil, NMR purity: 80%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 7.63 (dd, J = 7.9, 1.8 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.16 (dd, J = 7.7, 1.7 Hz, 1H), 4.81 (t, J = 5.7 Hz, 1H), 3.32 (s, 6H), 2.74 (d, J = 5.7 Hz, 2H), 2.36 (s, 3H). m/z (ESI): 280.0 [M+Na] ⁺ . Step 2: General Procedure 07 A solution of N-(2-chloro-3-methylphenyl)-3,3-dimethoxypropanamide (Int. A-053, 4.5 g, ^{13.97 mmol, 1.0 eq.) in DCM (5.0 mL) was added over 20 min. to stirring conc. H2SO4 (11.5} _{mL, 214.62 mmol, 15.4 eq.), maintaining the temperature between 0 and 5 °C. The result-} ing solution was stirred at 0 °C for 5 min. and allowed to warm to RT over a period of 20 min. After stirring at RT for 0.5 h, the volatiles were evaporated under reduced pressure. The liquid residue was poured onto ice−water and the resulting suspension was filtered. The filter cake was washed with water and Et ₂ O, and was dried under reduced pressure to yield crude 8-chloro-7-methyl-1,2-dihydroquinolin-2-one (Int. A-054, 2.018 g, 10.42 mmol, 73%, brown solid, UPLC purity: 98%) which was used as is in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.85 (s, 1H), 7.94 (d, J = 9.5 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 9.5 Hz, 1H), 2.46 (s, 3H). m/z (ESI): 193.9 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 03b using 8-chloro-7-methyl-1,2-di- hydroquinolin-2-one (Int. A-054, 2.0 g, 10.12 mmol, 1.0 eq.) and POCl ₃ (1.722 g, 11.23 mmol, Ryvu Therapeutics S.A. RVU305 111 R10107WO 1.1 eq.) in toluene (13.0 mL). The crude material was purified by FCC (0 to 60% EtOAc gra- dient in hexane) to yield 2,8-dichloro-7-methylquinoline (Int. A-055, 1.21 g, 5.71 mmol, 56%, beige solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 2.61 (s, 3H). m/z (ESI): 213.3 [M+H] ⁺ . Step 4: 7-(bromomethyl)-2,8-dichloroquinoline (Int. A-056, 0.55 g, 1.89 mmol, 78%, beige solid, UPLC purity: 96%) was prepared according to General Procedure 04 using 2,8-dichloro-7- methylquinoline (Int. A-055, 0.5 g, 2.33 mmol, 1.0 eq.), NBS (0.63 g, 3.54 mmol, 1.52 eq.) and (BzO) ₂ (0.02 g, 0.083 mmol, 0.035 eq.) in DMC (5.0 mL), followed by DIPEA (0.426 mL, 2.45 mmol, 1.05 eq.) and diethyl phosphite (0.32 g, 2.33 mmol, 1.0 eq.) in THF (5.0 mL). The crude material was purified by FCC (0 to 33% EtOAc gradient in hexane). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 5.00 (s, 2H). m/z (ESI): 291.9 [M+H] ⁺ . Step 1: Step 1 was performed according to General Procedure 06, using 2-methoxy-3-methylaniline (2.012 g, 14.67 mmol, 1.0 eq.), methyl 3,3-dimethoxypropionate (2.686 g, 18.13 mmol, 1.24 eq.) and KHMDS (1 M solution in THF, 22.0 mL, 22.0 mmol, 1.5 eq.) in anhydrous THF (30.0 mL). The obtained crude 3,3-dimethoxy-N-(2-methoxy-3-methylphenyl)propanamide (Int. A-057, 2.906 g, 7.92 mmol, 54%, brown oil, UPLC purity: 69%) was used in the next step without further purification. m/z (ESI): 276.2 [M+Na] ⁺ . Step 2: Step 2 was performed according to General Procedure 07, using 3,3-dimethoxy-N-(2-meth- oxy-3-methylphenyl)propanamide (Int. A-057, 2.899 g, 7.90 mmol, 1.0 eq.), conc. H ₂ SO ₄ (2.23 mL, 41.63 mmol, 15.0 eq.) in DCM (5.0 mL). After pouring the RM onto ice/water, the result- ing mixture was saturated with NaCl and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield 8-meth- oxy-7-methyl-1,2-dihydroquinolin-2-one (Int. A-058, 1.288 g, 6.19 mmol, 78%, white solid, UPLC purity: 91%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 7.86 (d, J = 9.5 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 8.0, 0.7 Hz, 1H), 6.45 (d, J = 9.5 Hz, 1H), 3.73 (s, 3H), 2.34 (s, 3H). m/z (ESI): 190.1 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 112 R10107WO Step 3: Step 3 was performed according to General Procedure 03b, using 8-methoxy-7-methyl-1,2- dihydroquinolin-2-one (Int. A-058, 1.229 g, 5.89 mmol, 1 eq.) and POCl ₃ (1.8 mL, 19.3 mmol, 3 eq.) in anhydrous toluene (2.0 mL). The obtained crude 2-chloro-8-methoxy-7- methylquinoline (Int. A-059, 1.203 g, 5.1 mmol, 85%, white solid, UPLC purity: 88%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 4.01 (s, 3H), 2.44 (s, 3H). m/z (ESI): 208.1 [M+H] ⁺ . Step 4: 2-Chloro-8-methoxy-7-methylquinoline (Int. A-059, 0.195 g, 0.8 mmol, 1 eq.), AIBN (0.135 mg, 0.8 mmol, 1 eq.) and NBS (0.226 g, 1.2 mmol, 1.5 eq.) were dissolved in anhydrous CCl ₄ (21.0 mL). The RM was refluxed for 1 h, 1 eq. of AIBN being added to the RM every 10 min. After coming back to RT, the RM was diluted with DCM and washed with sat. aq. NaHCO ₃ . The aqueous layer was extracted with DCM (2x) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield 7-(bromomethyl)-2-chloro-8-methoxyquinoline (Int. A-060, 0.207 g, 0.69 mmol, 85%, off-white solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 4.87 (s, 2H), 4.17 (s, 3H). m/z (ESI): 286.0 [M+H] ⁺ . 7-(Bromomethyl)-2-chloro-3-(difluoromethyl)quinoline (Int. A-062) Step 1: DAST (0.509 g, 3.16 mmol, 1.3 eq.) was added over 1 min. to a solution of 2-chloro-7- methylquinoline-3-carbaldehyde (0.5 g, 2.43 mmol, 1.0 eq.) in anhydrous DCM (10.0 mL) at 0 °C under argon, and the RM was stirred overnight at RT. A second portion of DAST (0.509 g, 3.16 mmol, 1.3 eq.) was added and the RM was stirred for another 24 h at RT. The reaction was quenched by addition of sat. aq. NaHCO ₃ followed by 30 min. stirring. The phases were separated and the aqueous phase was further extracted with DCM (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-chloro-3-(difluoromethyl)-7-methylquinoline (Int. A-061, 0.6 g, 2.64 mmol, 100%, brown oil, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.85 (s, 1H), 7.62 (dd, J = 8.4, 1.8 Hz, 1H), 7.34 (t, J = 54.1 Hz, 1H), 2.58 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -115.45 (d, J = 54.5 Hz). m/z (ESI): 229.0 [M+H] ⁺ . Step 2: The title compound was prepared according to General Procedure 04, using 2-chloro-3- (difluoromethyl)-7-methylquinoline (Int. A-061, 0.57 g, 2.30 mmol, 1.0 eq.), NBS (1.02 g, 5.76 Ryvu Therapeutics S.A. RVU305 113 R10107WO mmol, 2.5 eq.) and benzoyl peroxide (0.084 g, 0.35 mmol, 0.15 eq.) in DMC (10.0 mL), fol- lowed by DIPEA (0.4 mL, 2.30 mmol, 1.0 eq.), diethyl phosphite (0.316 g, 2.30 mmol, 1.0 eq.) in THF (10.0 mL). The crude material was purified by FCC (0 to 10% EtOAc gradient in hex- ane) to yield 7-(bromomethyl)-2-chloro-3-(difluoromethyl)quinoline (Int. A-062, 0.312 g, 1.02 mmol, 42%, white powder, NMR purity: 88%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.86 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 1.8 Hz, 1H), 7.37 (t, J = 54.0 Hz, 1H), 4.96 (s, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -115.96 (d, J = 54.1 Hz). _m/z (ESI): 307.8 [M+H] ⁺ . Methyl 7-(bromomethyl)-2-chloroquinoline-4-carboxylate (Int. A-065) Step 1: A pressure vessel was charged with 2-iodo-5-methylaniline (4.0 g, 17.16 mmol, 1.0 eq.), di- methyl maleate (3.216 g, 22.31 mmol, 1.3 eq.), TEA (1.91 mL, 13.73 mmol, 0.8 eq.), Pd(OAc) ₂ (0.39 g, 1.72 mmol, 0.1 eq.) and MeCN (11.0 mL). The RM was sparged with nitrogen for 15 min., the vessel was closed and the RM was stirred at 100 °C for 4 h. After coming back to RT, the RM was partitioned between water and DCM/iPrOH 3:1 v/v. The aqueous phase was extracted with DCM (x3) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 2% MeOH gradient in DCM, then isocratic) to afford methyl 7-methyl-2-oxo-1,2- dihydroquinoline-4-carboxylate (Int. A-063, 0.883 g, 4.06 mmol, 23%, black solid, UPLC pu- rity: 87%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.08 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.10 (dd, J = 8.5, 1.7 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 3.94 (s, 3H), 2.40 (s, 3H). m/z (ESI): 218.1 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 03b, using methyl 7-methyl-2-oxo- ^{1,2-dihydroquinoline-4-carboxylate (Int. A-063, 1.8 g, 7.87 mmol, 1.0 eq.) and POCl3 (3.621} _{g, 23.62 mmol, 3.0 eq.) in anhydrous toluene (31.0 mL) at 120 °C. The crude material was} purified by FCC (0 to 10% EtOAc gradient in hexane) to yield methyl 2-chloro-7-methylquin- oline-4-carboxylate (Int. A-064, 1.249 g, 5.3 mmol, 67%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (d, J = 8.7 Hz, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.65 (dd, J = 8.7, 1.8 Hz, 1H), 4.01 (s, 3H), 2.57 (s, 3H). m/z (ESI): 237.7 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 04, using 2-chloro-7-methylquino- line-4-carboxylate (Int. A-064, 1.0 g, 4.24 mmol, 1.0 eq.), NBS (1.888 g, 10.61 mmol, 2.5 eq.) and benzoyl peroxide (0.085 g, 0.35 mmol, 0.08 eq.) in DMC (34.0 mL), followed by DIPEA (2.217 mL, 12.72 mmol, 3.0 eq.) and diethyl phosphite (1.746 g, 12.72 mmol, 3.0 eq.) in THF (85.0 mL). The crude material was purified by FCC (70% to 100% DCM in hexane) to give Ryvu Therapeutics S.A. RVU305 114 R10107WO methyl 7-(bromomethyl)-2-chloroquinoline-4-carboxylate (Int. A-065, 1.149 g, 3.65 mmol, 85%, yellow solid, UPLC purity: 82%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.98 (s, 1H), 7.85 (dd, J = 8.9, 1.9 Hz, 1H), 4.96 (s, 2H), 4.02 (s, 3H). m/z (ESI): 315.8 [M+H] ⁺ . Step 1: NaBH ₄ (0.276 g, 7.30 mmol, 3.0 eq.) was added to a stirring solution of 2-chloro-7- methylquinoline-3-carbaldehyde (0.5 g, 2.43 mmol, 1.0 eq.) in anhydrous MeOH (12.0 mL) and the RM was stirred at RT for 30 min. The reaction was quenched with sat. aq. NH ₄ Cl and the mixture was stirred for 10 min. It was then partitioned between DCM and water and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under re- duced pressure. The obtained crude (2-chloro-7-methylquinolin-3-yl)methanol (Int. A-066, 0.518 g, 2.49 mmol, 99%, yellow solid, UPLC purity: 97%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.51 (dd, J = 8.3, 1.7 Hz, 1H), 5.68 (t, J = 5.5 Hz, 1H), 4.68 (dd, J = 5.4, 1.2 Hz, 2H), 2.54 (s, 3H). m/z (ESI): 209.2 [M+H] ⁺ . Step 2: Acetic anhydride (0.86 mL, 9.11 mmol, 4.0 eq.) was added to a solution of (2-chloro-7- methylquinolin-3-yl)methanol (Int. A-066, 0.49 g, 2.28 mmol, 1.0 eq.) in anhydrous toluene (4.6 mL) and the RM was stirred overnight at 100 °C under nitrogen. After coming back to RT, the RM was diluted with EtOAc and the solution was washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 20% EtOAc gradient in hexane) to yield (2-chloro-7-methylquinolin-3-yl)methyl acetate (Int. A-067, 0.497 g, 1.99 mmol, 87%, orange solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.79 (s, 1H), 7.55 (dd, J = 8.4, 1.7 Hz, 1H), 5.28 (s, 2H), 2.55 (s, 3H), 2.16 (s, 3H). m/z (ESI): 250.9 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 04, using (2-chloro-7-methylquino- lin-3-yl)methyl acetate (Int. A-067, 0.497 g, 1.99 mmol, 1.0 eq.), NBS (0.708 g, 3.98 mmol, 1.5 eq.) and benzoyl peroxide (0.154 g, 0.64 mmol, 0.32 eq.) in DMC (12.0 mL). The crude material was purified by FCC (0 to 15% EtOAc gradient in hexane) to yield [7-(bromome- thyl)-2-chloroquinolin-3-yl]methyl acetate (Int. A-068, 0.181 g, 0.55 mmol, 25%, white solid, UPLC purity: 66%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.07 (s, 1H), 7.75 (dd, J = 8.4, 1.7 Hz, 1H), 5.30 (s, 2H), 4.95 (s, 2H), 2.18 (s, 3H). m/z (ESI): 329.8 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 115 R10107WO 7-(Bromomethyl)-2-chloro-3-fluoroquinoline (Int. A-072) Step 1: A solution of 4-methyl-2-nitrobenzaldehyde (1 g, 6.06 mmol, 1.0 eq.) in EtOAc (6 mL) was added dropwise over 45 min. to a suspension of iron powder (1.353 g, 24.22 mmol, 4 eq.) in a mixture of water (9 mL) and AcOH (2.511 mL, 43.90 mmol, 7.25 eq.) and the RM was stirred for 1 h at RT. It was then filtered through a pad of Celite ^® , rinsing the filter cake with EtOAc. The filtrate was washed with sat. aq. NaHCO ₃ (3x), dried over anhydrous Na ₂ SO ₄ , fil- tered, and treated with activated charcoal (0.3 g) for 30 min. at RT. The resulting mixture was filtered through a pad of Celite ^® and the filtrate was evaporated to half of its volume. Heptane (20 mL) was added. The EtOAc was evaporated under reduced pressure and the resulting precipitate was filtered off and dried in air to yield 2-amino-4-methylbenzaldehyde (Int. A-069, 0.490 g, 3.62 mmol, 54%, beige solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.74 (d, J = 0.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.13 – 7.04 (m, 2H), 6.55 (s, 1H), 6.47 (dd, J = 8.1, 1.5 Hz, 1H), 2.22 (s, 3H). _m/z (ESI): 135.3 [M+H] ⁺ . Step 2: A solution of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (0.948 g, 3.92 mmol, 1.2 eq,) in anhydrous MeCN (1 mL) was added dropwise via syringe over 20 min. to a solution of 2- amino-4-methylbenzaldehyde (Int. A-069, 0.490 g, 3.26 mmol, 1 eq.), DBU (0.596 g, 3.92 mmol, 1.2 eq.) and anhydrous LiCl (0.166 g, 3.92 mmol, 1.2 eq.) in anhydrous MeCN (4 mL), and the RM was stirred at RT under nitrogen for 6 h. The RM was then diluted with water and the mixture was extracted with EtOAc (4x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield 3-fluoro-7-methyl-1,2- dihydroquinolin-2-one (Int. A-070, 0.377 g, 2.02 mmol, 62%, yellow solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H), 7.82 (d, J = 11.1 Hz, 1H), 7.54 (d, J = 8.0 Hz, ^{1H), 7.13 (s, 1H), 7.07 (dd, J = 8.0, 0.9 Hz, 1H), 2.38 (s, 3H). 19F NMR (376 MHz, DMSO-d6)} _{δ -133.50 (d, J = 11.1 Hz).} m/z (ESI): 178.1 [M+H] ⁺ . Step 3: Ryvu Therapeutics S.A. RVU305 116 R10107WO Step 3 was performed according to General Procedure 03b, using 3-fluoro-7-methyl-1,2-di- hydroquinolin-2-one (Int. A-070, 3.250 g, 17.98 mmol, 1 eq.) and POCl ₃ (3.032 g, 19.77 mmol, 1.1 eq.) in anhydrous toluene (33 mL). The crude material was purified by FCC (10% to 70% DCM gradient in hexane) to yield 2-chloro-3-fluoro-7-methylquinoline (Int. A-071, 3.2 g, 16.36 mmol, 91%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 2.52 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -123.37 (d, J = 9.2 Hz). _m/z (ESI): 196.0 [M+H] ⁺ . Step 4: Step 4 was performed according to General Procedure 04, using 2-chloro-3-fluoro-7- methylquinoline (Int. A-071, 0.730 g, 3.55 mmol, 1 eq.), NBS (0.946 g, 5.32 mmol, 1.5 eq.) and (Bz) ₂ O (0.026 g, 0.106 mmol, 0.03 eq.) in DMC (12 mL), followed by diethyl phosphite (0.486 g, 3.55 mmol, 1 eq.) and DIPEA (0.648 g, 3.72 mmol, 1.05 eq.) in a mixture of toluene (20 mL) and MeOH (5 mL). The crude material was purified by FCC (from DCM:hexane 3:7 to DCM:hexane:AcOEt 3:2:5) to yield 7-(bromomethyl)-2-chloro-3-fluoroquinoline (Int. A- ^{072, 0.800 g, 2.74 mmol, 76%, white solid, UPLC purity: 94%). 1H NMR (400 MHz, DMSO-d6)} _{δ 8.51 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.77 (ddd, J =} 8.5, 1.8, 0.8 Hz, 1H), 4.93 (s, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -121.19 (d, J = 9.2 Hz). m/z (ESI): 275.9 [M+H] ⁺ . 1-(2-Chloroquinolin-7-yl)methanamine (Int. A-073) 28% Aq. ammonia (18.0 mL) was added to a solution of 7-(bromomethyl)-2-chloroquinoline (Int. A-004,1.0 g, 3.55 mmol, 1.0 eq.) in ethanol (18.0 mL) and the RM was stirred at RT for 16 h. The resulting precipitate was filtered off and washed with water and isopropanol. The filtrate was concentrated in vacuo to yield crude 1-(2-chloroquinolin-7-yl)methanamine (Int. A-073, 0.54 g, 2.80 mmol, 70%, beige solid, UPLC purity: 89%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (dd, J = 8.7, 0.8 Hz, 1H), 8.32 (s, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.73 (dd, J = 8.4, 1.8 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 4.30 (s, 2H). m/z (ESI): 193.2 [M+H] ⁺ . 7-(Bromomethyl)-2-chloro-4-methylquinoline (Int. A-080) Ryvu Therapeutics S.A. RVU305 117 R10107WO Step 1: Methyl 3-oxobutanoate (10.125 g, 87.2 mmol, 1.5 eq.) was added to a solution of 3-bro- moaniline (10.0 g, 58.13 mmol, 1.0 eq.) in toluene (200.0 mL), the RM was stirred at reflux for 48 h before being evaporated in vacuo. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-(3-bromophenyl)-3-oxobutanamide (Int. A-074, 5.8 g, 22.65 mmol, 37%, pale yellow solid, UPLC purity: 94%). ¹ H NMR (400 MHz, Chloro- form-d) δ 9.28 (s, 1H), 7.85 (t, J = 2.0 Hz, 1H), 7.47 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.28 (ddd, J = 8.4, 1.8, 1.1 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 3.63 (s, 2H), 2.36 (s, 3H). m/z (ESI): 257.9 [M+H] ⁺ . Step 2: A solution of N-(3-bromophenyl)-3-oxobutanamide (Int. A-074, 5.8 g, 21.29 mmol, 1.0 eq.) in concentrated H ₂ SO ₄ (35.0 mL) was stirred at 95 °C for 2 h. The RM was poured on ice with stirring and the resulting precipitate was filtered off, washed with water and dried in vacuo to yield 7-bromo-4-methyl-1,2-dihydroquinolin-2-one (Int. A-075, 5.0 g, 21 mmol, 94%, pale yellow solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.68 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 6.45 (s, 1H), 2.42 (d, J = 1.3 Hz, 3H). m/z (ESI): 239.8 [M+H] ⁺ . Step 3: A mixture of 7-bromo-4-methyl-1,2-dihydroquinolin-2-one (Int. A-075, 2.0 g, 7.98 mmol, 1.0 eq.) and CuCN (0.86 g, 9.60 mmol, 1.20 eq.) in NMP (11.0 mL) was stirred overnight at 160 °C. After coming back to RT, the RM was diluted with water and extracted with DCM (x3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield crude 4-methyl-2-oxo-1,2-dihydroquino- line-7-carbonitrile (Int. A-076, 1.8 g, 9.772 mmol, 114%, brown solid, UPLC purity: 93%) ^{which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6)} _{δ 11.88 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.59 (dd, J = 8.2, 1.5 Hz, 1H), 6.58 (s,} 1H), 2.45 (s, 3H). m/z (ESI): 185.1 [M+H] ⁺ . Step 4: POCl ₃ (1.55 g, 10.11 mmol, 1.11 eq.) was added to a suspension of 4-methyl-2-oxo-1,2-dihy- droquinoline-7-carbonitrile (Int. A-076, 1.8 g, 9.10 mmol, 1.0 eq.) in toluene (90.0 mL) and the RM was stirred at reflux for 4 h. The RM was then poured on stirring ice/water and the mixture was carefully neutralized with aq.1 M NaOH. The mixture was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 30% EtOAc gradient in hexane) to yield 2-chloro-4-methylquinoline-7-carbonitrile (Int. A- 077, 1.358 g, 6.70 mmol, 73%, pale brown solid, UPLC purity: 99%). ¹ H NMR (400 MHz, Chlo- roform-d) δ 8.37 (dd, J = 1.6, 0.6 Hz, 1H), 8.09 (dd, J = 8.6, 0.6 Hz, 1H), 7.76 (dd, J = 8.6, 1.7 Hz, 1H), 7.41 (q, J = 1.0 Hz, 1H), 2.75 (d, J = 1.0 Hz, 3H). _m/z (ESI): 203.0 [M+H] ⁺ . Step 5: Diisobutylaluminum hydride (1.0 M in DCM, 3.576 mL, 3.58 mmol, 1.21 eq.) was added dropwise to a solution of 2-chloro-4-methylquinoline-7-carbonitrile (Int. A-077, 0.607 g, 2.97 Ryvu Therapeutics S.A. RVU305 118 R10107WO mmol, 1.0 eq.) in anhydrous DCM (12 mL) at -20 °C. After 2 h at -20 °C, the temperature was allowed to reach 0 °C and the RM was stirred at this temperature for 1 h. The reaction was quenched at 0 °C by addition of aq. 1 M Rochelle salt and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhy- drous MgSO ₄ , and evaporated under reduced pressure. The crude material was purified by FCC (0-10% EtOAc gradient in hexane) to yield 2-chloro-4-methylquinoline-7-carbaldehyde (Int. A-078, 0.61 g, 2.96 mmol, 99%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.05 (dd, J = 8.7, 1.7 Hz, 1H), 7.68 (q, J = 1.0 Hz, 1H), 2.75 (d, J = 1.0 Hz, 3H). m/z (ESI): 206.1 [M+H] ⁺ . Step 6: NaBH ₄ (0.167 g, 4.40 mmol, 1.5 eq.) was added to a solution of 2-chloro-4-methylquinoline- 7-carbaldehyde (Int. A-078, 0.610 g, 2.94 mmol, 1.0 eq.) in MeOH (15 mL) at 0 °C. After stirring at RT for 1 h, the reaction was quenched with sat. aq. NH ₄ Cl and the mixture was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 40% EtOAc gradient in hexane) to yield (2-chloro-4-methylquinolin-7-yl)methanol (Int. A-079, 0.538 g, 2.59 mmol, 87%, white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.08 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 1.1 Hz, 1H), 7.62 (dd, J = 1.7, 8.6 Hz, 1H), 7.45 (q, J = 1.0 Hz, 1H), 5.48 (t, J = 5.8 Hz, 1H), 4.72 (d, J = 5.8 Hz, 2H), 2.69 (d, J = 1.0 Hz, 3H). m/z (ESI): 208.0 [M+H] ⁺ . Step 7: PPh ₃ (1.1 g, 4.2 mmol, 2.0 eq.) was added to a solution of (2-chloro-4-methylquinolin-7- yl)methanol (Int. A-079, 0.440 g, 2.10 mmol, 1.0 eq.) in anhydrous DCM (14 mL), followed by CBr ₄ (1.4 g, 4.22 mmol, 2.02 eq.) at 0 °C under nitrogen. The RM was stirred under nitrogen overnight, being allowed to come back to RT. The RM was concentrated under reduced pressure and the crude material was purified by FCC (0 to 50% DCM gradient in hexane) to yield 7-(bromomethyl)-2-chloro-4-methylquinoline (Int. A-080, 0.47 g, 1.74 mmol, 66%, white solid, UPLC purity: 73%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.73 (dd, J = 8.6, 1.9 Hz, 1H), 7.51 (s, 1H), 4.93 (s, 2H), 2.69 (d, J = 1.0 Hz, 3H). m/z (ESI): 270.0 [M+H] ⁺ . 3-Chloro-6-(chloromethyl)-2-methylquinoxaline (Int. A-085) Step 1: Ryvu Therapeutics S.A. RVU305 119 R10107WO DIPEA (5.5 mL, 31.64 mmol, 2.0 eq.) was added to a solution of methyl (2R)-2-aminopro- panoate hydrochloride (2.7 g, 19.34 mmol, 1.22 eq.) and methyl 4-fluoro-3-nitrobenzoate (3.15 g, 15.82 mmol, 1.0 eq.) in anhydrous THF (65 mL) and the RM was stirred at RT for 16 h. It was diluted with EtOAc and washed with water, aq. 10% Na ₂ CO ₃ and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The obtained crude methyl 4-{[(2R)-1-methoxy-1-oxopropan-2-yl]amino}-3-nitrobenzoate (Int. A-081, 4.94 g, 15.75 mmol, 100%, yellow oil, UPLC purity: 90%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (d, J = 2.2 Hz, 1H), 8.65 (d, J = 7.3 Hz, 1H), 8.01 (dd, J = 9.1, 2.1 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 4.81 – 4.68 (m, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 1.52 (d, J = 6.9 Hz, 3H). _m/z (ESI): 283.2 [M+H] ⁺ . Step 2: Aq. sat. NH ₄ Cl (50 mL) and iron powder (4.398 g, 78.76 mmol, 5.0 eq.) were added to a solu- tion of methyl 4-{[(2R)-1-methoxy-1-oxopropan-2-yl]amino}-3-nitrobenzoate (Int. A-081, 4.94 g, 15.75 mmol, 1.0 eq.) in EtOH (100 mL) and the RM was stirred at 90 °C for 60 h. The RM was filtered through a pad of Celite ^® and the filter cake was washed with EtOAc and MeOH. The volatiles were evaporated in vacuo and the remaining aqueous mixture was extracted with EtOAc (4x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield crude methyl 2- methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Int. A-082, 3.4 g, 14.98 mmol, 95%, orange solid, UPLC purity: 97%) which was used in the next step without further purifi- cation. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.38 (s, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 6.84 (d, J = 1.5 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 3.96 (qd, J = 6.7, 1.6 Hz, 1H), 3.76 (s, 3H), 1.29 (d, J = 6.7 Hz, 3H). _m/z (ESI): 220.9 [M+H] ⁺ . Step 3: DDQ (2.825 g, 12.45 mmol, 0.83 eq.) was added to a suspension of methyl 2-methyl-3-oxo- 1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Int. A-082, 3.4 g, 14.98 mmol, 1.0 eq.) in diox- ane (30 mL). The RM was stirred overnight at RT and slowly added to stirring sat. aq. Na- HCO ₃ . The mixture was stirred at RT for 20 min. The resulting precipitate was filtered off, washed with water and dried under vacuum to yield crude methyl 2-methyl-3-oxo-3,4-dihy- droquinoxaline-6-carboxylate (Int. A-083, 3.0 g, 13.75 mmol, 89%, beige solid, UPLC purity: 97%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1H), 7.86 (dd, J = 1.7, 0.6 Hz, 1H), 7.73 (dd, J = 8.4, 0.6 Hz, 1H), 7.70 (dd, J = 8.3, 1.7 Hz, 1H), 3.88 (s, 3H), 2.41 (s, 3H). m/z (ESI): 218.9 [M+H] ⁺ . Step 4: LiAlH ₄ (2 M in THF, 0.79 mL, 1.58 mmol, 2.0 eq.) was added dropwise to a suspension of methyl 2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Int. A-083, 0.175 g, 0.79 mmol, 1.0 eq.) in anhydrous THF (5.5 mL) at 0 °C over a period of 5 minutes under nitro- gen. The RM was stirred at 0 °C for 1.5 hours and slowly poured into stirring aq. 1 M HCl at 0 °C. The mixture was concentrated in vacuo and the crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield 7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxa- lin-2-one (Int. A-084, 0.14 g, 0.74 mmol, 90%, beige solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.31 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.18 (dd, J Ryvu Therapeutics S.A. RVU305 120 R10107WO = 8.3, 1.7 Hz, 1H), 5.39 (t, J = 5.7 Hz, 1H), 4.58 (d, J = 5.7 Hz, 2H), 2.39 (s, 3H). m/z (ESI): 191.1 [M+H] ⁺ . Step 5: 3-Chloro-6-(chloromethyl)-2-methylquinoxaline (Int. A-085, 0.13 g, 0.57 mmol, 78%, beige solid, UPLC purity: 96%) was prepared according to General Procedure 03b, using 7-(hy- droxymethyl)-3-methyl-1,2-dihydroquinoxalin-2-one (Int. A-084, 0.14 g, 0.71 mmol, 1.0 eq.) and POCl ₃ (0.435 g, 2.84 mmol, 4.0 eq.) in anhydrous toluene (5.5 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 7.91 (dd, J = 8.7, 1.9 Hz, 1H), 5.03 (s, 2H), 2.78 (s, 3H). m/z (ESI): 228.9 [M+H] ⁺ . 7-(Bromomethyl)-2-chloro-4-(trifluoromethyl)quinoline (Int. A-088) Step 1: A solution of 3-methylaniline (1.0 g, 9.33 mmol, 1.00 eq.) and ethyl 4,4,4-trifluoro-3-oxobu- tanoate (1.974 g, 10.72 mmol, 1.15 eq.) in toluene (12.0 mL) was heated to reflux, water (0.15 mL) was added and reflux was continued for 21 h. The RM was evaporated under re- duced pressure, the oily residue was added over 30 min. to conc. H ₂ SO ₄ (12 mL) at 80 °C and the resulting mixture was stirred at this temperature for 1 h. After coming back to RT, the RM was poured onto ice/water and the resulting precipitate was washed with water and dried under vacuum to yield crude 7-methyl-4-(trifluoromethyl)-1,2-dihydroquinolin-2-one (Int. A-086, 0.513 g, 2.26 mmol, 23%, beige solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H), 7.60 (dq, J = 8.4, 2.5 Hz, 1H), 7.23 (s, 1H), 7.16 (dd, J = 8.4, 1.4 Hz, 1H), 6.91 (s, 1H), 2.41 (s, 3H). m/z (ESI): 226.0 [M-H]-. Step 2: 2-Chloro-7-methyl-4-(trifluoromethyl)quinoline (Int. A-087, 0.296 g, 1.12 mmol, 62%, beige solid, UPLC purity: 93%) was prepared according the General Procedure 03b, using 7-me- thyl-4-(trifluoromethyl)-1,2-dihydroquinolin-2-one (Int. A-086, 0.413 g, 1.76 mmol, 1.0 eq.) and POCl ₃ (4.866 g, 31.74 mmol, 18.0 eq.) in CHCl ₃ (20.0 mL). The crude material was puri- fied by FCC (0 to 10% EtOAc gradient in hexane). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (dq, J = 8.7, 2.2 Hz, 1H), 7.99 (s, 1H), 7.97 – 7.92 (m, 1H), 7.72 (dd, J = 8.7, 1.8 Hz, 1H), 2.58 (s, 3H). m/z (ESI): 246.0 [M+H] ⁺ . Step 3: 7-(Bromomethyl)-2-chloro-4-(trifluoromethyl)quinoline (Int. A-088, 0.05 g, 0.13 mmol, 40%, yellow solid, UPLC purity: 88%) was prepared according to General Procedure 04, using 2- chloro-7-methyl-4-(trifluoromethyl)quinoline (Int. A-087, 0.1 g, 0.37 mmol, 1.0 eq.), NBS (0.163 g, 0.91 mmol, 2.51 eq.) and benzoyl peroxide (0.013 g, 0.05 mmol, 0.15 eq.) in DMC (2 mL), followed by treatment with DIPEA (0.064 mL, 0.37 mmol, 1.0 eq.) and diethyl phosphite Ryvu Therapeutics S.A. RVU305 121 R10107WO (0.050 g, 0.37 mmol, 1.0 eq.) in THF (2 mL). The crude material was purified by FCC (0 to 2% EtOAc gradient in hexane). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (d, J = 1.8 Hz, 1H), 8.14 (dq, J = 8.6, 2.0 Hz, 1H), 8.09 (s, 1H), 7.93 (dd, J = 8.8, 1.8 Hz, 1H), 4.97 (s, 2H). m/z (ESI): 325.9 [M+H] ⁺ . 7-(Bromomethyl)-2-chloroquinazoline (Int. A-092) Step 1: 2-Amino-4-methylbenzoic acid (5.0 g, 33.08 mmol, 1.0 eq.) and urea (6.953 g, 115.77 mmol, 3.5 eq.) were finely ground together (pestle and mortar) and the resulting powder was heated to 200 °C for 2 h in air. After coming back to RT, the RM was triturated with water and the resulting solid was filtered off and washed with water. The obtained crude 7-me- thyl-1,2,3,4-tetrahydroquinazoline-2,4-dione (Int. A-089, 5.938 g, 18.54 mmol, 56%, beige solid, UPLC purity: 55%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.14 (s, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.00 (dd, J = 8.1, 1.5 Hz, 1H), 6.95 (s, 1H), 2.36 (s, 3H). m/z (ESI): 177.0 [M+H] ⁺ . Step 2: 7-Methyl-1,2,3,4-tetrahydroquinazoline-2,4-dione (Int. A-089, 5.938 g, 18.54 mmol, 1.0 eq.) was suspended in POCl ₃ (8.5 g, 55.44 mmol, 11.93 eq.) at 0 °C under nitrogen. N-N-dime- thylaniline (0.6 mL, 4.73 mmol, 1.02 eq.) was added and the RM was stirred at RT until gas production stopped (30 min.). It was then heated to reflux for 6 h and carefully poured into ice/water (≈ 100 mL). The mixture was carefully neutralized with aq.1 M NaOH and ex- tracted with DCM (x3). The combined organic layers were washed with brine, dried over an- hydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield 2,4-dichloro-7-methylquinazo- line (Int. A-090, 0.62 g, 2.91 mmol, 15%, yellow solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (d, J = 8.5 Hz, 1H), 7.87 – 7.84 (m, 1H), 7.75 (dd, J = 8.6, 1.6 Hz, 1H), 2.60 (s, 3H). m/z (ESI): 213.0 [M+H] ⁺ . Step 3: Brine (6.4 mL), zinc powder (0.531 g, 8.12 mmol, 3.0 eq.) and aq. 7 M NH ₄ OH (2.7 mL, 18.721 mmol, 6.92 eq.) were added to a solution of 2,4-dichloro-7-methylquinazoline (Int. A- 090, 0.62 g, 2.71 mmol, 1.0 eq.) in DCM (9.0 mL) and the RM was vigorously stirred at 50 °C overnight. After coming back to RT, the RM was partitioned between water and DCM and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under re- duced pressure. The crude material was purified by FCC (0 to 30% EtOAc gradient in hex- ane) to yield 2-chloro-7-methylquinazoline (Int. A-091, 0.272 g, 1.49 mmol, 55%, white solid, Ryvu Therapeutics S.A. RVU305 122 R10107WO UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.79 – 7.75 (m, 1H), 7.66 (dd, J = 8.4, 1.6 Hz, 1H), 2.59 (s, 3H). m/z (ESI): 179.0 [M+H] ⁺ . Step 4: Step 4 was performed according to General Procedure 04, using 2-chloro-7-methylquinazo- line (Int. A-091, 0.277 g, 1.47 mmol, 1.0 eq.), NBS (0.393 g, 2.21 mmol, 1.5 eq.) and benzoyl peroxide (0.029 g, 0.12 mmol, 0.08 eq.) in DMC (4.2 mL), followed by treatment with DIPEA (0.257 mL, 1.47 mmol, 1.0 eq.) and diethyl phosphite (0.202 g, 1.47 mmol, 1.0 eq.) in THF (2.5 mL). The crude material was purified by FCC (0 to 50% DCM gradient in hexane) to yield 7-(bromomethyl)-2-chloroquinazoline (Int. A-092, 0.278 g, 1.08 mmol, 63%, yellow solid, UPLC purity: 86%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.10 – 8.03 (m, 1H), 7.86 (dd, J = 8.4, 1.7 Hz, 1H), 4.96 (s, 2H). m/z (ESI): 257.0 [M+H] ⁺ . 2-Bromo-7-(bromomethyl)-3-chloroquinoline (Int. A-096) Step 1 A solution of methyl 4-formyl-3-nitrobenzoate (5 g, 23.91 mmol, 1 eq.) in a mixture of EtOAc (30 mL) and AcOH (8 mL) was added dropwise to a suspension of iron powder (5.34 g, 95.62 mmol, 4 eq.) in a mixture of AcOH (2 mL) and water (45 mL) at 35 °C over a period of 45 min. and the RM was stirred at this temperature for an extra hour. Celite ^® (5 g) was added and the RM was stirred for 10 min. It was then filtered through a pad of Celite ^® (20 g) and the filter cake was washed with EtOAc. The filtrate was washed with water (1x) and sat. aq. NaHCO ₃ (3x), dried over anhydrous Na ₂ SO ₄ and filtered. Activated carbon (1.5 g) was added to the filtrate and the mixture was stirred at RT for 30 min. It was then filtered over a pad of Celite ^® and the filter cake was washed with EtOAc. The filtrate was evapo- rated under reduced pressure to yield methyl 3-amino-4-formylbenzoate (Int. A-093, 3.91 g, 21.82 mmol, 83%, yellow solid, UPLC purity: 91%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 (d, J = 0.7 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.30 (s, 2H), 7.14 (dd, J = 8.1, 1.6 Hz, 1H), 3.85 (s, 3H). m/z (ESI): 179.5 [M+H] ⁺ . Step 2 LiCl (2.05 g, 48.35 mmol, 1.2 eq.) and DBU (7.36 g, 48.35 mmol, 1.2 eq.) were added to a so- lution of 3-amino-4-formylbenzoate (Int. A-093, 7.6 g, 40.30 mmol, 1 eq.) in MeCN (84 mL) under nitrogen at 30 °C. The RM was cooled to 0 °C and a solution of ethyl 2-chloro-2- (diethoxyphosphoryl)acetate (12.89 g, 48.35 mmol, 1.2 eq.) in MeCN (30 mL) was added Ryvu Therapeutics S.A. RVU305 123 R10107WO dropwise over a period of 25 min. The RM was stirred overnight at RT and concentrated un- der reduced pressure. The residue was suspended in MeOH (100 mL), and the suspension was distributed into three 50 mL round bottom flasks. Each portion was irradiated with blue LED light (Penn PhD Photoreactor M2, 100% intensity, stirring 1100 rpm, fan speed 2800 rpm) for 1 h before being combined and concentrated under reduced pressure. The residue was triturated with water (100 mL) for 10 min., filtered off and washed with water, followed by MTBE. Drying under vacuum yielded methyl 3-chloro-2-oxo-1,2-dihydroquinoline-7-car- boxylate (Int. A-094, 9 g, 36.74 mmol, 91%, beige solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.50 (s, 1H), 8.41 (s, 1H), 7.97 – 7.94 (m, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.75 (dd, J = 8.2, 1.5 Hz, 1H), 3.90 (s, 3H). _m/z (ESI): 237.8 [M+H] ⁺ . Step 3: A mechanically stirred solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoline-7-carboxylate (Int. A-094, 4.9 g, 20.41 mmol, 1.0 eq.) in anhydrous THF (75 mL) under nitrogen was cooled to 0 °C and LAH (2 M solution in THF, 11.23 mL, 22.46 mmol, 1.1 eq.) was added dropwise, keeping the temperature below 10 °C. The RM was kept at 5 °C for 1 h and stirred at RT for 1 h. It was then cooled back to 5 °C and MeOH (25 mL) was slowly added portionwise to quench the reaction, followed by water (25 mL). The pH was then adjusted to around 1 by addition of conc. HCl. The resulting clear solution was allowed to come back to RT and stirred for 15 min. The volatiles were evaporated under reduced pressure and the resulting precipitate was filtered off, washed with n-heptane (50 mL) and dried under vacuum to yield 3-chloro-7-(hydroxymethyl)-1,2-dihydroquinolin-2-one (Int. A-095, 3.98 g, 18.99 mmol, 93%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.30 (s, 1H), 8.27 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.34 (m, 1H), 7.15 (dd, J = 8.1, 1.5 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 4.58 (d, J = 5.1 Hz, 2H). m/z (ESI): 209.9 [M+H] ⁺ . Step 4: POBr ₃ (9.20 g, 32.09 mmol, 1.52 eq.) was added portion-wise to a solution of 3-chloro-7- (hydroxymethyl)-1,2-dihydroquinolin-2-one (Int. A-095, 4.5 g, 21.04 mmol, 1.0 eq.) and DI- PEA (7.5 mL, 43.06 mmol, 2.05 eq.) in MeCN (45 mL) and the resulting white slurry was re- fluxed for 16 h under nitrogen. The RM was then cooled to 0 °C and DCM (100 mL) was added followed by aq.2 M NaOH (50 mL). After 10 min. stirring at RT, the phases were sep- arated and the aqueous layer was extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (20% to 50% DCM gradient in hexane) to yield 2-bromo-7-(bromomethyl)-3-chloroquinoline (Int. A-096, 6.39 g, 18.67 mmol, 89%, white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J = 0.8 Hz, 1H), 8.04 (m, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.5, 1.8 Hz, 1H), 4.67 (s, 2H). m/z (ESI): 335.7 [M+H] ⁺ . 3-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-7-(iodomethyl)quino lin-2-amine (Int. A-100) Ryvu Therapeutics S.A. RVU305 124 R10107WO Step 1: POCl ₃ (2.8 mL, 30.01 mmol, 2.23 eq.) was added to a solution of methyl 3-chloro-2-oxo-1,2- dihydroquinoline-7-carboxylate (Int. A-094, 3.23 g, 13.46 mmol, 1.0 eq.) in MeCN (35 mL) and the RM was refluxed for 4.5 h. After cooling to 0 °C, the RM was diluted with DCM (35 mL) and the solution was basified to pH ≈ 8 by addition of 2 M aq. NaOH. Additional por- tions of DCM (60 mL) and water (40 mL) were added and the organic layer was separated. The aqueous layer was extracted with DCM (3x), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The result- ing residue was triturated with heptane, filtered and dried under vacuum to yield methyl 2,3- dichloroquinoline-7-carboxylate (Int. A-097, 3.264 g, 12.75 mmol, 94%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.74 (dd, J = 1.6, 0.8 Hz, 1H), 8.30 (s, 1H), 8.21 (dd, J = 8.5, 1.6 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 4.02 (s, 3H). m/z (ESI): 257.1 [M+H] ⁺ . Step 2: 1-(2,4-Dimethoxyphenyl)methanamine (1.286 g, 7.69 mmol, 1.1 eq.) and DIPEA (1.34 mL, 7.69 mmol, 1.0 eq.) were added to a suspension of methyl 2,3-dichloroquinoline-7-carbox- ylate (Int. A-097, 1.79 g, 6.99 mmol, 1.0 eq.) in toluene (5.0 mL) at RT and the RM was stirred at reflux for 20 h under nitrogen. After coming back to RT, the RM was partitioned between water and EtOAc and the mixture was stirred for 5 min. The layers were separated and the aqueous phase was extracted with EtOAc (1x). The combined organic layers were washed with a mixture of sat. aq. NH ₄ Cl and water (1:1) and with brine. They were then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (DCM/hexane/EtOAc gradient from 10:90:0 to 10:70:20) to yield methyl 3-chloro-2-{[(2,4-dimethoxyphenyl)methyl]amino}quinoline-7-c arboxylate (Int. A-098, 2.704 g, 6.57 mmol, 94%, white solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.36 (d, J = 0.8 Hz, 1H), 8.10 – 8.04 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.73 (dd, J = 8.4, 1.7 Hz, 1H), 7.37 (t, J = 5.9 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.45 (dd, J = 8.4, 2.4 Hz, 1H), 4.65 (d, J = 5.9 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.73 (s, 3H). m/z (ESI): 387.1 [M+H] ⁺ . Step 3: LiAlH ₄ (2 M solution in THF, 2.11 mL, 4.22 mmol, 1.05 eq.) was added dropwise to a solution of methyl 3-chloro-2-{[(2,4-dimethoxyphenyl)methyl]amino}quinoline-7-c arboxylate (Int. A- 098, 1.57 g, 4.02 mmol, 1.0 eq.) in dry THF (16 mL) at -8 °C under nitrogen and the RM was stirred at this temperature for 5 min. The reaction was quenched with EtOAc (5 mL) at Ryvu Therapeutics S.A. RVU305 125 R10107WO 0 °C and Rochelle salt (45% aq. solution, 13 mL) was added. The resulting mixture was stirred for 30 min. at RT and Celite ^® was added. The mixture was filtered through a pad of Celite ^® and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield (3-chloro-2-{[(2,4-dimethoxyphenyl)methyl]amino}quinolin-7-y l)methanol (Int. A-099, ^{1.453 g, 3.97 mmol, 99%, off-white solid, UPLC purity: 98%). 1H NMR (400 MHz, DMSO-d6)} _{δ 8.18 (d, J = 0.8 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.47 (dt, J = 1.6, 0.8 Hz, 1H), 7.17 (dd, J =} 8.2, 1.6 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.01 (t, J = 5.9 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 5.28 (t, J = 5.8 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 4.59 (d, J = 5.6 Hz, 2H), 3.86 (s, 3H), 3.72 (s, 3H). _m/z (ESI): 359.1 [M+H] ⁺ . Step 4: Imidazole (0.070 g, 1.03 mmol, 0.15 eq.) and triphenylphosphine (2.167 g, 8.26 mmol, 1.2 eq.) were dissolved in DCM (30 mL) and the solution was cooled to 0 °C in an ice bath. Io- dine (2.184 g, 8.61 mmol, 1.25 eq) was added in 2 portions and after 15 min. of stirring, (3- chloro-2-{[(2,4-dimethoxyphenyl)methyl]amino}quinolin-7-yl)m ethanol (Int. A-099, 2.6 g, 6.88 mmol, 1.0 eq.) was added as a solid. The RM was stirred overnight at RT and washed successively with 50% aq. K ₂ CO ₃ , sat. aq. Na ₂ SO ₃ and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude mate- rial was purified by FCC (50% to 100% EtOAc gradient in hexane) to yield 3-chloro-N-[(2,4- dimethoxyphenyl)methyl]-7-(iodomethyl)quinolin-2-amine (Int. A-100, 2.8 g, 5.67 mmol, 82%, light yellow solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.60 – 7.57 (m, 1H), 7.25 (dd, J = 8.3, 1.8 Hz, 1H), 7.22 – 7.14 (m, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.45 (dd, J = 8.4, 2.4 Hz, 1H), 4.74 (s, 2H), 4.63 (d, J = 6.1 Hz, 2H), 3.87 (s, 3H), 3.74 (s, 3H). m/z (ESI): 468.9 [M+H] ⁺ . N-[(2,4-dimethoxyphenyl)methyl]-7-(iodomethyl)-3-methyl-1,5- naphthyridin-2-amine (Int. Step 1: nBuLi (6.54 mL, 10.47 mmol, 1.1 eq.) was added dropwise over 5 min. to a stirring solution of diisopropylamine (1.54 mL, 10.94 mmol, 1.15 eq) in anhydrous THF (50 mL) at -78 °C under nitrogen. After 15 min., a solution of ethyl 6-methyl-5-nitropyridine-3-carboxylate (2.0 Ryvu Therapeutics S.A. RVU305 126 R10107WO g, 9.51 mmol, 1.0 eq.) in THF (12 mL) was added dropwise over 10 min. Ethyl pyruvate (1.657 g, 14.27 mmol, 1.5 eq.) was then rapidly added via syringe. The RM was stirred at -78 °C for 1 h and the reaction was quenched by addition of water. The mixture was warmed to RT, sat. aq. Na ₂ CO ₃ was added, and the mixture was extracted with EtOAc (3x). The com- bined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hex- ane) to yield ethyl 6-(3-ethoxy-2-hydroxy-2-methyl-3-oxopropyl)-5-nitropyridine- 3-carbox- ylate (Int. A-101, 0.715 g, 2.19 mmol, 42%, colorless oil, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.17 (d, J = 1.9 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H), 5.49 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.58 (s, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.33 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). m/z (ESI): 327.1 [M+H] ⁺ . Step 2: Iron powder (1.910 g, 34.21 mmol, 5.0 eq.) was added to a solution of ethyl 6-(3-ethoxy-2- hydroxy-2-methyl-3-oxopropyl)-5-nitropyridine-3-carboxylate (Int. A-101, 2.35 g, 6.84 mmol, 1.0 eq.) in acetic acid (16.0 mL). The RM was stirred at 80 °C for 45 min. After coming back to RT, it was diluted with EtOAc and filtered through a pad of Celite ^® . The filter cake was washed with EtOAc and the filtrate was concentrated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield ethyl 7-methyl-6- oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (Int. A-102, 1.47 g, 6.33 mmol, 88%, off- white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.09 (s, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.18 (dd, J = 1.9, 0.7 Hz, 1H), 7.94 (dq, J = 1.7, 1.1 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 2.20 (d, J = 1.3 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H). m/z (ESI): 233.1 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 03b, using POCl ₃ (11.289 g, 73.63 mmol, 18.0 eq.) and ethyl 7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (Int. A-102, 1.0 g, 4.09 mmol, 1.0 eq.) in toluene (22 mL) to yield ethyl 6-chloro-7-methyl-1,5- naphthyridine-3-carboxylate (Int. A-103, 1.084 g, 4.11 mmol, 100%, white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (d, J = 2.0 Hz, 1H), 8.80 (dd, J = 2.1, 0.9 Hz, 1H), 8.61 – 8.54 (m, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.62 (d, J = 1.1 Hz, 3H), 1.42 (t, J = 7.1 Hz, 3H). m/z (ESI): 251.8 [M+H] ⁺ . Step 4: Ethyl 6-chloro-7-methyl-1,5-naphthyridine-3-carboxylate (Int. A-103, 0.5 g, 1.89 mmol, 1.0 eq.) and 1-(2,4-dimethoxyphenyl)methanamine (0.95 g, 5.68 mmol, 3.0 eq.) were stirred in DMSO (5.0 mL) for 3 h at 100 °C. After coming back to RT, the RM was diluted with EtOAc and the solution was washed with brine (3x), dried over anhydrous Na ₂ SO ₄ , filtered and con- centrated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hexane) to afford ethyl 6-{[(2,4-dimethoxyphenyl)methyl]amino}-7-methyl-1,5- naphthyridine-3-carboxylate (Int. A-104, 0.752 g, 1.95 mmol, 100%, off-white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.94 (d, J = 2.0 Hz, 1H), 8.25 (dd, J = 2.0, 0.8 Hz, 1H), 7.96 – 7.88 (m, 1H), 7.23 (t, J = 5.8 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.45 (dd, J = 8.4, 2.4 Hz, 1H), 4.67 (d, J = 5.7 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.87 Ryvu Therapeutics S.A. RVU305 127 R10107WO (s, 3H), 3.74 (s, 3H), 2.39 (d, J = 1.2 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H). m/z (ESI): 382.2 [M+H] ⁺ . Step 5: LiAlH ₄ (2 M solution in THF, 1.26 mL, 2.53 mmol, 1.30 eq.) was added dropwise to a solution of ethyl 6-{[(2,4-dimethoxyphenyl)methyl]amino}-7-methyl-1,5-naphthyr idine-3-carboxylate (Int. A-104, 0.75 g, 1.947 mmol, 1.0 eq.) in dry THF (35 mL) at -8 °C under nitrogen and the RM was stirred at this temperature for 1 h. The reaction was quenched with 10% aq. NaOH, the resulting mixture was filtered through a pad of Celite ^® and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , fil- tered and concentrated under reduced pressure to yield (6-{[(2,4-dimethoxyphenyl)me- thyl]amino}-7-methyl-1,5-naphthyridin-3-yl)methanol (Int. A-105, 0.582 g, 1.63 mmol, 84%, off-white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J = 2.0 Hz, 1H), 7.82 – 7.77 (m, 1H), 7.71 (dt, J = 2.0, 0.9 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.90 (t, J = 5.8 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 8.4, 2.4 Hz, 1H), 5.31 (t, J = 5.8 Hz, 1H), 4.66 – 4.58 (m, 4H), 3.85 (s, 3H), 3.72 (s, 3H), 2.32 (d, J = 1.1 Hz, 3H). m/z (ESI): 340.3 [M+H] ⁺ . Step 6: 1H-imidazole (0.017 g, 2.43 mmol, 1.5 eq.) and triphenylphosphine (0.511 g, 1.95 mmol, 1.2 eq.) were dissolved in DCM (20 mL) and the solution was cooled to 0 °C in an ice bath. Io- dine (0.51 g, 2.02 mmol, 1.25 eq) was added in 2 portions and after 15 min. of stirring, (6- {[(2,4-dimethoxyphenyl)methyl]amino}-7-methyl-1,5-naphthyrid in-3-yl)methanol (Int. A- 105, 0.58 g, 1.62 mmol, 1.0 eq.) was added as a solid. The RM was stirred overnight at RT and washed successively with 50% aq. K ₂ CO ₃ , sat. aq. Na ₂ SO ₃ and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0% to 66% EtOAc gradient in hexane) to yield N-[(2,4- dimethoxyphenyl)methyl]-7-(iodomethyl)-3-methyl-1,5-naphthyr idin-2-amine (Int. A-106, 0.132 g, 0.29 mmol, 18%, light yellow solid, UPLC purity: 78%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.51 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.81 – 7.78 (m, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.02 (t, J = 5.8 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 6.43 (dd, J = 8.4, 2.5 Hz, 1H), 4.74 (s, 2H), 4.62 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 2.32 (d, J = 1.1 Hz, 3H). m/z (ESI): 450.1 [M+H] ⁺ . tert-Butyl N-[7-(bromomethyl)-3-fluoroquinolin-2-yl]-N-[(tert-butoxy)ca rbonyl]carbamate (Int. A-109) Step 1: Ryvu Therapeutics S.A. RVU305 128 R10107WO Step 1 was carried out according to General Procedure 23 using 2-chloro-3-fluoro-7- methylquinoline (Int. A-071, 0.507 g, 2.57 mmol, 1.0 eq.), tert-butyl carbamate (2.106 g, 17.98 mmol, 7.0 eq.), K ₃ PO ₄ as base (0.708 g, 3.33 mmol, 1.3 eq.) and XPhos Pd G3 (0.325 g, 0.38 mmol, 0.15 eq.) in dioxane (12.0 mL) at 110 °C under microwave irradiation for 1.5 h. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 3- fluoro-7-methylquinolin-2-amine (Int. A-107, 0.132 g, 0.71 mmol, 28%, light orange solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.76 (d, J = 11.9 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.31 (s, 1H), 7.06 (dd, J = 7.9, 1.0 Hz, 1H), 6.70 (s, 2H), 2.40 (s, 3H). m/z (ESI): 177.1 [M+H] ⁺ . Step 2: A solution of 3-fluoro-7-methylquinolin-2-amine (Int. A-107, 0.224 g, 0.80 mmol, 1.0 eq.), ^{Boc2O (0.44 g, 2.02 mmol, 2.51 eq.) TEA (0.11 mL, 0.79 mmol, 0.98 eq.) and DMAP (0.01 g,} _{0.08 mmol, 0.10 eq.) in anhydrous MeCN (4.5 mL) was stirred at 50 °C for 3 h under nitro-} gen. After coming back to RT, the RM was partitioned between water and EtOAc. The aque- ous layer was extracted with EtOAc (3x) and the combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 25% EtOAc gradient in hexane) to yield tert- butyl N-[(tert-butoxy)carbonyl]-N-(3-fluoro-7-methylquinolin-2-yl) carbamate (Int. A-108, 0.256 g, 0.68 mmol, 75%, white solid, UPLC purity: 89%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (d, J = 10.1 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 2.53 (s, 3H), 1.37 (s, 18H). m/z (ESI): 399.2 [M+Na] ⁺ . Step 3: Step 3 was performed according to General Procedure 04, using tert-butyl N-[(tert- butoxy)carbonyl]-N-(3-fluoro-7-methylquinolin-2-yl)carbamate (Int. A-108, 0.254 g, 0.60 mmol, 1.0 eq.), NBS (0.161 g, 0.91 mmol, 1.51 eq.) and AIBN as initiator (0.099 g, 0.60 mmol, 1.0 eq.) in anhydrous CCl ₄ (3.0 mL) at 80 °C, followed by DIPEA (0.314 mL, 1.80 mmol, 3.0 eq.) and diethyl phosphite (0.247 g, 1.80 mmol, 3.0 eq.) treatment in anhydrous THF (5.0 mL). The crude material was purified by FCC (0 to 15% EtOAc gradient in hexane) to yield tert-butyl N-[7-(bromomethyl)-3-fluoroquinolin-2-yl]-N-[(tert-butoxy)ca rbonyl]carbamate (Int. A-109, 0.278 g, 0.58 mmol, 97%, colorless oil, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 10.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.77 (dd, J = 8.5, 1.7 Hz, 1H), 4.94 (s, 2H), 1.37 (s, 18H). m/z (ESI): 477.1 [M+Na] ⁺ . 7-(Bromomethyl)-2-chloro-4-(methoxymethyl)quinoline (Int. A-114) Ryvu Therapeutics S.A. RVU305 129 R10107WO Step 1: Step 1 was performed according to General Procedure 04, using 2-chloro-4-methylquino- line-7-carbonitrile (Int. A-077, 0.449 g, 2.19 mmol, 1.0 eq.), NBS (0.664 g, 2.19 mmol, 1.0 eq.) and AIBN (0.036 g, 0.22 mmol, 0.1 eq.) as radical initiator in CCl ₄ (20 mL) at 80 °C, followed by treatment with DIPEA (0.382 mL, 2.19 mmol, 1.0 eq.) and diethyl phosphite (0.301 g, 2.19 mmol, 1.0 eq.) in THF (60 mL). The crude material was purified by FCC (0 to 100% DCM gradient in hexane) to yield 4-(bromomethyl)-2-chloroquinoline-7-carbonitrile (Int. A-110, 0.55 g, 1.95 mmol, 85%, white solid, UPLC purity: 78%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.44 (dd, J = 1.7, 0.7 Hz, 1H), 8.23 (dd, J = 8.6, 0.7 Hz, 1H), 7.85 (dd, J = 8.7, 1.7 Hz, 1H), ^{7.59 (s, 1H), 4.80 (d, J = 0.5 Hz, 2H).} m/z (ESI): 280.8 [M+H] ⁺ . Step 2: MeONa (30% w/w in MeOH, 0.292 mL, 1.57 mmol, 0.95 eq.) was added to a solution of 4- (bromomethyl)-2-chloroquinoline-7-carbonitrile (Int. A-110, 0.49 g, 1.65 mmol, 1.0 eq.) in anhydrous MeOH (30 mL). The RM was stirred at 55 °C under nitrogen for 15 minutes. Af- ter coming back to RT, the RM was evaporated under reduced pressure and the crude ma- terial was purified by FCC (0 to 100% DCM gradient in hexane) to yield 2-chloro-4-(methox- ymethyl)quinoline-7-carbonitrile (Int. A-111, 0.187 g, 0.80 mmol, 43%, white solid, UPLC pu- rity: 88%). m/z (ESI): 233.0 [M+H] ⁺ . Step 3: DIBAL-H (1.0 M in DCM, 0.981 mL, 0.98 mmol, 1.22 eq.) was added dropwise to a solution of 2-chloro-4-(methoxymethyl)quinoline-7-carbonitrile (Int. A-111, 0.187 g, 0.80 mmol, 1.0 eq.) in anhydrous DCM (5 mL) at -30 °C under nitrogen and the RM was allowed to reach RT over 1 h. The reaction was quenched by addition of aq.1 M sodium potassium tartrate and the RM was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield 2-chloro-4-(methoxyme- thyl)quinoline-7-carbaldehyde (Int. A-112, 0.167 g, 0.71 mmol, 84%, yellow solid, UPLC pu- rity: 95%). ¹ H NMR (400 MHz, Chloroform-d) δ 10.24 (d, J = 0.7 Hz, 1H), 8.52 (dd, J = 1.6, 0.6 Hz, 1H), 8.09 (dd, J = 8.6, 1.6 Hz, 1H), 8.04 (dt, J = 8.7, 0.7 Hz, 1H), 7.66 (t, J = 1.1 Hz, 1H), 4.95 (d, J = 1.2 Hz, 2H), 3.60 (s, 3H). m/z (ESI): 236.0 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 130 R10107WO Step 4: LiBH ₄ (2 M in THF, 0.475 mL, 0.95 mmol, 1.5 eq.) was added dropwise to a solution of 2- chloro-4-(methoxymethyl)quinoline-7-carbaldehyde (Int. A-112, 0.157 g, 0.63 mmol, 1.0 eq.) in anhydrous THF (3 mL) at 0 °C and the RM was stirred at this temperature for 5 min. The reaction was quenched with sat. aq. NH ₄ Cl and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gra- dient in hexane) to yield [2-chloro-4-(methoxymethyl)quinolin-7-yl]methanol (Int. A-113, 0.147 g, 0.62 mmol, 98%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.04 – 8.01 (m, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.63 (dd, J = 8.6, 1.7 Hz, 1H), 7.50 (t, J = 1.1 Hz, 1H), 4.93 (s, 2H), 4.93 (d, J = 1.1 Hz, 2H), 3.57 (s, 3H), 1.69 (s, 1H). m/z (ESI): 238.0 [M+H] ⁺ . Step 5: Triphenylphosphine (0.278 g, 1.06 mmol, 2.0 eq.) and CBr ₄ (0.352 g, 1.06 mmol, 2.0 eq.) were added to a solution of [2-chloro-4-(methoxymethyl)quinolin-7-yl]methanol (Int. A-113, 0.126 g, 0.53 mmol, 1.0 eq.) in degassed anhydrous DCM (3 mL) at 0 °C and the RM was stirred at RT overnight under nitrogen. The RM was evaporated under reduced pressure and the crude material was purified by FCC (0 to 100% DCM gradient in hexane) to yield 7-(bromo- methyl)-2-chloro-4-(methoxymethyl)quinoline (Int. A-114, 0.158 g, 0.53 mmol, 94%, white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.05 (dd, J = 1.8, 0.6 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.64 (dd, J = 8.6, 1.9 Hz, 1H), 7.52 (t, J = 1.1 Hz, 1H), 4.91 (d, J = 1.1 Hz, 2H), 4.67 (s, 2H), 3.56 (s, 3H). m/z (ESI): 301.9 [M+H] ⁺ . (3-Chloro-2-methylquinoxalin-6-yl)methanol (Int. A-116) Step 1: Step 1 was performed according to General Procedure 03b, using methyl 2-methyl-3-oxo- 3,4-dihydroquinoxaline-6-carboxylate (Int. A-083, 0.45 g, 2.0 mmol, 1.0 eq.) and POCl ₃ (6.1 g, 39.79 mmol, 19.9 eq.) in anhydrous toluene (15.0 mL). The crude material was purified by FCC (0 to 40% EtOAc in hexane) to yield methyl 3-chloro-2-methylquinoxaline-6-carbox- ylate (Int. A-115, 0.229 g, 0.97 mmol, 47%, beige solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (dd, J = 1.9, 0.6 Hz, 1H), 8.30 (dd, J = 8.7, 1.9 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 3.96 (s, 3H), 2.81 (s, 3H). m/z (ESI): 237.0 [M+H] ⁺ . Step 2: LAH (2 M in THF, 0.75 mL, 1.5 mmol, 2.03 eq.) was added dropwise to a slurry of methyl 3- chloro-2-methylquinoxaline-6-carboxylate (Int. A-115, 0.225 g, 0.92 mmol, 1.0 eq.) in anhy- drous THF (7.0 mL) at 0 °C under nitrogen, over a period of 5 minutes. The RM was stirred at 0 °C for 20 min., and was slowly poured into stirring aq. 1 M HCl at 0 °C. The resulting Ryvu Therapeutics S.A. RVU305 131 R10107WO mixture was extracted with EtOAc (3x) and the combined organic layers were dried over an- hydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield (3-chloro-2-methylquinoxalin-6-yl)methanol (Int. A-116, 0.145 g, 0.69 mmol, 72%, beige solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.80 (dd, J = 8.6, 1.9 Hz, 1H), 5.55 (t, J = 5.7 Hz, 1H), 4.74 (dd, J = 5.8, 1.0 Hz, 2H), 2.76 (s, 3H). m/z (ESI): 209.0 [M+H] ⁺ . Step 1: A mixture of NH ₄ Cl (0.167 g, 3.12 mmol, 1.2 eq.), sodium azide (0.203 g, 3.12 mmol, 1.2 eq.), and methyl 2,3-dichloroquinoline-7-carboxylate (Int. A-097, 0.7 g, 2.60 mmol, 1.0 eq.) in an- hydrous DMF (12 mL) was stirred at RT for 4 days. The RM was diluted with water and ex- tracted with EtOAc. The organic layer was washed with water and brine, dried over anhy- drous MgSO ₄ , filtered and evaporated under reduced pressure. The obtained crude methyl 2-azido-3-chloroquinoline-7-carboxylate (Int. A-117, 0.7 g, 2.66 mmol, 92%, yellowish solid, UPLC purity: 84%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (d, J = 0.9 Hz, 1H), 8.68 (d, J = 0.7 Hz, 1H), 8.32 (d, J = 1.1 Hz, 2H), 4.00 (s, 3H). m/z (ESI): 263.0 [M+H] ⁺ . Step 2: DIBAL-H (1.0 M in THF, 21.93 mL, 21.93 mmol, 10.0 eq.) was added dropwise to a solution of methyl 2-azido-3-chloroquinoline-7-carboxylate (Int. A-117, 0.64 g, 2.19 mmol, 1.0 eq.) in anhydrous THF (50 mL) at 0 °C and the RM was stirred at this temperature under nitrogen for 1 h. The reaction was quenched by careful addition of methanol (4.5 mL) and aq.1 M Rochelle’s salt (60 mL). The mixture was stirred overnight, then extracted with EtOAc (2x). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield (2-azido-3-chloroquinolin- 7-yl)methanol (Int. A-118, 0.4 g, 1.70 mmol, 74%, yellow solid, UPLC purity: 92%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 8.57 (m, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.81 – 7.69 (m, 1H), 5.71 (t, J = 5.7 Hz, 1H), 4.83 (dd, J = 5.7, 1.0 Hz, 2H). m/z (ESI): 234.9 [M+H] ⁺ . Step 3: Tributylphosphine (1.147 g, 5.67 mmol, 7.0 eq.) was added to a mixture of (2-azido-3-chlo- roquinolin-7-yl)methanol (Int. A-118, 0.2 g, 0.81 mmol, 1.0 eq.) in methanol (7.0 mL) and water (3 mL). The RM was refluxed overnight under argon and was partitioned between brine and EtOAc. The aqueous layer was extracted with EtOAc (2x) and the combined or- ganic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield (2-amino-3-chloroquinolin-7-yl)methanol (Int. A-119, 0.14 g, 0.67 mmol, 79%, white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 7.61 (d, J Ryvu Therapeutics S.A. RVU305 132 R10107WO = 8.2 Hz, 1H), 7.45 (dt, J = 1.6, 0.8 Hz, 1H), 7.17 (dd, J = 8.2, 1.6 Hz, 1H), 6.69 (s, 2H), 5.29 (t, J = 5.8 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H). m/z (ESI): 209.2 [M+H] ⁺ . 2-Bromo-7-(bromomethyl)-1,6-naphthyridine (Int. A-124) Step 1: NIS (1.320 g, 5.87 mmol, 1.05 eq.) was added to a solution of methyl 4‐aminopyridine‐2‐ carboxylate (0.850 g, 5.59 mmol, 1.0 eq.) in MeCN (15 mL) and the RM was stirred at 80 °C for 18 h. After coming back to RT, the RM was concentrated under reduced pressure and the residue was partitioned between sat. aq. Na ₂ CO ₃ and EtOAc. The aqueous layer was ex- tracted with EtOAc (3x) and the combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by FCC (0 to 35% EtOAc gradient in hexane) to afford methyl 4‐amino‐5‐ iodopyridine‐2‐carboxylate (Int. A-120, 1.006 g, 3.50 mmol, 63%, yellow solid, UPLC pu- rity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 7.34 (s, 1H), 6.51 (s, 2H), 3.81 (s, 3H). m/z (ESI): 279.0 [M+H] ⁺ . Step 2: Ethyl acrylate (3.01 mL, 27.63 mmol, 2 eq.), TEA (3.85 mL, 27.63 mmol, 2 eq.), Pd(OAc) ₂ (0.155 g, 0.69 mmol, 0.05 eq.), and tri(o-tolyl)phosphine (0.421 g, 1.38 mmol, 0.1 eq.) were added to a solution of methyl 4‐amino‐5‐iodopyridine‐2‐carboxylate (Int. A-120, 4.066 g, 13.82 mmol, 1 eq.) in DMF (40 mL). The RM was stirred at 100 °C for 2 h and allowed to come back to RT. It was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , filtered, and concen- trated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to afford methyl 4-amino-5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyri- dine-2-carboxylate (Int. A-121, 3.1 g, 12.14 mmol, 88%, yellow solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (s, 1H), 7.83 (dd, J = 15.9, 0.6 Hz, 1H), 7.35 (s, 1H), 6.83 (s, 2H), 6.61 (d, J = 15.9 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). m/z (ESI): 251.1 [M+H] ⁺ . Step 3: A solution of methyl 4-amino-5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyridine-2-carb oxylate (Int. A-121, 0.789 g, 3.09 mmol, 1.0 eq.) in anhydrous MeOH (18 mL) in a Biotage ^TM 20-mL microwave vial was sparged with argon for 10 min. The vial was sealed and the RM was ir- radiated with blue LED light (Penn PhD Photoreactor M2, 100% intensity, 450 nm, fan speed 4000 rpm) for 3 h. The resulting precipitate was filtered off and washed with diethyl ether to Ryvu Therapeutics S.A. RVU305 133 R10107WO yield methyl 2‐oxo‐1,2‐dihydro‐1,6‐naphthyridine‐7‐carboxyl ate (Int. A-122, 0.425 g, 2.01 mmol, 65%, white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.27 (s, 1H), 8.95 (s, 1H), 8.10 (dd, J = 9.6, 0.7 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 6.73 (d, J = 9.6 Hz, 1H), 3.91 (s, 3H). m/z (ESI): 205.0 [M+H] ⁺ . Step 4: DIBAL-H (1 M in toluene, 9.96 mL, 9.96 mmol, 5.0 eq.) was added dropwise over 10 min. to a solution of methyl 2‐oxo‐1,2‐dihydro‐1,6‐naphthyridine‐7‐carboxyl ate (Int. A-122, 0.442 g, 1.99 mmol, 1.0 eq.) in anhydrous THF (45 mL) at -78 °C under argon. The RM was warmed to 0-5 °C and stirred at this temperature for 4 h. EtOAc (3 mL) was added drop- wise followed by sat. aq. Rochelle’s salt (3 mL) and the mixture was stirred for 40 min., be- ing allowed to come back to RT. The mixture was filtered through a pad of Celite ^® and the filter cake was washed with EtOAc and MeOH. The filtrate was evaporated under reduced pressure and the crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield 7‐(hydroxymethyl)‐1,2‐dihydro‐1,6‐naphthyridin‐2 ‐one (Int. A-123, 0.270 g, 1.48 mmol, 75%, white solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.03 (s, 1H), 8.75 (s, 1H), 8.00 (dd, J = 9.5, 0.7 Hz, 1H), 7.38 – 7.33 (m, 1H), 6.55 (d, J = 9.6 Hz, 1H), 5.58 (t, J = 5.7 Hz, 1H), 4.61 (d, J = 5.6 Hz, 2H). m/z (ESI): 176.8 [M+H] ⁺ . Step 5: POBr ₃ (1.77 g, 6.19 mmol, 5.0 eq.) was added to a solution of 7‐(hydroxymethyl)‐1,2‐di- hydro‐1,6‐naphthyridin‐2‐one (Int. A-123, 0.225 g, 1.24 mmol, 1.0 eq.) in anhydrous tol- uene/ACN 9:1 v/v (10 mL) and the RM was stirred at 100 °C in a pressure reactor for 6 h. The temperature was raised to 120 °C and the RM was stirred at this temperature for an- other hour. After coming back to RT, the RM was poured onto ice and the mixture was neu- tralized by addition of sat. aq. NaHCO ₃ . The mixture was then extracted with EtOAc (3x) and the combined organic extracts were washed with brine, dried over anhydrous MgSO ₄ , fil- tered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 40% EtOAc gradient in hexane) to yield 2‐bromo‐7‐(bromomethyl)‐1,6‐naphthyridine (Int. A-124, 0.100 g, 0.31 mmol, 26%, yellow solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (d, J = 0.8 Hz, 1H), 8.54 (dd, J = 8.6, 0.8 Hz, 1H), 8.06 (s, 1H), 7.92 (d, J = 8.6 Hz, 1H), 4.92 (s, 2H). m/z (ESI): 300.7 [M+H] ⁺ . [7-(Bromomethyl)-2-chloroquinolin-3-yl]methanol (Int. A-125) LiOH monohydrate (0.062 g, 1.47 mmol, 2.5 eq.) was added to a solution of [7-(bromome- thyl)-2-chloroquinolin-3-yl]methyl acetate (Int. A-068, 0.277 g, 0.59 mmol, 1.0 eq.) in a mix- ture of THF (8.5 mL) and water (2.5 mL) and the RM was stirred at RT for 2 h. The pH was adjusted to ≈ 5 by addition of AcOH and the mixture was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in Ryvu Therapeutics S.A. RVU305 134 R10107WO hexane) to yield [7-(bromomethyl)-2-chloroquinolin-3-yl]methanol (Int. A-125, 0.196 g, 0.44 mmol, 74%, off-white solid, UPLC purity: 64%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, J = 1.1 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.70 (dd, J = 8.4, 1.8 Hz, 1H), 5.74 (t, J = 5.5 Hz, 1H), 4.93 (s, 2H), 4.69 (dd, J = 5.5, 1.3 Hz, 2H). m/z (ESI): 285.8 [M+H] ⁺ . N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-7-(iodomethyl)quino lin-2-amine (Int. A-130) Step 1 LiCl (2.0 g, 47.2 mmol, 1.4 eq.) and DBU (6.5 mL, 43.5 mmol, 1.3 eq.) were added to a solu- tion of methyl 3-amino-4-formylbenzoate (Int. A-093, 6.44 g, 34.1 mmol, 1.0 eq.) in MeCN (85 mL) under nitrogen at 30 °C. The RM was cooled to 0 °C and a solution of ethyl 2-(di- ethoxyphosphoryl)-2-fluoroacetate (10.0 g, 41.3 mmol, 1.2 eq.) in MeCN (37 mL) was added dropwise over a period of 25 min., keeping the temperature between 5-10 °C. The RM was stirred overnight at RT under nitrogen and concentrated under reduced pressure. The resi- due was suspended in MeOH (100 mL), and the suspension was distributed into three 50- mL round bottom flasks. Each portion was irradiated with blue LED light (Penn PhD Photo- reactor M2, 100% intensity, stirring 1100 rpm, fan speed 2800 rpm) for 16 h before being combined and concentrated under reduced pressure. The residue was triturated with water (100 mL) for 10 min., filtered off and washed with water, followed by MTBE. Drying under vacuum yielded methyl 3-fluoro-2-oxo-1,2-dihydroquinoline-7-carboxylate (Int. A-126, 6.54 g, 29.0 mmol, 85%, yellow solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.53 (s, 1H), 7.98 (m, 2H), 7.84 – 7.72 (m, 2H), 3.89 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 127.59 (dd, J = 10.9, 5.3 Hz). m/z (ESI): 222.1 [M+H] ⁺ . Step 2: POCl ₃ (6 mL, 65.2 mmol, 2.2 eq.) was added to a solution of methyl 3-fluoro-2-oxo-1,2-dihy- droquinoline-7-carboxylate (Int. A-126, 6.54 g, 29.0 mmol, 1.0 eq) in MeCN (85 mL) and the RM was refluxed for 4.5 h. After cooling to 0 °C, the RM was diluted with DCM (35 mL) and the solution was basified to pH ≈ 8 by addition of aq. 2 M NaOH. Additional portions of DCM (120 mL) and water (80 mL) were added and the organic layer was separated. The aqueous layer was extracted with DCM (3x), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was triturated with heptane, filtered and dried under vacuum to yield methyl 2- chloro-3-fluoroquinoline-7-carboxylate (Int. A-127, 6.03 g, 24.9 mmol, 86%, pink fluffy solid, Ryvu Therapeutics S.A. RVU305 135 R10107WO UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (dd, J = 9.0, 0.8 Hz, 1H), 8.51 – 8.48 (m, 1H), 8.18 – 8.15 (m, 2H), 3.95 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -118.26 (d, J = 9.0 Hz). m/z (ESI): 239.9 [M+H] ⁺ . Step 3: A suspension of 1-(2,4-dimethoxyphenyl)methanamine (9.5 mL, 65.8 mmol, 3.2 eq.) and me- thyl 2-chloro-3-fluoroquinoline-7-carboxylate (Int. A-127, 5.03 g, 20.8 mmol, 1.0 eq.) in tolu- ene (40.0 mL) was stirred at reflux for 20 h under nitrogen. After coming back to RT, the RM was partitioned between water and EtOAc and the mixture was stirred for 5 min. The layers were separated and the aqueous phase was extracted with EtOAc (1x). The combined or- ganic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 20% EtOAc gradient in hexane) to yield methyl 2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoroquinoline-7-c arboxylate (Int. A-128, 7.6 g, 19.5 mmol, 94%, off-white solid, UPLC purity: 91%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.07 (m, 1H), 7.93 (dd, J = 11.9, 0.8 Hz, 1H), 7.78 (dd, J = 8.7, 0.6 Hz, 1H), 7.72 (ddd, J = 8.3, 1.7, 0.7 Hz, 1H), 7.72 – 7.68 (m, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.4, 2.4 Hz, 1H), 4.61 (d, J = 5.8 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.73 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -132.43 (d, J = 11.9 Hz). m/z (ESI): 371.1 [M+H] ⁺ . Step 4: LiAlH ₄ (2 M in THF, 13 mL, 26.0 mmol, 1.2 eq.) was added dropwise to a solution of methyl 2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoroquinoline-7-c arboxylate (Int. A-128, 8.6 g, 21.1 mmol, 1.0 eq.) in dry THF (90 mL) at -8 °C under nitrogen, and the RM was stirred at this temperature for 30 min. The RM was diluted with MTBE (~ 50 mL) and the reaction was sequentially quenched with water (1 mL), aq. 3 M NaOH (1.5 mL) and water again (3 mL). The resulting mixture was stirred at RT for 15 min. Na ₂ SO ₄ (around 100 g) was added and the mixture was stirred for 15 min. The suspension was filtered and the filtrate was concentrated in vacuo. The crude material was purified by FCC (0 to 20% EtOAc gradient in DCM) to yield (2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoroquinolin-7-y l)methanol (Int. A-129, 5.57 g, 15.62 mmol, 74%, white solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d, J = 12.1 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.47 – 7.45 (m, 1H), 7.36 (td, J = 6.0, 1.6 Hz, 1H), 7.17 (dd, J = 8.2, 1.8 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.4, 2.4 Hz, 1H), 5.23 (t, J = 5.8 Hz, 1H), 4.61 – 4.56 (m, 4H), 3.85 (s, 3H), 3.72 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -137.37 (d, J = 12.2 Hz). m/z (ESI): 343.2 [M+H] ⁺ . Step 5: 1H-imidazole (2.0 g, 29.4 mmol, 2.1 eq.) and triphenylphosphine (7.5 g, 28.6 mmol, 2.0 eq.) were dissolved in DCM (10 mL) and the solution was cooled to 0 °C in an ice bath. Iodine (7.2 g, 28.4 mmol, 2.0 eq.) was added in 2 portions and after stirring for 15 min., (2-{[(2,4- dimethoxyphenyl)methyl]amino}-3-fluoroquinolin-7-yl)methanol (Int. A-129, 5.05 g, 14.2 mmol, 1.0 eq.) was added as a solid. The RM was stirred for 1 h at RT and washed succes- sively with sat. aq. NaHCO ₃ , sat. aq. Na ₂ S ₂ O ₃ and brine. The organic layer was dried over an- hydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (100% DCM isocratic) to yield N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-7- Ryvu Therapeutics S.A. RVU305 136 R10107WO (iodomethyl)quinolin-2-amine (Int. A-130, 4.6 g, 9.6 mmol, 68%, yellow solid, UPLC purity: 94%). ¹ H NMR (400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.45 – 7.38 (m, 2H), 7.30 – 7.26 (m, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 8.3, 2.4 Hz, 1H), 5.56 (s, 1H), 4.80 (d, J = 5.7 Hz, 2H), 4.61 (s, 2H), 3.89 (s, 3H), 3.83 (d, J = 0.6 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -138.28. m/z (ESI): 453.1 [M+H] ⁺ . N-[(2,4-dimethoxyphenyl)methyl]-7-(iodomethyl)-3-(trifluorom ethyl)quinolin-2-amine (Int. A-137) Step 1: Step 1 was performed according to General Procedure 1, using 7-bromo-3-(trifluorome- thyl)quinoline (0.95 g, 3.44 mmol, 1.0 eq.) and mCPBA (1.188 g, 6.88 mmol, 2.0 eq.) in DCM (30 mL). The obtained crude 7-bromo-3-(trifluoromethyl)quinolin-1-ium-1-olate (Int. A-131, 1.118 g, 3.71 mmol, 108%, beige solid, UPLC purity: 97%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (d, J = 1.5 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.07 (dd, J = 8.7, 2.0 Hz, 1H). m/z (ESI): 292.9 [M+H] ⁺ . Step 2: A mixture of 7-bromo-3-(trifluoromethyl)quinolin-1-ium-1-olate (Int. A-131, 1.018 g, 3.38 ^{mmol, 1.0 eq.) and POCl3 (8.813 g, 57.48 mmol, 17.0 eq.) in CHCl3 (35.0 mL) was stirred} _{overnight at 80 °C in a pressure vessel. After coming back to RT, the RM was washed wa-} ter and the aqueous layer was extracted with DCM. The combined organic layers were washed with sat. aq. NaHCO ₃ , dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 35% EtOAc in hexane) to yield 7-bromo-2-chloro-3-(trifluoromethyl)quinoline (Int. A-132, 0.565 g, 1.73 mmol, 51%, off-white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 8.7, 1.9 Hz, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -61.65. m/z (ESI): 311.7 [M+H] ⁺ . Step 3: Ryvu Therapeutics S.A. RVU305 137 R10107WO A mixture of 1-(2,4-dimethoxyphenyl)methanamine (1.115 g, 6.67 mmol, 4.0 eq.) and 7- bromo-2-chloro-3-(trifluoromethyl)quinoline (Int. A-132, 0.545 g, 1.67 mmol, 1.0 eq.) in tolu- ene (17.0 mL) was refluxed overnight under nitrogen. After coming back to RT, the mixture was partitioned between EtOAc and water and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 20% EtOAc gra- dient in hexane) to yield 7-bromo-N-[(2,4-dimethoxyphenyl)methyl]-3-(trifluorome- thyl)quinolin-2-amine (Int. A-133, 0.63 g, 1.371 mmol, 82%, yellow solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.42 (dd, J = 8.6, 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 5.8 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.3, 2.4 Hz, 1H), 4.65 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -62.89. m/z (ESI): 442.0 [M+H] ⁺ . Step 4: A Biotage ^TM microwave vial was charged with 7-bromo-N-[(2,4-dimethoxyphenyl)methyl]-3- (trifluoromethyl)quinolin-2-amine (Int. A-133, 0.63 g, 1.371 mmol, 1.0 eq.), Cs ₂ CO ₃ (1.340 g, 4.11 mmol, 3.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.422 g, 2.74 mmol, 2.0 eq.), dioxane (14.0 mL) and water (5 mL). The RM was sparged with nitrogen for 10 ^{min., Pd(PPh3)2Cl2 (0.096 g, 0.14 mmol, 0.1 eq.) was added and the vial was sealed. The re-} _{sulting RM was stirred at 80 °C in a DrySyn® for 2 h. After coming back to RT, the RM was} partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield N-[(2,4-di- methoxyphenyl)methyl]-7-ethenyl-3-(trifluoromethyl)quinolin- 2-amine (Int. A-134, 0.48 g, 1.19 mmol, 87%, yellow solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.53 (s, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 17.7, 11.0 Hz, 1H), 6.76 (t, J = 5.9 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 6.03 (d, J = 17.7 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H), 4.66 (d, J = 5.7 Hz, 2H), 3.86 (s, 3H), 3.72 (s, 3H). m/z (ESI): 389.3 [M+H] ⁺ . Step 5: N-[(2,4-dimethoxyphenyl)methyl]-7-ethenyl-3-(trifluoromethyl )quinolin-2-amine (Int. A- 134, 0.48 g, 1.19 mmol, 1.0 eq.) was dissolved in a mixture of dioxane (15 mL) and water (5 mL), and 4% aq. OsO ₄ (0.290 mL, 1.19 mmol, 1.0 eq.) was added. After stirring for 5 min. at RT, sodium periodate (1.015 g, 4.75 mmol, 4.0 eq.) was added. The RM was stirred for 60 min. at RT, diluted with aq.15% Na ₂ SO ₃ . and extracted with EtOAc (2x). The combined or- ganic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The obtained crude 2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-(trifluorome- thyl)quinoline-7-carbaldehyde (Int. A-135, 0.321 g, 0.75 mmol, 63%, yellow solid, UPLC pu- rity: 96%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.14 (s, 1H), 8.65 (s, 1H), 8.15 – 8.10 (m, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.66 (dd, J = 8.2, 1.5 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 5.8 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 4.70 (d, J = 5.7 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 3H). m/z (ESI): 391.4 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 138 R10107WO Step 6: NaBH ₄ (0.058 g, 1.53 mmol, 2.1 eq.) was added to a stirring solution of 2-{[(2,4-dimethoxy- phenyl)methyl]amino}-3-(trifluoromethyl)quinoline-7-carbalde hyde (Int. A-135, 0.319 g, 0.74 mmol, 1.0 eq.) in anhydrous MeOH (4.0 mL) and the RM was stirred at RT for 30 min. The reaction was quenched with sat. aq. NH ₄ Cl and the mixture was left with stirring for 10 min. It was partitioned between DCM and water and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude (2-{[(2,4- dimethoxyphenyl)methyl]amino}-3-(trifluoromethyl)quinolin-7- yl)methanol (Int. A-136, 0.314 g, 0.74 mmol, 100%, grey solid, UPLC purity: 93%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.48 (s, 1H), 7.22 (dd, J = 8.2, 1.6 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.71 (t, J = 5.8 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.3, 2.4 Hz, 1H), 5.34 (t, J = 5.8 Hz, 1H), 4.66 (d, J = 5.7 Hz, 2H), 4.62 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 3.72 (s, 3H). m/z (ESI): 393.3 [M+H] ⁺ . Step 7: Imidazole (0.101 g, 1.49 mmol, 2.0 eq.) and triphenylphosphine (0.390 g, 1.49 mmol, 2.0 eq.) were dissolved in DCM (4.0 mL) and the solution was cooled to 0 °C in an ice bath. Iodine (0.378 g, 1.49 mmol, 2.0 eq.) was added and after stirring for 15 min., (2-{[(2,4-dimethoxy- phenyl)methyl]amino}-3-(trifluoromethyl)quinolin-7-yl)methan ol (Int. A-136, 0.314 g, 0.74 mmol, 1.0 eq.) was added as a solid. The RM was stirred for 1 h at RT and was washed suc- cessively with aq. sat. NaHCO ₃ , sat. aq. Na ₂ SO ₃ and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (100% DCM isocratic) to yield N-[(2,4-dimethoxyphenyl)methyl]-7-(io- domethyl)-3-(trifluoromethyl)quinolin-2-amine (Int. A-137, 0.269 g, 0.46 mmol, 62%, brown oil, UPLC purity: 86%). m/z (ESI): 503.1 [M+H] ⁺ . 7-(Bromomethyl)-2-chloro-3-methylquinoline (Int. A-140) Step 1: n-BuLi (1.6 M in n-hexane, 7.32 mL, 11.71 mmol, 1.2 eq.) was added dropwise to stirred so- lution of 7-bromo-2-chloro-3-methylquinoline (2.5 g, 9.74 mmol, 1.0 eq.) in anhydrous THF (32.5 mL), at -78 °C under argon. The resulting mixture was stirred at -78 °C for 1 h, an- hydrous DMF (2.27 mL, 29.26 mmol, 3.0 eq.) was added at this temperature and stirring was continued for 1 h. The reaction was quenched at -78 °C with sat. aq. NH ₄ Cl (15 mL) and the mixture was allowed to reach RT. The mixture was partitioned between EtOAc and wa- ter and the aqueous layer was extracted with EtOAc (2x). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The obtained crude 2-chloro-3-methylquinoline-7-carbaldehyde (Int. A-138, 1.953 g, 8.26 mmol, 85%, yellow solid, UPLC purity: 87%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 8.55 – 8.52 (m, 1H), 8.50 – 8.47 (m, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.04 – 8.00 (m, 1H), 2.54 (d, J = 1.0 Hz, 3H). m/z (ESI): 205.9 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 139 R10107WO Step 2: NaBH ₄ (0.938 g, 24.79 mmol, 3.0 eq.) was added in small portions to a vigorously stirred so- lution of 2-chloro-3-methylquinoline-7-carbaldehyde (Int. A-138, 1.953 g, 8.26 mmol, 1.0 eq) in a mixture of THF (16 mL) and methanol (8 mL) at 0 °C. The RM was stirred for 4 hours at RT and evaporated to dryness. The residue was partitioned between sat. aq. NH ₄ Cl and DCM, and the aqueous layer was extracted with DCM (3x). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (10% to 40% EtOAc gradient in hexane) to yield (2- chloro-3-methylquinolin-7-yl)methanol (Int. A-139, 0.875 g, 3.96 mmol, 48%, yellow solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 – 8.31 (m, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.85 – 7.82 (m, 1H), 7.58 (dd, J = 8.4, 1.6 Hz, 1H), 5.46 (t, J = 5.8 Hz, 1H), 4.71 (dd, J = 5.8, 1.0 Hz, 2H), 2.49 (s, 3H). m/z (ESI): 208.8 [M+H] ⁺ . Step 3: PPh ₃ (2.078 g, 7.92 mmol, 2.0 eq.) was added to a solution of (2-chloro-3-methylquinolin-7- yl)methanol (Int. A-139, 0.875 g, 3.96 mmol, 1.0 eq.) in DCM (26.5 mL) at 0 °C, followed by CBr ₄ (2.627 g, 7.92 mmol, 2.0 eq.) and the RM was left with stirring overnight at RT under nitrogen. The mixture was evaporated under reduced pressure and the crude material was purified by FCC (0 to 90% EtOAc gradient in hexane) to yield 7-(bromomethyl)-2-chloro-3- methylquinoline (Int. A-140, 0.661 g, 1.95 mmol, 49%, yellow solid, UPLC purity: 80%). ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.24 (s, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 1.8 Hz, 1H), 4.78 (s, 2H), 2.57 (d, J = 1.0 Hz, 3H). m/z (ESI): 271.8 [M+H] ⁺ . 2-Chloroquinoline-7-carbaldehyde (Int. A-141) A solution of 7-(bromomethyl)-2-chloroquinoline (Int. A-004, 0.4 g, 1.48 mmol, 1.0 eq.) and 4-methylmorpholin-4-ium-4-olate (0.52 g, 4.439 mmol, 2.997 eq.) in dioxane (18.5 mL) was stirred at 80 °C for 1 hour. The mixture was partitioned between EtOAc and H ₂ O, and the organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by FCC (0 to 35% EtOAc gradient in hexane) to yield 2-chloroquinoline-7-carbaldehyde (Int. A-141, 0.25 g, 1.30 mmol, 81%, white solid, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 8.60 (d, J = 8.7 Hz, 1H), 8.58 (d, J = 0.9 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.06 (dd, J = 8.4, 1.6 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H). m/z (ESI): 192.9 [M+H] ⁺ . Amide intermediates N-(2-methanesulfonylphenyl)acetamide (Int. B-001), General Procedure 08: Ryvu Therapeutics S.A. RVU305 140 R10107WO ^{A mixture of 2-methanesulfonylaniline (0.144 g, 0.84 mmol, 1.0 eq.) and Ac2O (0.795 mL,} _{8.41 mmol, 10.0 eq.) was stirred at 75 °C for 3 h. After coming back to RT, the RM was} poured onto ice/water and the resulting aqueous mixture was extracted with DCM (3x). The combined organic layers were washed with aq. sat. Na ₂ CO ₃ and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield crude N-(2-methanesul- fonylphenyl)acetamide (0.172 g, 0.81 mmol, 96%, white solid, UPLC purity: 72%) which was used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 8.00 (dd, J = 8.2, 1.3 Hz, 1H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.73 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 7.43 (ddd, J = 8.4, 7.4, 1.2 Hz, 1H), 3.28 (s, 3H), 2.15 (s, 3H). m/z (ESI): 213.9 [M+H] ⁺ . Amides intermediates prepared similarly to the protocol described in General Procedure 08: Ryvu Therapeutics S.A. RVU305 141 R10107WO Ryvu Therapeutics S.A. RVU305 142 R10107WO N-[2-(ethanesulfonyl)phenyl]pyridine-3-carboxamide (Int. C-001), General Procedure 09 2-(Ethanesulfonyl)aniline (0.13 g, 0.70 mmol, 1.0 eq.) and DMAP (0.009 g, 0.07 mmol, 0.1 eq.) were dissolved in anhydrous pyridine (1.7 mL, 21 mmol, 30.0 eq.) and nicotinoyl chlo- Ryvu Therapeutics S.A. RVU305 143 R10107WO ride hydrochloride (0.225 g, 1.26 mmol, 1.8 eq.) was added. The RM was stirred at RT over- night under nitrogen and evaporated to dryness. The residue was partitioned between water and DCM, and the aqueous phase was extracted with DCM (3x). The combined organic lay- ers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in DCM) to yield N-[2-(ethanesulfonyl)phenyl]pyridine-3-carboxamide (Int. C-001, 0.194 g, 0.67 mmol, 89%, beige solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 9.12 (dd, J = 2.4, 0.9 Hz, 1H), 8.83 (dd, J = 4.8, 1.6 Hz, 1H), 8.29 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 8.22 (dd, J = 8.2, 1.2 Hz, 1H), 7.96 (dd, J = 7.9, 1.6 Hz, 1H), 7.85 (ddd, J = 8.9, 7.5, 1.6 Hz, 1H), 7.65 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.54 (td, J = 7.7, 1.2 Hz, 1H), 3.43 (q, J = 7.3 Hz, 2H), 1.12 (t, J = 7.3 Hz, 3H). m/z (ESI): 291.5 [M+H] ⁺ . Amide intermediates prepared similarly to the protocol described in General Procedure 09: Ryvu Therapeutics S.A. RVU305 144 R10107WO Ryvu Therapeutics S.A. RVU305 145 R10107WO Ryvu Therapeutics S.A. RVU305 146 R10107WO Ryvu Therapeutics S.A. RVU305 147 R10107WO Ryvu Therapeutics S.A. RVU305 148 R10107WO N-(2-methanesulfonylphenyl)-5-methyl-1,2-oxazole-3-carboxami de (Int. D-001), General Procedure 10 HOAt (0.321 g, 2.36 mmol, 1.0 eq.), 2-methanesulfonylaniline (0.404 g, 2.36 mmol, 1.0 eq.), 5-methyl-1,2-oxazole-3-carboxylic acid (0.3 g, 2.36 mmol, 1.0 eq.), DIPEA (1.03 mL, 5.9 mmol, 2.5 eq.) and HATU (1.795 g, 4.72 mmol, 2.0 eq.) were dissolved in anhydrous DMF (5.0 mL) and the RM was stirred overnight at RT under nitrogen. The RM was then diluted with DCM and the solution was washed with aq.1 N NaOH and brine. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(2-me- thanesulfonylphenyl)-5-methyl-1,2-oxazole-3-carboxamide (0.65 g, 2.319 mmol, 97%, beige solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 8.41 (dd, J = 8.3, 1.1 Hz, 1H), 7.97 (dd, J = 8.0, 1.6 Hz, 1H), 7.82 (td, J = 7.9, 1.6 Hz, 1H), 7.48 (td, J = 7.7, 1.2 Hz, 1H), 6.75 (d, J = 1.1 Hz, 1H), 3.33 (s, 3H), 2.54 (s, 3H). m/z (ESI): 281.4 [M+H] ⁺ . Amide intermediates prepared similarly to the protocol described in General Procedure 10: Ryvu Therapeutics S.A. RVU305 149 R10107WO Ryvu Therapeutics S.A. RVU305 150 R10107WO 2-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(2-methanesulfo nylphenyl)acetamide (Int. E- 001), General Procedure 11 2-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)acetyl chloride (0.236 g, 1.06 mmol, 1.2 eq.) was added to a solution of 2-methanesulfonylaniline (0.151 g, 0.88 mmol, 1.0 eq.) and TEA (0.25 mL, 1.79 mmol, 2.0 eq.) in anhydrous THF (5.0 mL) at 0 °C under nitrogen. The RM was al- lowed to warm up to RT and stirred overnight at 65 °C. The resulting precipitate was fil- tered off, washed with cold THF and dried in vacuo to yield 2-(1,3-dioxo-2,3-dihydro-1H- isoindol-2-yl)-N-(2-methanesulfonylphenyl)acetamide (Int. E-001, 0.207 g, 0.58 mmol, 63%, beige solid, UPLC purity: 96%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.01 – 7.85 (m, 6H), 7.76 (td, J = 7.9, 1.6 Hz, 1H), 7.49 (td, J = 7.7, 1.2 Hz, 1H), 4.54 (s, 2H), 3.26 (s, 3H). m/z (ESI): 357.0 [M-H]-. Amide intermediates prepared similarly to the protocol described in General Procedure 11: N-(2-methanesulfonylpyridin-3-yl)cyclopropanecarboxamide (Int. F-001), General Proce- dure 12 Ryvu Therapeutics S.A. RVU305 151 R10107WO 2-Methanesulfonylpyridin-3-amine (0.1 g, 0.58 mmol, 1.0 eq.) and DIPEA (0.303 mL, 1.7 mmol, 3.0 eq.) were dissolved in anhydrous DCM (5.0 mL). The solution was cooled to 0 °C and cyclopropanecarbonyl chloride (0.158 μL, 1.74 mmol, 3.0 eq.) was added under nitro- gen. The RM was left with stirring under nitrogen overnight at RT. It was then washed with sat. aq. NaHCO ₃ , aq. 5% AcOH and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 2% MeOH gra- dient in DCM) to yield N-(2-methanesulfonylpyridin-3-yl)cyclopropanecarboxamide (Int. F- 001, 0.134 g, 0.56 mmol, 96%, beige solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.09 (s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 4.5 Hz, 1H), 7.73 (dd, J = 8.6, 4.5 Hz, 1H), 3.43 (s, 3H), 1.91 – 1.78 (m, 1H), 1.29 – 1.21 (m, 2H), 0.91 – 0.87 (m, 2H). m/z (ESI): 241.1 [M+H] ⁺ . Amide intermediates prepared similarly to the protocol described in General Procedure 12: Ryvu Therapeutics S.A. RVU305 152 R10107WO Ryvu Therapeutics S.A. RVU305 153 R10107WO N-{3-cyano-5H,6H,7H-cyclopenta[b]pyridin-2-yl}acetamide (Int. G-001), General Procedure 13 A solution of 2-amino-5H,6H,7H-cyclopenta[b]pyridine-3-carbonitrile (0.25 g, 1.57 mmol, 1.0 eq.) in Ac ₂ O (2.23 mL, 23.56 mmol, 15.0 eq.) was stirred at 100 °C for 2 h under nitrogen. The reaction was then quenched with ice, the mixture was basified with aq. sat. NaHCO ₃ and extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was dissolved in MeOH (2.0 mL), K ₂ CO ₃ (0.177 g, 1.28 mmol, 0.8 eq.) was added and the RM was stirred at RT for 2 h in order to hydrolyze the bis-acylation product. The RM was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 30% EtOAc gradient in cyclohexane) to yield N-{3- cyano-5H,6H,7H-cyclopenta[b]pyridin-2-yl}acetamide (Int. G-001, 0.230 g, 1.14 mmol, 73%, beige solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.09 (s, 1H), 3.03 – 2.90 (m, 4H), 2.17 – 2.11 (m, 2H), 2.10 (s, 3H). m/z (ESI): 202.5 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 154 R10107WO N-(2-methanesulfonylphenyl)-2-(1H-pyrazol-1-yl)acetamide (Int. H-001), General Proce- dure 14 A pressure vessel was charged with BTFFH (0.554 g, 1.75 mmol, 1.2 eq.), 2- methanesulfonylaniline (0.25 g, 1.46 mmol, 1.0 eq.), 2-(1H-pyrazol-1-yl)acetic acid (0.184 g, 1.46 mmol, 1.0 eq.), DCM (4.0 mL) and DIPEA (0.64 mL, 3.65 mmol, 2.5 eq.). The vessel was sealed and the RM was stirred at 80 °C overnight. After coming back to RT, the RM was diluted with DCM and washed with water and brine. The organic layer was dried over anhy- drous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was pu- rified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(2-methanesulfonylphenyl)-2- (1H-pyrazol-1-yl)acetamide (Int. H-001, 0.12 g, 0.43 mmol, 29%, yellow oil, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.55 (s, 1H), 8.13 (dd, J = 8.3, 1.2 Hz, 1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.87 (dd, J = 2.4, 0.7 Hz, 1H), 7.76 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 7.58 (dd, J = 1.9, 0.7 Hz, 1H), 7.44 (td, J = 7.7, 1.2 Hz, 1H), 6.36 (t, J = 2.1 Hz, 1H), 5.17 (s, 2H), 3.20 (s, 3H). m/z (ESI): 280.0 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 155 R10107WO Methyl 4-cyclopropaneamido-1-methyl-1H-pyrazole-3-carboxylate (Int. I-001), General Pro- cedure 15 Cyclopropanecarbonyl chloride (0.337 g, 3.32 mmol, 2.0 eq.), methyl 4-amino-1-methyl-1H- pyrazole-3-carboxylate (0.250 g, 1.61 mmol, 1.0 eq.) and TEA (0.335 mL, 2.42 mmol, 1.5 eq.) were dissolved in DCM (2.0 mL) and the RM was stirred overnight at RT under nitrogen. The RM was then washed with water. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH in DCM) to yield methyl 4-cyclopropaneamido-1-methyl-1H-pyrazole-3-car- boxylate (Int. I-001, 0.356 g, 1.59 mmol, 97%, beige solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.22 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 2.04 (p, J = 6.2 Hz, 1H), 0.85 – 0.78 (m, 4H). m/z (ESI): 224.3 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 156 R10107WO Amides prepared according to General Procedure 15: Ryvu Therapeutics S.A. RVU305 157 R10107WO N-(2-methanesulfonylpyridin-3-yl)-4H,5H,6H-pyrrolo[1,2-b]pyr azole-2-carboxamide (Int. J- 001), General Procedure 16 CCl ₄ (0.37 mL, 3.82 mmol, 3.3 eq.) was added to a solution of 4H,5H,6H-pyrrolo[1,2- b]pyrazole-2-carboxylic acid (0.18 g, 1.18 mmol, 1.02 eq.), 2-methanesulfonylpyridin-3- amine (0.2 g, 1.16 mmol, 1.0 eq.) and triphenylphosphine (1.0 g, 3.81 mmol, 3.3 eq.) in acetonitrile (8.0 mL). The RM was refluxed for 1 h under nitrogen and evaporated under re- duced pressure. The residue was partitioned between DCM and water and the aqueous layer was further extracted with DCM (x2). The combined organic layers were dried over an- hydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM). The fractions containing the product were pooled and evaporated under reduced pressure. The residue was triturated in the min- imum amount of cold MeOH (5.0 mL). The resulting solid was filtered off and dried under reduced pressure to yield N-(2-methanesulfonylpyridin-3-yl)-4H,5H,6H-pyrrolo[1,2-b]pyr a- zole-2-carboxamide (Int. J-001, 0.22 g, 0.72 mmol, 57%, white solid, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.95 (s, 1H), 9.08 (dd, J = 8.6, 1.4 Hz, 1H), 8.47 (dd, J = 4.5, 1.4 Hz, 1H), 7.78 (ddd, J = 8.6, 4.5, 0.5 Hz, 1H), 6.59 (t, J = 0.9 Hz, 1H), 4.21 (t, J = 7.4 Hz, 2H), 3.46 (s, 3H), 2.92 (t, J = 7.4 Hz, 2H), 2.60 (p, J = 7.4 Hz, 2H). m/z (ESI): 307.0 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 158 R10107WO Ryvu Therapeutics S.A. RVU305 159 R10107WO Ryvu Therapeutics S.A. RVU305 160 R10107WO Ryvu Therapeutics S.A. RVU305 161 R10107WO 5-Chloro-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carboxa mide (Int. K-001), General Procedure 17 Phosphorus oxychloride (0.2 g, 1.30 mmol, 3.0 eq.) was added dropwise to a solution of 5- chloropyridine-3-carboxylic acid (0.103 g, 0.65 mmol, 1.5 eq.), 2-methanesulfonylpyridin-3- amine (0.075 g, 0.436 mmol, 1.0 eq.) and DMAP (0.016 g, 0.131 mmol, 0.301 eq.) in pyridine (4.4 mL) at 0 °C under nitrogen. The RM was stirred for 45 min at RT under nitrogen. The reaction was quenched with ice/water and the mixture was neutralized with sat. aq. Na- HCO ₃ . It was extracted with EtOAc (3x) and the combined organic layers were dried over an- hydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure. The crude material was Ryvu Therapeutics S.A. RVU305 162 R10107WO purified by FCC (0 to 60% EtOAc gradient in hexane) to yield 5-chloro-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide (Int. K-001, 0.127 g, 0.41 mmol, 79%, beige solid, UPLC purity: 85%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 9.05 (d, J = 1.9 Hz, 1H), 8.93 (d, J = 2.4 Hz, 1H), 8.64 (dd, J = 4.4, 0.9 Hz, 1H), 8.57 (dd, J = 8.4, 1.5 Hz, 1H), 8.38 (t, J = 2.2 Hz, 1H), 7.86 (dd, J = 8.5, 4.6 Hz, 1H), 3.44 (s, 3H). m/z (ESI): 313.0 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 163 R10107WO Ryvu Therapeutics S.A. RVU305 164 R10107WO Ryvu Therapeutics S.A. RVU305 165 R10107WO Ryvu Therapeutics S.A. RVU305 166 R10107WO Ryvu Therapeutics S.A. RVU305 167 R10107WO Ryvu Therapeutics S.A. RVU305 168 R10107WO Ryvu Therapeutics S.A. RVU305 169 R10107WO Ryvu Therapeutics S.A. RVU305 170 R10107WO Ryvu Therapeutics S.A. RVU305 171 R10107WO Ryvu Therapeutics S.A. RVU305 172 R10107WO Ryvu Therapeutics S.A. RVU305 173 R10107WO Ryvu Therapeutics S.A. RVU305 174 R10107WO Ryvu Therapeutics S.A. RVU305 175 R10107WO Ryvu Therapeutics S.A. RVU305 176 R10107WO Ryvu Therapeutics S.A. RVU305 177 R10107WO Ryvu Therapeutics S.A. RVU305 178 R10107WO Ryvu Therapeutics S.A. RVU305 179 R10107WO Ryvu Therapeutics S.A. RVU305 180 R10107WO Ryvu Therapeutics S.A. RVU305 181 R10107WO Ryvu Therapeutics S.A. RVU305 182 R10107WO Ryvu Therapeutics S.A. RVU305 183 R10107WO Ryvu Therapeutics S.A. RVU305 184 R10107WO Ryvu Therapeutics S.A. RVU305 185 R10107WO N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-1-methyl -2-oxo-1,2-dihydropyridine-4- carboxamide (Int. L-001), General Procedure 18 Ryvu Therapeutics S.A. RVU305 186 R10107WO A solution of 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.836 g, 5.46 mmol, 5.0 eq.) in thionyl chloride (4.5 mL) was heated at 90 °C for 2.5 h in a sealed tube. The RM was then evaporated and co-evaporated with DCM (3x). The residue was dissolved in anhy- drous pyridine (4.5 mL) under nitrogen and 7-amino-2,3-dihydro-1λ⁶-benzothiophene-1,1- dione (0.2 g, 1.09 mmol, 1.0 eq.) was added, followed by DMAP (0.04 g, 0.33 mmol, 0.3 eq.) at 0 °C. The RM was stirred overnight at RT, evaporated and co-evaporated with toluene (2x). The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield a 9/1 mixture of N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-1-methyl -N-(1-methyl-2- oxo-1,2-dihydropyridine-4-carbonyl)-2-oxo-1,2-dihydropyridin e-4-carboxamide (Int. L-001b) and N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-1-methyl -2-oxo-1,2-dihydro- pyridine-4-carboxamide (Int. L-001). This mixture was dissolved in MeOH (7.0 mL) and K ₂ CO ₃ (0.394 g, 2.85 mmol, 2.6 eq.) was added. The RM was stirred at 40 °C for 1.5 h and evaporated under reduced pressure. The crude material was purified by two consecutive FCCs (first: 0 to 10% MeOH gradient in DCM, second: 0 to 15% MeOH gradient in EtOAc) to yield N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-1-methyl -2-oxo-1,2-dihydro- pyridine-4-carboxamide (Int. L-001, 0.151 g, 0.47 mmol, 43%, beige solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 7.88 (d, J = 6.9 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.55 (dd, J = 6.9, 2.0 Hz, 1H), 3.65 (t, J = 6.8 Hz, 2H), 3.50 (s, 2H), 3.37 (t, J = 6.2 Hz, 3H). m/z (ESI): 319.0 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 187 R10107WO N-(2-methanesulfonylpyridin-3-yl)acetamide (Int. M-001) Acetyl chloride (0.269 mL, 3.79 mmol, 2.6 eq.) was added to a solution of 2-methanesul- fonylpyridin-3-amine (0.251 g, 1.46 mmol, 1.0 eq.) and triethylamine (0.8 mL, 4.76 mmol, 4 eq.) in anhydrous DCM (7.0 mL) at 0 °C under nitrogen. The RM was allowed to come back to RT and left with stirring under nitrogen for 3 days. Water was added and the mixture was extracted with DCM (2x). The combined organic layers were washed with aq. sat. NH ₄ Cl, ^{water and brine, dried over anhydrous Na} ₂ ^SO ₄ ^{, filtered and evaporated under reduced pres-} sure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(2-methanesulfonylpyridin-3-yl)acetamide (Int. M-001, 0.194 g, 0.906 mmol, 61%, yellow solid, UPLC purity: 98%). ¹ H NMR (400 MHz, Chloroform-d) δ 9.85 (s, 1H), 9.05 (d, J = 8.6 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 7.51 (dd, J = 8.8, 4.4 Hz, 1H), 3.35 (s, 3H), 2.24 (s, 3H). m/z (ESI): 215.2 [M+H] ⁺ . N‐{2‐[(4‐methoxyphenyl)methyl]‐1‐oxo‐2,3‐dihyd ro‐1H‐isoindol‐4‐yl}acetam- ide (Int. M-004) Step 1: Ryvu Therapeutics S.A. RVU305 188 R10107WO 1-(4-Methoxyphenyl)methanamine (0.513 g, 3.74 mmol, 2.0 eq.) was added to a solution of methyl 2-(bromomethyl)-3-nitrobenzoate (0.5 g, 1.82 mmol, 1.0 eq.) in THF (5.0 mL) and the RM was stirred at 50 °C overnight. After coming back to RT, the RM was partitioned be- tween 10% aq. KHSO ₄ and EtOAc. The organic layer was separated, sequentially washed with 10% aq. KHSO ₄ , water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 2-[(4-methoxyphenyl)methyl]-4-nitro-2,3-dihydro-1H-isoindol- 1- one (Int. M-002, 0.5 g, 1.68 mmol, 89%, yellow solid, UPLC purity: 97%). The crude material was used in the next step without further purification. ¹ H NMR (400 MHz, Chloroform-d) δ 8.37 (dd, J = 8.2, 1.0 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.31 – 7.24 (m, 2H), 6.91 – 6.82 (m, 2H), 4.78 (s, 2H), 4.73 (s, 2H), 3.79 (s, 3H). _m/z (ESI): 297.1 [M+H] ⁺ . Step 2: A mixture of 10% Pd/C (0.692 g) and 2-[(4-methoxyphenyl)methyl]-4-nitro-2,3-dihydro-1H- isoindol-1-one (Int. M-002, 0.5 g, 1.62 mmol, 1.0 eq.) in EtOAc/MeOH 1:1 v/v (20.0 mL) was hydrogenated in a Parr apparatus (4 bar) for 2 h at RT. The RM was filtered through a pad of Celite ^® and the filter cake was washed with methanol. The filtrate was concentrated un- der reduced pressure to yield 4-amino-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoin- dol-1-one (Int. M-003, 0.436 g, 1.62 mmol, 99%, beige solid, UPLC purity: 99%). The crude material was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.31 – 7.13 (m, 3H), 7.00 – 6.89 (m, 3H), 6.77 (d, J = 8.0 Hz, 1H), 5.39 (s, 2H), 4.67 (s, 2H), 4.10 (s, 2H), 3.76 (s, 3H). m/z (ESI): 269.4 [M+H] ⁺ . Step 3: N‐{2‐[(4‐methoxyphenyl)methyl]‐1‐oxo‐2,3‐dihyd ro‐1H‐isoindol‐4‐ yl}acetamide (Int. M-004, 0.441 g, 1.42 mmol, 73%, beige solid, UPLC purity: 92%) was ob- tained from 4-amino-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol- 1-one (Int. M- 003, 0.42 g, 1.55 mmol, 1.0 eq.) and acetic anhydride (0.73 mL, 7.75 mmol, 5.0 eq.) following General Procedure 08. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.74 (s, 1H), 7.85 (dd, J = 7.2, 1.7 Hz, 1H), 7.50 (dd, J = 7.6, 1.7 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.29 – 7.20 (m, 2H), 6.96 – 6.92 (m, 2H), 4.68 (s, 2H), 4.30 (s, 2H), 3.75 (s, 3H), 2.06 (s, 3H). m/z (ESI): 311.3 [M+H] ⁺ . N-(2-methanesulfonyl-6-methylphenyl)acetamide (Int. M-006) Step 1: Acetyl chloride (0.14 mL, 1.96 mmol, 1.2 eq.) was added dropwise to a solution of 2-methyl- 6-(methylsulfanyl)aniline (0.25 g, 1.63 mmol, 1.0 eq.) and triethylamine (0.7 mL, 5.02 mmol, 3.1 eq.) in anhydrous DCM (8.0 mL), and the reaction was stirred 3 h at RT under nitrogen. The RM was diluted with water and extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under re- Ryvu Therapeutics S.A. RVU305 189 R10107WO duced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hex- ane) to yield N-[2-methyl-6-(methylsulfanyl)phenyl]acetamide (Int. M-005, 0.209 g, 1.07 mmol, 63%, off white solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (s, 1H), 7.23 – 7.18 (m, 1H), 7.08 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 2.38 (s, 3H), 2.12 (s, 3H), 2.03 (s, 3H). m/z (ESI): 195.9 [M+H] ⁺ . Step 2: 3-Chloroperbenzoic acid (0.3 g, 1.34 mmol, 2.5 eq.) was added to a solution of N-[2-methyl- 6-(methylsulfanyl)phenyl]acetamide (Int. M-005, 0.109 g, 0.54 mmol, 1.0 eq.) in DCM (5.0 mL) at 0 °C. The RM was stirred 30 min at 0 °C and then overnight at RT. It was then di- luted with DCM and washed with aq. sat. Na ₂ SO ₃ and aq. sat. Na ₂ CO ₃ . The combined aque- ous layers were extracted with DCM and the combined organic layers were dried over anhy- drous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was pu- rified by FCC (0 to 33% EtOAc gradient in hexane) to yield N-(2-methanesulfonyl-6- methylphenyl)acetamide (Int. M-006, 0.108 g, 0.475 mmol, 82%, white solid, UPLC purity: 93.0%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.20 (br s, 1H), 7.89 (dd, J = 7.9, 1.1 Hz, 1H), 7.59 (dd, J = 7.7, 0.9 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 3.04 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H). m/z (ESI): 227.1 [M+H] ⁺ . N-(4-chloro-1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl) acetamide (Int. M-008) Step 1: Acetyl chloride (0.14 mL, 1.96 mmol, 1.2 eq.) was added dropwise to a solution of (0.3 g, 1.64 mmol, 1.0 eq.) in pyridine (2.7 mL). The reaction was stirred for 3 h at RT under nitro- gen. The RM was then diluted with water and extracted with DCM (3x). The combined or- ganic layers were washed with aq.1M HCl, sat. aq. NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to give N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothio- phen-7-yl)acetamide (Int. M-007, 0.314 g, 1.39 mmol, 85%, off-white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.39 (d, J = 8.3 Hz, 1H), 8.22 (br s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.08 (dd, J = 7.6, 0.7 Hz, 1H), 3.56 (dd, J = 7.2, 0.9 Hz, 1H), 3.54 (dd, J = 7.2, 0.5 Hz, 1H), 3.40 (t, J = 6.9 Hz, 2H), 2.27 (s, 3H). m/z (ESI): 247.9 [M+Na] ⁺ . Step 2: NCS (0.15 g, 1.123 mmol, 1.1 eq.) was added to a solution of N-(1,1-dioxo-2,3-dihydro-1λ⁶- benzothiophen-7-yl)acetamide (Int. M-007, 0.23 g, 1.02 mmol, 1.0 eq.) in acetic acid (5.0 mL), and the reaction was stirred overnight at 60 °C. The RM was then concentrated in vacuo and co-evaporated with MeOH. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(4-chloro-1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen- Ryvu Therapeutics S.A. RVU305 190 R10107WO 7-yl)acetamide (Int. M-008, 0.236 g, 0.91 mmol, 89%, off white solid, UPLC purity: 100.0%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 8.8 Hz, 1H), 8.18 (br s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 3.59 (t, J = 6.5 Hz, 2H), 3.39 (t, J = 6.9 Hz, 2H), 2.26 (s, 3H). m/z (ESI): 257.9 [M-H]. N-(3-methanesulfonylthiophen-2-yl)acetamide (Int. M-009) To an ice-chilled solution of 3-methanesulfonylthiophen-2-amine (0.09 g, 0.51 mmol, 1.0 eq.) in anhydrous MeCN (4.0 mL) was added pyridine (0.045 mL, 0.56 mmol, 1.1 eq.) fol- lowed by acetyl chloride (0.055 mL, 0.77 mmol, 1.5 eq.) and the RM was heated at 100 °C for 30 min in a pressure vessel. It was then evaporated under reduced pressure and the res- idue was partitioned between water and DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give crude N-(3- methanesulfonylthiophen-2-yl)acetamide (Int. M-009, 0.11 g, 0.502 mmol, 96%, brown solid, UPLC purity: 97%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 7.18 (s, 2H), 3.31 (s, 3H), 2.26 (s, 3H). m/z (ESI): 217.9 [M-H]-. N-[2-(benzylsulfanyl)phenyl]acetamide (Int. M-011) Step 1: Sodium hydride (60% in mineral oil; 0.077 g, 2.0 mmol, 1.0 eq.) was added at 0 °C to a so- lution of 2-aminobenzene-1-thiol (0.25 g, 2.0 mmol, 1.0 eq.) in anhydrous DMF (10.0 mL) under nitrogen. The mixture was stirred at 0 °C for 5 min., benzyl bromide (0.342 g, 2.0 mmol, 1.0 eq.) was added and the RM was stirred at 0 °C for 30 min. under nitrogen. The reaction was quenched with water and the mixture was extracted with EtOAc (x2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in cyclohexane) to yield 2-(benzylsulfanyl)aniline (Int. M-010, 0.31 g, 1.4 mmol, 71%, yellow solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.31 – 7.19 (m, 5H), 7.09 (dd, J = 7.7, 1.5 Hz, 1H), 7.02 (td, J = 7.7, 1.5 Hz, 1H), 6.72 (dd, J = 8.1, 1.4 Hz, 1H), 6.46 (td, J = 7.4, 1.3 Hz, 1H), 5.29 (s, 2H), 3.96 (s, 2H). m/z (ESI): 216.8 [M+H] ⁺ . Step 2: A solution of 2-(benzylsulfanyl)aniline (Int. M-010, 0.31 g, 1.41 mmol, 1.0 eq.) and pyridine (0.34 mL, 4.23 mmol, 3.0 eq.) in anhydrous DCM (7.0 mL) was cooled to 0 °C and acetyl chloride (0.11 mL, 1.55 mmol, 1.1 eq.) was added dropwise under nitrogen. The RM was Ryvu Therapeutics S.A. RVU305 191 R10107WO stirred at RT for 2 h at which point it was diluted with water and extracted with DCM (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hexane) to yield N-[2-(benzylsulfanyl)phenyl]acetamide (Int. M-011, 0.354 g, 1.38 mmol, 86%, beige solid, UPLC purity: 88%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 7.63 – 7.08 (m, 9H), 4.14 (s, 2H), 2.04 (s, 3H). m/z (ESI): 258.0 [M+H] ⁺ . Methyl 2-acetamidobenzoate (Int. M-012) Pyridine (0.064 mL, 0.79 mmol, 1.2 eq.) was added to a solution of methyl 2-aminobenzoate (0.1 g, 0.66 mmol, 1.0 eq.) in anhydrous DCE (3.0 mL) at 0 °C, followed by acetic anhydride (0.078 mL, 0.83 mmol, 1.25 eq.). The RM was left with stirring overnight at RT under nitro- gen. The RM was then diluted with DCM, washed with aq.1 M HCl and water, dried over anhydrous Na ₂ SO ₄ , and evaporated under reduced pressure. The residue was triturated in hexane/Et ₂ O 9/1, filtered and dried in vacuo to yield 2-acetamidobenzoate (Int. M-012, 0.115 g, 0.59 mmol, 90%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 8.23 (dd, J = 8.4, 1.2 Hz, 1H), 7.92 (dd, J = 7.9, 1.7 Hz, 1H), 7.61 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H), 7.20 (ddd, J = 8.3, 7.4, 1.2 Hz, 1H), 3.87 (s, 3H), 2.14 (s, 3H). m/z (ESI): 216.2 [M+Na] ⁺ . N-{2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol -4-yl}pyridine-3-carbox- amide (Int. M-013) TEA (0.510 mL, 3.66 mmol, 5.0 eq.) was added to a solution of 7-amino-2-[(4-methoxy- phenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (Int. M-003, 0.2 g, 0.73 mmol, 1.0 eq.) in an- hydrous THF (4.0 mL), followed by nicotinoyl chloride hydrochloride (0.286 g, 1.60 mmol, 2.2 eq.) at 0 °C. The RM was left with stirring overnight at RT under nitrogen. It was then evaporated under reduced pressure and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with 10% aq. KHSO ₄ , sat. aq. NaHCO ₃ sat. and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to yield N-{2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-iso- indol-4-yl}pyridine-3-carboxamide (Int. M-013, 0.2 g, 0.536 mmol, 71%, beige solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.48 (s, 1H), 9.19 (d, J = 2.4 Hz, 1H), 8.86 Ryvu Therapeutics S.A. RVU305 192 R10107WO (dd, J = 4.8, 1.6 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.35 (dt, J = 8.1, 2.0 Hz, 1H), 7.69 (dd, J = 8.0, 4.8 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.35 – 7.25 (m, 3H), 6.98 – 6.91 (m, 2H), 4.71 (s, 2H), 4.43 (s, 2H), 3.75 (s, 3H). m/z (ESI): 374.5 [M+H] ⁺ . N-[2-(dimethylsulfamoyl)phenyl]pyridine-3-carboxamide (Int. M-014) Nicotinoyl chloride hydrochloride (0.568 g, 3.20 mmol, 3.1 eq.) was added to a solution of 2- amino-N,N-dimethylbenzene-1-sulfonamide (0.2 g, 1.00 mmol, 1.0 eq.), TEA (0.7 mL, 5.022 mmol, 5.03 eq.) and DMAP (0.003 g, 0.03 mmol, 0.03 eq.) in anhydrous DCM (5.0 mL) under nitrogen. The RM was stirred at RT overnight. The reaction was quenched by addition of sat. aq. NaHCO ₃ followed by 20 min. stirring and the mixture was extracted with EtOAc (x6). The combined organic layers were washed with brine (x3), dried over anhydrous Na ₂ SO ₄ , fil- tered, and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-[2-(dimethylsulfamoyl)phenyl]pyridine-3-car- boxamide (Int. M-014, 0.128 g, 0.419 mmol, 41%, yellow solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.42 (s, 1H), 9.14 (d, J = 2.3 Hz, 1H), 8.83 (dd, J = 4.9, 1.6 Hz, 1H), 8.32 (dt, J = 8.0, 2.0 Hz, 1H), 8.23 (dd, J = 8.3, 1.2 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.80 (td, J = 7.8, 1.6 Hz, 1H), 7.65 (dd, J = 7.9, 4.8 Hz, 1H), 7.50 (td, J = 7.7, 1.2 Hz, 1H), 2.64 (s, 6H). m/z (ESI): 306.7 [M+H] ⁺ . N-(5-methanesulfonyl-1-methyl-1H-pyrazol-4-yl)pyridine-3-car boxamide (Int. M-015) A mixture of (±)-trans-1,2-diaminocyclohexane (0.007 g, 0.06 mmol, 0.11 eq.), pyridine-3- carboxamide (0.08 g, 0.66 mmol, 1.2 eq.), CuI (0.011 g, 0.06 mmol, 0.11 eq.), K ₃ PO ₄ (0.23 g, 1.08 mmol, 2.0 eq.) and 4-bromo-5-methanesulfonyl-1-methyl-1H-pyrazole (0.13 g, 0.54 mmol, 1.0 eq.) in anhydrous dioxane (6.0 mL) in a sealed Biotage ^TM microwave vial was heated at 110 °C overnight in a DrySyn ^® . After coming back to RT, the RM was filtered through a pad of Celite ^® and the filter cake was washed with dichloromethane and water. The filtrate was neutralized with aq. 1 M HCl and the phases were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by Ryvu Therapeutics S.A. RVU305 193 R10107WO FCC (0 to 100% EtOAc gradient in hexane) to yield N-(5-methanesulfonyl-1-methyl-1H-py- razol-4-yl)pyridine-3-carboxamide (Int. M-015, 0.076 g, 0.271 mmol, 49%, yellow solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.98 (s, 1H), 9.07 (dd, J = 2.3, 0.9 Hz, 1H), 8.81 (dd, J = 4.8, 1.7 Hz, 1H), 8.25 (dt, J = 8.0, 2.0 Hz, 1H), 7.97 (s, 1H), 7.62 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 4.11 (s, 3H), 3.52 (s, 3H). m/z (ESI): 281.6 [M+H] ⁺ . Step 1: A solution of 2-amino-3-chlorobenzene-1-thiol (0.42 g, 2.29 mmol, 1.0 eq.) in anhydrous DMF (4.5 mL) was cooled to 0 °C and NaH (60% in mineral oil; 0.09 g, 2.35 mmol, 1.03 eq.) was added. The mixture was stirred at 0 °C under nitrogen for 15 min. and iodomethane (0.143 mL, 2.29 mmol, 1.0 eq.) was added dropwise. The reaction was stirred at 0 °C for 45 min and was quenched with water. The mixture was extracted with DCM (2x) and the com- bined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% DCM gradient in hexane) to yield 2-chloro-6-(methylsulfanyl)aniline (Int. M-016, 0.31 g, 1.78 mmol, 78%, colorless oil, UPLC purity: 99%). ¹ H NMR (400 MHz, Chloroform-d) δ 7.30 (dd, J = 8.0, 1.2 Hz, 1H), 7.22 (dd, J = 8.0, 1.5 Hz, 1H), 6.66 (t, J = 7.9 Hz, 1H), 4.70 (s, 2H), 2.40 (s, 3H). m/z (ESI): 175.0 [M+H] ⁺ . Step 2: A mixture of 2-chloro-6-(methylsulfanyl)aniline (Int. M-016, 0.11 g, 0.63 mmol, 1.0 eq.) and acetic anhydride (0.24 mL, 2.54 mmol, 4.06 eq.) in anhydrous toluene (1.0 mL) was refluxed overnight under nitrogen. After coming back to RT, the RM was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was dissolved in MeOH (2.0 mL), K ₂ CO ₃ (0.261 g, 1.89 mmol, 3.01 eq.) was added and the mixture was stirred at RT for 2 h in order to hydrolyze the bis-acylation product. It was then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-[2-chloro-6-(methylsulfanyl)phenyl]acetamide (Int. M-017, 0.122 g, 0.57 mmol, 89%, beige solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 8.0, 2.0 Hz, 1H), 7.23 (dd, J = 7.3, 2.1 Hz, 1H), 2.42 (s, 3H), 2.04 (s, 3H). m/z (ESI): 216.9 [M+H] ⁺ . Step 3: A solution of N-[2-chloro-6-(methylsulfanyl)phenyl]acetamide (Int. M-017, 0.1 g, 0.46 mmol, 1.0 eq.) and mCPBA (0.257 g, 1.15 mmol, 2.5 eq.) in DCM (5.0 mL) was stirred at RT for 2 h. The RM was then diluted with DCM and washed with aq. sat. Na ₂ SO ₃ and aq. sat. Na ₂ CO ₃ , Ryvu Therapeutics S.A. RVU305 194 R10107WO dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 80% EtOAc gradient in hexane) to yield N-(2-chloro-6- methanesulfonylphenyl)acetamide (Int. M-018, 0.12 g, 0.48 mmol, 90%, yellow solid, UPLC purity: 85%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.92 (s, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1H), 3.22 (s, 3H), 2.10 (s, 3H). m/z (ESI): 247.9 [M+H] ⁺ . N-(2-methanesulfonylphenyl)-1-methyl-2-oxo-1,2-dihydropyridi ne-4-carboxamide (Int. M- Step 1: Methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (0.4 g, 2.61 mmol, 1.0 eq.) was suspended in anhydrous DMF (8.0 mL) and the mixture was gently heated under nitrogen with a heat gun until complete dissolution. After coming back to RT, NaH (60% in mineral oil, 0.251 g, 6.55 mmol, 2.5 eq.) was added, and the RM was stirred for 30 min. under nitrogen. MeI (0.75 g, 5.284 mmol, 2.023 eq.) was added and the RM was stirred at RT under nitrogen for 60 hours. The reaction was quenched with aq. sat. NH ₄ Cl and the mixture was extracted with DCM/iPrOH 3:1 v/v (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield methyl 1-methyl-2-oxo-1,2-dihydropyridine-4-car- boxylate (Int. M-019, 0.266 g, 1.59 mmol, 49%, beige solid, UPLC purity: 80%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (dd, J = 7.0, 0.7 Hz, 1H), 6.87 (dd, J = 1.9, 0.7 Hz, 1H), 6.56 (dd, J = 7.0, 2.0 Hz, 1H), 3.86 (s, 3H), 3.48 (s, 3H). m/z (ESI): 168.4 [M+H] ⁺ . Step 2: Lithium hydroxide monohydrate (0.268 g, 6.39 mmol, 5.0 eq.) was added to a solution of me- thyl 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (Int. M-019, 0.266 g, 1.27 mmol, 1.0 eq.) in a mixture of THF (6.0 mL) and water (3.0 mL). The RM was stirred 3 h at RT and 1.5 h at 50 °C. It was then acidified with aq. 1 M HCl to pH ≈ 5 and extracted with DCM/iPrOH 3:1 v/v (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield 1-methyl-2-oxo-1,2-dihydropyridine-4-carbox- ylic acid (Int. M-020, 0.189 g, 1.23 mmol, 97%, beige solid, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.46 (s, 1H), 7.82 (d, J = 7.0 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H), 6.55 (dd, J = 6.9, 1.9 Hz, 1H), 3.47 (s, 3H). m/z (ESI): 152.3 [M-H]-. Step 3: Ryvu Therapeutics S.A. RVU305 195 R10107WO Step 3 was performed according to General Procedure 10 using 1-methyl-2-oxo-1,2-dihy- dropyridine-4-carboxylic acid (Int. M-020, 0.234 g, 1.42 mmol, 1.0 eq.), 2-methanesulfonyl- aniline (0.242 g, 1.41 mmol, 1.0 eq.), HATU (1.613 g, 4.24 mmol, 3.0 eq.) and DIPEA (0.27 mL, 1.55 mmol, 1.1 eq.) in anhydrous DMF (4.5 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in DCM followed by 0 to 10% MeOH gradient in EtOAc) to yield N-(2-methanesulfonylphenyl)-1-methyl-2-oxo-1,2-dihydropyridi ne-4-carboxamide (Int. M- ^{021, 0.095 g, 0.31 mmol, 14%, beige solid, UPLC purity: 66%). 1H NMR (400 MHz, DMSO-d6)} _{δ 10.45 (s, 1H), 8.13 (dd, J = 8.2, 1.2 Hz, 1H), 7.99 (dd, J = 8.0, 1.6 Hz, 1H), 7.91 (d, J = 7.0} Hz, 1H), 7.81 (td, J = 7.8, 1.5 Hz, 1H), 7.53 (td, J = 7.7, 1.3 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.57 (dd, J = 7.0, 2.0 Hz, 1H), 3.50 (s, 3H), 3.33 (s, 3H). _m/z (ESI): 307.3 [M+H] ⁺ . N-(2-methanesulfonylpyridin-3-yl)-4-methylpyridine-3-carboxa mide (Int. M-022) Oxalyl chloride (0.997 mL, 11.61 mmol, 4.0 eq.) was added dropwise to a solution of 4- methylpyridine-3-carboxylic acid (1.195 g, 8.71 mmol, 3.0 eq.) in anhydrous THF (20.0 mL) at 0 °C under nitrogen, followed by the addition of 3 drops of DMF. The RM was allowed to come back to RT, stirred for 1 h and evaporated under reduced pressure. Anhydrous THF (10.0 mL) was added to the residue and the suspension was cooled to 0 °C under nitrogen. A solution of 2-methanesulfonylpyridin-3-amine (0.5 g, 2.90 mmol, 1.0 eq.) in anhydrous pyridine (25.0 mL) was then added dropwise and the RM was stirred overnight at RT. It was evaporated under reduced pressure and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM, and the combined organic layers were washed with sat. aq. NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-(2-methanesulfonylpyridin-3-yl)-4-methylpyridine-3-carbox- amide (Int. M-022, 0.226 g, 0.78 mmol, 26%, beige solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H), 8.82 (s, 1H), 8.69 – 8.55 (m, 3H), 7.85 (dd, J = 8.3, 4.5 Hz, 1H), 7.42 (d, J = 5.1 Hz, 1H), 3.44 (s, 3H), 2.51 (s, 3H). m/z (ESI): 292.1 [M+H] ⁺ . N-(5-fluoro-2-methanesulfonylphenyl)acetamide Step 1: Ryvu Therapeutics S.A. RVU305 196 R10107WO mCPBA (1.1 g, 6.36 mmol, 4.0 eq.) was added to a solution of 5-fluoro-2-(methylsulfa- nyl)aniline (0.25 g, 1.59 mmol, 1.0 eq.) in DCM (5.0 mL) at 0 °C and the RM was left with stirring at this temperature for 1 h. The reaction was quenched by addition of 10% aq. Na ₂ S ₂ O ₃ and aq. sat. NaHCO ₃ and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under re- duced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hex- ane) to yield 5-fluoro-2-methanesulfonylaniline (Int. M-023, 0.133 g, 0.70 mmol, 44%, yellow solid, UPLC purity: 84%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.59 (dd, J = 8.9, 6.5 Hz, 1H), 6.66 (dd, J = 11.7, 2.5 Hz, 1H), 6.53 (ddd, J = 8.8, 8.2, 2.5 Hz, 1H), 6.32 (s, 2H), 3.12 (s, 3H). m/z (ESI): 190.3 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 08 using 5-fluoro-2-methanesul- fonylaniline (Int. M-023, 0.13 g, 0.68 mmol, 1.0 eq.) and Ac ₂ O (0.6 mL) at 80 °C to yield N- (5-fluoro-2-methanesulfonylphenyl)acetamide (Int. M-024, 0.131 g, 0.58 mmol, 85%, off- white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.68 (s, 1H), 8.04 (dd, J = 11.5, 2.6 Hz, 1H), 7.98 (dd, J = 8.9, 6.3 Hz, 1H), 7.27 (ddd, J = 8.9, 7.9, 2.7 Hz, 1H), 3.32 (s, 3H), 2.18 (s, 3H). m/z (ESI): 232.1 [M+H] ⁺ . N-{4,4-dioxo-5H,6H,7H-4λ⁶-pyrazolo[3,2-b][1,3]thiazin-3-y l}pyridine-3-carboxamide (Int. Step 1: LiHMDS (1 M solution in THF, 7.24 mL, 7.24 mmol, 1.0 eq.) was added to a solution of tri- phenylmethanethiol (2.0 g, 7.24 mmol, 1.0 eq.) in anhydrous THF (20.0 mL) at 0 °C under nitrogen. The solution was stirred at this temperature until the thiolate precipitated and was allowed to warm up to RT.1,3-Dibromopropane (960 µL, 1.90 g, 9.41 mmol, 1.3 eq.) was added and the RM was stirred for 1 hour at RT. The solvent was evaporated under reduced pressure, the residue was taken up in EtOAc and the solution was washed with water (3x). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% DCM gradient in hexane) to af- ford {[(3-bromopropyl)sulfanyl]diphenylmethyl}benzene (Int. M-025, 1.85 g, 4.65 mmol, 64%, white solid, UPLC purity: 81%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.40 – 7.31 (m, 12H), 7.27 (m, 3H), 3.43 (t, J = 6.4 Hz, 2H), 2.27 (t, J = 7.3 Hz, 2H), 1.74 (p, J = 6.8 Hz, 2H). Ryvu Therapeutics S.A. RVU305 197 R10107WO Step 2: A pressure vessel was charged with 4-nitro-1H-pyrazole (0.511 g, 4.52 mmol, 1.0 eq.), {[(3- bromopropyl)sulfanyl]diphenylmethyl}benzene (Int. M-025, 1.79 g, 4.52 mmol, 1.0 eq.), Cs ₂ CO ₃ (4.42 g, 13.57 mmol, 3.0 eq.) and THF (40.0 mL). The vessel was closed and the RM was stirred at 90 °C for 3 days. After coming back to RT, the volatiles were evaporated un- der reduced pressure. The residue was partitioned between DCM and water and the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The obtained crude 4-nitro-1-{3-[(triphenylmethyl)sulfanyl]propyl}-1H- pyrazole (Int. M-026, 1.92 g, 4.48 mmol, 99%, yellow solid, UPLC purity: 86%) was used in the next step without further purification. ¹ H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.95 (s, 1H), 7.47 – 7.39 (m, 6H), 7.34 – 7.27 (m, 6H), 7.27 – 7.21 (m, 3H), 4.10 (t, J = 6.6 Hz, 2H), 2.14 (t, J = 6.9 Hz, 2H), 1.93 (p, J = 6.8 Hz, 2H). Step 3: 4-Nitro-1-{3-[(triphenylmethyl)sulfanyl]propyl}-1H-pyrazole (Int. M-026, 1.80 g, 4.2 mmol, 1.0 eq.) was stirred in a mixture of DCM (30.0 mL), TFA (3.22 mL, 42 mmol, 10.0 eq.) and triethylsilane (1.68 mL, 10.5 mmol, 2.5 eq.) for 2 hours at RT. The RM was then evaporated under reduced pressure and the crude material was purified by FCC (0 to 25% EtOAc gradi- ent in hexane) to yield 3-(4-nitro-1H-pyrazol-1-yl)propane-1-thiol (Int. M-027, 0.668 g, 3.57 mmol, 83%, colorless oil, UPLC purity: 98%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 8.11 (s, 1H), 4.37 (t, J = 6.7 Hz, 2H), 2.56 (dt, J = 8.1, 6.7 Hz, 2H), 2.23 (p, J = 6.6 Hz, 2H), 1.89 (s, 1H). m/z (ESI): 188.1 [M+H] ⁺ . Step 4: LiHMDS (1 M solution in THF, 8.4 mL, 8.4 mmol, 2.4 eq.) was added dropwise to a solution of 3-(4-nitro-1H-pyrazol-1-yl)propane-1-thiol (Int. M-027, 0.668 g, 3.5 mmol, 1.0 eq.) in an- hydrous THF (15.0 mL) at -78 °C under nitrogen. The RM was stirred at -78 °C for 1 hour, and hexachloroethane (0.993 g, 4.2 mmol, 1.2 eq.) was added as a solution in anhydrous THF (3.0 mL). The RM was left with stirring overnight, being allowed to come back slowly to RT. The reaction was quenched with sat. aq. NH ₄ Cl and the mixture was partitioned be- tween water and EtOAc. The organic layer was separated and the aqueous layer was further extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 3-nitro-5H,6H,7H-pyra- zolo[3,2-b][1,3]thiazine (Int. M-028, 0.215 g, 1.16 mmol, 33%, white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H), 4.29 (t, J = 5.9 Hz, 2H), 3.16 (m, 2H), 2.50 – 2.43 (m, 2H). m/z (ESI): 186.1 [M+H] ⁺ . Step 5: 3-Chloroperbenzoic acid (0.637 g, 2.84 mmol, 2.5 eq.) was added to a solution of 3-nitro- 5H,6H,7H-pyrazolo[3,2-b][1,3]thiazine (Int. M-028, 0.215 g, 1.14 mmol, 1.0 eq.) in DCM (10.0 mL) at 0 °C. The reaction mixture was stirred for 30 min. at 0 °C and overnight at RT. The RM was diluted with DCM and washed successively with aq. sat. Na ₂ SO ₃ and aq. sat. Na ₂ CO ₃ . The combined aqueous layers were extracted with DCM (3x) and the combined Ryvu Therapeutics S.A. RVU305 198 R10107WO organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield crude 3-nitro-5H,6H,7H-4λ⁶-pyrazolo[3,2-b][1,3]thiazine-4,4-dio ne (Int. M-029, 0.235 g, 1.08 mmol, 95%, yellow solid, UPLC purity: 85%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 4.46 (t, J = 5.8 Hz, 2H), 3.95 – 3.84 (m, 2H), 2.64 – 2.55 (m, 2H). m/z (ESI): 259.2 [M+MeCN+H] ⁺ . Step 6: A Biotage ^TM microwave vial was charged with iron powder (0.18 g, 3.22 mmol, 7.0 eq.), NH ₄ Cl (0.296 g, 5.53 mmol, 12.0 eq.), 3-nitro-5H,6H,7H-4λ⁶-pyrazolo[3,2-b][1,3]thiazine- 4,4-dione (Int. M-029, 0.1 g, 0.46 mmol, 1.0 eq.), ethanol (10.0 mL) and water (3.0 mL). The vial was sealed and the reaction was stirred at 80 °C for an hour. It was then filtered through a pad of NH ₂ functionalized silica and the filtrate was concentrated under reduced pressure to give crude 3-amino-5H,6H,7H-4λ⁶-pyrazolo[3,2-b][1,3]thiazine-4,4-dio ne (Int. M-030, 0.092 g, 0.59 mmol, 94%, brown solid, UPLC purity: 93%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.09 (s, 1H), 4.62 (s, 2H), 4.11 (t, J = 5.9 Hz, 2H), 3.64 – 3.49 (m, 2H), 2.51 – 2.44 (m, 2H). m/z (ESI): 188.5 [M+H] ⁺ . Step 7: The title compound was prepared according to General Procedure 09 using 3-amino- 5H,6H,7H-4λ⁶-pyrazolo[3,2-b][1,3]thiazine-4,4-dione (Int. M-030, 0.13 g, 0.69 mmol, 1.0 eq.), DMAP (0.017 g, 0.14 mmol, 0.2 eq.) and nicotinoyl chloride hydrochloride (0.247 g, 1.39 mmol, 2.0 eq.) in Py/THF 1:1 v/v (10.0 mL). The crude material was purified by FCC (0 to 3% MeOH gradient in DCM) to yield N-{4,4-dioxo-5H,6H,7H-4λ⁶-pyrazolo[3,2-b][1,3]thia- zin-3-yl}pyridine-3-carboxamide (Int. M-031, 0.141 g, 0.48 mmol, 69%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 9.07 (d, J = 2.2 Hz, 1H), 8.78 (dd, J = 4.8, 1.7 Hz, 1H), 8.27 (dt, J = 8.0, 2.0 Hz, 1H), 7.87 (s, 1H), 7.59 (dd, J = 7.9, 4.7 Hz, 1H), 4.36 (t, J = 6.0 Hz, 2H), 3.79 – 3.67 (m, 2H), 2.65 – 2.55 (m, 2H). m/z (ESI): 293.3 [M+H] ⁺ . N-(1,1-dioxo-1λ⁶-benzothiophen-7-yl)acetamide (Int. M-033) Step 1: 3-Chloroperbenzoic acid (1.052 g, 4.69 mmol, 2.5 eq.) was added to a solution of 7-bromo- 1-benzothiophene (0.4 g, 1.88 mmol, 1.0 eq.) in anhydrous DCM (4.0 mL) and the RM was refluxed for 5 h. After coming back to RT, the reaction was quenched by addition of aq. sat. NaHCO ₃ and the RM was stirred for a further 15 min. The phases were separated and the aqueous phase was extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. Ryvu Therapeutics S.A. RVU305 199 R10107WO The crude material was purified by FCC (0 to 66% EtOAc gradient in hexane) to yield 7- bromo-1λ⁶-benzothiophene-1,1-dione (Int. M-032, 0.413 g, 1.68 mmol, 90%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 – 7.76 (m, 1H), 7.62 – 7.57 (m, 3H), 7.45 (d, J = 6.9 Hz, 1H). m/z (ESI): 246.9 [M+H] ⁺ . Step 2: General Procedure 19 A Biotage ^TM microwave vial was charged with 7-bromo-1λ⁶-benzothiophene-1,1-dione (Int. M-032, 0.3 g, 1.22 mmol, 1.0 eq.), Cs ₂ CO ₃ (0.56 g, 1.72 mmol, 1.4 eq.), acetamide (0.072 g, 1.22 mmol, 1.0 eq.) and anhydrous dioxane (7.0 mL). The RM was sparged with nitrogen for 10 min. XPhos (0.035 g, 0.07 mmol, 0.06 eq.) was added followed by Pd(OAc) ₂ (0.008 g, 0.04 mmol, 0.03 eq.) and the vial was sealed. The resulting RM was stirred overnight at 110 °C in a DrySyn ^® . After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . The filtrate was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 66% EtOAc gradient in hexane) to yield N-(1,1-dioxo-1λ⁶-benzothiophen-7-yl)acetamide (Int. M-033, 0.07 g, 0.31 mmol, 24%, beige solid, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.75 (s, 1H), 7.68 (dd, J = 8.3, 1.2 Hz, 1H), 7.63 (dd, J = 8.2, 7.2 Hz, 1H), 7.61 (d, J = 6.9 Hz, 1H), 7.38 (dd, J = 7.1, 1.2 Hz, 1H), 7.35 (d, J = 6.8 Hz, 1H), 2.13 (s, 3H). m/z (ESI): 224.1 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 200 R10107WO N-{2-[(4-methoxyphenyl)methyl]-3-methyl-1,1-dioxo-2H-1λ⁶, 2,4-benzothiadiazin-8-yl}pyri- Step 1: Benzyl mercaptan (1.129 g, 9.09 mmol, 1.0 eq.) was added dropwise to a mixture of 1- ^{bromo-2-fluoro-3-nitrobenzene (2.0 g, 9.09 mmol, 1.0 eq.) and K2CO3 (1.33 g, 9.62 mmol,} _{1.06 eq.) in DMF (9.0 mL) under argon at 0 °C. The RM was stirred for 3 h, being allowed} to slowly come back to RT. It was then diluted with water and extracted with DCM (6x). The combined organic layers were washed with brine (x3), dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The obtained crude 2-(benzylsulfanyl)-1-bromo-3- nitrobenzene (Int. M-034, 2.90 g, 8.95 mmol, 98%, yellow solid, NMR purity: 94%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.27 – 7.22 (m, 3H), 7.15 – 7.09 (m, 2H), 4.17 (s, 2H). Step 2: NCS (1.9 g, 14.23 mmol, 3.0 eq.) was added portionwise to a solution of 2-(benzylsulfanyl)- 1-bromo-3-nitrobenzene (Int. M-034, 1.53 g, 4.73 mmol, 1.0 eq.) in a mixture of MeCN (47.0 mL), AcOH (0.6 mL) and water (1.2 mL) at 0 °C. The reaction was stirred at 0 °C for 1 h and concentrated under reduced pressure. The residue was taken up in DCM and the pH was adjusted to 7 by addition of aq. sat. NaHCO ₃ at 0 °C under vigorous stirring. The phases were separated and the organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The obtained crude 2-bromo-6-nitrobenzene-1-sulfonyl chloride (Int. M-035, 2.282 g, 3.79 mmol, 80%, yellow solid, NMR purity ≈ 50%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.84 (dd, J = 7.9, 1.2 Hz, 1H), 7.54 (dd, J = 8.0, 1.2 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H). Step 3: 4-Methoxybenzylamine (1.25 g, 9.11 mmol, 1.2 eq.) was added to a mixture of 2-bromo-6- nitrobenzene-1-sulfonyl chloride (Int. M-035, 2.282 g, 7.59 mmol, 1.0 eq.) in pyridine (16.0 mL). The RM was stirred at RT for 2 h under nitrogen and concentrated in vacuo. The resi- due was partitioned between water and DCM and the aqueous layer was extracted with Ryvu Therapeutics S.A. RVU305 201 R10107WO DCM (6x). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hexane) to afford 2-bromo-N-[(4-methoxyphenyl)methyl]-6-nitroben- zene-1-sulfonamide (Int. M-036, 1.425 g, 3.55 mmol, 44%, pink solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (t, J = 6.2 Hz, 1H), 7.95 (dd, J = 8.0, 1.2 Hz, 1H), 7.85 (dd, J = 8.0, 1.2 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.15 – 7.06 (m, 2H), 6.83 – 6.72 (m, 2H), 4.09 (d, J = 6.2 Hz, 2H), 3.70 (s, 3H). _m/z (ESI): 400.9 [M-H]-. Step 4: Iron powder (0.471 g, 8.43 mmol, 2.5 eq.) was added to a solution of 2-bromo-N-[(4-meth- oxyphenyl)methyl]-6-nitrobenzene-1-sulfonamide (Int. M-036, 1.425 g, 3.37 mmol, 1.0 eq.) ^{and NH4Cl (0.089 g, 1.66 mmol, 0.5 eq.) in a mixture of EtOH (22.5 mL) and water (5.0 mL),} _{and the RM was stirred at 80 °C for 4 h. After coming back to RT, the RM was diluted with} EtOAc and filtered through a pad of Celite ^® . The filtrate was washed with water and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude material was purified by FCC (0 to 66% EtOAc in hexane) to afford 2-amino-6-bromo-N-[(4-methox- yphenyl)methyl]benzene-1-sulfonamide (Int. M-037, 0.954 g, 2.57 mmol, 66%, light pink solid, UPLC purity: 86%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (t, J = 6.3 Hz, 1H), 7.20 – 7.14 (m, 2H), 7.02 (dd, J = 8.4, 7.6 Hz, 1H), 6.84 (dd, J = 7.6, 1.2 Hz, 1H), 6.82 – 6.79 (m, 2H), 6.79 (dd, J = 8.4, 1.2 Hz, 1H), 6.57 (s, 2H), 3.97 (d, J = 6.3 Hz, 2H), 3.71 (s, 3H). m/z (ESI): 370.9 [M-H]-. Step 5: A mixture of 2-amino-6-bromo-N-[(4-methoxyphenyl)methyl]benzene-1-sulfona mide (Int. M-037, 0.932 g, 2.16 mmol, 1.0 eq.) and triethyl orthoacetate (12.26 g, 75.55 mmol, 35.0 eq.) was heated at 130 °C for 3 h under argon. After coming back to RT, the RM was parti- tioned between water and EtOAc and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hex- ane) to afford 8-bromo-2-[(4-methoxyphenyl)methyl]-3-methyl-2H-1λ⁶,2,4-b enzothiadia- zine-1,1-dione (Int. M-038, 0.708 g, 1.79 mmol, 74%, orange solid, UPLC purity: 89%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (dd, J = 8.0, 1.1 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.52 (dd, J = 8.2, 1.1 Hz, 1H), 7.28 – 7.21 (m, 2H), 6.97 – 6.93 (m, 2H), 5.15 (s, 2H), 3.74 (s, 3H), 2.38 (s, 3H). m/z (ESI): 416.9 [M+Na] ⁺ . Step 6: The title compound was prepared according to General Procedure 19, using 8-bromo-2-[(4- methoxyphenyl)methyl]-3-methyl-2H-1λ⁶,2,4-benzothiadiazin e-1,1-dione (Int. M-038, 0.708 g, 1.59 mmol, 1.0 eq.), niacinamide (0.245 g, 2.01 mmol, 1.3 eq.), Cs ₂ CO ₃ (0.730 g, 2.24 mmol, 1.4 eq.), X-Phos (0.46 g, 0.96 mmol, 0.6 eq.) and Pd(OAc) ₂ (0.107 g, 0.48 mmol, 0.3 eq.) in anhydrous dioxane (8.0 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-{2-[(4-methoxyphenyl)methyl]-3-methyl-1,1-dioxo- 2H-1λ⁶,2,4-benzothiadiazin-8-yl}pyridine-3-carboxamide (Int. M-039, 0.069 g, 0.16 mmol, 9%, yellow solid, UPLC purity: 86%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.52 (s, 1H), 9.15 Ryvu Therapeutics S.A. RVU305 202 R10107WO (dd, J = 2.3, 0.9 Hz, 1H), 8.81 (dd, J = 4.8, 1.7 Hz, 1H), 8.32 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.62 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.47 (dd, J = 8.2, 1.1 Hz, 1H), 7.28 – 7.21 (m, 2H), 6.97 – 6.90 (m, 2H), 5.13 (s, 2H), 3.74 (s, 3H), 2.40 (s, 3H). m/z (ESI): 437.5 [M+H] ⁺ . N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyr an-8-yl)pyridine-3-carboxamide Step 1: 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. M-040, 2.48 g, 9.49 mmol, 83%, white solid, UPLC purity: 93%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). m/z (ESI): 259.2 [M-H]-. Step 2: A solution of 3-[(2-bromophenyl)sulfanyl]propanoic acid (Int. M-040, 2.46 g, 8.76 mmol, 1.0 eq.) in thionyl chloride (6.4 mL) was refluxed for 2 h under nitrogen and concentrated to dryness in vacuo. 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 Na ₂ SO ₄ , 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. M-041, 1.82 g, 7.49 mmol, 83%, yellow solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). m/z (ESI): 243.0 [M+H] ⁺ . Step 3: Ryvu Therapeutics S.A. RVU305 203 R10107WO A mixture of 8-bromo-3,4-dihydro-2H-1-benzothiopyran-4-one (Int. M-041, 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 nitrogen. After coming back to RT, the RM was diluted with DCM and the solution was slowly added to stirring sat. aq. Na ₂ CO ₃ at 0 °C. The phases were separated and the aque- ous phase was extracted with DCM (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (100% hexane) to yield 8-bromo-4,4-difluoro-3,4-dihy- dro-2H-1-benzothiopyran (Int. M-042, 0.149 g, 0.56 mmol, 47%, colorless oil, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -82.93 (t, J = 14.0 Hz). m/z (ESI): 265.8 [M+H] ⁺ . Step 4: A mixture of 8-bromo-4,4-difluoro-3,4-dihydro-2H-1-benzothiopyran (Int. M-042, 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. Na ₂ S ₂ O ₃ followed by aq. sat. NaHCO ₃ . The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hexane) to yield 8-bromo-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran-1, 1-dione (Int. M-043, 0.170 g, 0.54 mmol, 96%, white solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -84.67 (t, J = 13.5 Hz). m/z (ESI): 340.8 [M+2Na-H] ⁺ . Step 5: A Biotage ^TM microwave vial was charged with 8-bromo-4,4-difluoro-3,4-dihydro-2H-1λ⁶- benzothiopyran-1,1-dione (Int. M-043, 0.15 g, 0.47 mmol, 1.0 eq.), Cs2CO3 (0.387 g, 1.19 mmol, 2.5 eq.), pyridine-3-carboxamide (0.116 g, 0.95 mmol, 2.0 eq.) and anhydrous dioxane (5.0 mL). The RM was sparged with nitrogen for 10 min. BINAP (0.018 g, 0.03 mmol, 0.06 eq.) was added followed by Pd ₂ (dba) ₃ (0.013 g, 0.01 mmol, 0.03 eq.) and the vial was sealed. The resulting RM was stirred overnight at 110 °C in a DrySyn ^® . After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . The filtrate was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyr an-8-yl)pyridine-3-carbox- amide (Int. M-044, 0.116 g, 0.34 mmol, 71%, beige solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 9.11 (dd, J = 2.3, 0.9 Hz, 1H), 8.80 (dd, J = 4.8, 1.7 Hz, 1H), 8.27 (ddd, J = 7.9, 2.4, 1.7 Hz, 1H), 7.98 (dd, J = 7.9, 1.2 Hz, 1H), 7.92 (t, J = 7.9 Hz, 1H), 7.83 (dd, J = 7.9, 1.4 Hz, 1H), 7.62 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 3.95 – 3.88 (m, 2H), 3.11 – 2.96 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -84.54 (t, J = 13.6 Hz). m/z (ESI): 339.7 [M+H] ⁺ . N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyr an-8-yl)acetamide (Int. M-045) Ryvu Therapeutics S.A. RVU305 204 R10107WO A Biotage ^TM microwave vial was charged with 8-bromo-4,4-difluoro-3,4-dihydro-2H-1λ⁶- benzothiopyran-1,1-dione (Int. M-043, 0.131 g, 0.39 mmol, 1.0 eq.), Cs2CO3 (0.32 g, 0.98 mmol, 2.5 eq.), acetamide (0.026 g, 0.44 mmol, 1.1 eq.) and anhydrous dioxane (1.5 mL) and the RM was sparged with nitrogen for 10 min. BINAP (0.015 g, 0.02 mmol, 0.06 eq.) was ^{added followed by Pd2(dba)3 (0.011 g, 0.01 mmol, 0.03 eq.) and the vial was sealed. The re-} _{sulting RM was stirred overnight at 110 °C in a DrySyn®. After coming back to RT, the RM} was diluted with EtOAc and filtered through a pad of Celite ^® . The filtrate was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hexane) to yield N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl )acetamide (Int. M-045, 0.097 g, 0.35 mmol, 84%, white solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.70 (dd, J = 7.8, 1.4 Hz, 1H), 3.93 – 3.84 (m, 2H), 3.09 – 2.90 (m, 2H), 2.09 (s, 3H). m/z (ESI): 275.6 [M+H] ⁺ . N-(1,3-benzothiazol-4-yl)pyridine-3-carboxamide (Int. M-046) A microwave vial was charged with pyridine-3-carboxamide (0.143 g, 1.17 mmol, 1.1 eq.), Cs ₂ CO ₃ (0.864 g, 2.65 mmol, 2.5 eq.), 4-chloro-1,3-benzothiazole (0.18 g, 1.06 mmol, 1.0 eq.) and anhydrous dioxane (12.0 mL), and the RM was sparged with nitrogen for 10 min. XPhos Pd G3 (0.090 g, 0.11 mmol, 0.1 eq.) was added and the vial was sealed. The resulting RM was stirred at 100 °C under microwave irradiation for 2 h. After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . The filtrate was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by two consecutive FCCs (first: 0 to 5% MeOH gradient in DCM, second: 0 to 100% EtOAc gradient in hexane) to yield N-(1,3-benzothiazol-4-yl)pyridine-3- carboxamide (Int. M-046, 0.14 g, 0.55 mmol, 49%, white solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.57 (s, 1H), 9.45 (s, 1H), 9.20 (d, J = 2.4 Hz, 1H), 8.82 (dd, J = 4.9, 1.6 Hz, 1H), 8.40 (dt, J = 8.0, 2.0 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 8.02 (dd, J = 8.1, 1.0 Hz, 1H), 7.66 – 7.59 (m, 1H), 7.56 (t, J = 8.0 Hz, 1H). m/z (ESI): 256.5 [M+H] ⁺ . N-(2-methanesulfonyl-5-methylpyridin-3-yl)pyridine-3-carboxa mide (Int. M-049) Ryvu Therapeutics S.A. RVU305 205 R10107WO Step 1: A mixture of 2-chloro-5-methyl-3-nitropyridine (0.5 g, 2.90 mmol, 1.0 eq.) and zinc dust (1.894 g, 28.97 mmol, 10.0 eq.) was stirred in acetone (6.0 mL) and aq. sat NH ₄ Cl (2.0 mL) was added at RT for 1 h. It was then filtered through a pad of Celite ^® and the filtrate was partitioned between DCM and water. The aqueous phase was extracted with DCM (x2) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated un- der reduced pressure. The obtained crude 2-chloro-5-methylpyridin-3-amine (Int. M-047, 0.324 g, 2.27 mmol, 62%, beige solid, UPLC purity: 79%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.42 (dq, J = 2.0, 0.6 Hz, 1H), 6.93 (dq, J = 2.0, 0.6 Hz, 1H), 5.45 (s, 2H), 2.16 (s, 3H). m/z (ESI): 142.9 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 09, using 2-chloro-5-methylpyridin- 3-amine (Int. M-047, 0.174 g, 0.96 mmol, 1.0 eq.), nicotinoyl chloride hydrochloride (0.257 g, 1.45 mmol, 1.5 eq.) and DMAP (0.012 g, 0.1 mmol, 0.1 eq.) in pyridine (2.3 mL). The crude material was purified by FCC (0 to 3% MeOH gradient in DCM) to yield N-(2-chloro-5- methylpyridin-3-yl)pyridine-3-carboxamide (Int. M-048, 0.261 g, 1.05 mmol, 105%, off white solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.43 (s, 1H), 9.14 (dd, J = 2.3, 0.9 Hz, 1H), 8.81 (dd, J = 4.8, 1.7 Hz, 1H), 8.33 (ddd, J = 7.9, 2.3, 1.7 Hz, 1H), 8.19 (dq, J = 2.3, 0.7 Hz, 1H), 7.96 – 7.92 (m, 1H), 7.61 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 2.35 (t, J = 0.7 Hz, 3H). m/z (ESI): 248.9 [M+H] ⁺ . Step 3: General Procedure 20 A solution of CuI (0.038 g, 0.20 mmol, 0.2 eq.), sodium methanesulfinate (0.247 g, 2.42 mmol, 2.4 eq.), L-Pro-ONa (0.055 g, 0.40 mmol, 0.4 eq.), N-(2-chloro-5-methylpyridin-3- yl)pyridine-3-carboxamide (Int. M-048, 0.26 g, 1.01 mmol, 1.0 eq.) in anhydrous DMSO (4.0 mL) was stirred at 100 °C overnight under nitrogen. After coming back to RT, the RM was filtered through a pad of Celite ^® , rinsing the filter cake with EtOAc. The filtrate was washed with water and the aqueous phase was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-(2-methanesulfonyl-5-methylpyridin-3-yl)pyridine-3-carboxa mide (Int. M-049, 0.205 g, 0.704 mmol, 68%, beige solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.73 (s, 1H), 9.11 (dd, J = 2.4, 0.9 Hz, 1H), 8.83 (dd, J = 4.8, 1.6 Hz, 1H), 8.57 – 8.52 (m, 1H), 8.47 – 8.42 (m, 1H), 8.27 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 7.65 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 3.40 (s, 3H), 2.46 (s, 3H). _m/z (ESI): 292.5 [M+H] ⁺ . N-[2-methanesulfonyl-4-(trifluoromethyl)phenyl]pyridine-3-ca rboxamide (Int. M-051) Ryvu Therapeutics S.A. RVU305 206 R10107WO Step 1: Step 1 was performed according to General Procedure 09, using 2-iodo-4-(trifluorome- thyl)aniline (1.01 g, 3.52 mmol, 1.0 eq.) and nictotinoyl chloride hydrochloride (1.15 g, 6.46 mmol, 1.84 eq.) in pyridine (8.5 mL). After aqueous work up, the crude material was tritu- rated with iPrOH. The precipitate was filtered off and dried under vacuum to yield N-[2- iodo-4-(trifluoromethyl)phenyl]pyridine-3-carboxamide (Int. M-050, 1.24 g, 3.16 mmol, 85%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.48 (s, 1H), 9.20 (dd, J = 2.3, 0.9 Hz, 1H), 8.83 (dd, J = 4.8, 1.7 Hz, 1H), 8.36 (dt, J = 8.0, 1.9 Hz, 1H), 8.29 (d, J = 1.7 Hz, 1H), 7.87 (dd, J = 8.4, 2.1 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.64 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H). _m/z (ESI): 393.0 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 20, using N-[2-iodo-4-(trifluorome- thyl)phenyl]pyridine-3-carboxamide (Int. M-050, 0.85 g, 2.06 mmol, 1.0 eq.), CuI (0.039 g, 0.21 mmol, 0.1 eq.), sodium methanesulfinate (0.253 g, 2.48 mmol, 1.2 eq.) and sodium L- Pro-ONa (0.057 g, 0.42 mmol, 0.2 eq.) in anhydrous DMSO (20.0 mL). The crude material was purified by trituration with iPrOH, filtration and drying in vacuo to yield N-[2-me- thanesulfonyl-4-(trifluoromethyl)phenyl]pyridine-3-carboxami de (Int. M-051, 0.695 g, 2.019 mmol, 98%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.77 (s, 1H), 9.21 – 9.08 (m, 1H), 8.92 – 8.80 (m, 1H), 8.59 (d, J = 8.6 Hz, 1H), 8.30 (dt, J = 8.1, 1.9 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.23 (dd, J = 8.7, 2.3 Hz, 1H), 7.68 (dd, J = 8.0, 4.7 Hz, 1H), 3.51 (s, 3H). m/z (ESI): 345.5 [M+H] ⁺ . N-[2-methanesulfonyl-5-(trifluoromethyl)pyridin-3-yl]pyridin e-3-carboxamide (Int. M-053) Step 1: Step 1 was performed according to General Procedure 09, using 2-chloro-5-(trifluorome- thyl)pyridin-3-amine (0.372 g, 1.90 mmol, 1.0 eq.), nicotinoyl chloride hydrochloride (0.51 g, 2.86 mmol, 1.5 eq.) and DMAP (0.023 g, 0.19 mmol, 0.1 eq.) in anhydrous pyridine (4.6 mL). The crude material was purified by FCC (0 to 66% EtOAc gradient in hexane) to yield N-[2- chloro-5-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxamid e (Int. M-052, 0.47 g, 1.56 mmol, 82%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 9.16 (dd, J = 2.3, 0.9 Hz, 1H), 8.83 (dd, J = 4.8, 1.7 Hz, 1H), 8.81 – 8.79 (m, 1H), 8.60 (m, 1H), Ryvu Therapeutics S.A. RVU305 207 R10107WO 8.34 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 7.63 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H). m/z (ESI): 301.9 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 20, using N-[2-chloro-5-(trifluorome- thyl)pyridin-3-yl]pyridine-3-carboxamide (Int. M-052, 0.408 g, 1.35 mmol, 1.0 eq.), CuI (0.026 g, 0.14 mmol, 0.1 eq.), sodium methanesulfinate (0.165 g, 1.62 mmol, 1.2 eq.) and L- Pro-ONa (0.038 g, 0.28 mmol, 0.2 eq.) in anhydrous DMSO (12 mL). The crude material was purified by FCC (0 to 66% EtOAc gradient in hexane) and trituration with MeOH to yield N- [2-methanesulfonyl-5-(trifluoromethyl)pyridin-3-yl]pyridine- 3-carboxamide (Int. M-053, 0.179 g, 0.52 mmol, 38%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.95 (s, 1H), 9.18 – 9.15 (m, 1H), 9.13 (dd, J = 2.4, 0.9 Hz, 1H), 9.06 – 9.02 (m, 1H), 8.86 (dd, J = 4.8, 1.6 Hz, 1H), 8.30 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 7.68 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 3.51 (s, 3H). m/z (ESI): 346.4 [M+H] ⁺ . N-(3-methanesulfonylpyridin-4-yl)pyridine-3-carboxamide (Int. M-055) Step 1: Step 1 was performed according to General Procedure 09, using 3-iodopyridin-4-amine (0.3 g, 1.36 mmol, 1.0 eq.), nicotinoyl chloride hydrochloride (0.364 g, 2.04 mmol, 1.5 eq.) and DMAP (0.017 g, 0.14 mmol, 0.10 eq.) in pyridine (3.3 mL). The crude material was purified by trituration, successively with iPrOH and with hexane to yield N-(3-iodopyridin-4-yl)pyri- dine-3-carboxamide (Int. M-054, 0.187 g, 0.57 mmol, 40%, white solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 9.17 (dd, J = 2.4, 0.9 Hz, 1H), 8.97 (d, J = 0.5 Hz, 1H), 8.83 (dd, J = 4.8, 1.7 Hz, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.34 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 7.72 (dd, J = 5.2, 0.6 Hz, 1H), 7.63 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H). m/z (ESI): 326.0 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 20, using N-(3-iodopyridin-4-yl)pyri- dine-3-carboxamide (Int. M-054, 0.3 g, 0.91 mmol, 1.0 eq.), CuI (0.018 g, 0.09 mmol, 0.10 eq.), sodium methanesulfinate (0.112 g, 1.10 mmol, 1.2 eq.) and L-Pro-ONa (0.025 g, 0.182 mmol, 0.2 eq.) in anhydrous DMSO (9.0 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-(3-methanesulfonylpyridin-4-yl)pyridine-3-car- boxamide (Int. M-055, 0.213 g, 0.768 mmol, 82%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.78 (s, 1H), 9.09 (dd, J = 2.4, 0.9 Hz, 1H), 9.01 (s, 1H), 8.86 (dd, J = 4.8, 1.7 Hz, 1H), 8.84 (d, J = 5.9 Hz, 1H), 8.53 (d, J = 5.8 Hz, 1H), 8.27 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.68 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 3.54 (s, 3H). m/z (ESI): 278.5 [M+H] ⁺ . N-(5-fluoro-2-methanesulfonylpyridin-3-yl)acetamide (Int. M-057) Ryvu Therapeutics S.A. RVU305 208 R10107WO Step 1: Step 1 was performed according to General Procedure 08, using 3-amino-2-bromo-5-fluoro- pyridine (0.59 g, 3.09 mmol, 1 eq.) in acetic anhydride (7.0 mL). The crude material was pu- rified by FCC (0 to 25% EtOAc gradient in hexane) to yield N-(2-bromo-5-fluoropyridin-3- yl)acetamide (Int. M-056, 0.7 g, 3.0 mmol, 92%, white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 8.30 (dd, J = 2.9, 0.6 Hz, 1H), 8.14 (dd, J = 10.1, 2.9 Hz, 1H), 2.17 (s, 3H). m/z (ESI): 234.8 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 20, using N-(2-bromo-5-fluoro- pyridin-3-yl)acetamide (Int. M-056, 1.0 g, 4.29 mmol, 1.0 eq.), CuI (0.070 g, , 0.37 mmol, 0.09 eq.), sodium methanesulfinate (0.490 g, 4.80 mmol, 1.12 eq.) and L-Pro-ONa (0.011 g, 0.82 mmol, 0.9 eq.) in MeCN (80.0 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-(5-fluoro-2-methanesulfonylpyridin-3-yl)acetamide (Int. M-057, ^{0.720 g, 2.57 mmol, 60%, off-white solid, UPLC purity: 83%). 1H NMR (400 MHz, DMSO-d6)} _{δ 9.98 (s, 1H), 8.59 (dd, J = 11.1, 2.6 Hz, 1H), 8.55 (dd, J = 2.5, 0.6 Hz, 1H), 3.40 (s, 3H),} 2.18 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -117.68 (d, J = 11.0 Hz). m/z (ESI): 232.9 [M+H] ⁺ . N-(4-ethyl-2-methanesulfonylphenyl)acetamide (Int. M-059) Step 1: Step 1 was performed according to General Procedure 08, using 2-bromo-4-ethylaniline (0.3 g, 1.499 mmol, 1.0 eq.) in acetic anhydride (20.0 mL). The crude material was purified by FCC (0 to 20% EtOAc gradient in hexane) to yield N-(2-bromo-4-ethylphenyl)acetamide (Int. M-058, 0.201 g, 0.83 mmol, 54%, pink solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.42 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.21 (dd, J = 8.2, 2.0 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 2.07 (s, 3H), 1.18 (t, J = 7.6 Hz, 3H). m/z (ESI): 243.2 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 20, using N-(2-bromo-4- ethylphenyl)acetamide (Int. M-058, 0.199 g, 0.8 mmol, 1.0 eq.), CuI (0.060 g, 0.32 mmol, 0.4 eq.), sodium methanesulfinate (0.2 g, 1.92 mmol, 2.4 eq.) and L-Pro-ONa (0.044 g, 0.04 Ryvu Therapeutics S.A. RVU305 209 R10107WO mmol, 0.4 eq.) in anhydrous DMSO (6.0 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(4-ethyl-2-methanesulfonylphenyl)acetamide (Int. M-059, 0.155 g, 0.64 mmol, 72%, white solid, UPLC purity: 89%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.51 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 8.3, 2.2 Hz, 1H), 3.25 (s, 3H), 2.70 (q, J = 7.6 Hz, 2H), 2.12 (s, 3H), 1.22 (t, J = 7.6 Hz, 3H). m/z (ESI): 240.1 [M-H]-. N-(4-methyl-1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl) acetamide (Int. M-061) Step 1: NBS (0.226 g, 1.27 mmol, 1.1 eq.) was added to a solution of N-(1,1-dioxo-2,3-dihydro-1λ⁶- benzothiophen-7-yl)acetamide (Int. M-007, 0.26 g, 1.15 mmol, 1.0 eq.) in glacial acetic acid (5.0 mL) and the reaction was stirred at 65 °C overnight. After coming back to RT, the RM was evaporated under reduced pressure and the residue was purified by FCC (0 to 40% EtOAc gradient in hexane) to yield N-(4-bromo-1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen- 7-yl)acetamide (Int. M-060, 0.296 g, 0.973 mmol, 84%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.35 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 3.59 (t, J = 6.9 Hz, 2H), 3.35 (t, J = 6.8 Hz, 2H), 2.26 (s, 3H). m/z (ESI): 304.9 [M+H] ⁺ . Step 2: A Biotage ^TM microwave vial was charged with N-(4-bromo-1,1-dioxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)acetamide (Int. M-060, 0.241 g, 0.79 mmol, 1.0 eq.), Pd(dppf)Cl ₂ .DCM (0.065 g, 0.079 mmol, 0.1 eq.) and anhydrous dioxane (10.0 mL). The RM was sparged with argon for 5 min., dimethylzinc (2 M solution in toluene, 1.98 mL, 3.96 mmol, 5.0 eq.) was added slowly under Ar and the vial was sealed. The resulting RM was stirred at 80 °C over- night in a DrySyn ^® . After coming back to RT, the RM was cooled to 0 °C and the excess di- methylzinc was quenched by careful addition of MeOH. The resulting mixture was then ad- sorbed on silica by evaporation and the crude material was purified by FCC (0 to 40% EtOAc gradient in hexane) to yield N-(4-methyl-1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl) ac- etamide (Int. M-061, 0.153 g, 0.64 mmol, 80%, beige solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 3.61 (t, J = 6.9 Hz, 2H), 3.23 (t, J = 6.9 Hz, 2H), 2.28 (s, 3H), 2.08 (s, 3H). _m/z (ESI): 262.0 [M+Na] ⁺ . N-(4-fluoro-1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl) acetamide (Int. M-063) Ryvu Therapeutics S.A. RVU305 210 R10107WO Step 1: A Biotage ^TM microwave vial was charged with hexabutylditin (0.086 g, 0.15 mmol, 1.5 eq.), Pd(dppf)Cl ₂ (0.007 g, 0.01 mmol, 0.1 eq.), N-(4-bromo-1,1-dioxo-2,3-dihydro-1λ⁶-benzothi- ophen-7-yl)acetamide (Int. M-060, 0.03 g, 0.10 mmol, 1.0 eq.) and anhydrous dioxane (1.0 mL). The RM was sparged with nitrogen for 5 min. and the vial was sealed. The reaction was stirred at 100 °C for 3 h in a DrySyn ^® and the volatiles were evaporated in vacuo. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-[1,1-di- oxo-4-(tributylstannyl)-2,3-dihydro-1λ⁶-benzothiophen-7-y l]acetamide (Int. M-062, 0.02 g, 0.04 mmol, 39%, white solid, UPLC purity: 71%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 3.59 (t, J = 6.9 Hz, 2H), 3.39 (t, J = 6.9 Hz, 2H), 2.27 (s, 3H), 1.72 – 1.62 (m, 6H), 1.44 – 1.25 (m, 12H), 0.95 (t, J = 7.3 Hz, 9H). m/z (ESI): 515.5 [M+H] ⁺ . Step 2: AgOTf (0.04 g, 0.16 mmol, 4.04 eq.) and SelectFluor ^TM (0.017 g, 0.05 mmol, 1.25 eq.) were added to a solution of N-[1,1-dioxo-4-(tributylstannyl)-2,3-dihydro-1λ⁶-benzothi ophen-7- yl]acetamide (Int. M-062, 0.02 g, 0.04 mmol, 1.0 eq.) in anhydrous acetone (1.3 mL) and the mixture was stirred for 20 min. at RT under nitrogen. The RM was then partitioned between water and DCM, and the aqueous phase was extracted with DCM (2x). The combined or- ganic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(4-fluoro-1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl) acetamide (Int. M-063, 0.003 g, 0.012 mmol, 24%, white solid, UPLC purity: 78%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.38 (dd, J = 9.0, 4.0 Hz, 1H), 8.09 (s, 1H), 7.27 (t, J = 8.6 Hz, 1H), 3.58 (t, J = 6.8 Hz, 2H), 3.40 (t, J = 6.9 Hz, 2H), 2.26 (s, 3H). 19F NMR (376 MHz, Chloroform-d) δ -123.96 (dd, J = 8.3, 4.0 Hz). m/z (ESI): 266.0 [M+Na] ⁺ . Step 1: Ryvu Therapeutics S.A. RVU305 211 R10107WO 3-Nitrobenzene-1,2-diamine (1.5 g, 9.79 mmol, 1.0 eq.) was dissolved in formic acid (20.0 mL) and the RM was refluxed under argon for 7 h. After coming back to RT, the RM was neutralized with sat. aq. NaHCO ₃ . The resulting yellow precipitate was filtered off and re- crystallized from DCM/hexane to yield 4-nitro-1H-1,3-benzodiazole as its formate salt (Int. M-064, 1.5 g, 7.17 mmol, 73%, yellow solid, NMR purity: 100%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.34 (s, 1H), 12.77 (s, 1H), 8.48 (s, 1H), 8.20 (m, 2H), 8.15 (s, 1H), 7.45 (t, J = 8.1 Hz, 1H). Step 2: A mixture of 4-nitro-1H-1,3-benzodiazole formate salt (Int. M-064, 1.4 g, 6.69 mmol, 1.0 eq.), K ₂ CO ₃ (2.348 g, 16.99 mmol, 2.54 eq.) and iodomethane (0.721 mL, 11.58 mmol, 1.73 eq.) in anhydrous MeCN (25.0 mL) was stirred at 80 °C for 18 h in a sealed tube. Upon re- action completion, solids were filtered off, washed with hot MeCN, and the filtrate was evaporated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield 1-methyl-4-nitro-1H-1,3-benzodiazole (Int. M-065, 0.42 g, 2.37 mmol, 35%, beige solid, NMR purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 8.12 – 8.05 (m, 2H), 7.50 (t, J = 8.0 Hz, 1H), 3.96 (s, 3H). Step 3: A mixture of 1-methyl-4-nitro-1H-1,3-benzodiazole (Int. M-065, 0.42 g, 2.28 mmol, 1.0 eq.), iron powder (0.381 g, 6.83 mmol, 3.0 eq.) and ammonium chloride (0.365 g, 6.83 mmol, 3.0 eq.) in a mixture of EtOH (3.0 mL) and water (2.0 mL) was stirred at 85 °C for 1 h. After coming back to RT, the RM was filtered through a pad of Celite ^® and the filtrate was evapo- rated under reduced pressure. The residue was dissolved in DCM and the solution was washed with brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and evapo- rated under reduced pressure to yield crude 1-methyl-1H-1,3-benzodiazol-4-amine (Int. M- 066, 0.3 g, 2.04 mmol, 85%, beige solid, NMR purity: 100%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.95 (s, 1H), 6.96 (t, J = 7.8 Hz, 1H), 6.70 (dd, J = 8.0, 1.0 Hz, 1H), 6.39 (dd, J = 7.6, 1.0 Hz, 1H), 5.26 (s, 2H), 3.75 (s, 3H). NOESY confirms the regioselectivity of the previous step’s methylation. Step 4: Nicotinic acid (0.167 g, 1.36 mmol, 1.5 eq.) was refluxed in thionyl chloride (2.56 mL, 35.34 mmol, 39.0 eq.) for 4 h under nitrogen. The solution was evaporated and the residue was co-evaporated with anhydrous toluene (3x) under reduced pressure. To the residue was added a solution of 1-methyl-1H-1,3-benzodiazol-4-amine (Int. M-066, (0.15 g, 0.97 mmol, 1.0 eq.) in anhydrous pyridine (5.0 mL) and the RM was stirred overnight at RT under nitro- gen. It was then concentrated under reduced pressure and the residue was partitioned be- tween aq. 1 M NaOH and DCM. The aqueous phase was extracted with DCM (2x) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-(1-methyl-1H-1,3-benzodiazol-4-yl)pyridine-3-carboxamide (Int. M-067, 0.2 g, 0.77 mmol, 80%, white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 9.18 (dd, J = 2.4, 0.9 Hz, 1H), 8.79 (dd, J = 4.8, 1.6 Hz, 1H), 8.38 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 8.24 (s, 1H), 7.82 (dd, J = 7.7, 1.0 Hz, 1H), 7.60 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 7.43 (dd, J = 8.1, 1.0 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 3.89 (s, 3H). m/z (ESI): 253.5 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 212 R10107WO Step 1: A solution of CuCl (0.006 g, 0.06 mmol, 0.11 eq.), sodium methanesulfinate (0.113 g, 1.11 mmol, 2.01 eq.), quinoline (0.007 g, 0.05 mmol, 0.1 eq.) and 2-chloro-3-nitroquinoline (0.115 g, 0.551 mmol, 1.0 eq.) in anhydrous NMP (4.0 mL) was stirred at 100 °C for 10 min under microwave irradiation. After coming back to RT, the mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 2-methanesulfonyl-3-nitroquinoline (Int. M-068, 0.054 g, 0.21 mmol, 36%, yellow solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 8.38 (dd, J = 8.3, 1.4 Hz, 1H), 8.33 (dd, J = 8.6, 0.9 Hz, 1H), 8.19 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 8.02 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 3.61 (s, 3H). m/z (ESI): 253.0 [M+H] ⁺ . Step 2: 10% Pd/C (0.026 g) was added to a solution of 2-methanesulfonyl-3-nitroquinoline (Int. M- 068, 0.114 g, 0.41 mmol, 1.0 eq.) in ethanol (20.0 mL) and the atmosphere was first replaced by argon, with two cycles of vacuum/argon, then by hydrogen with two cycles of vac- uum/hydrogen. The RM was stirred under hydrogen (1 atm) for 2 h and an additional por- tion of 10% Pd/C (0.051 g) was added. Stirring under hydrogen (1 atm) was pursued over- night at RT. Another portion of 10% Pd/C (0.061 g) was added and the RM was stirred un- ^{der hydrogen (1 atm) for 60 h. It was then filtered through a pad of Celite® and the filtrate} was evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 2-methanesulfonylquinolin-3-amine (Int. M-069, 0.063 g, 0.283 mmol, 65%, yellow oil, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.90 – 7.85 (m, 1H), 7.77 (dd, J = 8.2, 1.5 Hz, 1H), 7.65 (d, J = 0.9 Hz, 1H), 7.56 (ddd, J = 8.2, 6.7, 1.4 Hz, 1H), 7.51 (ddd, J = 8.3, 6.8, 1.6 Hz, 1H), 6.15 (s, 2H), 3.47 (s, 3H). m/z (ESI): 223.1 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 08, using 2-methanesulfonylquinolin- 3-amine (Int. M-069, 0.061 g, 0.26 mmol, 1.0 eq.) in acetic anhydride (2 mL). The crude N- (2-methanesulfonylquinolin-3-yl)acetamide (Int. M-070, 0.06 g, 0.23 mmol, 84%, yellow solid, UPLC purity: 96%) was used in the next step without further purification. m/z (ESI): 265.4 [M+H] ⁺ . N-{1,1-dioxo-2H,3H-1λ⁶-thieno[3,2-b]pyridin-7-yl}acetamid e (Int. M-072) Ryvu Therapeutics S.A. RVU305 213 R10107WO Step 1: A pressure vessel was charged with 7-chlorothieno[3,2-b]pyridine (3.5 g, 20.63 mmol, 1.0 eq.), acetamide (1.47 g, 24.89 mmol, 1.2 eq.), Cs ₂ CO ₃ (16.81 g, 51.58 mmol, 2.5 eq.) and an- hydrous dioxane (65.0 mL). The RM was sparged with nitrogen for 10 min. Pd ₂ dba ₃ (0.568 g, 0.62 mmol, 0.03 eq.) was added followed by BINAP (0.771 g, 1.24 mmol, 0.06 eq.) and the vessel was closed. The resulting RM was stirred overnight at 110 °C in an oil bath. After coming back to RT, the RM was diluted with EtOAc/MeOH 1/1 and filtered through a pad of Celite ^® . The filtrate was evaporated under reduced pressure and the crude material was pu- rified by two consecutive FCCs (first: 0 to 10% MeOH gradient in DCM; second: 0 to 10% MeOH gradient in EtOAc) to yield N-{thieno[3,2-b]pyridin-7-yl}acetamide (Int. M-071, 2.26 g, 11.76 mmol, 57%, yellow solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.09 (dd, J = 5.5, 0.4 Hz, 1H), 7.81 (d, J = 5.3 Hz, 1H), 7.52 (d, J = 5.5 Hz, 1H), 2.21 (s, 3H). m/z (ESI): 192.9 [M+H] ⁺ . Step 2: A pressure vessel was charged with N-{thieno[3,2-b]pyridin-7-yl}acetamide (Int. M-071, 2.257 g, 11.74 mmol, 1.0 eq.), mCPBA (20.27 g, 117.40 mmol, 10.0 eq.) and anhydrous DCM (65.0 mL). The vessel was closed and the RM was stirred overnight at 50 °C in an oil bath. An additional portion of mCPBA (2.03 g, 11.74 mmol, 1.0 eq.) was added and the RM was stirred for an additional 3 h at 50 °C. After coming back to RT, the RM was partitioned be- tween sat. aq. NH ₄ Cl and DCM. The aqueous phase was extracted with DCM (4x) and the combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was stirred in water for 10 min. and the resulting solid was filtered off and discarded. The filtrate was evaporated under reduced pressure and the resi- due was dissolved in MeOH (40.0 mL). The solution was sparged with argon for 10 min. and Pd/C (0.75 g, 3.52 mmol, 0.3 eq.) was added. The RM was hydrogenated for 60 h in a Paar apparatus under 3 bar of hydrogen pressure. The RM was filtered through a pad of Celite ^® and the filtrate was evaporated under reduced pressure. The crude material was purified by FCC (0 to 7% MeOH gradient in EtOAC) to give N-{1,1-dioxo-2H,3H-1λ⁶-thieno[3,2-b]pyri- din-7-yl}acetamide (Int. M-072, 0.234 g, 1.03 mmol, 8%, orange solid, UPLC purity: 91%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.63 (s, 1H), 8.65 (d, J = 5.7 Hz, 1H), 8.00 (d, J = 5.7 Hz, 1H), 3.74 (dd, J = 7.5, 6.4 Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H), 2.22 (s, 3H). m/z (ESI): 227.0 [M+H] ⁺ . N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-7-yl)pyri dine-3-carboxamide (Int. M- 075) Ryvu Therapeutics S.A. RVU305 214 R10107WO Step 1: NaH (60% in mineral oil, 0.188 g, 4.9 mmol, 1.6 eq.) was added to a solution of 7-nitro-1H- indazole (0.5 g, 3.07 mmol, 1.0 eq.) in anhydrous DMF (7.0 mL) at RT under nitrogen. The RM was stirred at RT for 45 min., cooled to 0 °C and SEM-Cl (0.766 g, 4.59 mmol, 1.5 eq.) was added. After stirring for 3 h at RT, the reaction was quenched with water and the mix- ture was extracted with EtOAc. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 20% EtOAc gradient in hexane) to yield 7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Int. M-073, 0.552 g, 1.88 mmol, 60%, beige solid, UPLC purity: 82%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (s, 1H), 8.32 (dd, J = 8.0, 1.0 Hz, 1H), 8.22 (dd, J = 7.7, 1.0 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 5.87 (s, 2H), 3.16 (t, J = 7.9 Hz, 2H), 0.62 (t, J = 7.9 Hz, 2H), -0.20 (s, 9H). m/z (ESI): 293.2 [M+H] ⁺ . Step 2: Zinc dust (1.2 g, 18.43 mmol, 10.0 eq.) and aq. sat. NH ₄ Cl (5.0 mL) were successively added to a solution of 7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Int. M-073, 0.552 g, 1.84 mmol, 1.0 eq.) in acetone (2.0 mL). The RM was stirred at RT for 5 h and was filtered through a pad of Celite ^® . The filtrate was partitioned between water and EtOAc and the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 20% EtOAc gradient in hexane) to yield 1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-indazol-7-amine (Int. M-074, 0.48 g, 1.82 mmol, 88%, off- white solid, UPLC purity: 89%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.94 (s, 1H), 7.01 (dd, J = 8.0, 0.9 Hz, 1H), 6.90 (dd, J = 8.0, 7.3 Hz, 1H), 6.63 (dd, J = 7.3, 1.0 Hz, 1H), 5.81 (s, 2H), 5.22 (s, 2H), 3.51 (t, J = 8.2 Hz, 2H), 0.84 (t, J = 8.1 Hz, 2H), -0.08 (s, 9H). m/z (ESI): 263.9 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 09, using 1-{[2-(trimethylsilyl)eth- oxy]methyl}-1H-indazol-7-amine (Int. M-074, 0.2 g, 0.68 mmol, 1.0 eq.), nicotinoyl chloride hydrochloride (0.144 g, 0.81 mmol, 1.2 eq.) in pyridine (5.0 mL). The crude material was pu- rified by FCC (0 to 33% EtOAc in hexane) to yield N-(1-{[2-(trimethylsilyl)ethoxy]methyl}- 1H-indazol-7-yl)pyridine-3-carboxamide (Int. M-075, 0.218 g, 0.59 mmol, 86%, white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 9.21 (d, J = 2.2 Hz, 1H), 8.81 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.22 (s, 1H), 7.76 (dd, J = 8.0, 1.0 Hz, 1H), 7.62 (dd, J = 7.9, 4.8 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 5.78 (s, 2H), 3.39 – 3.34 (m, 2H), 0.72 (t, J = 8.1 Hz, 2H), -0.16 (s, 9H). m/z (ESI): 369.3 [M+H] ⁺ . 2‐Cyclopropoxy‐N‐(2‐methanesulfonylpyridin‐3‐yl) acetamide (Int. M-077) Ryvu Therapeutics S.A. RVU305 215 R10107WO Step 1: NaH (60% in mineral oil, 0.736 g, 19.20 mmol, 2.65 eq.) was added to a solution of cyclopro- panol (0.517 g, 8.91 mmol, 1.23 eq.) in anhydrous THF (4.8 mL) at 0 °C under argon. The reaction was stirred for 2 h at RT, after which 2-bromoacetic acid (1.01 g, 7.24 mmol, 1.0 eq.) was added. The RM was stirred at RT overnight, after which a white solid was formed. The reaction was carefully quenched with water and the mixture was stirred until a clear solution was obtained. The solution was washed with Et ₂ O (2x) and the combined organic layers were discarded. The aqueous layer was acidified with aq. 2 M HCl to pH ≈ 1 and ex- tracted with Et ₂ O (3x). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to yield crude 2-cyclopropoxyacetic acid (Int. M-076, 0.762 g, 5.58 mmol, 77%, brown oil, NMR purity: 85%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.58 (s, 1H), 4.00 (s, 2H), 3.48 (tt, J = 6.0, 3.0 Hz, 1H), 0.54 – 0.51 (m, 2H), 0.44 – 0.41 (m, 2H). Step 2: Step 2 was performed according to General Procedure 14, using 2-cyclopropoxyacetic acid (Int. M-076, 0.104 g, 0.85 mmol, 1 eq.), BTFFH (0.311 g, 0.98 mmol, 1.16 eq.), 2-methanesul- fonylaniline (0.146 g, 0.85 mmol, 1.0 eq.), DIPEA (0.360 mL, 2.07 mmol, 2.44 eq.) in anhy- drous DCM (2.4 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 2‐cyclopropoxy‐N‐(2‐methanesulfonylpyridin‐3‐yl) acetamide (Int. M-077, 0.055 g, 0.20 mmol, 23%, beige semi-solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 8.96 (dd, J = 8.6, 1.4 Hz, 1H), 8.47 (dd, J = 4.4, 1.4 Hz, 1H), 7.76 (ddd, J = 8.6, 4.4, 0.5 Hz, 1H), 4.17 (s, 2H), 3.56 (tt, J = 5.9, 2.9 Hz, 1H), 3.44 (s, 3H), 0.70 – 0.63 (m, 2H), 0.56 – 0.47 (m, 2H). m/z (ESI): 271.2 [M+H] ⁺ . 3,3-Difluoro-N-(2-methanesulfonylpyridin-3-yl)butanamide (Int. M-079) Step 1: A mixture of ethyl 3,3-difluorobutanoate (1.5 g, 9.86 mmol, 1.0 eq.), formic acid (1.66 mL, 39.43 mmol, 4.0 eq.) and aq. 20% HCl (20.0 mL) was stirred at reflux for 2 days. After com- Ryvu Therapeutics S.A. RVU305 216 R10107WO ing back to RT, the RM was saturated with NaCl and extracted with DCM (3x). The com- bined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to yield 3,3-difluorobutanoic acid (Int. M-078, 1.24 g, 9.99 mmol, 99%, NMR purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.72 (s, 1H), 3.00 (t, J = 15.1 Hz, 2H), 1.75 (t, J = 19.2 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -85.01 (qt, J = 19.2, 15.0 Hz). Step 2: Step 2 was performed according to General Procedure 17, using 2-methanesulfonylpyridin- 3-amine (1.0 g, 5.81 mmol, 1.0 eq.), 3,3-difluorobutanoic acid (Int. M-078, 1.103 g, 8.71 mmol, 1.5 eq.), DMAP (0.213 g, 1.74 mmol, 0.3 eq.) and POCl ₃ (2.671 g, 17.42 mmol, 3.0 eq.) in anhydrous pyridine (6.0 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 3,3-difluoro-N-(2-methanesulfonylpyridin-3-yl)butanamide (Int. M-079, 0.242 g, 0.87 mmol, 14%, yellow oil, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.05 (s, 1H), 8.54 (dd, J = 4.5, 1.5 Hz, 1H), 8.52 (dd, J = 8.4, 1.4 Hz, 1H), 7.77 (dd, J = 8.4, 4.5 Hz, 1H), 3.41 (s, 3H), 3.22 (t, J = 15.5 Hz, 2H), 1.79 (t, J = 19.3 Hz, 3H).19F NMR (376 MHz, DMSO-d ₆ ) δ -84.33 (qt, J = 19.3, 15.5 Hz). m/z (ESI): 279.1 [M+H] ⁺ . Ethyl 1-(difluoromethyl)-4-(pyridine-3-amido)-1H-pyrazole-5-carbox ylate (Int. M-082) Step 1: A solution of ethyl 4-nitro-1H-pyrazole-5-carboxylate (1.0 g, 5.40 mmol, 1.0 eq.), diethyl (bromodifluoromethyl)phosphonate (1.44 g, 5.40 mmol, 1.0 eq.) and KF (0.63 g, 10.8 mmol, 2.0 eq.) in anhydrous MeCN (14.0 mL) was stirred overnight at RT under argon. The RM was then partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 20% EtOAc gra- dient in hexane) to yield ethyl 1-(difluoromethyl)-4-nitro-1H-pyrazole-5-carboxylate (Int. M- 080, 0.786 g, 3.34 mmol, 60%, colorless oil, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.56 (t, J = 0.8 Hz, 1H), 7.96 (t, J = 57.9 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, DMSO-d ₆ ) δ -97.21 (d, J = 58.1 Hz). Step 2: 10% Pd/C (0.071 g) was added to a solution of ethyl 1-(difluoromethyl)-4-nitro-1H-pyra- zole-5-carboxylate (Int. M-080, 0.288 g, 1.11 mmol, 1.0 eq.) in ethanol (15.0 mL) and the at- mosphere was first replaced by argon, with two cycles of vacuum/argon, then by hydrogen with two cycles of vacuum/hydrogen. The RM was stirred under hydrogen (1 atm) overnight at RT. It was then filtered through a pad of Celite ^® and the filtrate was evaporated under re- duced pressure to give crude ethyl 4-amino-1-(difluoromethyl)-1H-pyrazole-5-carboxylate (Int. M-081, 0.231 g, 1.13 mmol, 96%, orange oil, UPLC purity: 95%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.94 (t, J = 59.2 Hz, Ryvu Therapeutics S.A. RVU305 217 R10107WO 1H), 7.50 (s, 1H), 5.57 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).19F NMR (376 MHz, DMSO-d ₆ ) δ -95.11 (d, J = 59.4 Hz). Step 3: Step 3 was performed according to General Procedure 17, using ethyl 4-amino-1-(difluoro- methyl)-1H-pyrazole-5-carboxylate (Int. M-081, 0.229 g, 1.06 mmol, 1.0 eq.), DMAP (0.039 g, 0.32 mmol, 0.3 eq.), pyridine-3-carboxylic acid (0.131 g, 1.06 mmol, 1.0 eq.) and POCl ₃ (0.325 g, 2.12 mmol, 2.0 eq.). The crude material was purified by FCC (0 to 50% EtOAc in hexane) to yield ethyl 1-(difluoromethyl)-4-(pyridine-3-amido)-1H-pyrazole-5-carbox ylate (Int. M-082, 0.238 g, 0.77 mmol, 71%, white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 9.12 (dd, J = 2.4, 0.9 Hz, 1H), 8.83 (dd, J = 4.8, 1.7 Hz, 1H), 8.40 (s, 1H), 8.31 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 8.12 (t, J = 58.4 Hz, 1H), 7.64 (ddd, J = 8.0, 4.8, ^{0.9 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, DMSO-d6)} _{δ -96.09 (d, J = 58.3 Hz). m/z (ESI): 311.2 [M+H]+.} Ethyl N-(2-methanesulfonylpyridin-3-yl)carbamate (Int. M-083) Ethyl chloroformate (0.83 mL, 8.72 mmol, 5.0 eq.) was added to a solution of 2-methanesul- fonylpyridin-3-amine (0.3 g, 1.74 mmol, 1.0 eq.) and DIPEA (0.91 mL, 5.23 mmol, 3.0 eq.) in DCE (9.0 mL) at 0 °C. The RM was stirred at 70 °C overnight under nitrogen. After coming back to RT, it was washed with sat. aq. NH ₄ Cl and the aqueous layer was extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The obtained crude ethyl N-(2- methanesulfonylpyridin-3-yl)carbamate (Int. M-083, 0.36 g, 1.47 mmol, 84%, white solid, ^{UPLC purity: 99%) was used in the next step without further purification. 1H NMR (400 MHz,} DMSO-d ₆ ) δ 9.33 (s, 1H), 8.62 (dd, J = 8.6, 1.4 Hz, 1H), 8.44 (dd, J = 4.4, 1.4 Hz, 1H), 7.76 (dd, J = 8.6, 4.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.43 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). m/z (ESI): 245.6 [M+H] ⁺ . N-(2-ethoxy-4-fluorophenyl)pyridine-3-carboxamide (Int. M-086) Step 1: A mixture of 5-fluoro-2-nitrophenol (1.0 g, 6.36 mmol, 1.0 eq.), iodoethane (0.62 mL, 7.71 mmol, 1.2 eq.), K ₂ CO ₃ (1.76 g, 12.73 mmol, 2.0 eq.) and acetone (11.0 mL) was heated at re- Ryvu Therapeutics S.A. RVU305 218 R10107WO flux for 15 h, and then concentrated under reduced pressure. Water was added to the resi- due and the resulting mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ S0 ₄ , and concentrated under reduced pressure to yield crude 2-ethoxy-4-fluoro-1-nitrobenzene (Int. M-084, 1.15 g, 6.21 mmol, 97%, orange oil, UPLC purity: 97%) which was used in the next step without further purifica- tion. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.01 (dd, J = 9.1, 6.1 Hz, 1H), 7.31 (dd, J = 11.1, 2.6 Hz, 1H), 6.97 (ddd, J = 9.0, 7.8, 2.6 Hz, 1H), 4.23 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). Step 2: 10% Pd/C (0.39 g) was added to a solution of 2-ethoxy-4-fluoro-1-nitrobenzene (Int. M-084, 1.15 g, 6.15 mmol, 1.0 eq.) in ethanol (30.0 mL) and the atmosphere was first replaced by argon, with two cycles of vacuum/argon, then by hydrogen by two cycles of vacuum/hydro- gen. The RM was stirred under hydrogen (1 atm) for 16 h at RT. It was then filtered through a pad of Celite ^® and the filtrate was evaporated under reduced pressure. The crude material was purified by FCC (0 to 40% EtOAc gradient in hexane) to yield 2-ethoxy-4-fluoroaniline (Int. M-085, 0.75 g, 4.833 mmol, 73%, orange oil, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.69 (dd, J = 10.8, 2.8 Hz, 1H), 6.58 (dd, J = 8.6, 6.1 Hz, 1H), 6.48 (td, J = 8.6, 2.8 Hz, 1H), 4.50 (s, 2H), 4.00 (q, J = 6.9 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -126.70 (ddd, J = 11.0, 8.7, 6.2 Hz). m/z (ESI): 156.3 [M+H] ⁺ . Step 3 Step 3 was performed according to General Procedure 09, using 2-ethoxy-4-fluoroaniline (Int. M-085, 0.75 g, 4.5 mmol, 1.0 eq.) and nicotinoyl chloride hydrochloride (0.96 g, 5.393 mmol, 1.2 eq.) in anhydrous pyridine (7.5 mL). The crude material was purified by FCC (0 to 80% EtOAc gradient in hexane) to yield N-(2-ethoxy-4-fluorophenyl)pyridine-3-carboxamide (Int. M-086, 1.13 g, 4.34 mmol, 93%, beige solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 9.10 (s, 1H), 8.76 (dd, J = 4.8, 1.7 Hz, 1H), 8.28 (dt, J = 8.1, 1.7 Hz, 1H), 7.63 (dd, J = 8.8, 6.5 Hz, 1H), 7.57 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.03 (dd, J = 11.0, 2.8 Hz, 1H), 6.80 (td, J = 8.6, 2.8 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -112.58 – -115.09 (m). m/z (ESI): 261.6 [M+H] ⁺ . N-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazin-3-yl}pyridine-3-carbo xamide (Int. M-090) Step 1: Ryvu Therapeutics S.A. RVU305 219 R10107WO K ₂ CO ₃ (1.8 g, 13.2 mmol, 1.5 eq.) and 3-bromo-propanol (880 ^L, 9.7 mmol, 1.1 eq.) were added to a stirred solution of 4-nitro-1H-pyrazole (1.0 g, 8.9 mmol, 1 eq.) in anhydrous MeCN (15.0 mL), and the mixture was stirred at 75 °C for 6 h under nitrogen. The solvent was evaporated in vacuo and the residue was partitioned between water and EtOAc. The layers were separated and the aqueous phase extracted with EtOAc (2x). The combined or- ganic layers were dried over anhydrous MgSO ₄ , filtered and the solvent evaporated in vacuo to afford crude 3-(4-nitro-1H-pyrazol-1-yl)propan-1-ol (Int. M-087, 1.3 g, 7.59 mmol, 77%, yellow oil, NMR purity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J = 0.7 Hz, 1H), 8.28 (d, J = 0.8 Hz, 1H), 4.66 (t, J = 5.0 Hz, 1H), 4.26 (t, J = 7.0 Hz, 2H), 3.41 (td, J = 6.1, 5.0 Hz, 2H), 2.01 – 1.92 (m, 2H). Step 2: Lithium bis(trimethylsilyl) amide (1 M in THF, 8.2 mL, 8.20 mmol, 2.4 eq.) was added drop- wise to a stirred solution of 3-(4-nitro-1H-pyrazol-1-yl)propan-1-ol (Int. M-087, 0.65 g, 3.42 mmol, 1.0 eq.) in anhydrous THF (20.0 mL) at -78 °C under nitrogen. The RM was stirred at -78 °C for 2 h and hexachloroethane (0.971 g, 4.10 mmol, 1.2 eq.) was added dropwise as a solution in anhydrous THF (4.0 mL). The RM was allowed to stir at RT for 20 h, the re- action was quenched with sat. aq. NH ₄ Cl and the mixture was extracted with DCM. The or- ganic layer was dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pres- sure. The crude material was purified by FCC to give 3-nitro-5H,6H,7H-pyrazolo[3,2- b][1,3]oxazine (Int. M-088, 0.36 g, 2.13 mmol, 59%, off white solid, UPLC purity: 90%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (s, 1H), 4.56 (t, J = 5.3 Hz, 2H), 4.12 (t, J = 6.1 Hz, 2H), 2.27 (m, 2H). m/z (ESI): 169.9 [M+H] ⁺ . Step 3: 10% Pd/C (0.016 g) was added to a solution of 3-nitro-5H,6H,7H-pyrazolo[3,2-b][1,3]oxa- zine (Int. M-088, 0.16 g, 0.889 mmol, 1.0 eq.) in EtOH (10.0 mL) and the atmosphere was first replaced by argon, with two cycles of vacuum/argon, then by hydrogen with two cycles of vacuum/hydrogen. The RM was stirred under hydrogen (1 atm) at RT overnight. It was then filtered through a pad of Celite ^® and the filtrate was evaporated under reduced pres- sure to yield crude 5H,6H,7H-pyrazolo[3,2-b][1,3]oxazin-3-amine (Int. M-089, 0.11 g, 0.79 mmol, 84%, dark violet solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.86 (s, 1H), 4.23 – 4.17 (m, 2H), 3.97 (t, J = 6.1 Hz, 2H), 3.33 (s, 2H), 2.15 – 2.05 (m, 2H). m/z (ESI): 140.1 [M+H] ⁺ . Step 4: Nicotinic acid (0.214 g, 1.74 mmol, 1.5 eq.) was refluxed in thionyl chloride (3.28 mL, 45.26 mmol, 39.0 eq.) for 4 h under nitrogen. The solution was then evaporated and the residue was co-evaporated with anhydrous toluene (3x) under reduced pressure. 5H,6H,7H-pyra- zolo[3,2-b][1,3]oxazin-3-amine (Int. M-089, 0.17 g, 1.16 mmol, 1.0 eq.) was added to the residue as a solution in anhydrous pyridine (5.0 mL) and the RM was stirred at RT overnight under nitrogen. It was then evaporated under reduced pressure and the residue was parti- tioned between aq. 1 M NaOH and DCM. The aqueous layer was extracted with DCM (2x) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered and concen- Ryvu Therapeutics S.A. RVU305 220 R10107WO trated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gra- dient in DCM) to yield N-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazin-3-yl}pyridine-3-carbo xamide (Int. M-090, 0.24 g, 0.98 mmol, 83%, white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 9.07 (dd, J = 2.3, 0.9 Hz, 1H), 8.73 (dd, J = 4.8, 1.7 Hz, 1H), 8.26 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 7.53 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.43 (s, 1H), 4.36 – 4.28 (m, 2H), 4.10 (t, J = 6.2 Hz, 2H), 2.19 (m, 2H). m/z (ESI): 245.1 [M+H] ⁺ . N-[4-fluoro-2-(1H-pyrazol-1-yl)phenyl]pyridine-3-carboxamide (Int. M-093) Step 1: To a solution of 2,4‐difluoro‐1‐nitrobenzene (1.008 g, 6.34 mmol, 1.0 eq.) in anhydrous DMSO (25.0 mL) under argon atmosphere were slowly added NaOH (0.251 g, 6.28 mmol, 1.0eq.) and pyrazole (0.524 g, 7.70 mmol, 1.22 eq.) in sequence. The RM was stirred for 2.5 h at RT, water was added and the mixture was extracted with EtOAc (3x). The combined or- ganic layers were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to provide crude 1‐(5‐fluoro‐2‐nitrophenyl)‐1H‐ pyrazole (Int. M-091, 1.364 g, 4.94 mmol, 78%, yellow oil, UPLC purity: 75%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (dd, J = 2.6, 0.6 Hz, 1H), 8.11 (dd, J = 9.0, 5.4 Hz, 1H), 7.84 (dd, J = 9.4, 2.7 Hz, 1H), 7.78 (dd, J = 1.8, 0.6 Hz, 1H), 7.51 (ddd, J = 9.0, 7.8, 2.7 Hz, 1H), 6.60 (dd, J = 2.6, 1.8 Hz, 1H). m/z (ESI): 208.1 [M+H] ⁺ . Step 2: NH ₄ Cl (0.132 g, 2.47 mmol, 0.50 eq.) and iron powder (1.04 g, 18.62 mmol, 3.8 eq.) were added to a solution of 1-(5-fluoro-2-nitrophenyl)-1H-pyrazole (Int. M-091, 1.355 g, 4.91 mmol, 1.0 eq.) in a mixture of EtOH (25.0 mL) and water (8.0 mL), and the RM was refluxed for 1 h. After coming back to RT, it was filtered through a pad of Celite ^® and evaporated un- der reduced pressure. The residue was partitioned between water and EtOAc and the aque- ous layer was extracted with EtOAc. The combined organic layers were dried over anhy- drous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was pu- rified by FCC (0 to 50% EtOAc gradient in hexane) to yield 4-fluoro-2-(1H-pyrazol-1-yl)ani- line (Int. M-092, 0.8 g, 4.51 mmol, 89%, orange oil, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (dd, J = 2.5, 0.6 Hz, 1H), 7.77 (dd, J = 1.9, 0.6 Hz, 1H), 7.21 (dd, J = 9.7, 2.9 Hz, 1H), 6.99 (ddd, J = 9.0, 8.2, 2.9 Hz, 1H), 6.87 (dd, J = 8.9, 5.5 Hz, 1H), 6.53 (dd, J = 2.5, 1.9 Hz, 1H), 5.53 (s, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -128.31 – -128.43 (m). m/z (ESI): 178.1 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 09, using 4-fluoro-2-(1H-pyrazol-1- yl)aniline (Int. M-092, 0.8 g, 4.38 mmol, 1.0 eq.) and nicotinoyl chloride hydrochloride (0.94 Ryvu Therapeutics S.A. RVU305 221 R10107WO g, 5.28 mmol, 1.2 eq.) in anhydrous pyridine (7.0 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-[4-fluoro-2-(1H-pyrazol-1-yl)phe- nyl]pyridine-3-carboxamide (Int. M-093, 0.89 g, 3.15 mmol, 71%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 9.04 (dd, J = 2.4, 0.9 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.35 (dd, J = 2.5, 0.6 Hz, 1H), 8.22 (dt, J = 8.0, 2.0 Hz, 1H), 8.09 (dd, J = 9.0, 5.9 Hz, 1H), 7.89 (dd, J = 1.9, 0.6 Hz, 1H), 7.64 (dd, J = 9.7, 2.9 Hz, 1H), 7.59 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.34 (ddd, J = 9.0, 8.0, 2.9 Hz, 1H), 6.59 (dd, J = 2.6, 1.9 Hz, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -115.10 (td, J = 8.8, 5.8 Hz). m/z (ESI): 283.6 [M+H] ⁺ . Step 1: Step 1 was performed according to General Procedure 19, using 7-bromo-2,3-dihydro-1H- inden-1-one (1.97 g, 9.33 mmol, 1.0 eq.), niacinamide (1.17 g, 9.58 mmol, 1.03 eq.), Cs ₂ CO ₃ (4.322 g, 13.27 mmol, 1.42 eq.), XPhos (2.711 g, 5.69 mmol, 0.61 eq.) and Pd(OAc) ₂ (0.632 g, 2.81 mmol, 0.30 eq.) in anhydrous dioxane (31 mL). The crude material was purified by FCC (0 to 35% EtOAc gradient in hexane) to yield N-(3-oxo-2,3-dihydro-1H-inden-4-yl)pyridine- 3-carboxamide (Int. M-094, 0.847 g, 3.36 mmol, 36%, orange solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.35 (s, 1H), 9.15 (dd, J = 2.4, 1.0 Hz, 1H), 8.85 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 (dd, J = 8.0, 0.9 Hz, 1H), 8.32 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.68 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.33 (dd, J = 7.6, 0.9 Hz, 1H), 3.17 – 3.10 (m, 2H), 2.81 – 2.74 (m, 2H). m/z (ESI): 253.4 [M+H] ⁺ . Step 2: NaBH ₄ (0.056 g, 1.48 mmol, 1.63 eq.) was added to a solution of N-(3-oxo-2,3-dihydro-1H- inden-4-yl)pyridine-3-carboxamide (Int. M-094, 0.232 g, 0.911 mmol, 1.0 eq.) in anhydrous methanol (5 mL) at 0 °C and the RM was stirred at RT for 1 h. The reaction was quenched with sat. aq. NH ₄ Cl and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with sat. aq. NaHCO ₃ , dried over anhydrous MgSO ₄ , filtered and con- centrated under reduced pressure. The obtained crude N-(3-hydroxy-2,3-dihydro-1H-inden- 4-yl)pyridine-3-carboxamide (Int. M-095, 0.227 g, 0.893 mmol, 97%, yellow solid, UPLC pu- rity: 95%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.21 (s, 1H), 9.09 (dd, J = 2.4, 0.9 Hz, 1H), 8.80 (dd, J = 4.8, 1.6 Hz, 1H), 8.26 (ddd, J Ryvu Therapeutics S.A. RVU305 222 R10107WO = 8.0, 2.3, 1.7 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.61 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.05 (dd, J = 7.5, 1.0 Hz, 1H), 5.85 (d, J = 6.5 Hz, 1H), 5.40 (q, J = 6.8 Hz, 1H), 3.01 – 2.90 (m, 1H), 2.83 – 2.70 (m, 1H), 2.47 – 2.36 (m, 1H), 1.87 (m, 1H). m/z (ESI): 255.3 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 15, using N-(3-hydroxy-2,3-dihydro- 1H-inden-4-yl)pyridine-3-carboxamide (Int. M-095, 0.660 g, 2.47 mmol, 1.0 eq.), TEA (1.375 mL, 9.86 mmol, 4.0 eq.) and acetyl chloride (0.368 mL, 5.19 mmol, 2.1 eq.) in CHCl ₃ (10 mL). The crude material was purified by FCC (0 to 40% EtOAc gradient in hexane) to yield 7-(pyr- idine-3-amido)-2,3-dihydro-1H-inden-1-yl acetate (Int. M-096, 0.387 g, 1.31 mmol, 48%, yellow solid, UPLC purity: 85%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.23 (s, 1H), 9.09 (dd, J = 2.3, 0.9 Hz, 1H), 8.78 (dd, J = 4.8, 1.7 Hz, 1H), 8.27 (dt, J = 8.0, 1.8 Hz, 1H), 7.59 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 6.38 (dd, J = 6.8, 3.2 Hz, 1H), 3.15 – 3.00 (m, 1H), 2.97 – 2.85 (m, 1H), 2.48 – 2.41 (m, 1H), 2.04 – 1.95 (m, 1H), 1.85 (s, 3H). m/z (ESI): 297.1 [M+H] ⁺ . N-(5-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxamide (Int. M-098) Step 1: Step 1 was performed according to General Procedure 09, using DMAP (0.065 g, 0.53 mmol, 0.10 eq.), 2-bromo-5-fluoroaniline (1.0 g, 5.26 mmol, 1.0 eq.) and nicotinoyl chloride hydro- chloride (1.41 g, 7.92 mmol, 1.50 eq.) in anhydrous pyridine (13 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(2-bromo-5-fluoro- phenyl)pyridine-3-carboxamide (Int. M-097, 1.4 g, 4.74 mmol, 89%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.36 (s, 1H), 9.15 (dd, J = 2.3, 0.9 Hz, 1H), 8.80 (dd, J = 4.8, 1.7 Hz, 1H), 8.33 (ddd, J = 7.9, 2.3, 1.6 Hz, 1H), 7.79 (dd, J = 8.9, 5.9 Hz, 1H), 7.60 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.57 (dd, J = 9.9, 3.1 Hz, 1H), 7.18 (ddd, J = 8.9, 8.1, 3.1 Hz, 1H). m/z (ESI): 296.1 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 20, using N-(2-bromo-5-fluoro- phenyl)pyridine-3-carboxamide (Int. M-097, 1.0 g, 3.35 mmol, 1.0 eq.), CuI (0.064 g, 0.34 mmol, 0.1 eq.), sodium methanesulfinate (0.411 g, 4.03 mmol, 1.2 eq.) and L-Pro-ONa (0.092 g, 0.67 mmol, 0.2 eq.) in anhydrous DMSO (33 mL). The crude material was purified by FCC (0 to 66% EtOAc gradient in hexane) to yield N-(5-fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int. M-098, 0.324 g, 1.10 mmol, 30%, white solid, UPLC purity: 92%).1H NMR (400 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 9.10 (dd, J = 2.4, 0.9 Hz, 1H), 8.84 (dd, J = 4.8, 1.6 Hz, 1H), 8.27 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 8.22 (dd, J = 11.2, 2.6 Hz, Ryvu Therapeutics S.A. RVU305 223 R10107WO 1H), 8.06 (dd, J = 8.9, 6.2 Hz, 1H), 7.65 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.37 (ddd, J = 8.9, 7.9, 2.7 Hz, 1H), 3.38 (s, 3H). m/z (ESI): 295.5 [M+H] ⁺ . N-(2-tert-Butyl-1,1-dioxo-2,3-dihydro-1λ⁶,2-benzothiazol- 7-yl)pyridine-3-carboxamide (Int. Step 1: K ₂ CO ₃ (0.392 g, 2.84 mmol, 1.1 eq.) was added to a solution of 2-fluoro-1-methyl-3-nitro- benzene (0.4 g, 2.58 mmol, 1.0 eq.) in anhydrous DMF (12.5 mL). Benzyl mercaptan (0.320 g, 2.58 mmol, 1.0 eq.) was added dropwise and the RM was stirred at RT for 2 h under nitro- gen. The RM was diluted with water and extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield crude 2-(benzylsulfanyl)-1-methyl-3-nitrobenzene (Int. M-099, 0.733 g, 2.83 mmol, 100%, yellow oil, UPLC purity: 91%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.62 (dd, J = 7.8, 1.5 Hz, 1H), 7.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.27 – 7.20 (m, 3H), 7.09 (m, 2H), 4.00 (s, 2H), 2.36 (s, 3H). m/z (ESI): 260.0 [M+H] ⁺ . Step 2: NCS (1.030 g, 7.72 mmol, 3.0 eq.) was added portionwise to a solution of 2-(benzylsulfanyl)- 1-methyl-3-nitrobenzene (Int. M-099, 0.733 g, 2.57 mmol, 1.0 eq.) in a mixture of MeCN (20 mL), AcOH (0.33 mL) and water (0.65 mL) at 0 °C, and the RM was stirred for 1 h at RT. It was then evaporated under reduced pressure and the residue was taken up in DCM. The solution was neutralized with sat. aq. NaHCO ₃ at 0 °C and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to yield crude 2-methyl-6-nitroben- zene-1-sulfonyl chloride (Int. M-100, 1.30 g, 5.52 mmol, 94%, yellow oil) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47 – 7.30 (m, 2H), 7.29 – 7.22 (m, 1H), 2.58 (s, 3H). m/z (ESI): 258.0 [M+Na] ⁺ . Step 3: tert-Butyl amine (2.18 mL, 20.75 mmol, 1.2 eq.) was added to a mixture of 2-methyl-6-nitro- benzene-1-sulfonyl chloride (Int. M-100, 6.07 g, 17.26 mmol, 1.0 eq.) in anhydrous pyridine (33.5 mL) and the RM stirred overnight at RT under nitrogen. It was then concentrated in vacuo, water and brine were added and the mixture was extracted with DCM (3x). The com- Ryvu Therapeutics S.A. RVU305 224 R10107WO bined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under re- duced pressure. The crude material was purified by FCC (10% to 25% EtOAc gradient in hexane) followed by crystallization from hexane/EtOAc 9:1 v/v to yield N-tert-butyl-2-me- thyl-6-nitrobenzene-1-sulfonamide (Int. M-101, 1.714 g, 6.29 mmol, 35%, white solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (s, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.66 – 7.59 (m, 2H), 2.68 (s, 3H), 1.10 (s, 9H). m/z (ESI): 271.2 [M-H]-. Step 4: A mixture of H ₅ IO ₆ (9.522 g, 41.78 mmol, 8.0 eq.) in MeCN (70.0 mL) was stirred vigorously at RT for 1 h, and CrO ₃ (0.052 g, 0.52 mmol, 0.1 eq.) was added followed by Ac ₂ O (3.95 mL, 41.79 mmol, 8.0 eq.). The resulting orange solution was cooled to 0 °C and N-tert-butyl-2- methyl-6-nitrobenzene-1-sulfonamide (Int. M-101, 1.451 g, 5.22 mmol, 1.0 eq.) was added portionwise at this temperature. After stirring at 0 °C for 15 min, the RM was allowed to warm to RT and stirred for 20 h. The solvent was evaporated under reduced pressure, the residue was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc (x2). The combined organic layers were washed with sat. aq. NaHCO ₃ and brine, dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure to yield crude 2-tert-butyl-7-nitro-2,3-dihydro-1λ⁶,2-benzothiazole-1,1, 3-trione (Int. M-102, 0.925 g, 3.25 mmol, 60%, yellow solid, UPLC purity: 90%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (dd, J = 8.2, 1.0 Hz, 1H), 8.46 (dd, J = 7.6, 1.0 Hz, 1H), 8.23 (dd, J = 8.2, 7.7 Hz, 1H), 1.73 (s, 9H). m/z (ESI): 303.0 [M+H ₂ O+H] ⁺ . Step 5: Borane dimethyl sulfide complex (0.573 mL, 1.15 mmol, 5.0 eq.) was added to a solution of 2-tert-butyl-7-nitro-2,3-dihydro-1λ⁶,2-benzothiazole-1,1, 3-trione (Int. M-102, 1.12 g, 3.9 mmol, 1.0 eq.) in anhydrous THF (35.0 mL) and the RM was stirred at 65 °C under nitrogen for 2 days. Borane dimethyl sulfide complex (0.344 mL, 0.69 mmol, 3.0 eq.) was added and the RM was stirred for a further 24 h at 65 °C. Borane dimethyl sulfide complex (0.573 mL, 1.15 mmol, 5.0 eq.) was added and the RM was stirred for a further 3 h at 65 °C. The reac- tion was cooled to RT and carefully quenched with aq. 2 M HCl. The RM was extracted with EtOAc (4x) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by FCC (0 to 25% EtOAc gradient in hexane) to yield 7-amino-2-tert-butyl-2,3-dihydro-1λ⁶,2-benzothiazole- 1,1-dione (Int. M-103, 0.485 g, 2.02 mmol, 50%, yellow solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.29 (dd, J = 8.1, 7.4 Hz, 1H), 6.70 (dd, J = 8.2, 0.8 Hz, 1H), 6.58 (dd, J = 7.4, 0.8 Hz, 1H), 5.63 (s, 2H), 4.38 (t, J = 0.8 Hz, 2H), 1.45 (s, 9H). m/z (ESI): 241.2 [M+H] ⁺ . Step 6: Step 6 was performed according the General Procedure 09, using 7-amino-2-tert-butyl-2,3- dihydro-1λ⁶,2-benzothiazole-1,1-dione (Int. M-103, 0.435 g, 1.74 mmol, 1.0 eq.), DMAP (0.043 g, 0.35 mmol, 0.2 eq.) and nicotinoyl chloride hydrochloride (0.619 g, 3.48 mmol, 2.0 eq.) in a mixture of anhydrous THF (3.5 mL) and anhydrous pyridine (3.5 mL), for 16 h at RT followed by 5 h at 70 °C. The crude material was purified by FCC (20% to 100% EtOAc gra- Ryvu Therapeutics S.A. RVU305 225 R10107WO dient in hexane) to yield N-(2-tert-butyl-1,1-dioxo-2,3-dihydro-1λ⁶,2-benzothiazol- 7-yl)pyr- idine-3-carboxamide (Int. M-104, 0.411 g, 1.19 mmol, 68%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 9.09 (dd, J = 2.3, 0.9 Hz, 1H), 8.80 (dd, J = 4.8, 1.7 Hz, 1H), 8.26 (ddd, J = 7.9, 2.4, 1.7 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.66 (dd, J = 7.9, 0.9 Hz, 1H), 7.61 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.49 (dd, J = 7.6, 0.9 Hz, 1H), 4.58 (s, 2H), 1.48 (s, 9H). m/z (ESI): 346.8 [M+H] ⁺ . Step 1: A solution of 2-bromoacetic acid (1.543 g, 11.11 mmol, 1.05 eq.), 2-bromobenzene-1-thiol (2.0 g, 10.58 mmol, 1.0 eq.), sodium hydroxide (1.269 g, 31.73 mmol, 3.0 eq.) in water (50.0 mL) was stirred for 3 h at 50 °C. The RM was diluted with water (50 mL) and the pH was adjusted to around 2 by addition of aq. 1 M HCl. The resulting precipitate was filtered off, washed with cold water and then pentane, and dried under vacuum to yield crude 2-[(2- bromophenyl)sulfanyl]acetic acid (Int. M-105, 2.44 g, 9.87 mmol, 93%, white solid, UPLC pu- rity: 100%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 7.61 (dd, J = 7.9, 1.3 Hz, 1H), 7.38 (ddd, J = 8.0, 7.3, 1.4 Hz, 1H), 7.30 (dd, J = 8.0, 1.6 Hz, 1H), 7.11 (ddd, J = 7.9, 7.3, 1.6 Hz, 1H), 3.91 (s, 2H). m/z (ESI): 311.1 [M+MeCN+Na] ⁺ . Step 2: A mixture of 2-[(2-bromophenyl)sulfanyl]acetic acid (Int. M-105, 1.0 g, 4.05 mmol, 1.0 eq.) and SOCl ₂ (2.952 mL, 40.47 mmol, 10.0 eq.) was heated to reflux for 2 hours. The RM was concentrated at reduced pressure and the residue was taken up in chlorobenzene (50.0 mL). AlCl ₃ (0.594 g, 4.45 mmol, 1.1 eq.) was added at 0 °C and the RM was stirred for 1 h at this temperature. The reaction was quenched by addition of ice/water and the mixture was extracted with toluene (x3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield crude 7-bromo-2,3-dihy- dro-1-benzothiophen-3-one (Int. M-106, 0.67 g, 2.92 mmol, 68%, purple solid, UPLC purity: 94%), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (dd, J = 7.7, 1.1 Hz, 1H), 7.73 (dd, J = 7.6, 1.1 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 4.09 (s, 2H). m/z (ESI): 228.8 [M+H] ⁺ . Step 3: Ryvu Therapeutics S.A. RVU305 226 R10107WO mCPBA (2.464 g, 11.0 mmol, 4.0 eq.) was added to a solution of 7-bromo-2,3-dihydro-1- benzothiophen-3-one (Int. M-106, 0.67 g, 2.75 mmol, 1.0 eq.) in DCM (10.0 mL) at 0 °C and the RM was stirred overnight at RT. The reaction was quenched by addition of 10% aq. Na ₂ S ₂ O ₃ and sat. aq. NaHCO ₃ and the phases were separated. The aqueous phase was ex- tracted with DCM and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , fil- tered and evaporated under reduced pressure to yield crude 7-bromo-2,3-dihydro-1λ⁶-ben- zothiophene-1,1,3-trione (Int. M-107, 0.655 g, 2.51 mmol, 82%, beige solid, UPLC purity: 90%), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (dd, J = 7.8, 0.9 Hz, 1H), 8.02 (dd, J = 7.7, 0.9 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 4.67 (s, 2H). _m/z (ESI): 258.9 [M-H]-. Step 4: NaBH ₄ (0.156 g, 4.14 mmol, 3.0 eq.) was added to a solution of 7-bromo-2,3-dihydro-1λ⁶- benzothiophene-1,1,3-trione (Int. M-107, 0.4 g, 1.38 mmol, 1.0 eq.) in anhydrous THF (6.0 mL) at 0 °C and the RM was stirred at RT for 5 h. EtOAc was added to the mixture which was then washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield crude 7-bromo-3-hydroxy-2,3-dihydro- 1λ⁶-benzothiophene-1,1-dione (Int. M-108, 0.343 g, 1.30 mmol, 90%, beige solid, UPLC pu- rity: 95%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.82 (ddd, J = 7.1, 1.9, 0.7 Hz, 1H), 7.69 (dd, J = 6.0, 0.7 Hz, 1H), 7.66 (t, J = 7.1 Hz, 1H), 6.40 (s, 1H), 5.36 (dd, J = 7.2, 4.7 Hz, 1H), 4.06 (dd, J = 13.7, 7.2 Hz, 1H), 3.42 (dd, J = 13.7, 4.7 Hz, 1H). m/z (ESI): 260.9 [M-H]-. Step 5: Step 5 was performed according to General Procedure 19, using 7-bromo-3-hydroxy-2,3- dihydro-1λ⁶-benzothiophene-1,1-dione (Int. M-108, 0.1 g, 0.38 mmol, 1.0 eq.), acetamide (0.090 g, 1.52 mmol, 4.0 eq.), X-Phos (0.036 g, 0.08 mmol, 0.2 eq.), Cs ₂ CO ₃ (0.310 g, 0.95 mmol, 2.5 eq.) and Pd(OAc) ₂ (0.009 g, 0.04 mmol, 0.1 eq.) in anhydrous dioxane (6 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-(3-hydroxy- 1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)acetamide (Int. M-109, 0.02 g, 0.08 mmol, 20%, yellow oil, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 7.73 – 7.67 (m, 2H), 7.45 (dd, J = 6.2, 1.5 Hz, 1H), 6.31 (d, J = 6.3 Hz, 1H), 5.41 – 5.31 (m, 1H), 4.00 (dd, J = 13.4, 6.9 Hz, 1H), 3.36 (dd, J = 13.4, 5.3 Hz, 1H), 2.10 (s, 3H). m/z (ESI): 242.0 [M+H] ⁺ . N-(2-methanesulfonylphenyl)-5-methylpyridine-3-carboxamide (Int. M-110) Oxalyl chloride (5.5 g, 43.33 mmol, 9.90 eq.) was added to a solution of 5-methylpyridine-3- carboxylic acid (0.6 g, 4.37 mmol, 1.0 eq.) in anhydrous DCM (10 mL) at 0 °C, followed by a drop of DMF. The RM was stirred for 2 h under nitrogen, being allowed to come back slowly Ryvu Therapeutics S.A. RVU305 227 R10107WO to RT. The RM was then evaporated to dryness under reduced pressure and the residue was taken up in anhydrous DCM (5 mL). This solution was added dropwise to a solution of 2-methanesulfonylaniline (0.75 g, 4.38 mmol, 1.0 eq.) in anhydrous pyridine (15 mL) and the RM was stirred overnight at RT under nitrogen. The mixture was then partitioned between EtOAc and sat. aq. NaHCO ₃ . The organic layer was washed with sat. aq. NaHCO ₃ (2x), water (2x) and brine (2x). It was then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated un- der reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(2-methanesulfonylphenyl)-5-methylpyridine-3-carboxamide (Int. M-110, 0.326 g, 1.12 mmol, 25%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 8.92 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.13 (dd, J = 8.1, 1.1 Hz, 1H), 8.10 (t, J = 2.0 Hz, 1H), 7.99 (dd, J = 7.9, 1.5 Hz, 1H), 7.81 (td, J = 7.7, 1.5 Hz, 1H), 7.52 (td, J = 7.7, 1.1 Hz, 1H), 3.32 (s, 3H), 2.41 (s, 3H). m/z (ESI): 291.0 [M+H] ⁺ . N-(2-methanesulfonyl-5-methylpyridin-3-yl)-5-(trifluoromethy l)pyridine-3-carboxamide (Int. M-112) Step 1: General Procedure 39 T3P (50% wt. in EtOAc, 5.110 mL, 8.58 mmol, 5.0 eq.) was added to a solution of 5-(trifluo- romethyl)pyridine-3-carboxylic acid (0.328 g, 1.72 mmol, 1.0 eq.), pyridine (0.415 mL, 5.15 mmol, 3.0 eq.) and DMAP (0.042 g, 0.34 mmol, 0.2 eq.) in anhydrous THF (10.0 mL) at RT. The RM was stirred for 20 minutes and 2-chloro-5-methylpyridin-3-amine (0.255 g, 1.72 mmol, 1.0 eq.) was added. The resulting mixture was stirred at RT overnight and was parti- tioned between EtOAc and water. The organic layer was washed with water (2x) and brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude material was purified by FCC (33% to 66% EtOAc gradient in hexane) to yield N-(2-chloro-5- methylpyridin-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamid e (Int. M-111, 0.488 g, 1.546 mmol, 84%, white solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 9.39 (d, J = 2.0 Hz, 1H), 9.29 – 9.20 (m, 1H), 8.70 (t, J = 2.2 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 2.35 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -60.92. m/z (ESI): 316.0 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 20, using N-(2-chloro-5-methylpyri- din-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (Int. M-111, 0.56 g, 1,774 mmol, 1.0 eq.), CuI (0.068 g, 0.35 mmol, 0.2 eq.), L-Pro-ONa (0.097 g, 0.710 mmol, 0.4 eq.) and sodium methanesulfinate (0.435 g, 4,258 mmol, 2.4 eq.) in anhydrous DMSO (6 mL). The crude ma- terial was purified by crystallization from EtOH/water 95:5 v/v, yielding N-(2-methanesul- fonyl-5-methylpyridin-3-yl)-5-(trifluoromethyl)pyridine-3-ca rboxamide (Int. M-112, 0.547 g, 1.51 mmol, 85%, white crystals, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.84 Ryvu Therapeutics S.A. RVU305 228 R10107WO (s, 1H), 9.37 (s, 1H), 9.27 (s, 1H), 8.62 (t, J = 2.0 Hz, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 3.38 (s, 3H), 2.47 (s, 3H). m/z (ESI): 360.4 [M+H] ⁺ . Further Intermediates prepared according to General Procedure 39: N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyr an-8-yl)-2-(propan-2-yloxy)ac- etamide (Int. M-114) Step 1: A pressure vessel was charged with 8-bromo-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothi- opyran-1,1-dione (Int. M-043, 0.65 g, 2.2 mmol, 1.0 eq.), Cs ₂ CO ₃ (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 in a DrySyn ^® . After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . The filtrate was evaporated under reduced pressure and the residue was dissolved in a mixture of DCM (5 mL) and TFA (5 mL). The RM was stirred for 2 h at RT and evaporated under reduced pressure. The residue was par- titioned between DCM and aq. 1 M NaOH. The aqueous phase was extracted with DCM (2x) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 8-amino-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran-1, 1-dione (Int. M-113, 0.349 g, 1.5 mmol, 68%, off-white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 83.82 (t, J = 13.8 Hz). m/z (ESI): 234.0 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 229 R10107WO Step 2: Step 2 was performed according to General Procedure 14, using 2-(propan-2-yloxy)acetic acid (0.2 g, 1.69 mmol, 1.1 eq.), 8-amino-4,4-difluoro-3,4-dihydro-2H-1λ⁶-benzothiopyran- 1,1-dione (Int. M-113, 0.35 g, 1.5 mmol, 1.0 eq.), DIPEA (0.8 mL, 4.59 mmol, 3.1 eq.) and BTFFH (1.2 g, 3.79 mmol, 2.5 eq.) in anhydrous DCM (5 mL). The crude material was puri- fied by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(4,4-difluoro-1,1-dioxo-3,4-dihy- dro-2H-1λ⁶-benzothiopyran-8-yl)-2-(propan-2-yloxy)acetami de (Int. M-114, 0.21 g, 0.63 mmol, 42%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 4.12 (d, J = 0.7 Hz, 2H), 4.04 – 3.97 (m, 2H), 3.77 (hept, J = 6.0 Hz, 1H), 3.11 – 2.95 (m, 2H), 1.20 (d, J = 6.0 Hz, 6H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -83.93 (t, J = 13.8 Hz). m/z (ESI): 332.1 [M-H]-. N-(2-methanesulfonylphenyl)-2-methylpyrimidine-5-carboxamide (Int. M-115) Oxalyl chloride (1.911 g, 15.06 mmol, 8.0 eq.) was added to a solution of 2-methylpyrimi- dine-5-carboxylic acid (0.26 g, 1.88 mmol, 1.0 eq.) in anhydrous DCM (10 mL) at 0 °C, fol- lowed by a drop of DMF. The RM was stirred for 30 h under nitrogen, being allowed to come back slowly to RT. The RM was then evaporated under reduced pressure and the residue was taken up in anhydrous DCM (5 mL). This solution was added dropwise to a solution of 2-methanesulfonylaniline (0.34 g, 1.99 mmol, 1.06 eq.) in anhydrous pyridine (5 mL) and the RM was stirred overnight at RT under nitrogen. The mixture was then partitioned between EtOAc and sat. aq. NaHCO ₃ . The organic layer was washed with sat. aq. NaHCO ₃ (2x), water (2x) and brine (2x). It was then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated un- der reduced pressure. The crude material was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield N-(2-methanesulfonylphenyl)-2-methylpyrimidine-5-carboxamide (Int. M- 115, 0.071 g, 0.244 mmol, 13%, white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.55 (s, 1H), 9.15 (s, 2H), 8.05 (dd, J = 8.2, 1.2 Hz, 1H), 8.01 (dd, J = 7.9, 1.6 Hz, 1H), 7.82 (td, J = 7.7, 1.6 Hz, 1H), 7.55 (td, J = 7.7, 1.2 Hz, 1H), 3.31 (s, 3H), 2.74 (s, 3H). m/z (ESI): 292.5 [M+H] ⁺ . N-(2-methanesulfonyl-5-methylpyridin-3-yl)-2-(trifluoromethy l)pyrimidine-5-carboxamide (Int. M-117) Ryvu Therapeutics S.A. RVU305 230 R10107WO Step 1: Step 1 was performed according to General Procedure 17, using 2-(trifluoromethyl)pyrimi- dine-5-carboxylic acid (0.51 g, 2.65 mmol, 1.0 eq.), 2-chloro-5-methylpyridin-3-amine (0.45 g, 3.16 mmol, 1.2 eq.), POCl ₃ (0.8 g, 5.2 mmol, 2.0 eq.) and DMAP (0.15 g, 1.22 mmol, 0.5 eq.) in pyridine (15 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(2-chloro-5-methylpyridin-3-yl)-2-(trifluoromethyl)pyrimid ine-5-car- boxamide (Int. M-116, 0.62 g, 1.96 mmol, 55%, yellow solid, UPLC purity: 74%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.78 (s, 1H), 9.51 (s, 2H), 8.22 (dd, J = 2.3, 0.9 Hz, 1H), 8.00 (dd, J = 2.3, 0.8 Hz, 1H), 2.36 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.16. m/z (ESI): 317.7 [M+H] ⁺ . Step 2: Step 2 was performed according the General Procedure 20, using N-(2-chloro-5-methylpyri- din-3-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide (Int. M-116, 0.048 g, 0.15 mmol, 1.0 eq.), sodium methanesulfinate (0.4 g, 3.92 mmol, 2.7 eq.), L-Pro-ONa (0.1 g, 0.73 mmol, 0.5 eq.) and CuI (0.1 g, 0.525 mmol, 0.362 eq.) in DMSO (7 mL). The crude material was purified by FCC (0 to 40% EtOAc gradient in hexane) to yield N-(2-methanesulfonyl-5-methylpyri- din-3-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide (Int. M-117, 0.061 g, 0.17 mmol, 9%, yellow solid, UPLC purity: 81%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.94 (s, 1H), 9.47 (s, 2H), 8.53 (dd, J = 1.9, 0.7 Hz, 1H), 8.31 (dd, J = 1.9, 0.9 Hz, 1H), 3.38 (s, 3H), 2.48 (t, J = 0.7 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO) δ -69.17. m/z (ESI): 361.1 [M+H] ⁺ . N-{1,1-dioxo-2H,3H-1λ⁶-thieno[3,2-b]pyridin-7-yl}pyridine -3-carboxamide (Int. M-119) Step 1: A solution of N-{1,1-dioxo-2H,3H-1λ⁶-thieno[3,2-b]pyridin-7-yl}acetamid e (Int. M-072, 0.161 g, 0.626 mmol, 1.0 eq.) in a mixture of EtOH (6.0 mL) and conc. HCl (0.6 mL) was stirred at reflux for 3 h. After coming back to RT, the RM was basified to pH ≈ 9 by addition of aq. 1 M NaOH and evaporated to dryness. The residue was taken up in MeOH and the solution was evaporated with silica. The crude material was purified by FCC (0 to 8% MeOH gradient in DCM) to yield 7-amino-2H,3H-1λ⁶-thieno[3,2-b]pyridine-1,1-dione (Int. M-118, 0.062 g, 0.34 mmol, 89%, white solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ Ryvu Therapeutics S.A. RVU305 231 R10107WO 8.09 (d, J = 5.9 Hz, 1H), 6.76 (s, 2H), 6.55 (d, J = 5.9 Hz, 1H), 3.57 (dd, J = 7.7, 6.4 Hz, 2H), 3.20 (dd, J = 7.8, 6.4 Hz, 2H). m/z (ESI): 185.4 [M+H] ⁺ . Step 2: A solution of 7-amino-2H,3H-1λ⁶-thieno[3,2-b]pyridine-1,1-dione (Int. M-118, 0.159 g, 0.84 mmol, 1.0 eq.) and NaH (60% dispersion in mineral oil, 0.161 g, 4.20 mmol, 5 eq.) was stirred for 20 min. under nitrogen at RT. The solution was cooled to 0 °C and nicotinoyl chloride hydrochloride (0.392 g, 2.20 mmol, 2.6 eq.) was added. The ice bath was removed and the RM was stirred overnight at RT. The RM was partitioned between sat. aq. NH ₄ Cl, and DCM/iPrOH 3:1 v/v and the aqueous layer was extracted with DCM/iPrOH 3:1 v/v (2x) fol- lowed by DCM/n-BuOH 3:1 v/v (2x). The combined organic extracts were dried over anhy- drous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was pu- rified by FCC (0 to 10% MeOH gradient in DCM) to yield N-{1,1-dioxo-2H,3H-1λ⁶- thieno[3,2-b]pyridin-7-yl}pyridine-3-carboxamide (Int. M-119, 0.06 g, 0.207 mmol, 36%, beige solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.41 (s, 1H), 9.07 (dd, J = 2.3, 0.9 Hz, 1H), 8.83 (dd, J = 4.8, 1.7 Hz, 1H), 8.78 (d, J = 5.6 Hz, 1H), 8.26 (ddd, J = 7.9, 2.3, 1.7 Hz, 1H), 7.93 (d, J = 5.6 Hz, 1H), 7.64 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 3.78 (t, J = 6.9 Hz, 2H), 3.45 (t, J = 6.8 Hz, 2H). m/z (ESI): 290.5 [M+H] ⁺ . N-{2-[(4-methoxyphenyl)methyl]-1-oxo-1,2,3,4-tetrahydroisoqu inolin-8-yl}pyridine-3-car- boxamide (Int. M-121) Step 1: NaH (60% in mineral oil, 0.061 g, 1.59 mmol, 1.2 eq.) was added to a solution of 8-bromo- 1,2,3,4-tetrahydroisoquinolin-1-one (0.3 g, 1.33 mmol, 1.0 eq.) in anhydrous DMF (4.0 mL) at 0 °C under nitrogen. The RM was stirred at this temperature for 20 min. and 1-(chloro- methyl)-4-methoxybenzene (0.311 g, 1.99 mmol, 1.5 eq.) was added. The RM was stirred at RT for 1 h and the reaction was quenched with water at 0 °C. The RM was extracted with DCM (3x) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hexane) to yield 8-bromo-2-[(4-methoxyphenyl)methyl]-1,2,3,4- tetrahydroisoquinolin-1-one (Int. M-120, 0.52 g, 1.17 mmol, 88%, colorless oil, UPLC purity: 78%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.62 (dd, J = 7.0, 2.2 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.28 – 7.24 (m, 2H), 6.95 – 6.90 (m, 2H), 4.63 (s, 2H), 3.74 (s, 3H), 3.43 (t, J = 6.3 Hz, 2H), 2.88 (t, J = 6.2 Hz, 2H). m/z (ESI): 347.9 [M+H] ⁺ . Step 2: A Biotage ^TM microwave vial was charged with 8-bromo-2-[(4-methoxyphenyl)methyl]- 1,2,3,4-tetrahydroisoquinolin-1-one (Int. M-120, 0.47 g, 1.06 mmol, 1.0 eq.), Cs ₂ CO ₃ (0.86 g, Ryvu Therapeutics S.A. RVU305 232 R10107WO 2.64 mmol, 2.5 eq.), pyridine-3-carboxamide (0.25 g, 2.05 mmol, 1.933 eq.) and anhydrous dioxane (11 mL). The RM was sparged with nitrogen for 10 min. Pd ₂ (dba) ₃ (0.029 g, 0.03 mmol, 0.03 eq.) and BINAP (0.04 g, 0.06 mmol, 0.06 eq.) were added and the vial was sealed. The resulting RM was stirred overnight at 110 °C in a DrySyn ^® . After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . The filtrate was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (silica 50 ^m, 0 to 50% EtOAc gradient in hexane) to yield N-{2-[(4-methoxyphenyl)methyl]-1-oxo-1,2,3,4-tetrahydroisoqu inolin-8- yl}pyridine-3-carboxamide (Int. M-121, 0.36 g, 0.90 mmol, 85%, off-white solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.61 (s, 1H), 9.15 (dd, J = 2.4, 0.7 Hz, 1H), 8.82 (dd, J = 4.8, 1.7 Hz, 1H), 8.68 – 8.62 (m, 1H), 8.31 (dt, J = 8.1, 2.0 Hz, 1H), 7.66 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 7.54 (dd, J = 8.4, 7.4 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.05 (dd, J = 7.5, 0.8 Hz, 1H), 6.97 – 6.89 (m, 2H), 4.72 (s, 2H), 3.73 (s, 3H), 3.51 (t, J = 6.6 Hz, 2H), 2.96 (t, J = 6.7 Hz, 2H). m/z (ESI): 388.5 [M+H] ⁺ . N-(2-methanesulfonylpyridin-3-yl)prop-2-enamide (Int. M-122) Acryloyl chloride (0.15 mL, 1.80 mmol, 1.4 eq.) was added dropwise to a suspension of 2- ^{methanesulfonylpyridin-3-amine (0.222 g, 1.29 mmol, 1.0 eq.) and K2CO3 (0.356 g, 2.58} _{mmol, 2.0 eq.) in anhydrous acetone (6 mL) at 0 °C. The RM was stirred at RT overnight} under nitrogen and was filtered through a pad of Celite ^® , rinsing the filter cake with EtOAc. The filtrate was evaporated under reduced pressure and the residue was suspended in MeOH (7 mL) with K ₂ CO ₃ (0.356 g, 2.58 mmol, 2.0 eq.). The RM was stirred at RT for 3 h and was evaporated to dryness over silica. The crude material was purified by FCC (0 to 60% EtOAc gradient in hexane) to yield N-(2-methanesulfonylpyridin-3-yl)prop-2-enamide (Int. M-122, 0.136 g, 0.60 mmol, 46%, off-white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 8.62 (dd, J = 8.4, 1.4 Hz, 1H), 8.52 (dd, J = 4.5, 1.5 Hz, 1H), 7.77 (dd, J = 8.4, 4.5 Hz, 1H), 6.49 (dd, J = 17.0, 10.2 Hz, 1H), 6.30 (dd, J = 17.1, 1.5 Hz, 1H), 5.89 (dd, J = 10.3, 1.5 Hz, 1H), 3.41 (s, 3H). m/z (ESI): 227.0 [M+H] ⁺ . N-{imidazo[1,2-a]pyridin-8-yl}pyridine-3-carboxamide (Int. M-123) A mixture of imidazo[1,2-a]pyridin-8-amine (0.5 g, 3.75 mmol, 1.0 eq.) and nicotinoyl chlo- ride hydrochloride (1.203 g, 6.76 mmol, 1.8 eq.) in anhydrous dioxane (18 mL) was refluxed Ryvu Therapeutics S.A. RVU305 233 R10107WO overnight. After coming back to RT, the mixture was evaporated under reduced pressure and the residue was partitioned between aq. 1 M NaOH and DCM/MeOH 9:1 v/v. The aque- ous layer was extracted with DCM/MeOH 9:1 v/v (2x) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure to yield N-{imidazo[1,2-a]pyridin-8-yl}pyridine-3-carboxamide (Int. M-123, 0.848 g, 3.56 mmol, 93%, purple solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.33 (s, 1H), 9.15 (dd, J = 2.4, 0.9 Hz, 1H), 8.79 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (dd, J = 6.8, 1.1 Hz, 1H), 8.36 (ddd, J = 7.9, 2.3, 1.7 Hz, 1H), 8.04 (d, J = 1.2 Hz, 1H), 7.89 (dd, J = 7.4, 1.1 Hz, 1H), 7.60 (d, J = 1.3 Hz, 1H), 7.60 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 6.94 (dd, J = 7.5, 6.8 Hz, 1H). m/z (ESI): 239.4 [M+H] ⁺ . 2-Ethyl-N-(4-fluoro-2-methanesulfonylphenyl)pyrimidine-5-car boxamide (Int. M-124) The title compound was prepared according to General Procedure 20, using 2-ethyl-N-(4- fluoro-2-iodophenyl)pyrimidine-5-carboxamide (Int. K-070, 0.34 g, 0.89 mmol, 1.0 eq.), so- dium methanesulfinate (0.218 g, 2.14 mmol, 2.4 eq.), CuI (0.034 g, 0.18 mmol, 0.2 eq.) and L-ProONa (0.05 g, 0.36 mmol, 0.41 eq.) in anhydrous DMSO (4.2 mL). The crude material was taken up in DCM and the solution was passed through a short pad of NH ₂ functional- ized silica, rinsing with DCM. The filtrate was evaporated to yield 2-ethyl-N-(4-fluoro-2-me- thanesulfonylphenyl)pyrimidine-5-carboxamide (Int. M-124, 0.28 g, 0.83 mmol, 94%, beige solid, UPLC purity: 96%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.52 (s, 1H), 9.19 (s, 2H), 7.98 (dd, J = 8.9, 4.9 Hz, 1H), 7.83 (dd, J = 8.2, 3.0 Hz, 1H), 7.74 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 3.37 (s, 3H), 3.03 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -112.89 (td, J = 8.2, 4.9 Hz). m/z (ESI): 324.5 [M+H] ⁺ . N-(4-fluoro-2-methanesulfonylphenyl)-2-(propan-2-yl)pyrimidi ne-5-carboxamide (Int. M- 126) Step 1: Step 1 was performed according to General Procedure 17, using 4-fluoro-2-iodoaniline (0.428 g, 1.80 mmol, 0.89 eq.), 2-(propan-2-yl)pyrimidine-5-carboxylic acid (0.337 g, 2.03 mmol, 1.0 eq.), DMAP (0.084 g, 0.69 mmol, 0.34 eq.) and POCl ₃ (0.830 g, 5.42 mmol, 2.67 eq.) in pyridine (10 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in Ryvu Therapeutics S.A. RVU305 234 R10107WO DCM) to yield N-(4-fluoro-2-iodophenyl)-2-(propan-2-yl)pyrimidine-5-carbox amide (Int. M- ^{125, 0.647 g, 1.51 mmol, 75%, yellow solid, UPLC purity: 90%). 1H NMR (400 MHz, DMSO-d6)} _{δ 10.43 (s, 1H), 9.26 (s, 2H), 7.88 (dd, J = 8.2, 2.9 Hz, 1H), 7.50 (dd, J = 8.8, 5.6 Hz, 1H),} 7.38 (td, J = 8.5, 2.9 Hz, 1H), 3.26 (hept, J = 6.9 Hz, 1H), 1.34 (d, J = 6.9 Hz, 6H). m/z (ESI): 385.8 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 20, using N-(4-fluoro-2-iodophenyl)- 2-(propan-2-yl)pyrimidine-5-carboxamide (Int. M-125, 0.647 g, 1.51 mmol, 1.0 eq.), sodium methanesulfinate (0.388 g, 3.80 mmol, 2.52 eq.), CuI (0.066 g, 0.35 mmol, 0.23 eq.) and L- Pro-ONa (0.094 g, 0.69 mmol, 0.45 eq.) in anhydrous DMSO (8 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(4-fluoro-2-methanesul- fonylphenyl)-2-(propan-2-yl)pyrimidine-5-carboxamide (Int. M-126, 0.337 g, 0.92 mmol, 61%, white solid, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 9.21 (s, 2H), 7.99 (dd, J = 8.9, 4.9 Hz, 1H), 7.83 (dd, J = 8.3, 3.0 Hz, 1H), 7.74 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 3.37 (s, 3H), 3.27 (hept, J = 6.9 Hz, 1H), 1.34 (d, J = 6.9 Hz, 6H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -112.94. m/z (ESI): 338.3 [M+H] ⁺ . N-(4-fluoro-2-methanesulfonylphenyl)-2-(oxan-4-yl)pyrimidine -5-carboxamide (Int. M-132) Step 1: Oxane-4-carbonitrile (0.5 g, 4.50 mmol, 1.0 eq.) was dissolved in a mixture of 4 M HCl in di- oxane (8.435 mL, 33.74 mmol, 7.5 eq.) and anhydrous EtOH (0.85 mL), and the RM was stirred at RT overnight. The volatiles were evaporated under reduced pressure and the re- sulting solid was triturated with diethyl ether, filtered off and dried under reduced pressure to yield ethyl oxane-4-carboximidate hydrochloride (Int. M-127, 0.521 g, 2.69 mmol, 60%, white solid, NMR purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.53 (br s, 1H), 11.20 (br s, 1H), 4.43 (q, J = 7.0 Hz, 2H), 3.92 (ddd, J = 11.6, 4.4, 1.9 Hz, 2H), 3.35 (td, J = 11.7, 2.2 Hz, 2H), 2.98 (tt, J = 11.7, 3.9 Hz, 1H), 1.88 – 1.76 (m, 2H), 1.68 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H). Ryvu Therapeutics S.A. RVU305 235 R10107WO Step 2: Ethyl oxane-4-carboximidate hydrochloride (Int. M-127, 0.521 g, 2.69 mmol, 1.0 eq.) was stirred in 7 N ammonia in MeOH (11.53 mL, 80.70 mmol, 30.0 eq.) in a pressure vessel at RT for 24 hours. The volatiles were evaporated under reduced pressure and the resulting crude oxane-4-carboximidamide hydrochloride (Int. M-128, 0.474 g, 2.68 mmol, 100%, white solid, NMR purity: 93%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 2H), 8.83 (s, 2H), 3.95 (ddd, J = 11.6, 4.5, 1.9 Hz, 2H), 3.32 (td, J = 11.6, 2.6 Hz, 2H), 2.74 (tt, J = 11.8, 4.2 Hz, 1H), 1.79 (ddd, J = 12.9, 11.7, 4.4 Hz, 2H), 1.74 – 1.66 (m, 2H). Step 3: A round-bottom flask equipped with a magnetic stirrer and a reflux condenser was purged with nitrogen. The flask was then charged sequentially with methyl 3,3-dimethoxypropano- ate (0.522 g, 3.52 mmol, 1.0 eq.), anhydrous DME (10.0 mL) and NaH (60% in mineral oil, 0.176 g, 4.58 mmol, 1.3 eq.), and the mixture was stirred at 40-50 °C under nitrogen until the observed evolution of hydrogen gas subsided. The RM was then cooled in an ice bath and methyl formate (0.54 mL, 8.81 mmol, 2.5 eq.) was added. The RM was slowly allowed to reach RT overnight with stirring under nitrogen, and anhydrous diethyl ether (5 mL) was added. The resulting suspension was filtered under nitrogen and the solid was washed with anhydrous diethyl ether (10 mL), before being dried under vacuum to sodium (1Z)-2-(di- methoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (Int. M-129, 0.555 g, 2.80 mmol, 80%, hygroscopic white powder, NMR purity: 98%). ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.91 (s, 1H), 5.34 (s, 1H), 3.61 (s, 3H), 3.37 (s, 6H). Step 4: Sodium (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (Int. M-129, 0.55 g, 2.78 mmol, 1.13 eq.) was added to a solution of oxane-4-carboximidamide hydrochloride (Int. M-128, 0.434 g, 2.45 mmol, 1.0 eq.) in anhydrous DMF (4 mL) and the RM was stirred at 100 °C under nitrogen for 20 minutes. After coming back to RT, the RM was evaporated under reduced pressure and the crude material was purified by FCC (0 to 66% EtOAc gradi- ent in hexane) to yield methyl 2-(oxan-4-yl)pyrimidine-5-carboxylate (Int. M-130, 0.257 g, 1.16 mmol, 47%, white solid, UPLC purity: 87%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (s, 2H), 3.95 (ddd, J = 11.4, 4.4, 2.1 Hz, 2H), 3.91 (s, 3H), 3.48 (td, J = 11.5, 2.4 Hz, 2H), 3.19 (tt, J = 11.4, 4.1 Hz, 1H), 1.94 – 1.87 (m, 2H), 1.87 – 1.74 (m, 2H). m/z (ESI): 223.1 [M+H] ⁺ . Step 5: Aqueous 1 M NaOH (3.5 mL) was added to a solution of methyl 2-(oxan-4-yl)pyrimidine-5- carboxylate (Int. M-130, 0.257 g, 1.16 mmol, 1.0 eq.) in MeOH (3.5 mL) and the RM was stirred at RT for 1 h. The volatiles were evaporated under reduced pressure and the result- ing suspension was filtered and the filtrate was stirred in an ice bath. Aqueous 4 M HCl was added until pH ≈ 2-3 and the resulting solid was filtered off, washed with water and dried overnight under vacuum at 40 °C to yield 2-(oxan-4-yl)pyrimidine-5-carboxylic acid (Int. M-131, 0.225 g, 1.71 mmol, 93%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.16 (s, 2H), 3.95 (ddd, J = 11.4, 4.4, 2.1 Hz, 2H), 3.48 (td, J = 11.5, 2.4 Hz, 2H), 3.17 (tt, J = 11.3, 4.1 Hz, 1H), 1.90 (m, 3H), 1.87 – 1.75 (m, 2H). m/z (ESI): 209.0 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 236 R10107WO Step 6: Step 6 was performed according to General Procedure 17, using 4-fluoro-2-methanesul- fonylaniline (0.100 g, 0.53 mmol, 1.0 eq.), 2-(oxan-4-yl)pyrimidine-5-carboxylic acid (Int. M- 131, 0.110 g, 0.53 mmol, 1.0 eq.), DMAP (0.019 g, 0.16 mmol, 0.3 eq.) and POCl ₃ (0.243 g, 1.59 mmol, 3.0 eq.) in pyridine (1 mL). The RM was evaporated under reduced pressure and the residue was triturated with water. The solid was filtered off, washed with iPrOH, diethyl ether, and dried under vacuum to yield N-(4-fluoro-2-methanesulfonylphenyl)-2-(oxan-4- yl)pyrimidine-5-carboxamide (Int. M-132, 0.154 g, 0.41 mmol, 77%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 9.21 (s, 2H), 7.96 (dd, J = 8.9, 4.9 Hz, 1H), 7.82 (dd, J = 8.3, 3.0 Hz, 1H), 7.73 (td, J = 8.4, 3.1 Hz, 1H), 3.97 (ddd, J = 11.4, 4.3, 2.0 Hz, 2H), 3.50 (td, J = 11.5, 2.5 Hz, 2H), 3.35 (s, 3H), 3.21 (tt, J = 11.3, 4.1 Hz, 1H), 1.99 – 1.90 (m, 2H), 1.90 – 1.76 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -112.87 (td, J = 8.2, 4.9 Hz). m/z (ESI): 380.0 [M+H] ⁺ . N-(2-methanesulfonylpyridin-3-yl)-2-(morpholin-4-yl)-1,3-thi azole-5-carboxamide (Int. M- Step 1: A solution of ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.600 g, 2.54 mmol, 1.0 eq.) and morpholine (0.738 mL, 7.62 mmol, 3.0 eq.) in dioxane (10.0 mL) was sonicated without sup- plementary heating for 1.5 h (the temperature remained below 60 °C). The RM was parti- tioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over with anhydrous Na ₂ SO ₄ , fil- tered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 66% EtOAc gradient in hexane) to yield ethyl 2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (Int. M-133, 0.6 g, 2.23 mmol, 88%, yellow solid, UPLC purity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (s, 1H), 4.23 (q, J = 7.0 Hz, 2H), 3.71 (t, J = 5.0 Hz, 4H), 3.51 (t, J = 5.0 Hz, 4H), 1.26 (t, J = 7.1 Hz, 3H). m/z (ESI): 243.4 [M+H] ⁺ . Step 2: LiOH monohydrate (0.390 g, 9.29 mmol, 5.0 eq.) was added to a solution of ethyl 2-(morpho- lin-4-yl)-1,3-thiazole-5-carboxylate (Int. M-133, 0.5 g, 1.86 mmol, 1.0 eq.) in a mixture of THF (8.0 mL) and water (2.0 mL) and the RM was stirred at 50 °C for 2 h. After coming back to RT, the pH was adjusted to ≈ 5 with aq. 1 M HCl and the mixture was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhy- Ryvu Therapeutics S.A. RVU305 237 R10107WO drous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was trit- urated with the minimum amount of isopropanol, filtered off and dried under vacuum to yield 2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid (Int. M-134, 0.45 g, 1.60 mmol, 86%, white solid, UPLC purity: 76%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.63 (s, 1H), 7.80 (s, 1H), 3.71 (dd, J = 5.8, 4.2 Hz, 4H), 3.49 (dd, J = 5.8, 4.1 Hz, 4H). m/z (ESI): 215.3 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 17, using 2-methanesulfonylpyridin- 3-amine (0.183 g, 1.06 mmol, 1.0 eq.), 2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid (Int. M-134, 0.078 g, 0.32 mmol, 0.3 eq.), DMAP (0.039 g, 0.32 mmol, 0.3 eq.) and POCl ₃ (0.326 g, 2.13 mmol, 2.0 eq.) in pyridine (5 mL). The crude material was purified by FCC (0 to 66% EtOAc gradient in hexane) to yield N-(2-methanesulfonylpyridin-3-yl)-2-(morpholin-4-yl)- 1,3-thiazole-5-carboxamide (Int. M-135, 0.082 g, 0.17 mmol, 16%, white solid, UPLC purity: 75%). m/z (ESI): 369.4 [M+H] ⁺ . N-(2-methanesulfonylpyridin-3-yl)-2-(oxan-4-yl)-1,3-thiazole -5-carboxamide (Int. M-139) Step 1: A pressure vessel was charged with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (1.557 g, 7.41 mmol, 1.34 eq.), ethyl 2-bromo-1,3-thiazole-5-carboxylate (1.31 g, 5.55 mmol, 1.0 eq.), K ₂ CO ₃ (2.459 g, 17.79 mmol, 3.21 eq.), dioxane (28 mL) and wa- ter (6 mL). The RM was sparged with nitrogen for 15 min., Pd(PPh ₃ ) ₄ (0.685 g, 0.59 mmol, 0.11 eq.) was added and the vessel was sealed. The RM was stirred at 100 °C overnight (oil bath). After coming back to RT, the RM was partitioned between DCM and water and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 20% EtOAc gradient in hexane) to yield ethyl 2-(3,6-dihydro-2H- pyran-4-yl)-1,3-thiazole-5-carboxylate (Int. M-136, 0.725 g, 2.88 mmol, 52%, yellow solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 6.93 – 6.88 (m, 1H), 4.32 (q, J = 7.3 Hz, 2H), 4.27 (dd, J = 5.6, 2.7 Hz, 2H), 3.83 (t, J = 5.4 Hz, 2H), 2.59 – 2.53 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H). m/z (ESI): 240.3 [M+H] ⁺ . Step 2: 10% Pd/C (wet, 0.2 g) was added to a solution of ethyl 2-(3,6-dihydro-2H-pyran-4-yl)-1,3- thiazole-5-carboxylate (Int. M-136, 0.921 g, 3.62 mmol, 1.0 eq.) in methanol (47 mL) and the Ryvu Therapeutics S.A. RVU305 238 R10107WO atmosphere was first replaced by argon, with two cycles of vacuum/argon, then by hydro- gen with two cycles of vacuum/hydrogen. The RM was stirred under hydrogen (1 atm) for 24 h and filtered through a pad of Celite ^® . The filtrate was evaporated under reduced pres- sure and the crude material was purified by FCC (0 to 30% EtOAc gradient in hexane) to yield ethyl 2-(oxan-4-yl)-1,3-thiazole-5-carboxylate (Int. M-137, 0.733 g, 2.98 mmol, 82%, white solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.93 (ddd, J = 11.7, 4.4, 2.1 Hz, 2H), 3.47 (td, J = 11.6, 2.1 Hz, 2H), 3.38 – 3.27 (m, 1H), 2.04 – 1.93 (m, 2H), 1.81 – 1.65 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). m/z (ESI): 242.3 [M+H] ⁺ . Step 3: Aqueous 1 M NaOH (15 mL) was added to a solution of ethyl 2-(oxan-4-yl)-1,3-thiazole-5- carboxylate (Int. M-137, 0.733 g, 2.98 mmol, 1.0 eq.) in ethanol (10 mL). The resulting solu- tion was stirred at RT for 90 min. Aqueous 6 M HCl was added dropwise until pH~ 3-4 was reached and the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2x) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure. The obtained crude 2-(oxan-4- yl)-1,3-thiazole-5-carboxylic acid (Int. M-138, 0.617 g, 2.83 mmol, 95%, white solid, UPLC purity: 98%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.45 (s, 1H), 8.26 (s, 1H), 3.93 (ddd, J = 11.6, 4.4, 2.0 Hz, 2H), 3.46 (td, J = 11.7, 2.1 Hz, 2H), 3.34 – 3.25 (m, 1H), 2.02 – 1.94 (m, 2H), 1.73 (m, 2H). m/z (ESI): 214.2 [M+H] ⁺ . Step 4: Step 4 was performed according to General Procedure 17, using 2-methanesulfonylpyridin- 3-amine (1.034 g, 6.01 mmol, 2.15 eq.), 2-(oxan-4-yl)-1,3-thiazole-5-carboxylic acid (Int. M- 138, 0.606 g, 2.79 mmol, 1.0 eq.) and POCl ₃ (0.855 g, 5.57 mmol, 2.0 eq.) in pyridine (14 mL). The crude material was purified by FCC (0 to 60% EtOAc gradient in hexane) to yield N-(2- methanesulfonylpyridin-3-yl)-2-(oxan-4-yl)-1,3-thiazole-5-ca rboxamide (Int. M-139, 0.954 g, 2.57 mmol, 92%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.62 – 8.55 (m, 2H), 8.36 (s, 1H), 7.81 (dd, J = 8.1, 4.8 Hz, 1H), 3.94 (ddd, J = 11.4, 4.4, 2.0 Hz, 2H), 3.48 (td, J = 11.6, 2.1 Hz, 2H), 3.43 (s, 3H), 3.40 – 3.34 (m, 1H), 2.06 – 1.95 (m, 2H), 1.82 – 1.69 (m, 2H). m/z (ESI): 368.3 [M+H] ⁺ . N-(4-fluoro-2-methanesulfonylphenyl)-6-(oxolan-3-yl)pyridine -3-carboxamide (Int. M-141) Step 1: Ryvu Therapeutics S.A. RVU305 239 R10107WO A Biotage ^TM microwave vial was charged with 2-(2,5-dihydro-3-furanyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (0.152 g, 0.77 mmol, 1.0 eq.), 6-bromo-N-(4-fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int. K-082, 0.35 g, 0.93 mmol, 1.2 eq.), dioxane (9.0 mL) and water (1.0 mL). The RM was sparged with nitrogen for 5 min., Pd(dppf)Cl ₂ (0.034 g, ^{0.046 mmol, 0.1 eq.) was added followed by K2CO3 (0.321 g, 2.32 mmol, 3.0 eq.), the vial was} _{sealed and the RM was stirred at 100 °C for 2 h in a DrySyn®. After coming back to RT, the} RM was partitioned between DCM and water. The aqueous layer was extracted with DCM (2x) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 2% MeOH gra- dient in DCM) to yield 6-(2,5-dihydrofuran-3-yl)-N-(4-fluoro-2-methanesulfonylpheny l)pyri- dine-3-carboxamide (Int. M-140, 0.27 g, 0.60 mmol, 77%, yellow solid, UPLC purity: 80%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.44 (s, 1H), 9.05 (dd, J = 2.4, 0.9 Hz, 1H), 8.28 (dd, J = 8.3, 2.3 Hz, 1H), 8.08 (dd, J = 9.0, 4.9 Hz, 1H), 7.90 (dd, J = 8.3, 0.9 Hz, 1H), 7.81 (dd, J = 8.3, 3.0 Hz, 1H), 7.72 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 7.04 – 6.97 (m, 1H), 5.04 – 4.97 (m, 2H), 4.86 – 4.79 (m, 2H), 3.36 (s, 3H). m/z (ESI): 363.3 [M+H] ⁺ . Step 2: 10% Pd/C (0.013 g) was added to a solution of 6-(2,5-dihydrofuran-3-yl)-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide (Int. M-140, 0.031 g, 0.08 mmol, 1.0 eq.) in EtOAc (10 mL) and the atmosphere was first replaced by argon, with two cycles of vac- uum/argon, then by hydrogen with two cycles of vacuum/hydrogen. The RM was stirred un- der hydrogen (1 atm) for 1 h and filtered through a pad of Celite ^® . The filtrate was evapo- rated under reduced pressure to yield N-(4-fluoro-2-methanesulfonylphenyl)-6-(oxolan-3- yl)pyridine-3-carboxamide (Int. M-141, 0.021 g, 0.05 mmol, 64%, white solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.41 (s, 1H), 9.05 (dd, J = 2.3, 0.8 Hz, 1H), 8.22 (dd, J = 8.2, 2.4 Hz, 1H), 8.07 (dd, J = 9.0, 5.0 Hz, 1H), 7.80 (dd, J = 8.3, 3.1 Hz, 1H), 7.71 (ddd, J = 9.0, 8.0, 3.1 Hz, 1H), 7.55 (dd, J = 8.3, 0.8 Hz, 1H), 4.11 (t, J = 7.8 Hz, 1H), 3.95 (td, J = 8.1, 5.1 Hz, 1H), 3.84 (dt, J = 8.3, 7.3 Hz, 1H), 3.77 (dd, J = 8.1, 7.3 Hz, 1H), 3.72 – 3.63 (m, 1H), 3.36 (s, 3H), 2.37 – 2.27 (m, 1H), 2.23 – 2.12 (m, 1H). m/z (ESI): 365.4 [M+H] ⁺ . N-{1,1-dioxo-2H,3H-1λ⁶-thieno[3,2-b]pyridin-7-yl}-6-(trif luoromethyl)pyridine-3-carbox- amide (Int. U-001), General Procedure 40 DMAP (0.008 g, 0.05 mmol, 0.05 eq.), DIPEA (0.579 mL, 3.33 mmol, 2.5 eq.) and T3P (50 weight % in EtOAc, 1.693 g, 2.66 mmol, 2.0 eq.) were added to a solution of 7-amino-2H,3H- 1λ⁶-thieno[3,2-b]pyridine-1,1-dione (Int. M-118, 0.250 g, 1.33 mmol, 1.0 eq.) and 6-(trifluo- romethyl)nicotinic acid (0.280 g, 1.46 mmol, 1.1 eq.) in anhydrous toluene (4.5 mL) and the RM was refluxed overnight under nitrogen. After coming back to RT, the RM was partitioned Ryvu Therapeutics S.A. RVU305 240 R10107WO between water and DCM. The aqueous layer was extracted with DCM (2x) and the com- bined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under re- duced pressure. The crude material was triturated with the minimum amount of iPrOH, fil- tered off and dried under vacuum to yield N-{1,1-dioxo-2H,3H-1λ⁶-thieno[3,2-b]pyridin-7- yl}-6-(trifluoromethyl)pyridine-3-carboxamide (Int. U-001, 0.420 g, 1.16 mmol, 87%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.78 (s, 1H), 9.19 (d, J = 2.1 Hz, 1H), 8.80 (d, J = 5.6 Hz, 1H), 8.51 (dd, J = 8.1, 2.2 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.92 (d, J ^{= 5.6 Hz, 1H), 3.78 (t, J = 6.9 Hz, 2H), 3.46 (t, J = 6.8 Hz, 2H). 19F NMR (376 MHz, DMSO-d6} + ⁾ _{δ -66.71. m/z (ESI): 358.4 [M+H] .} Further Intermediates prepared according to General Procedure 40: Ryvu Therapeutics S.A. RVU305 241 R10107WO N-(2-methanesulfonylpyridin-3-yl)-6-methyl-5-(trifluoromethy l)pyridine-3-carboxamide (Int. M-143) Ryvu Therapeutics S.A. RVU305 242 R10107WO Step 1: A mixture of K ₂ CO ₃ (0.519 g, 3.76 mmol, 3.0 eq.), tricyclohexylphosphine (0.105 g, 0.38 mmol, 0.3 eq.), Pd ₂ (dba) ₃ (0.115 g, 0.12 mmol, 0.1 eq.), methylboronic acid (0.150 g, 2.50 mmol, 2.0 eq.) and methyl 6-chloro-5-(trifluoromethyl)pyridine-3-carboxylate (0.3 g, 1.25 mmol, 1.0 eq.) in anhydrous dioxane (5.0 mL) was heated to 110 °C overnight. After coming back to RT, the RM was dilluted with EtOAc and filtered through a pad of Celite ^® . The filtrate was washed with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was dissolved in a mixture of THF (4 mL) and water (1 mL), LiOH monohydrate (0.157 g, 3.76 mmol, 3.0 eq.) was added and the RM was stirred for 2 h at 50 °C. After coming back to RT, the reaction was quenched by addition of aq.1 M HCl until pH ≈ 8. The mixture was extracted with DCM (3x) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under re- duced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield 6-methyl-5-(trifluoromethyl)pyridine-3-carboxylic acid (Int. M-142, 0.133 g, 0.545 mmol, 44%, yellow solid, UPLC purity: 84%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.79 (s, 1H), 9.17 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 2.73 (q, J = 1.7 Hz, 3H). m/z (ESI): 206.0 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 40, using 2-methanesulfonylpyridin- 3-amine (0.094 g, 0.54 mmol, 1.0 eq.), 6-methyl-5-(trifluoromethyl)pyridine-3-carboxylic acid (Int. M-142, 0.133 g, 0.54 mmol, 1.0 eq.), DMAP (0.020 g, 0.16 mmol, 0.3 eq.) and DI- PEA (0.237 mL, 1.36 mmol, 2.5 eq.) in toluene was added T3P (0.693 g, 1.09 mmol, 2.0 eq.). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-(2- methanesulfonylpyridin-3-yl)-6-methyl-5-(trifluoromethyl)pyr idine-3-carboxamide (Int. M- ^{143, 0.077 g, 0.21 mmol, 39%, yellow solid, UPLC purity: 98%). 1H NMR (400 MHz, DMSO-d6)} _{δ 10.85 (s, 1H), 9.21 (d, J = 2.1 Hz, 1H), 8.64 (dd, J = 4.5, 1.5 Hz, 1H), 8.56 (dd, J = 8.4, 1.5} Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 7.85 (dd, J = 8.4, 4.5 Hz, 1H), 3.42 (s, 3H), 2.76 (q, J = 1.7 Hz, 3H). m/z (ESI): 360.4 [M+H] ⁺ . N-(2-methanesulfonylpyridin-3-yl)-2-[6-(trifluoromethyl)pyri din-3-yl]-1,3-thiazole-5-car- boxamide (Int. M-146) Ryvu Therapeutics S.A. RVU305 243 R10107WO Step 1: In a 20-mL Biotage ^TM microwave vial, a mixture of K ₃ PO ₄ (0.719 g, 3.39 mmol, 2.0 eq.), [6- (trifluoromethyl)pyridin-3-yl]boronic acid (0.485 g, 2.54 mmol, 1.5 eq.) and ethyl 2-bromo- 1,3-thiazole-5-carboxylate (0.4 g, 1.69 mmol, 1.0 eq.) in a mixture of THF (8 mL) and water (0.8 mL) was sparged with Ar for 30 min. SPhos Pd G3 (0.066 g, 0.08 mmol, 0.05 eq.) was added and the vial was sealed. The RM was stirred at 80 °C overnight. After coming back to RT, the RM was diluted with DCM and filtered through a pad of Celite ^® . The filtrate was washed with sat. aq. NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gra- dient in hexane) to yield ethyl 2-[6-(trifluoromethyl)pyridin-3-yl]-1,3-thiazole-5-carboxyla te (Int. M-144, 0.16 g, 0.50 mmol, 24%, white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (d, J = 2.2 Hz, 1H), 8.70 (dd, J = 8.3, 2.2 Hz, 1H), 8.66 (s, 1H), 8.10 (dd, J = 8.3, 0.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -66.64. m/z (ESI): 303.0 [M+H] ⁺ . Step 2: A solution of LiOH (0.03 g, 1.25 mmol, 3.22 eq.) in water (5 mL) was added to a solution of ethyl 2-[6-(trifluoromethyl)pyridin-3-yl]-1,3-thiazole-5-carboxyla te (Int. M-144, 0.12 g, 0.39 mmol, 1.0 eq.) in a mixture of THF (5 mL) and MeOH (5 mL) and the RM was stirred at RT for 2 h. The mixture was then acidified to pH ≈ 3 with aq.1 M HCl, diluted with water and extracted with EtOAc (4x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The obtained crude 2-[6-(trifluorome- thyl)pyridin-3-yl]-1,3-thiazole-5-carboxylic acid (Int. M-145, 0.09 g, 0.29 mmol, 74%, white solid, UPLC purity: 87%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.87 (s, 1H), 9.39 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 2.2, 8.3 Hz, 1H), 8.57 (s, 1H), 8.09 (d, J = 8.3 Hz, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -66.63. m/z (ESI): 274.9 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 17, using 2-[6-(trifluoromethyl)pyri- din-3-yl]-1,3-thiazole-5-carboxylic acid (Int. M-145, 0.197 g, 0.62 mmol, 1.0 eq.), 2-me- thanesulfonylpyridin-3-amine (0.12 g, 0.70 mmol, 1.11 eq.), POCl ₃ (0.192 g, 1.25 mmol, 2.0 eq.) and DMAP (0.019 g, 0.16 mmol, 0.25 eq.) in pyridine (10 mL). The crude material was purified by FCC (0 to 10% MeCN gradient in DCM) to yield N-(2-methanesulfonylpyridin-3- Ryvu Therapeutics S.A. RVU305 244 R10107WO yl)-2-[6-(trifluoromethyl)pyridin-3-yl]-1,3-thiazole-5-carbo xamide (Int. M-146, 0.12 g, 0.25 mmol, 40%, white solid, NMR purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.84 (s, 1H), 9.42 (d, J = 2.2 Hz, 1H), 8.70 (dd, J = 8.2, 2.2 Hz, 1H), 8.65 (s, 1H), 8.63 – 8.58 (m, 1H), 8.55 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.88 – 7.76 (m, 1H), 3.44 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -66.59. m/z (ESI): 429.0 [M+H] ⁺ . 6-(1-Cyanocyclopropyl)-N-(4-fluoro-2-methanesulfonylphenyl)p yridine-3-carboxamide (Int. M-151) Step 1: A mixture of methyl 6-fluoropyridine-3-carboxylate (2.035 g, 13.12 mmol, 1.0 eq.), tert-butyl 2-cyanoacetate (3.240 g, 22.95 mmol, 1.75 eq.) and Cs ₂ CO ₃ (6.900 g, 21.18 mmol, 1.61 eq.) in anhydrous DMF (30 mL) was stirred at 65 °C for 1 h. After coming back to RT, the RM was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with brine (3x), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield methyl 6-[2-(tert-butoxy)-1-cyano-2-ox- oethyl]pyridine-3-carboxylate (Int. M-147, 2.720 g, 9.65 mmol, 74%, yellow solid, UPLC pu- rity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.63 (s, 1H), 8.56 (dd, J = 6.9, 2.1 Hz, 1H), 8.04 (dd, J = 9.4, 2.1 Hz, 1H), 7.16 (dd, J = 9.4, 1.7 Hz, 1H), 3.84 (s, 3H), 1.50 (s, 9H). m/z (ESI): 276.9 [M+H] ⁺ . Step 2: A solution of methyl 6-[2-(tert-butoxy)-1-cyano-2-oxoethyl]pyridine-3-carboxylate (Int. M- 147, 2.25 g, 7.98 mmol, 1.0 eq.) in a mixture of DCM (100 mL) and TFA (7 mL) was stirred at RT for 24 h. The mixture was neutralized by slow addition of sat. aq. Na ₂ CO ₃ (50 mL), fol- lowed by slow addition of aq.5 M NaOH until pH ≈ 9. The phases were separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine (2x), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pres- sure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield methyl 6-(cyanomethyl)pyridine-3-carboxylate (Int. M-148, 1.05 g, 5.72 mmol, 72%, beige solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (dd, J = 2.2, 0.9 Hz, 1H), 8.34 Ryvu Therapeutics S.A. RVU305 245 R10107WO (dd, J = 8.1, 2.3 Hz, 1H), 7.59 (dd, J = 8.1, 0.8 Hz, 1H), 4.37 (s, 2H), 3.90 (s, 3H). m/z (ESI): 177.0 [M+H] ⁺ . Step 3: NaH (60% in mineral oil, 0.125 g, 3.27 mmol, 3.0 eq.) was slowly added to a solution methyl 6-(cyanomethyl)pyridine-3-carboxylate (Int. M-148, 0.2 g, 1.09 mmol, 1.0 eq.) in DMF (5.0 mL) at 0 °C under nitrogen. The RM was allowed to reach RT and was stirred for 15 min. 1,2-Dibromoethane (0.282 mL, 3.27 mmol, 3.0 eq.) was added and the RM was stirred at RT for 3 h. The reaction was quenched by addition of aq. 1 M KHSO ₄ until pH ≈ 7 and water was added. The mixture was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under re- duced pressure. The crude material was purified by FCC (0 to 25% EtOAc gradient in hex- ane) to yield methyl 6-(1-cyanocyclopropyl)pyridine-3-carboxylate (Int. M-149, 0.17 g, 0.84 mmol, 77%, off-white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (dd, J = 2.3, 0.9 Hz, 1H), 8.33 (dd, J = 8.3, 2.2 Hz, 1H), 7.72 (dd, J = 8.3, 0.9 Hz, 1H), 3.89 (s, 3H), 1.95 – 1.90 (m, 2H), 1.82 – 1.76 (m, 2H). m/z (ESI): 203.0 [M+H] ⁺ . Step 4: A solution of LiOH (0.189 g, 7.91 mmol, 3.0 eq.) in water (2 mL) was added to a solution of methyl 6-(1-cyanocyclopropyl)pyridine-3-carboxylate (Int. M-149, 0.55 g, 2.64 mmol, 1.0 eq.) in a mixture of THF (5 mL) and MeOH (5 mL) and the RM was stirred at RT for 2 h. The pH was adjusted to ≈ 3 with aq. 1 M HCl and the mixture was extracted with DCM (5x). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield 6-(1-cyanocyclopropyl)pyridine-3-carboxylic acid (Int. M-150, 0.493 g, 2.62 mmol, 99%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.46 (s, 1H), 8.97 (dd, J = 2.2, 0.9 Hz, 1H), 8.30 (dd, J = 8.3, 2.2 Hz, 1H), 7.69 (dd, J = 8.2, 0.9 Hz, 1H), 1.95 – 1.87 (m, 2H), 1.80 – 1.73 (m, 2H). _m/z (ESI): 189.0 [M+H] ⁺ . Step 5: Step 5 was carried out according to General Procedure 17, using 6-(1-cyanocyclopropyl)pyr- idine-3-carboxylic acid (Int. M-150, 0.470 g, 2.50 mmol, 1.0 eq.), 4-fluoro-2-(methyl- sulfonyl)aniline (0.520 g, 2.75 mmol, 1.10 eq.), DMAP (0.061 g, 0.5 mmol, 0.20 eq.) and POCl ₃ (0.756 g, 5.00 mmol, 2.00 eq.). The crude material was purified by FCC (0 to 5% EtOH gradient in DCM) to yield 6-(1-cyanocyclopropyl)-N-(4-fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int. M-151, 0.723 g, 1.99 mmol, 80%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.45 (s, 1H), 9.02 (dd, J = 2.4, 0.9 Hz, 1H), 8.33 (dd, J = 8.3, 2.3 Hz, 1H), 8.03 (dd, J = 9.0, 5.0 Hz, 1H), 7.80 (dd, J = 8.2, 3.0 Hz, 1H), 7.75 (dd, J = 8.3, 0.9 Hz, 1H), 7.71 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 3.35 (s, 3H), 1.96 – 1.90 (m, 2H), 1.83 – 1.78 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -113.15 – -113.60 (m). m/z (ESI): 360.0 [M+H] ⁺ . N-(4-fluoro-2-methanesulfonylphenyl)-6-(oxetan-3-yl)pyridine -3-carboxamide (Int. M-152) Ryvu Therapeutics S.A. RVU305 246 R10107WO A 20-mL Biotage ^TM reactor was charged with anhydrous DMA (12 mL), 4,4-di-tert-butyl-2,2- dipyridyl (0.055 g, 0.2 mmol, 0.15 eq.), NiCl ₂ .DME (0.050 g, 0.23 mmol, 0.16 eq.), NaI (0.088 g, 0.59 mmol, 0.42 eq.), 6-bromo-N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carbo x- amide (Int. K-082, 0.536 g, 1.41 mmol, 1 eq.), 3-iodooxetane (0.800 g, 4.35 mmol, 3.09 eq.), zinc powder 0.807 g, 12.34 mmol, 8.77 eq.), and TFA (0.010 mL, 0.141 mmol, 0.10 eq.). The RM was sparged with nitrogen for 5 min., the vial was capped, and the RM was stirred at 60 °C for 9 h. After coming back to RT, the RM was diluted with, filtered through a pad of Celite ^® , and the pad was washed with EtOAc. The filtrate was then washed with aq.5% NH ₄ OH (2x) and brine, dried over anhydrous MgSO ₄ , filtered end evaporated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-(4-fluoro-2-methanesulfonylphenyl)-6-(oxetan-3-yl)pyridine -3-carboxamide (Int. M- 152, 0.112 g, 0.31 mmol, 22%, off-white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 9.14 (dd, J = 2.4, 0.8 Hz, 1H), 8.25 (dd, J = 8.1, 2.4 Hz, 1H), 8.06 (dd, J = 9.0, 5.0 Hz, 1H), 7.81 (dd, J = 8.3, 3.0 Hz, 1H), 7.72 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 4.94 (dd, J = 8.5, 5.6 Hz, 2H), 4.82 (dd, J = 6.8, 5.6 Hz, 2H), 4.52 (tt, J = 8.5, 6.8 Hz, 1H), 3.36 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -111.81 – -115.62 (m). m/z (ESI): 351.4 [M+H] ⁺ . 6-(3,3-Difluoropyrrolidin-1-yl)-N-(2-methanesulfonylpyridin- 3-yl)pyridine-3-carboxamide Step 1: K ₂ CO ₃ (0.39 g, 2.82 mmol, 1.82 eq.) was added to a stirred solution of 3,3-difluoropyrrolidine (0.15 g, 1.40 mmol, 0.90 eq.) and ethyl 6-chloropyridine-3-carboxylate (0.300 g, 1.55 mmol, 1.0 eq.) in DMF (5 mL) and the resulting mixture was stirred with heating at 75 °C over- night. After coming back to RT, the RM was partitioned between water and DCM. The or- ganic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated under re- duced pressure. The crude material was purified by FCC (0 to 35% EtOAc gradient in hex- ane) to yield Ryvu Therapeutics S.A. RVU305 247 R10107WO ethyl 6-(3,3-difluoropyrrolidin-1-yl)pyridine-3-carboxylate (Int. M-153, 0.395 g, 1.43 mmol, 92%, white solid, UPLC purity: 93%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 6.48 (d, J = 9.0 Hz, 1H), 4.39 (t, J = 7.2 Hz, 2H), 4.01 (t, J = 12.7 Hz, 2H), 3.92 (m, 2H), 2.58 (tt, J = 7.3, 13.8 Hz, 2H), 1.46 – 1.36 (m, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -101.07 (m). m/z (ESI): 257.0 [M+H] ⁺ . Step 2: LiOH monohydrate (0.18 g, 4.29 mmol, 3.01 eq.) was added to a solution of ethyl 6-(3,3- difluoropyrrolidin-1-yl)pyridine-3-carboxylate (Int. M-153, 0.392 g, 1.42 mmol, 1.0 eq.) in a mixture of THF (7 mL) and water (8 mL) and the RM was stirred at RT for 2 h, and at 60 °C for 2 h. The RM was then cooled to 0 °C (ice bath) and aq.2 M HCl was added until pH ≈ 4. The resulting white precipitate was filtered off, washed with water and MTBE and dried under vacuum to yield 6-(3,3-difluoropyrrolidin-1-yl)pyridine-3-carboxylic acid (Int. M-154, 0.208 g, 0.90 mmol, 63%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.59 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.8, 2.4 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 3.92 (t, J = 13.2 Hz, 2H), 3.70 (t, J = 7.3 Hz, 2H), 2.64 – 2.52 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -99.38 – -100.81 (m). m/z (ESI): 229.1 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 17, using of 2-(methylsulfonyl)-3- pyridinamine (0.153 g, 0.89 mmol, 1.0 eq.), 6-(3,3-difluoropyrrolidin-1-yl)pyridine-3-carbox- ylic acid (Int. M-154, 0.205 g, 0.89 mmol, 1.0 eq.), DMAP (0.035 g, 0.29 mmol, 0.32 eq.) and POCl ₃ (0.42 g, 2.74 mmol, 3.08 eq.) in pyridine (6 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 6-(3,3-difluoropyrrolidin-1-yl)-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Int. M-155, 0.085 g, 0.20 mmol, 22%, white solid, UPLC purity: 89%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.52 (s, 1H), 8.87 (dd, J = 8.5, 1.5 Hz, 1H), 8.71 (d, J = 2.3 Hz, 1H), 8.51 (dd, J = 4.4, 1.4 Hz, 1H), 8.03 (dd, J = 8.9, 2.5 Hz, 1H), 7.79 (dd, J = 8.5, 4.4 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 3.96 (t, J = 13.1 Hz, 2H), 3.75 (d, J = 7.3 Hz, 2H), 3.46 (s, 3H), 2.66 – 2.53 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 100.02. m/z (ESI): 383.2 [M+H] ⁺ . 5-Chloro-6-cyano-N-(2-methanesulfonylpyridin-3-yl)pyridine-3 -carboxamide (Int. M-158) Step 1: NaCN (0.196 g, 4.00 mmol, 1.5 eq.) and DMAP (0.033 g, 0.27 mmol, 0.1 eq.) were added to a solution of methyl 5,6-dichloropyridine-3-carboxylate (0.55 g, 2.67 mmol, 1.0 eq.) in NMP (25 mL) and the RM was stirred at 100 °C overnight. After coming back to RT, the RM was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (2x) Ryvu Therapeutics S.A. RVU305 248 R10107WO and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , fil- tered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 15% EtOAc gradient in hexane) to yield methyl 5-chloro-6-cyanopyridine-3-carboxylate (Int. M-156, 0.275 g, 1.33 mmol, 50%, off-white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H), 3.94 (s, 3H). m/z (ESI): 196.9 [M+H] ⁺ . Step 2: A mixture of LiOH monohydrate (0.113 g, 2.68 mmol, 3.0 eq.) and methyl 5-chloro-6-cyano- pyridine-3-carboxylate (Int. M-156, 0.185 g, 0.89 mmol, 1.0 eq.) in THF (4.0 mL) and water (1.0 mL) was stirred at RT for 15 min. The mixture was acidified to pH ≈ 8 with aq.1 M HCl and extracted with DCM (3x). The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The obtained crude 5-chloro-6-cyanopyridine-3-carboxylic acid (Int. M-157, 0.118 g, 0.59 mmol, 66%, white solid, UPLC purity: 91%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.27 (s, 1H), 9.10 (d, J = 1.7 Hz, 1H), 8.61 (d, J = 1.6 Hz, 1H). m/z (ESI): 182.9 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 40, using 2-methanesulfonylpyridin- 3-amine (0.101 g, 0.59 mmol, 1.0 eq.), 5-chloro-6-cyanopyridine-3-carboxylic acid (Int. M- 157, 0.118 g, 0.59 mmol, 1.0 eq.), DMAP (0.022 g, 0.18 mmol, 0.3 eq.), DIPEA (0.256 mL, 1.47 mmol, 2.5 eq.) and T3P (50 wt. % in EtOAc, 0.7 mL, 2.35 mmol, 4.0 eq.) in toluene (5.0 mL). The crude material was triturated with the minimum amount of iPrOH, filtered off and dried under vacuum to yield 5-chloro-6-cyano-N-(2-methanesulfonylpyridin-3-yl)pyridine-3 -car- boxamide (Int. M-158, 0.12 g, 0.35 mmol, 59%, white solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.96 (s, 1H), 9.13 (d, J = 1.8 Hz, 1H), 8.67 (dd, J = 4.6, 1.5 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.46 (dd, J = 8.3, 1.5 Hz, 1H), 7.87 (dd, J = 8.3, 4.5 Hz, 1H), 3.33 (s, 3H). m/z (ESI): 335.0 [M-H]-. N-(4-fluoro-2-methanesulfonylphenyl)-6-(2-hydroxypropan-2-yl )pyridine-3-carboxamide Methylmagnesium bromide (3.0 M in diethyl ether, 1.04 mL, 3.12 mmol, 5.01 eq.) was added to a solution of ethyl 5-[(4-fluoro-2-methanesulfonylphenyl)carbamoyl]pyridine-2-ca rbox- ylate (Int. K-088, 0.24 g, 0.62 mmol, 1.0 eq.) in anhydrous THF (5 mL) at -30 °C under ni- trogen. The RM was allowed to slowly warm up to 0 °C over 3 h and was poured into ice/sat. aq. NH ₄ Cl. After vigorous stirring, the mixture was extracted with EtOAc and the Ryvu Therapeutics S.A. RVU305 249 R10107WO combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 80% EtOAc gradient in hex- ane) to yield N-(4-fluoro-2-methanesulfonylphenyl)-6-(2-hydroxypropan-2-yl )pyridine-3- carboxamide (Int. M-159, 0.105 g, 0.29 mmol, 46%, beige solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.40 (s, 1H), 9.02 (dd, J = 2.4, 0.8 Hz, 1H), 8.26 (dd, J = 8.3, 2.3 Hz, 1H), 8.08 (dd, J = 9.0, 4.9 Hz, 1H), 7.85 (dd, J = 8.3, 0.8 Hz, 1H), 7.80 (dd, J = 8.3, 3.0 Hz, 1H), 7.71 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 5.40 (s, 1H), 3.36 (s, 3H), 1.48 (s, 6H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -113.74 (dt, J = 8.2, 4.2 Hz). m/z (ESI): 353.3 [M+H] ⁺ . 6-Cyclobutyl-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-car boxamide (Int. M-162) Step 1: Cyclobutylzinc bromide (0.5 M in THF, 4.63 mL, 2.31 mmol, 1.0 eq.) was added dropwise to a solution of methyl 6‐bromopyridine‐3‐carboxylate (0.500 g, 2.31 mmol, 1.0 eq.) and Pd(dppf)Cl ₂ .DCM (0.189 g, 0.23 mmol, 0.1 eq.) in anhydrous THF (20 mL) under Ar. The RM was placed in preheated oil bath at 75 °C and stirred for 2 h at this temperature under Ar. The RM was then cooled to 50 °C and another portion of cyclobutylzinc bromide (0.5 M in THF, 4.63 mL, 2.31 mmol, 1.0 eq.) was added. The RM was stirred at 75 °C for 30 min. and at RT overnight under Ar. The RM was diluted with EtOAc and poured onto ice. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined or- ganic layers were filtered and the solid was washed with MeOH and DCM. The filtrate was evaporated under reduced pressure and the residue was redissolved in EtOAc and coevapo- rated with toluene. The crude material was purified by FCC (0 to 20% EtOAc gradient in hexane) to yield methyl 6‐cyclobutylpyridine‐3‐carboxylate (Int. M-160, 0.320 g, 1.61 mmol, 69%, colorless oil, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (dd, J = 2.3, 1.0 Hz, 1H), 8.20 (dd, J = 8.1, 2.2 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 3.88 (s, 3H), 3.74 (p, J = 8.6 Hz, 1H), 2.30 (td, J = 8.9, 6.1 Hz, 4H), 2.11 – 1.95 (m, 1H), 1.86 (dq, J = 11.3, 5.9 Hz, 1H). m/z (ESI): 192.1 [M+H] ⁺ . Step 2: ^{A solution of LiOH monohydrate (0.083 g, 1.98 mmol, 1.5 eq.) in H2O (5 mL) was added to a} _{solution of methyl 6‐cyclobutylpyridine‐3‐carboxylate (Int. M-160, 0.262 g, 1.32 mmol, 1} eq.) in THF (10 mL) at 0 °C. The RM was stirred for 2 h, being allowed to slowly come back to RT. It was then neutralized to pH ≈ 7 with aq.1 M HCl. The solvent was evaporated un- der reduced pressure and the residue was redissolved in a mixture of H ₂ O and MeCN, and the solution was lyophilized to yield 6‐cyclobutylpyridine‐3‐carboxylic acid contaminated with LiCl (1.5 eq.) (Int. M-161, 0.313 g, 1.26 mmol, 96%, white solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (d, J = 2.1 Hz, 1H), 8.10 (dd, J = 8.0, 2.2 Hz, 1H), 7.25 (d, Ryvu Therapeutics S.A. RVU305 250 R10107WO J = 8.0 Hz, 1H), 3.67 (p, J = 8.7 Hz, 1H), 2.32 – 2.23 (m, 4H), 2.02 (m, 1H), 1.89 – 1.77 (m, 1H). m/z (ESI): 178.0 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 17, using 2‐methanesulfonylpyri- din‐3‐amine (0.225 g, 1.31 mmol, 1.0 eq.), 6‐cyclobutylpyridine‐3‐carboxylic acid (Int. M-161, 0.239 g, 1.31 mmol, 1.0 eq.), POCl ₃ (0.24 mL, 2.61 mmol, 2 eq.) and DMAP (0.032 g, 0.26 mmol, 0.2 eq.) in pyridine (7.0 mL). The crude material was purified by FCC (0 to 25% EtOAc gradient in DCM) to yield 6‐cyclobutyl‐N‐(2‐methanesulfonylpyridin‐3‐yl)py ri- dine‐3‐carboxamide (Int. M-162, 0.260 g, 0.74 mmol, 57%, white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 9.06 (dd, J = 2.4, 0.8 Hz, 1H), 8.75 (dd, J = 8.4, 1.5 Hz, 1H), 8.58 (dd, J = 4.5, 1.5 Hz, 1H), 8.18 (dd, J = 8.2, 2.4 Hz, 1H), 7.83 (dd, J = 8.5, 4.5 Hz, 1H), 7.51 – 7.44 (m, 1H), 3.76 (p, J = 8.6 Hz, 1H), 3.45 (s, 3H), 2.37 – 2.28 (m, 4H), 2.11 – 1.98 (m, 1H), 1.94 – 1.82 (m, 1H). m/z (ESI): 332.4 [M+H] ⁺ . 2-Cyclobutyl-N-(2-methanesulfonylpyridin-3-yl)pyrimidine-5-c arboxamide (Int. M-165) Step 1: Cyclobutylzinc bromide (0.5 M in THF, 2.80 mL, 1.40 mmol, 1.04 eq) was added dropwise to a solution of ethyl 2-chloropyrimidine-5-carboxylate (0.25 g, 1.34 mmol, 1.0 eq.) and ^{Pd(PPh3)4 (0.1 g, 0.087 mmol, 0.06 eq.) in anhydrous THF (7.5 mL) under Ar. The RM was} _{placed in preheated oil bath at 75 °C and stirred at reflux for 75 min. under Ar. After com-} ing back to RT, the RM was partitioned between sat. aq. NH ₄ Cl and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic lay- ers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 30% EtOAc gradient in hexane) to yield ethyl 2-cy- clobutylpyrimidine-5-carboxylate (Int. M-163, 0.175 g, 0.63 mmol, 47%, colorless oil, UPLC purity: 74%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.85 (p, J = 8.7 Hz, 1H), 2.42 – 2.29 (m, 4H), 2.12 – 1.98 (m, 1H), 1.94 – 1.83 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H). m/z (ESI): 207.2 [M+H] ⁺ . Step 2: A solution of LiOH monohydrate (0.027 g, 0.64 mmol, 1.2 eq.) in water (1 mL) was added to a solution of ethyl 2-cyclobutylpyrimidine-5-carboxylate (Int. M-163, 0.15 g, 0.54 mmol, 1.0 eq.) in a mixture of THF (1 mL) and MeOH (1 mL), and the RM was left with stirring at RT for 45 min. The RM was concentrated, coevaporated with EtOH (2x) and lyophilized to yield 2-cyclobutylpyrimidine-5-carboxylate as its lithium salt (Int. M-164, 0.13 g, 0.63 mmol, Ryvu Therapeutics S.A. RVU305 251 R10107WO 118%, white solid, UPLC purity: 90%) which was used in the next step without further purifi- cation. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 2H), 3.73 (p, J = 8.6 Hz, 1H), 2.42 – 2.22 (m, 4H), 2.10 – 1.95 (m, 1H), 1.91 – 1.78 (m, 1H). m/z (ESI): 179.2 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 17, using lithio 2-cyclobutylpyrimi- dine-5-carboxylate (Int. M-164, 0.175 g, 0.98 mmol, 1.0 eq.), 2-methanesulfonylpyridin-3- amine (0.21 g, 1.22 mmol, 1.24 eq.), POCl ₃ (0.45 g, 2.93 mmol, 2.99 eq.) and DMAP (0.035 g, 0.29 mmol, 0.29 eq.) in pyridine (5.0 mL). The crude material was purified by FCC (0 to 70% EtOAc gradient in hexane) to yield 2-cyclobutyl-N-(2-methanesulfonylpyridin-3-yl)pyrimi- dine-5-carboxamide (Int. M-165, 0.295 g, 0.84 mmol, 86%, yellow solid, UPLC purity: 95%). NMR (400 MHz, DMSO-d ₆ ) δ 10.77 (s, 1H), 9.20 (s, 2H), 8.62 (dd, J = 4.5, 1.5 Hz, 1H), 8.59 (dd, J = 8.4, 1.4 Hz, 1H), 7.85 (dd, J = 8.4, 4.5 Hz, 1H), 3.88 (p, J = 8.6 Hz, 1H), 3.43 (s, 3H), 2.47 – 2.29 (m, 4H), 2.15 – 2.00 (m, 1H), 1.98 – 1.85 (m, 1H). m/z (ESI): 333.3 [M+H] ⁺ . 5-Cyano-6-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyrid ine-3-carboxamide (Int. M- Step 1: A mixture of methyl 5-bromo-6-chloropyridine-3-carboxylate (1.0 g, 3.99 mmol, 1.0 eq.) and CuCN (0.429 g, 4.79 mmol, 1.2 eq.) in NMP (3 mL) was heated overnight at 110 °C. After coming back to RT, the RM was diluted with water and extracted with CHCl ₃ /iPrOH 3:1 v/v (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hexane) to yield methyl 6-chloro-5-cyanopyridine-3-car- boxylate (Int. M-166, 0.23 g, 0.95 mmol, 24%, white solid, UPLC purity: 81%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.14 (d, J = 2.3 Hz, 1H), 8.92 (d, J = 2.3 Hz, 1H), 3.93 (s, 3H). m/z (ESI): 196.9 [M+H] ⁺ . Step 2: A mixture of methyl 6-chloro-5-cyanopyridine-3-carboxylate (Int. M-166, 0.23 g, 0.95 mmol, 1.0 eq.), cyclopropylboronic acid (0.244 g, 2.84 mmol, 3.0 eq.), K ₃ PO ₄ (1.00 g, 4.74 mmol, 5.0 Ryvu Therapeutics S.A. RVU305 252 R10107WO eq.), tricyclohexylphosphine (0.053 g, 0.19 mmol, 0.2 eq.), Pd(OAc) ₂ (0.021 g, 0.09 mmol, 0.1 eq.), toluene (18.0 mL) and water (2.0 mL) was sparged with nitrogen for 5 minutes and stirred at 95 °C for 90 min. under nitrogen. The RM was cooled to RT and filtered through a pad of Celite ^® . The filter cake was rinsed with EtOAc and water and the filtrate was ex- tracted with EtOAc (2x). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield methyl 5-cyano- 6-cyclopropylpyridine-3-carboxylate (Int. M-167, 0.151 g, 0.747 mmol, 79%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 2.1 Hz, 1H), 3.89 (s, 3H), 2.54 – 2.46 (m, 1H), 1.32 – 1.25 (m, 2H), 1.21 – 1.16 (m, 2H). m/z (ESI): 203.0 [M+H] ⁺ . Step 3: LiOH monohydrate (0.138 g, 3.28 mmol, 3.0 eq.) was added to a suspension of methyl 5-cy- ano-6-cyclopropylpyridine-3-carboxylate (Int. M-167, 0.221 g, 1.09 mmol, 1.0 eq.) in a mix- ture of MeOH (2.0 mL) and water (2.0 mL), and the RM was stirred at RT for 2 h. The MeOH was evaporated and 35% aq. HCl was added dropwise until the end of the precipitate for- mation. The slurry was extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield 5-cy- ano-6-cyclopropylpyridine-3-carboxylic acid (Int. M-168, 0.206 g, 1.09 mmol, 100%, beige solid, UPLC purity: 100%). m/z (ESI): 188.8 [M+H] ⁺ . Step 4: Step 4 was performed according to General Procedure 40, using 2-methanesulfonylpyridin- 3-amine (0.167 g, 0.97 mmol, 1.0 eq.), 5-cyano-6-cyclopropylpyridine-3-carboxylic acid (Int. M-168, 0.183 g, 0.97 mmol, 1.00 eq.), DIPEA (0.422 mL, 2.42 mmol, 2.50 eq.), T3P (50% in EtOAc, 0.577 mL, 1.94 mmol, 2.0 eq.) and DMAP (0.006 g, 0.05 mmol, 0.05 eq.). The crude material was triturated with iPrOH, filtered and dried under vacuum to yield 5-cyano-6-cy- clopropyl-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carbox amide (Int. M-169, 0.252 g, 0.74 mmol, 76%, beige solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.73 (s, 1H), 9.13 (d, J = 2.3 Hz, 1H), 8.63 (dd, J = 3.5, 1.8 Hz, 2H), 8.55 (dd, J = 8.4, 1.5 Hz, 1H), 7.84 (dd, J = 8.4, 4.5 Hz, 1H), 3.42 (s, 3H), 2.51 (m, 1H), 1.29 (dt, J = 7.8, 3.1 Hz, 2H), 1.21 (dt, J = 4.4, 3.0 Hz, 2H). m/z (ESI): 343.3 [M+H] ⁺ . 6-Cyano-N-(2-methanesulfonyl-4-methylphenyl)pyridine-3-carbo xamide (Int. M-172) Step 1: Step 1 was performed according to General Procedure 20, using sodium methanesulfinate (0.744 g, 7.28 mmol, 1.25 eq.) 2-chloro-4-methyl-1-nitrobenzene (1.0 g, 5.83 mmol, 1.0 eq.) Ryvu Therapeutics S.A. RVU305 253 R10107WO in DMSO (3 mL), without need for CuI nor L-ProONa. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 2-methanesulfonyl-4-methyl-1-nitroben- zene (Int. M-170, 1.025 g, 4.71 mmol, 81%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.03 (dd, J = 1.9, 0.8 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.64 – 7.56 (m, 1H), 3.47 (s, 3H), 2.57 (d, J = 0.8 Hz, 3H). m/z (ESI): 215.8 [M+H] ⁺ . Step 2: Iron powder (2.620 g, 46.9 mmol, 10.0 eq.) and conc. aq. HCl (2.536 mL, 30.43 mmol, 6.5 eq.) were added to a solution of 2-methanesulfonyl-4-methyl-1-nitrobenzene (Int. M-170, 1.02 g, 4.69 mmol, 1.0 eq.) in EtOH (50.0 mL). The RM was refluxed for 30 min. and left with stirring at RT overnight. The RM was diluted with EtOAc and filtered through a pad of Celite ^® . The filter cake was washed with EtOAc and the filtrate was neutralized with sat. aq. NaHCO ₃ . The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The resi- due was triturated with hexane, filtered and dried under vacuum to yield 2-methanesul- fonyl-4-methylaniline (Int. M-171, 0.82 g, 4.29 mmol, 92%, white solid). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.34 (dd, J = 2.2, 1.0 Hz, 1H), 7.19 (dd, J = 8.4, 2.2 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 5.83 (s, 2H), 3.08 (s, 3H), 2.20 (s, 3H). m/z (ESI): 186.1 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 40, using 6-cyanonicotinic acid (0.700 g, 4.72 mmol, 1.1 eq.), DIPEA (1.870 mL, 10.73 mmol, 2.5 eq.), DMAP (0.026 g, 0.21 mmol, 0.05 eq.), 2-methanesulfonyl-4-methylaniline (Int. M-171, 0.82 g, 4.29 mmol, 1.0 eq.) and T3P (50% in EtOAc, 2.556 mL, 8.59 mmol, 2.0 eq.) in toluene (13.0 mL). The crude ma- terial was purified by trituration with iPrOH to yield 6-cyano-N-(2-methanesulfonyl-4- methylphenyl)pyridine-3-carboxamide (Int. M-172, 0.419 g, 1.13 mmol, 26%, yellow solid, UPLC purity: 85%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 9.20 (dd, J = 2.2, 0.9 Hz, 1H), 8.48 (dd, J = 8.1, 2.2 Hz, 1H), 8.29 (dd, J = 8.1, 0.9 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.2, 2.0 Hz, 1H), 3.28 (s, 3H), 2.43 (s, 3H). m/z (ESI): 316.3 [M+H] ⁺ . tert-Butyl 7-[(4-fluoro-2-methanesulfonylphenyl)carbamoyl]-1,2,3,4-tetr ahydro-1,5-naph- thyridine-1-carboxylate (Int. M-179)

Ryvu Therapeutics S.A. RVU305 254 R10107WO Step 1: ^Boc ₂ ^{O (3.75 g, 17.18 mmol, 2.52 eq.) and DMAP (0.085 g, 0.70 mmol, 0.10 eq.) were added} to a solution of methyl 5-amino-6-chloropyridine-3-carboxylate (2.16 g, 8.54 mmol, 1.0 eq.) in THF (38 mL) and the RM was stirred at RT for 60 hours. The solvent was removed in vacuo, the residue was taken up in methanol (5 mL), K ₂ CO ₃ (2.36 g, 17.08 mmol, 2.0 eq.) was added and the RM was stirred at RT for 4 h. Sat. aq. NH ₄ Cl was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhy- drous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude material was purified by FCC (0 to 30% EtOAc gradient in hexane) to yield methyl 5-{[(tert-butoxy)carbonyl]amino}-6- chloropyridine-3-carboxylate (Int. M-173, 0.9 g, 3.11 mmol, 46%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.14 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H), 3.90 (s, 3H), 1.50 (s, 9H). m/z (ESI): 287.0 [M+H] ⁺ . Step 2: 2-Ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.97 g, 6.30 mmol, 2.03 eq.), Pd(PPh ₃ ) ₄ (0.179 g, 0.16 mmol, 0.05 eq.) and K ₂ CO ₃ (1.29 g, 9.334 mmol, 3.00 eq.) were added to a de- gassed solution of methyl 5-{[(tert-butoxy)carbonyl]amino}-6-chloropyridine-3-carboxyl ate (Int. M-173, 0.9 g, 3.11 mmol, 1.0 eq.) in a mixture of DME (18.3 mL) and water (1.8 mL) and the RM was heated under microwave irradiation at 120 °C for 1 hour. The RM was then partitioned between water, and EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and then concentrated under reduced pressure. The crude ma- terial was purified by FCC (0 to 60% EtOAc gradient in hexane) to yield methyl 5-{[(tert- butoxy)carbonyl]amino}-6-ethenylpyridine-3-carboxylate (Int. M-174, 0.775 g, 2.73 mmol, 88%, yellow solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 16.8, 10.6 Hz, 1H), 6.44 (dd, J = 16.8, Ryvu Therapeutics S.A. RVU305 255 R10107WO 2.4 Hz, 1H), 5.61 (dd, J = 10.6, 2.4 Hz, 1H), 3.89 (s, 3H), 1.48 (s, 9H). m/z (ESI): 279.1 [M+H] ⁺ . Step 3: NaH (60 % in mineral oil, 0.145 g, 3.78 mmol, 1.60 eq.) was added to a solution of methyl 5- {[(tert-butoxy)carbonyl]amino}-6-ethenylpyridine-3-carboxyla te (Int. M-174, 0.67 g, 2.36 mmol, 1.0 eq.) in DMF (15 mL) under argon at 0 °C. After stirring at RT for 10 min., allyl bromide (0.8 g, 6.61 mmol, 2.80 eq.) was added and the RM was stirred at RT for 40 min. The reaction was quenched with sat. aq. NH ₄ Cl and the mixture was partitioned between water and EtOAc. The organic layer was washed with water (2x), brine, dried over anhy- drous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by FCC (0 to 30% EtOAc gradient in hexane) to yield methyl 5-{[(tert-butoxy)carbonyl](prop-2-en-1- yl)amino}-6-ethenylpyridine-3-carboxylate (Int. M-175, 0.68 g, 2.093 mmol, 82%, colorless oil, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 17.0, 10.6 Hz, 1H), 6.52 (dd, J = 17.0, 2.3 Hz, 1H), 5.95 – 5.78 (m, 1H), 5.70 (dd, J = 10.6, 2.3 Hz, 1H), 5.11 (s, 1H), 5.08 (d, J = 10.0 Hz, 1H), 4.39 – 4.20 (m, 1H), 4.20 – 4.03 (m, 1H), 3.90 (s, 3H), 1.59 – 1.16 (m, 9H). m/z (ESI): 319.2 [M+H] ⁺ . Step 4: Hoveyda-Grubbs Catalyst ^® 2nd Generation (0.06 g, 0.096 mmol, 0.05 eq.) was added to a so- lution of methyl 5-{[(tert-butoxy)carbonyl](prop-2-en-1-yl)amino}-6-ethenylpy ridine-3-car- boxylate (Int. M-175, 0.625 g, 1.92 mmol, 1.0 eq.) in anhydrous DCE (20 mL) and the RM was stirred at 80° C for 3 h under nitrogen. After coming back to RT, the RM was evapo- rated over silica and the crude material was purified by FCC (0 to 40% EtOAc gradient in hexane) to yield 1-tert-butyl 7-methyl 1,2-dihydro-1,5-naphthyridine-1,7-dicarboxylate (Int. M-176, 0.53 g, 1.81 mmol, 87%, beige solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.69 (d, J = 1.9 Hz, 1H), 8.42 (d, J = 1.9 Hz, 1H), 6.69 – 6.61 (m, 1H), 6.55 (dt, J = 9.9, 4.0 Hz, 1H), 4.47 (dd, J = 4.0, 1.9 Hz, 2H), 3.89 (s, 3H), 1.50 (s, 9H). m/z (ESI): 291.0 [M+H] ⁺ . Step 5: 10% Pd/C (0.480 g) was added to a solution of 1-tert-butyl 7-methyl 1,2-dihydro-1,5-naph- thyridine-1,7-dicarboxylate (Int. M-176, 0.53 g, 1.807 mmol, 1.0 eq.) in MeOH (18.0 mL) and the atmosphere was first replaced by argon, with two cycles of vacuum/argon, then by hy- drogen with two cycles of vacuum/hydrogen. The RM was stirred under hydrogen (1 atm) for 2.5 h at RT. The mixture was then filtered through a pad of Celite ^® and the filtrate was evaporated under reduced pressure. The residue was taken up in DCM/MeOH 9:1 v/v and the solution was filtered through a syringe microfilter. The filtrate was evaporated under re- duced pressure to yield 1-tert-butyl 7-methyl 1,2,3,4-tetrahydro-1,5-naphthyridine-1,7-di- carboxylate (Int. M-177, 0.500 g, 1.69 mmol, 94%, dark beige solid, UPLC purity: 99%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (d, J = 1.9 Hz, 1H), 8.61 (d, J = 1.9 Hz, 1H), 3.88 (s, 3H), 3.78 – 3.66 (m, 2H), 2.95 (t, J = 6.5 Hz, 2H), 2.01 – 1.89 (m, 2H), 1.50 (s, 9H). m/z (ESI): 293.1 [M+H] ⁺ . Step 6: Ryvu Therapeutics S.A. RVU305 256 R10107WO TMSOK (0.435 g, 3.39 mmol, 2.00 eq.) was added to a suspension of 1-tert-butyl 7-methyl 1,2,3,4-tetrahydro-1,5-naphthyridine-1,7-dicarboxylate (Int. M-177, 0.5 g, 1.69 mmol, 1.0 eq.) in anhydrous THF (11 mL), and the RM was stirred at RT for 3 h under nitrogen. It was diluted with ethyl acetate and aq.1 M HCl was added until pH ≈ 5 was reached. The or- ganic phase was separated and the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to yield 5-[(tert-butoxy)carbonyl]-5,6,7,8-tetrahydro-1,5-naphthy- ridine-3-carboxylic acid (Int. M-178, 0.425 g, 1.45 mmol, 85%, beige solid, UPLC purity: 95%) ^{which was used in the next step without futher purification. 1H NMR (400 MHz, DMSO-d6)} _{δ 13.29 (s, 1H), 8.65 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 1.9 Hz, 1H), 3.77 – 3.65 (m, 2H), 2.94 (t,} J = 6.6 Hz, 2H), 1.99 – 1.86 (m, 2H), 1.49 (s, 9H). m/z (ESI): 279.1 [M+H] ⁺ . Step 7: Step 7 was performed according to General Procedure 17, using 5-[(tert-butoxy)carbonyl]- 5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylic acid (Int. M-178, 0.25 g, 0.85 mmol, 1.0 eq.), 4-fluoro-2-methanesulfonylaniline (0.18 g, 0.95 mmol, 1.12 eq.), DMAP (0.032 g, 0.26 mmol, 0.31 eq.) and POCl ₃ (0.4 g, 2.61 mmol, 3.06 eq.) in pyridine (5.0 mL). The crude mate- rial was purified by FCC (0 to 70% EtOAc gradient in hexane) to yield tert-butyl 7-[(4-fluoro- 2-methanesulfonylphenyl)carbamoyl]-1,2,3,4-tetrahydro-1,5-na phthyridine-1-carboxylate (Int. M-179, 0.215 g, 0.47 mmol, 55%, beige solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.40 (s, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.08 (dd, J = 9.0, 4.9 Hz, 1H), 7.80 (dd, J = 8.3, 3.0 Hz, 1H), 7.71 (td, J = 8.5, 3.1 Hz, 1H), 3.76 – 3.70 (m, 2H), 3.35 (s, 3H), 2.96 (t, J = 6.6 Hz, 2H), 2.03 – 1.89 (m, 2H), 1.50 (s, 9H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -113.78 (td, J = 8.1, 4.9 Hz). _m/z (ESI): 450.2 [M+H] ⁺ . 6-Cyclopropyl-5-fluoro-N-(2-methanesulfonylpyridin-3-yl)pyri dine-3-carboxamide (Int. M- In a pressure vessel, 6-bromo-5-fluoro-N-(2-methanesulfonylpyridin-3-yl)pyridine-3 -car- boxamide (Int. K-092, 0.267 g, 0.71 mmol, 1.0 eq.), K ₂ CO ₃ (0.15 g, 1.08 mmol, 1.52 eq.) and cyclopropylboronic acid (0.32 g, 3.72 mmol, 5.22 eq.) were dissolved in a mixture of toluene (10 mL) and water (1 mL), and the mixture was sparged with nitrogen for 5 min. Pd(dppf)Cl ₂ (0.028 g, 0.04 mmol, 0.05 eq.) was added, the vessel was sealed and the RM was stirred at 110 °C for 5 h. After coming back to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 60% EtOAc gradient in hexane) to yield 6-cyclopropyl-5-fluoro-N-(2-methanesulfonylpyridin-3-yl)pyri dine-3-carboxamide (Int. M-180, 0.21 g, 0.62 mmol, 87%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO- Ryvu Therapeutics S.A. RVU305 257 R10107WO d ₆ ) δ 10.70 (s, 1H), 8.81 (t, J = 1.5 Hz, 1H), 8.64 (dd, J = 8.4, 1.4 Hz, 1H), 8.60 (dd, J = 4.5, 1.4 Hz, 1H), 8.04 (dd, J = 10.4, 1.8 Hz, 1H), 7.83 (dd, J = 8.4, 4.5 Hz, 1H), 3.43 (s, 3H), 2.46 – 2.37 (m, 1H), 1.21 – 1.05 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -130.03 (d, J = 10.2 Hz). m/z (ESI): 336.5 [M+H] ⁺ . 6-Cyclopropyl-N-(2-methanesulfonyl-5-methylpyridin-3-yl)pyri dine-3-carboxamide (Int. M- 182) Step 1: Step 1 was performed according to General Procedure 17, using 2-chloro-5-methylpyridin- 3-amine (0.6 g, 4.21 mmol, 1.0 eq.), DMAP (0.180 g, 1.47 mmol, 0.35 eq.), 6-cyclopropylpyri- dine-3-carboxylic acid (0.687 g, 4.21 mmol, 1.0 eq.) and POCl ₃ (1.290 g, 8.42 mmol, 2.0 eq.) in anhydrous pyridine (20 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in DCM) to yield N-(2-chloro-5-methylpyridin-3-yl)-6-cyclopropylpyridine-3-ca r- boxamide (Int. M-181, 0.863 g, 2.85 mmol, 68%, beige solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 8.97 (dd, J = 2.3, 0.8 Hz, 1H), 8.17 (m, 1H), 8.17 (dd, J = 8.3, 2.5 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.3, 0.8 Hz, 1H), 2.34 (s, 3H), 2.22 (tt, J = 7.9, 4.9 Hz, 1H), 1.05 (dt, J = 7.8, 2.5 Hz, 2H), 1.02 (dt, J = 4.9, 2.6 Hz, 2H). m/z (ESI): 289.0 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 20, using N-(2-chloro-5-methylpyri- din-3-yl)-6-cyclopropylpyridine-3-carboxamide (Int. M-181, 0.827 g, 2.73 mmol, 1.0 eq.), so- dium methanesulfinate (1.338 g, 13.11 mmol, 4.8 eq.), CuI (0.156 g, 0.82 mmol, 0.3 eq.) and L-ProONa (0.150 g, 1.09 mmol, 0.4 eq.) in DMSO (9.0 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 6-cyclopropyl-N-(2-methanesulfonyl-5- methylpyridin-3-yl)pyridine-3-carboxamide (Int. M-182, 0.462 g, 1.31 mmol, 48%, off-white solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.93 (dd, J = 2.4, 0.8 Hz, 1H), 8.61 – 8.58 (m, 1H), 8.44 – 8.40 (m, 1H), 8.10 (dd, J = 8.2, 2.4 Hz, 1H), 7.53 (dd, J = 8.3, 0.9 Hz, 1H), 3.40 (s, 3H), 2.45 (s, 3H), 2.24 (tt, J = 7.9, 4.9 Hz, 1H), 1.07 (dt, J = 8.1, 2.5 Hz, 2H), 1.03 (dt, J = 4.9, 2.6 Hz, 2H). m/z (ESI): 332.0 [M+H] ⁺ . N-(4-fluoro-2-methanesulfonylphenyl)-2-(morpholin-4-yl)pyrim idine-5-carboxamide (Int. M-185) Ryvu Therapeutics S.A. RVU305 258 R10107WO Step 1: A mixture of ethyl 2-chloropyrimidine-5-carboxylate (0.55 g, 2.95 mmol, 1.0 eq.) and mor- pholine (0.77 mL, 8.80 mmol, 3.0 eq.) in MeCN (7.0 mL) was stirred at 60 °C for 2 h. After coming back to RT, the RM was diluted with water and extracted with EtOAc (2x). The com- bined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was diluted with hexane and evaporated under reduced pressure to yield ethyl 2- (morpholin-4-yl)pyrimidine-5-carboxylate (Int. M-183, 0.678 g, 2.86 mmol, 97%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.84 (dd, J = 5.7, 4.1 Hz, 4H), 3.67 (dd, J = 5.6, 4.1 Hz, 4H), 1.30 (t, J = 7.1 Hz, 3H). m/z (ESI): 238.2 [M+H] ⁺ . Step 2: Aq. 1 M NaOH (8.0 mL) was added to a solution of ethyl 2-(morpholin-4-yl)pyrimidine-5- carboxylate (Int. M-183, 0.635 g, 2.68 mmol, 1.0 eq.) in EtOH (15.0 mL) and the RM was stirred at RT for 4 h. The volatiles were evaporated and the white residue was taken up in water. The pH was adjusted to ≈ 2 by addition of aq.2 M HCl and the mixture was ex- tracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The obtained crude 2- (morpholin-4-yl)pyrimidine-5-carboxylic acid (Int. M-184, 0.42 g, 1.97 mmol, 73%, white solid, UPLC purity: 98%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 8.79 (s, 2H), 3.83 (dd, J = 5.6, 4.1 Hz, 4H), 3.67 (dd, J = 5.6, 4.1 Hz, 4H). m/z (ESI): 210.0 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 40, using 2-(morpholin-4-yl)pyrimi- dine-5-carboxylic acid (Int. M-184, 0.28 g, 1.31 mmol, 1.0 eq.), T3P (50% in DMF, 1.56 mL, 2.62 mmol, 2.0 eq.), 4-fluoro-2-methanesulfonylaniline (0.27 g, 1.43 mmol, 1.1 eq.), DIPEA (0.57 mL, 3.28 mmol, 2.5 eq.) and DMAP (0.08 g, 0.655 mmol, 0.5 eq.) in a mixture of toluene (6 mL) and DMF (1.5 mL), at 90 °C overnight. Extra portions of DIPEA (0.57 mL, 3.28 mmol, 2.5 eq.) and T3P (50% in DMF, 1.56 mL, 2.62 mmol, 2.0 eq.) were added at 0 °C and stir- ring at 90 °C was pursued for 2 h. The reaction was quenched with sat. aq. Na ₂ CO ₃ and the mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was triturated with the minimum amount of iPrOH/EtOAc 95:5 v/v, filtered-off and dried under vacuum to yield N-(4-fluoro-2-methanesulfonylphenyl)-2-(morpholin-4-yl)py- rimidine-5-carboxamide (Int. M-185, 0.193 g, 0.43 mmol, 32%, white solid, UPLC purity: 84%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 (s, 1H), 8.87 (s, 2H), 8.07 (dd, J = 9.0, 4.9 Hz, Ryvu Therapeutics S.A. RVU305 259 R10107WO 1H), 7.78 (dd, J = 8.3, 3.0 Hz, 1H), 7.69 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 3.85 (dd, J = 5.7, 4.0 Hz, 4H), 3.69 (dd, J = 5.6, 4.1 Hz, 4H), 3.34 (s, 3H). m/z (ESI): 381.2 [M+H] ⁺ . N-(2-methanesulfonylpyridin-3-yl)-6-[1-(trifluoromethyl)cycl opropyl]pyridine-3-carbox- Step 1: A pressure vessel was charged with methyl 6-bromopyridine-3-carboxylate (0.6 g, 2.78 mmol, 1.0 eq.), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-diox aborinane (0.863 g, 3.89 mmol, 1.4 eq.), K ₂ CO ₃ (0.844 g, 6.11 mmol, 2.2 eq.), MeCN (14.5 mL) and water (2.4 mL), and the mixture was sparged with argon for 20 min. Pd(dppf)Cl ₂ .DCM (0.227 g, 0.28 mmol, 0.1 eq.) was added, the vessel was sealed, and the RM was stirred at 80 °C for 1.5 h. After coming back to RT, the RM was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated _{in vacuo} below 40 °C. The crude material was purified by FCC (0 to 80% EtOAc gradient in hexane) to yield methyl 6-(3,3,3-trifluoroprop- 1-en-2-yl)pyridine-3-carboxylate (Int. M-186, 0.287 g, 1.23 mmol, 44%, yellow solid, UPLC purity: 99%). ¹ H NMR (400 MHz, Chloroform-d) δ 9.24 (dd, J = 2.2, 0.9 Hz, 1H), 8.35 (dd, J = 8.4, 2.2 Hz, 1H), 7.64 – 7.57 (m, 1H), 6.77 (q, J = 1.9 Hz, 1H), 6.27 (q, J = 1.3 Hz, 1H), 3.99 (s, 3H). m/z (ESI): 232.0 [M+H] ⁺ . Step 2: NaHMDS (2 M in THF, 0.843 mL, 1.69 mmol, 1.6 eq.) was added to a suspension of methyl 6-(3,3,3-trifluoroprop-1-en-2-yl)pyridine-3-carboxylate (Int. M-186, 0.246 g, 1.05 mmol, 1.0 eq.) and diphenyl(methyl)sulfonium tetrafluoroborate (0.395 g, 1.37 mmol, 1.3 eq.) in anhy- drous THF (15.0 mL) at 0 °C under nitrogen. The RM was stirred at 0 °C for 10 min and at RT for 1.5 h. Methanol (15.0 mL) was added to quench the reaction. After stirring for 30 min., 1.5 mL of aq. 1 M NaOH was added and the mixture was left with stirring overnight at RT. The RM was then evaporated under reduced pressure and the residue was suspended in water (15 mL). The suspension was filtered and the filtrate was washed with EtOAc (2x). The aqueous phase was acidified to pH ≈ 3 by addition of aq. 2 M HCl and extracted with DCM (2x). The combined DCM layers were dried over anhydrous Na ₂ SO ₄ , filtered and con- centrated in vacuo to yield 6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxylic acid (Int. Ryvu Therapeutics S.A. RVU305 260 R10107WO M-187, 0.218 g, 0.91 mmol, 86%, off-white solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.46 (s, 1H), 9.02 (dd, J = 2.3, 0.9 Hz, 1H), 8.30 (dd, J = 8.3, 2.2 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 1.51 (s, 4H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -65.68. m/z (ESI): 232.0 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 17, using 2-(methylsulfonyl)-3-pyri- dinamine (0.154 g, 0.89 mmol, 1.0 eq.), DMAP (0.054 g, 0.45 mmol, 0.5 eq.), 6-[1-(trifluoro- methyl)cyclopropyl]pyridine-3-carboxylic acid (Int. M-187, 0.215 g, 0.89 mmol, 1.0 eq.) and POCl ₃ (0.274 g, 1.79 mmol, 2.0 eq.). The crude N-(2-methanesulfonylpyridin-3-yl)-6-[1-(tri- fluoromethyl)cyclopropyl]pyridine-3-carboxamide (Int. M-188, 0.326 g, 0.761 mmol, 85%, beige solid, UPLC purity: 91%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.75 (s, 1H), 9.06 (dd, J = 2.4, 0.9 Hz, 1H), 8.68 (dd, J = 8.4, 1.4 Hz, 1H), 8.60 (dd, J = 4.5, 1.5 Hz, 1H), 8.31 (dd, J = 8.3, 2.4 Hz, 1H), 7.84 (dd, J = 8.4, 4.5 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 3.43 (s, 3H), 1.53 (d, J = 2.9 Hz, 4H). m/z (ESI): 386.0 [M+H] ⁺ . 5-Chloro-6-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyri dine-3-carboxamide (Int. M- 191) Step 1: Aq. 1 M NaOH (6.41 mL, 6.41 mmol, 5 eq.) was added to a solution of methyl 6-bromo-5- chloropyridine-3-carboxylate (0.321 g, 1.28 mmol, 1.0 eq.) in MeOH (4.3 mL) and the RM was stirred at RT for 1 h. The mixture was acidified to pH ≈ 3-4 by with aq.1 M HCl and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over anhydrous MgSO ₄ , filtered, and concentrated un- der reduced pressure. The obtained crude 6-bromo-5-chloropyridine-3-carboxylic acid (Int. M-189, 0.291 g, 1.11 mmol, 86%, white solid, UPLC purity: 90%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.92 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H). m/z (ESI): 237.7 [M+H] ⁺ . Step 2: Step 2 was carried out according to General Procedure 17, using 6-bromo-5-chloropyridine- 3-carboxylic acid (Int. M-189, 0.291 g, 1.11 mmol, 1.0 eq.), 2-methanesulfonylpyridin-3- amine (0.381 g, 2.21 mmol, 2.0 eq.) and POCl ₃ (0.340 g, 2.21 mmol, 2.0 eq.). The obtained crude 6-bromo-5-chloro-N-(2-methanesulfonylpyridin-3-yl)pyridine-3 -carboxamide (Int. M- 190, 0.472 g, 1.09 mmol, 98%, orange solid, UPLC purity: 97%) was used for next step with- out purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.84 – 10.76 (m, 1H), 8.85 (d, J = 2.1 Hz, Ryvu Therapeutics S.A. RVU305 261 R10107WO 1H), 8.62 (dd, J = 4.6, 1.4 Hz, 1H), 8.51 (dd, J = 8.4, 1.4 Hz, 1H), 8.49 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 8.3, 4.5 Hz, 1H), 3.41 (s, 3H). m/z (ESI): 391.8 [M+H] ⁺ . Step 3: A Biotage ^TM microwave vial was charged with 6-bromo-5-chloro-N-(2-methanesulfonylpyri- din-3-yl)pyridine-3-carboxamide (Int. M-190, 0.272 g, 0.63 mmol, 1.0 eq.), K ₂ CO ₃ (0.135 g, 0.98 mmol, 1.56 eq.), cyclopropylboronic acid (0.285 g, 3.32 mmol, 5.30 eq.), toluene (8 mL) and water (1 mL). The RM was sparged with argon for 10 min., Pd(dppf)Cl ₂ (0.06 g, 0.08 mmol, 0.13 eq.) was added, the vial was sealed, and the RM was stirred at 110 °C for 1 h in a DrySyn ^® . After coming back to RT, the RM was partitioned between DCM and water. The aqueous layer was extracted with DCM (2x) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 35% EtOAc gradient in hexane) to yield 5-chloro-6-cyclopropyl-N- (2-methanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Int. M-191, 0.173 g, 0.53 mmol, 85%, white solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.60 (m, 2H), 8.28 (d, J = 2.0 Hz, 1H), 7.87 – 7.80 (m, 1H), 3.42 (s, 3H), 2.63 – 2.54 (m, 1H), 1.17 (dt, J = 8.3, 3.0 Hz, 2H), 1.12 (dt, J = 5.0, 2.8 Hz, 2H). m/z (ESI): 352.8 [M+H] ⁺ . 6-Cyano-5-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyrid ine-3-carboxamide (Int. M- Step 1: A solution of 5-bromo-6-chloro-N-(2-methanesulfonylpyridin-3-yl)pyridine-3 -carboxamide (Int. U-006, 0.774 g, 1.84 mmol, 1.0 eq.), NaCN (0.140 g, 2.86 mmol, 1.55 eq.) and DMAP (0.023 g, 0.19 mmol, 0.10 eq.) in NMP (20.0 mL) was stirred overnight at 100 °C under ni- trogen. After coming back to RT, the RM was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 5- bromo-6-cyano-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-ca rboxamide (Int. M-192, 0.276 g, 0.58 mmol, 31%, yellow solid, UPLC purity: 80%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 9.15 (d, J = 1.8 Hz, 1H), 8.76 (d, J = 1.8 Hz, 1H), 8.67 (dd, J = 4.5, 1.5 Hz, 1H), 8.45 (dd, J = 8.3, 1.5 Hz, 1H), 7.87 (dd, J = 8.3, 4.5 Hz, 1H), 3.41 (s, 3H). m/z (ESI): 382.8 [M+H] ⁺ . Step 2: Ryvu Therapeutics S.A. RVU305 262 R10107WO A pressure vessel was charged with potassium cyclopropyltrifluoroborate (0.171 g, 1.16 mmol, 2.00 eq.), Cs ₂ CO ₃ (0.377 g, 1.16 mmol, 2.0 eq.), 5-bromo-6-cyano-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide (Int. M-192, 0.276 g, 0.58 mmol, 1.0 eq.), toluene (11.0 mL) and water (1.0 mL), and the mixture was sparged with nitrogen for 10 min. Pd(dppf)Cl ₂ (0.085 g, 0.12 mmol, 0.2 eq.) was added, the vessel was sealed and the RM was stirred at 110 °C. After coming back to RT, the RM was filtered through a pad of Celite ^® , rinsing the filter cake with EtOAc. The filtrate was washed with water and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield 6-cyano-5-cyclo- propyl-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carboxami de (Int. M-193, 0.070 g, 0.20 mmol, 35%, off-white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H), 8.96 (d, J = 1.9 Hz, 1H), 8.64 (dd, J = 4.5, 1.4 Hz, 1H), 8.53 (dd, J = 8.3, 1.4 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.3, 4.5 Hz, 1H), 3.42 (s, 3H), 2.31 (tt, J = 8.5, 4.8 Hz, 1H), 1.31 – 1.25 (m, 2H), 1.02 – 0.96 (m, 2H). m/z (ESI): 343.2 [M+H] ⁺ . 2-(3,3-Difluorocyclobutyl)-N-(2-methanesulfonylpyridin-3-yl) pyrimidine-5-carboxamide (Int. Step 1: 3,3-difluorocyclobutane-1-carbonitrile (1.0 g, 8.54 mmol, 1.0 eq.) was dissolved in a mixture of 4 M HCl in dioxane (16.0 mL, 64.0 mmol, 7.5 eq.) and anhydrous EtOH (1.8 mL), and the RM was stirred overnight at RT. The volatiles were evaporated under reduced pressure and the resulting solid was triturated with diethyl ether, filtered off and dried under reduced pressure to ethyl 3,3-difluorocyclobutane-1-carboximidate hydrochloride (Int. M-194, 1.225 g, 6.14 mmol, 72%, white solid, NMR purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.62 – 3.42 (m, 1H), 3.04 – 2.89 (m, 4H), 1.38 (t, J = 7.0 Hz, 3H). Step 2: Ryvu Therapeutics S.A. RVU305 263 R10107WO Ethyl 3,3-difluorocyclobutane-1-carboximidate hydrochloride (Int. M-194, 1.225 g, 6.14 mmol, 1.0 eq.) was stirred in 7 N ammonia in MeOH (26.31 mL, 184.17 mmol, 30.0 eq.) in a pressure vessel at RT for 24 hours. The volatiles were evaporated under reduced pressure and the resulting crude 3,3-difluorocyclobutane-1-carboximidamide hydrochloride (Int. M- 195, 1.025 g, 6.01 mmol, 98%, white solid, NMR purity: 100%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (br s, 4H), 3.31 (m, 1H), 3.08 – 2.80 (m, 4H). Step 3: Sodium (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (Int. M-129, 0.64 g, 3.75 mmol, 1.0 eq.) was added to a solution of 3,3-difluorocyclobutane-1-carboximidamide hydrochloride (Int. M-195, 0.64 g, 3.75 mmol, 1.0 eq.) in anhydrous DMF (5 mL) and the RM was stirred at 120 °C under nitrogen for 48 h. After coming back to RT, the RM was evapo- rated under reduced pressure and the crude material was purified by FCC (0 to 66% EtOAc gradient in hexane) to yield methyl 2-(3,3-difluorocyclobutyl)pyrimidine-5-carboxylate (Int. M-196, 0.329 g, 1.355 mmol, 36%, as white solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (s, 2H), 3.92 (s, 3H), 3.79 – 3.65 (m, 1H), 3.14 – 2.90 (m, 4H). m/z (ESI): 229.0 [M+H] ⁺ . Step 4: Aqueous 1 M NaOH (3.0 mL) was added to a solution methyl 2-(3,3-difluorocyclobutyl)py- rimidine-5-carboxylate (Int. M-196, 0.304 g, 1.25 mmol, 1.0 eq.) in MeOH (3.0 mL) and the RM was stirred at RT for 1 h. The volatiles were evaporated under reduced pressure and the resulting suspension was filtered and the filtrate was stirred in an ice bath. Aqueous 4 M HCl was added until pH ≈ 2-3 was reached and the resulting solid was filtered off, washed with water and dried overnight under vacuum at 40 °C to yield 2-(3,3-difluorocyclobu- tyl)pyrimidine-5-carboxylic acid (Int. M-197, 0.189 g, 0.80 mmol, 64%, white solid, UPLC pu- rity: 91%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.78 (s, 1H), 9.20 (s, 2H), 3.79 – 3.66 (m, 1H), 3.14 – 2.86 (m, 4H). m/z (ESI): 215.0 [M+H] ⁺ . Step 5: Step 5 was performed according to General Procedure 17, using 2-methanesulfonylpyridin- 3-amine (0.117 g, 0.68 mmol, 1.0 eq.), 2-(3,3-difluorocyclobutyl)pyrimidine-5-carboxylic acid (Int. M-197, 0.160 g, 0.68 mmol, 1.0 eq.), DMAP (0.025 g, 0.204 mmol, 0.3 eq.) and POCl ₃ (0.208 g, 1.36 mmol, 2.0 eq.) in pyridine (11 mL). The obtained crude 2-(3,3-difluorocyclo- butyl)-N-(2-methanesulfonylpyridin-3-yl)pyrimidine-5-carboxa mide (Int. M-198, 0.249 g, 0.60 mmol, 89%, white solid, UPLC purity: 89%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 9.25 (s, 2H), 8.64 (dd, J = 4.5, 1.4 Hz, 1H), 8.56 (dd, J = 8.3, 1.5 Hz, 1H), 7.86 (dd, J = 8.3, 4.5 Hz, 1H), 3.83 – 3.68 (m, 1H), 3.42 (s, 3H), 3.18 – 2.91 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -80.05 – -81.21 (m), - 94.85 (dtt, J = 190.0, 17.6, 14.2 Hz). _m/z (ESI): 369.3 [M+H] ⁺ . 6-Cyano-N-(4-fluoro-2-methanesulfonylphenyl)-5-(morpholin-4- yl)pyridine-3-carboxamide (Int. M-200) Ryvu Therapeutics S.A. RVU305 264 R10107WO Step 1: A solution of 5-bromo-6-chloro-N-(4-fluoro-2-methanesulfonylphenyl)pyridin e-3-carbox- amide (Int. K-097, 0.356 g, 0.84 mmol, 1.0 eq.), NaCN (0.117 g, 2.39 mmol, 2.85 eq.) and DMAP (0.032 g, 0.26 mmol, 0.31 eq.) in propanenitrile (4.2 mL) was stirred overnight at 100 °C under nitrogen. After coming back to RT, the RM was partitioned between sat. aq. Na- HCO ₃ and DCM and the aqueous layer was extracted with DCM (3x). The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated un- der reduced pressure. The crude material was purified by FCC (0 to 40% EtOAc gradient in hexane) to yield 5-bromo-6-cyano-N-(4-fluoro-2-methanesulfonylphenyl)pyridine -3-carbox- amide (Int. M-199, 0.273 g, 0.65 mmol, 78%, white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 9.15 (d, J = 1.8 Hz, 1H), 8.76 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.9, 5.0 Hz, 1H), 7.83 (dd, J = 8.3, 3.0 Hz, 1H), 7.74 (td, J = 8.4, 3.0 Hz, 1H), 3.34 (s, 3H). m/z (ESI): 398.0 [M+H] ⁺ . Step 2: 5-Bromo-6-cyano-N-(4-fluoro-2-methanesulfonylphenyl)pyridine -3-carboxamide (Int. M- 199, 0.213 g, 0.51 mmol, 1.0 eq.), CuI (0.044 g, 0.23 mmol, 0.45 eq.), L-proline (0.012 g, 0.11 mmol, 0.21 eq.), Cs ₂ CO ₃ (0.508 g, 1.56 mmol, 3.07 eq.) and morpholine (0.436 mL, 5.01 mmol, 9.88 eq.) were combined in a Biotage ^TM microwave vial fitted with a septum. The tube was evacuated and backfilled with argon (3x). Anhydrous DMSO (2.3 mL) was added, and the septum was replaced with a crimped septum cap. The RM was heated in a microwave at 140 °C for 1 h. After coming back to RT, the RM was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc (2x). The combined organic ex- tracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude ma- terial was purified by FCC (0 to 40% EtOAc gradient in hexane) to yield 6-cyano-N-(4- fluoro-2-methanesulfonylphenyl)-5-(morpholin-4-yl)pyridine-3 -carboxamide (Int. M-200, 0.052 g, 0.13 mmol, 25%, light green solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.59 (s, 1H), 8.72 (d, J = 1.7 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.93 (dd, J = 8.9, 4.9 Hz, 1H), 7.83 (dd, J = 8.3, 3.0 Hz, 1H), 7.73 (td, J = 8.4, 3.0 Hz, 1H), 3.82 (t, J = 4.6 Hz, 4H), 3.34 (s, 3H), 3.34 – 3.31 (m, 4H). m/z (ESI): 405.2 [M+H] ⁺ . 6-(3,3-Difluoroazetidin-1-yl)-N-(2-methanesulfonylpyridin-3- yl)pyridine-3-carboxamide (Int. M-201) Ryvu Therapeutics S.A. RVU305 265 R10107WO A Biotage ^TM 20-mL microwave vial was charged with 6-bromo-N-(2-methanesulfonylpyridin- 3-yl)pyridine-3-carboxamide (Int. K-093, 0.6 g, 1.6 mmol, 1.0 eq.), 3,3-difluoroazetidine hy- drochloride (0.398 g, 3.07 mmol, 1.92 eq.), Cs ₂ CO ₃ (6.257 g, 19.20 mmol, 12.0 eq.) and anhy- drous dioxane (5 mL) and the mixture was sparged with nitrogen for 10 min. Pd ₂ (dba) ₃ (0.146 g, 0.16 mmol, 0.1 eq.) and Xantphos (0.185 g, 0.32 mmol, 0.2 eq.) were added, the vial was sealed and the RM was stirred at 100 °C overnight. After coming back to RT, the RM was filtered through a pad of Celite ^® , rinsing the filter cake with EtOAc. The filtrate was washed with water and the aqueous layer was extracted with EtOAc (2x). The combined or- ^{ganic layers were washed with brine, dried over anhydrous Na} ₂ ^SO ₄ ^{, filtered and evaporated} under reduced pressure. The crude material was purified by FCC (0 to 66% EtOAc gradient in hexane) to yield 6-(3,3-difluoroazetidin-1-yl)-N-(2-methanesulfonylpyridin-3- yl)pyridine-3-carboxamide (Int. M-201, 0.215 g, 0.52 mmol, 33%, off-white solid, UPLC purity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 8.81 (dd, J = 8.5, 1.5 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.53 (dd, J = 4.4, 1.5 Hz, 1H), 8.07 (dd, J = 8.8, 2.4 Hz, 1H), 7.80 (dd, J = 8.5, 4.4 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.53 (t, J = 12.4 Hz, 4H), 3.45 (s, 3H). m/z (ESI): 368.9 [M+H] ⁺ . 6-Cyano-N-(2-methanesulfonylpyridin-3-yl)-5-methylpyridine-3 -carboxamide (Int. M-202) NaCN (0.123 g, 2.52 mmol, 2.0 eq.) was added to a solution of 6-fluoro-N-(2-methanesul- fonylpyridin-3-yl)-5-methylpyridine-3-carboxamide (Int. U-007, 0.397 g, 1.26 mmol, 1.0 eq.) and DMAP (0.015 g, 0.13 mmol, 0.1 eq.) in NMP (10.0 mL), and the RM was stirred at 100 °C overnight. After coming back to RT, the RM was partitioned between water and DCM and the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield 6-cyano- N-(2-methanesulfonylpyridin-3-yl)-5-methylpyridine-3-carboxa mide (Int. M-202, 0.31 g, 0.94 mmol, 75%, white solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 9.03 (d, J = 2.1 Hz, 1H), 8.65 (dd, J = 4.6, 1.4 Hz, 1H), 8.53 (dd, J = 8.3, 1.5 Hz, 1H), 8.40 Ryvu Therapeutics S.A. RVU305 266 R10107WO (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 8.3, 4.5 Hz, 1H), 3.42 (s, 3H), 2.62 (s, 3H). m/z (ESI): 317.3 [M+H] ⁺ . 2-{5-[(4-Fluoro-2-methanesulfonylphenyl)carbamoyl]pyridin-2- yl}-2-methylpropyl acetate Step 1: LDA (2 M in THF/hexane/EtPhe, 17.05 mL, 34.1 mmol, 2.0 eq.) was slowly added to a solu- tion of methyl 2-methylpropanoate (3.482 g, 34.09 mmol, 2.0 eq.) in anhydrous THF (20 mL) at -78 °C under argon and the RM was stirred at this temperature for 1 h. A solution of 5- bromo-2-fluoropyridine (3.0 g, 17.047 mmol, 1.0 eq.) in anhydrous THF (5 mL) was then slowly added via syringe at -78 °C and the mixture was stirred for 2 h, being allowed to come back to RT. The reaction was quenched with sat. aq. NH ₄ Cl, the phases were sepa- rated and the aqueous phase was extracted with EtOAc (3x). The combined organic layers ^{were dried over anhydrous Na} ₂ ^SO ₄ ^{, filtered and evaporated under reduced pressure. The} crude material was purified by FCC (0 to 10% EtOAc gradient in hexane) to yield methyl 2- (5-bromopyridin-2-yl)-2-methylpropanoate (Int. M-203, 3.169 g, 11.79 mmol, 69%, yellow oil, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (dd, J = 2.5, 0.8 Hz, 1H), 8.04 (dd, J = 8.5, 2.5 Hz, 1H), 7.41 (dd, J = 8.5, 0.8 Hz, 1H), 3.58 (d, J = 0.7 Hz, 3H), 1.51 (s, 6H). m/z (ESI): 259.8 [M+H] ⁺ . Step 2: NaBH ₄ (1.784 g, 47.15 mmol, 4.0 eq.) was added to a solution of methyl 2-(5-bromopyridin- 2-yl)-2-methylpropanoate (Int. M-203, 3.169 g, 11.79 mmol, 1.0 eq.) in a mixture of THF (20.0 mL) and MeOH (5.0 mL) and the RM was stirred for 2 h at 0 °C and 1 h at RT. The reaction was quenched with sat. aq. NH ₄ Cl and the mixture was partitioned between water Ryvu Therapeutics S.A. RVU305 267 R10107WO and EtOAc. The aqueous layer was extracted with EtOAc (2x) and the combined organic lay- ers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 66% EtOAc gradient in hexane) to yield 2-(5-bro- mopyridin-2-yl)-2-methylpropan-1-ol (Int. M-204, 2.49 g, 10.497 mmol, 89%, colorless oil, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 2.5 Hz, 1H), 7.94 (dd, J = 8.6, 2.5 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 4.66 (t, J = 5.5 Hz, 1H), 3.52 (d, J = 5.5 Hz, 2H), 1.23 (s, 6H). _m/z (ESI): 231.8 [M+H] ⁺ . Step 3: Acetic anhydride (0.956 mL, 10.12 mmol, 4.0 eq.) was added to a solution of 2-(5-bro- mopyridin-2-yl)-2-methylpropan-1-ol (Int. M-204, 0.6 g, 2.53 mmol, 1.0 eq.) and TEA (1.057 mL, 7.59 mmol, 3.0 eq.) in DCM (5.0 mL) and the RM was stirred overnight at RT under ni- trogen. The mixture was diluted with EtOAc, and the solution was washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 25% EtOAc gradient in hexane) to yield 2-(5-bromopyridin-2-yl)-2-methylpropyl acetate (Int. M-205, 0.641 g, 2.36 mmol, 93%, colorless oil, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (d, J = 2.3 Hz, 1H), 8.00 (dd, J = 8.5, 2.5 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 4.21 (s, 2H), 1.93 (d, J = 0.8 Hz, 3H), 1.30 (s, 6H). m/z (ESI): 273.8 [M+H] ⁺ . Step 4: A microwave vial was charged with tri-tert-butylphosphonium tetrafluoroborate (0.137 g, 0.47 mmol, 0.2 eq.), hexacarbonylmolybdenum (0.622 g, 2.36 mmol, 1.0 eq.), DBU (1.057 mL, 7.07 mmol, 3.0 eq.), cataCXium ^® C (0.222 g, 0.24 mmol, 0.1 eq.) and 2-(5-bromopyridin-2- yl)-2-methylpropyl acetate (Int. M-205, 0.641 g, 2.36 mmol, 1.0 eq.), dioxane (4.0 mL) and water (0.4 mL). The RM was sparged with argon for 5 min, the vial was sealed and stirred at 140 °C under microwave irradiation for 30 min. After coming back to RT, the RM was di- luted with DCM and filtered through a pad of Celite ^® . The filtrate was washed with sat. aq. NH ₄ Cl and the aqueous phase was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The obtained crude 6-[1-(acetyloxy)-2-methylpropan-2-yl]pyridine-3-carboxylic acid (Int. M- 206, 0.438 g, 1.62 mmol, 69%, colorless oil, UPLC purity: 88%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.32 (s, 1H), 9.02 (d, J = 2.2 Hz, 1H), 8.22 (dd, J = 8.3, 2.3 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 4.27 (s, 2H), 1.92 (s, 3H), 1.34 (s, 6H). m/z (ESI): 238.1 [M+H] ⁺ . Step 5: Step 5 was performed according to General Procedure 17, using 4-fluoro-2-methanesul- fonylaniline (0.307 g, 1.62 mmol, 1.0 eq.), 6-[1-(acetyloxy)-2-methylpropan-2-yl]pyridine-3- carboxylic acid (Int. M-206, 0.438 g, 1.62 mmol, 1.0 eq.), DMAP (0.060 g, 0.49 mmol, 0.3 eq.) and POCl ₃ (0.498g, 3.25 mmol, 2.0 eq.) in pyridine (8 mL). After completion of the reaction, the RM was poured in ice cold sat. aq. NaHCO ₃ and the mixture was stirred for 30 min. The mixture was then extracted with EtOAc (2x) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to yield the crude 2-{5-[(4-fluoro-2-me- thanesulfonylphenyl)carbamoyl]pyridin-2-yl}-2-methylpropyl acetate (Int. M-207, 0.474 g, Ryvu Therapeutics S.A. RVU305 268 R10107WO 1.15 mmol, 71%, beige solid, UPLC purity: 99%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.42 (s, 1H), 9.06 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 8.4, 2.4 Hz, 1H), 8.06 (dd, J = 9.0, 4.9 Hz, 1H), 7.80 (dd, J = 8.3, 3.0 Hz, 1H), 7.72 (td, J = 8.5, 3.2 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 4.30 (s, 2H), 3.37 (s, 3H), 1.94 (s, 3H), 1.36 (s, 6H). m/z (ESI): 409.5 [M+H] ⁺ . N‐[(2‐chloroquinolin‐7‐yl)methyl] amide intermediates N-[(2-chloroquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl )acetamide (Int. N-001), General Procedure 21: NaH (60% in mineral oil, 0.012 g, 0.31 mmol, 1.1 eq.) was added to a solution of N-(2-me- thanesulfonylphenyl)acetamide (Int. B-001, 0.06 g, 0.21 mmol, 1.0 eq.) in DMF (1.5 mL) at 0 °C under nitrogen. The cooling bath was removed and the RM was stirred at RT for 30 min.7-(Bromomethyl)-2-chloroquinoline (Int. A-004, 0.073 g, 0.284 mmol, 1 eq.) was added in one portion and the RM was stirred overnight at RT under nitrogen. The reaction was quenched with sat. aq. NH ₄ Cl and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concen- trated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gra- dient in DCM) to yield N-[(2-chloroquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl )acet- amide (Int. N-001, 0.1 g, 0.26 mmol, 69%, yellow solid, UPLC purity: 75%).8/2 mixture of re- stricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 8.5 Hz, 1H), 8.15 (dd, J = 7.7, 1.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.68 (td, J = 7.6, 1.5 Hz, 1H), 7.62 (ddd, J = 11.4, 8.0, 1.9 Hz, 2H), 7.60 (d, J = 8.6 Hz, 1H), 7.02 (dd, J = 7.6, 1.5 Hz, 1H), 5.77 (d, J = 15.2 Hz, 1H), 4.37 (d, J = 15.3 Hz, 1H), 3.40 (s, 3H), 1.83 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.98 – 7.94 (m, 1H), 7.85 (s, 1H), 7.71 – 7.49 (m, 3H), 7.38 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 9.0 Hz, 1H), 5.46 (d, J = 17.0 Hz, 1H), 4.79 (d, J = 16.9 Hz, 1H), 3.20 (s, 3H), 2.35 (s, 3H). m/z (ESI): 389.4 [M+H] ⁺ . N‐[(2‐chloroquinolin‐7‐yl)methyl] amide and analog intermediates prepared according to General Procedure 21: Ryvu Therapeutics S.A. RVU305 269 R10107WO Ryvu Therapeutics S.A. RVU305 270 R10107WO Ryvu Therapeutics S.A. RVU305 271 R10107WO Ryvu Therapeutics S.A. RVU305 272 R10107WO Ryvu Therapeutics S.A. RVU305 273 R10107WO Ryvu Therapeutics S.A. RVU305 274 R10107WO Ryvu Therapeutics S.A. RVU305 275 R10107WO Ryvu Therapeutics S.A. RVU305 276 R10107WO Ryvu Therapeutics S.A. RVU305 277 R10107WO Ryvu Therapeutics S.A. RVU305 278 R10107WO Ryvu Therapeutics S.A. RVU305 279 R10107WO Ryvu Therapeutics S.A. RVU305 280 R10107WO Ryvu Therapeutics S.A. RVU305 281 R10107WO Ryvu Therapeutics S.A. RVU305 282 R10107WO Ryvu Therapeutics S.A. RVU305 283 R10107WO Ryvu Therapeutics S.A. RVU305 284 R10107WO Ryvu Therapeutics S.A. RVU305 285 R10107WO Ryvu Therapeutics S.A. RVU305 286 R10107WO Ryvu Therapeutics S.A. RVU305 287 R10107WO Ryvu Therapeutics S.A. RVU305 288 R10107WO Ryvu Therapeutics S.A. RVU305 289 R10107WO Ryvu Therapeutics S.A. RVU305 290 R10107WO Ryvu Therapeutics S.A. RVU305 291 R10107WO Ryvu Therapeutics S.A. RVU305 292 R10107WO Ryvu Therapeutics S.A. RVU305 293 R10107WO N-[(2-chloroquinolin-7-yl)methyl]-N-[2-(ethanesulfonyl)pheny l]pyridine-3-carboxamide (Int. O-001), General Procedure 22 A mixture of N-[2-(ethanesulfonyl)phenyl]pyridine-3-carboxamide (Int. C-001, 0.194 g, 0.63 mmol, 1.0 eq.), 7-(bromomethyl)-2-chloroquinoline (Int. A-004, 0.190 g, 0.691 mmol, 1.1 eq.) and cesium carbonate (0.246 g, 0.75 mmol, 1.2 eq.) in MeCN (2.0 mL) was heated at 65 °C for 2 h. The RM was cooled to RT and diluted with water. The mixture was extracted with ^{DCM (3x) and the combined organic layers were dried over anhydrous Na} ₂ ^SO ₄ ^{, filtered and} concentrated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in MeOH) to yield N-[(2-chloroquinolin-7-yl)methyl]-N-[2-(ethanesul- fonyl)phenyl]pyridine-3-carboxamide (Int. O-001, 0.182 g, 0.39 mmol, 53%, yellow solid, UPLC purity: 85%).7/3 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (dd, J = 2.3, 0.8 Hz, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.43 (dd, J = 4.8, 1.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.86 (dd, J = 7.9, 1.6 Hz, 1H), 7.77 (dd, J = 8.3, 1.7 Hz, 1H), 7.73 (dt, J = 8.0, 2.0 Hz, 1H), 7.68 – 7.56 (m, 2H), 7.53 (td, J = 7.9, 1.3 Hz, 1H), 7.43 (dd, J = 7.9, 1.3 Hz, 1H), 7.26 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 5.77 (d, J = 15.2 Hz, 1H), 4.79 (d, J = 15.2 Hz, 1H), 3.20 – 3.04 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (d, J = 1.5 Hz, 1H), 8.72 (dd, J = 4.8, 1.4 Hz, 1H), 8.46 – 8.43 (m, 1H), 8.14 (dt, J = 7.9, 1.8 Hz, 1H), 8.05 (dd, J = 7.1, 2.3 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.66 – 7.56 (m, 5H), 7.23 (dd, J = 7.3, 1.7 Hz, 1H), 5.30 (d, J = 16.2 Hz, 1H), 4.87 (d, J = 16.2 Hz, 1H), 3.19 – 3.05 (m, 2H), 1.18 (t, J = 7.3 Hz, 3H). _m/z (ESI): 467.0 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 294 R10107WO N‐[(2‐chloroquinolin‐7‐yl)methyl] amide intermediates prepared according to General Procedure 22: Ryvu Therapeutics S.A. RVU305 295 R10107WO Ryvu Therapeutics S.A. RVU305 296 R10107WO Ryvu Therapeutics S.A. RVU305 297 R10107WO Ryvu Therapeutics S.A. RVU305 298 R10107WO Ryvu Therapeutics S.A. RVU305 299 R10107WO Ryvu Therapeutics S.A. RVU305 300 R10107WO Ryvu Therapeutics S.A. RVU305 301 R10107WO Ryvu Therapeutics S.A. RVU305 302 R10107WO Ryvu Therapeutics S.A. RVU305 303 R10107WO Ryvu Therapeutics S.A. RVU305 304 R10107WO Ryvu Therapeutics S.A. RVU305 305 R10107WO Ryvu Therapeutics S.A. RVU305 306 R10107WO Ryvu Therapeutics S.A. RVU305 307 R10107WO Ryvu Therapeutics S.A. RVU305 308 R10107WO Ryvu Therapeutics S.A. RVU305 309 R10107WO Ryvu Therapeutics S.A. RVU305 310 R10107WO Ryvu Therapeutics S.A. RVU305 311 R10107WO Ryvu Therapeutics S.A. RVU305 312 R10107WO Ryvu Therapeutics S.A. RVU305 313 R10107WO Ryvu Therapeutics S.A. RVU305 314 R10107WO Ryvu Therapeutics S.A. RVU305 315 R10107WO Ryvu Therapeutics S.A. RVU305 316 R10107WO Ryvu Therapeutics S.A. RVU305 317 R10107WO Ryvu Therapeutics S.A. RVU305 318 R10107WO Ryvu Therapeutics S.A. RVU305 319 R10107WO Ryvu Therapeutics S.A. RVU305 320 R10107WO Ryvu Therapeutics S.A. RVU305 321 R10107WO Ryvu Therapeutics S.A. RVU305 322 R10107WO Ryvu Therapeutics S.A. RVU305 323 R10107WO Ryvu Therapeutics S.A. RVU305 324 R10107WO Ryvu Therapeutics S.A. RVU305 325 R10107WO Ryvu Therapeutics S.A. RVU305 326 R10107WO Ryvu Therapeutics S.A. RVU305 327 R10107WO Ryvu Therapeutics S.A. RVU305 328 R10107WO Ryvu Therapeutics S.A. RVU305 329 R10107WO Ryvu Therapeutics S.A. RVU305 330 R10107WO Ryvu Therapeutics S.A. RVU305 331 R10107WO Ryvu Therapeutics S.A. RVU305 332 R10107WO Ryvu Therapeutics S.A. RVU305 333 R10107WO Ryvu Therapeutics S.A. RVU305 334 R10107WO Ryvu Therapeutics S.A. RVU305 335 R10107WO Ryvu Therapeutics S.A. RVU305 336 R10107WO Ryvu Therapeutics S.A. RVU305 337 R10107WO Ryvu Therapeutics S.A. RVU305 338 R10107WO Ryvu Therapeutics S.A. RVU305 339 R10107WO Ryvu Therapeutics S.A. RVU305 340 R10107WO Ryvu Therapeutics S.A. RVU305 341 R10107WO Ryvu Therapeutics S.A. RVU305 342 R10107WO Ryvu Therapeutics S.A. RVU305 343 R10107WO Ryvu Therapeutics S.A. RVU305 344 R10107WO Ryvu Therapeutics S.A. RVU305 345 R10107WO Ryvu Therapeutics S.A. RVU305 346 R10107WO Ryvu Therapeutics S.A. RVU305 347 R10107WO Ryvu Therapeutics S.A. RVU305 348 R10107WO Ryvu Therapeutics S.A. RVU305 349 R10107WO Ryvu Therapeutics S.A. RVU305 350 R10107WO Ryvu Therapeutics S.A. RVU305 351 R10107WO Ryvu Therapeutics S.A. RVU305 352 R10107WO Ryvu Therapeutics S.A. RVU305 353 R10107WO Ryvu Therapeutics S.A. RVU305 354 R10107WO Ryvu Therapeutics S.A. RVU305 355 R10107WO Ryvu Therapeutics S.A. RVU305 356 R10107WO Ryvu Therapeutics S.A. RVU305 357 R10107WO Ryvu Therapeutics S.A. RVU305 358 R10107WO Ryvu Therapeutics S.A. RVU305 359 R10107WO Ryvu Therapeutics S.A. RVU305 360 R10107WO Ryvu Therapeutics S.A. RVU305 361 R10107WO Ryvu Therapeutics S.A. RVU305 362 R10107WO Ryvu Therapeutics S.A. RVU305 363 R10107WO Ryvu Therapeutics S.A. RVU305 364 R10107WO Ryvu Therapeutics S.A. RVU305 365 R10107WO Ryvu Therapeutics S.A. RVU305 366 R10107WO Ryvu Therapeutics S.A. RVU305 367 R10107WO Ryvu Therapeutics S.A. RVU305 368 R10107WO Ryvu Therapeutics S.A. RVU305 369 R10107WO Ryvu Therapeutics S.A. RVU305 370 R10107WO Ryvu Therapeutics S.A. RVU305 371 R10107WO Ryvu Therapeutics S.A. RVU305 372 R10107WO Ryvu Therapeutics S.A. RVU305 373 R10107WO Ryvu Therapeutics S.A. RVU305 374 R10107WO Ryvu Therapeutics S.A. RVU305 375 R10107WO Ryvu Therapeutics S.A. RVU305 376 R10107WO Ryvu Therapeutics S.A. RVU305 377 R10107WO Ryvu Therapeutics S.A. RVU305 378 R10107WO Ryvu Therapeutics S.A. RVU305 379 R10107WO Ryvu Therapeutics S.A. RVU305 380 R10107WO Ryvu Therapeutics S.A. RVU305 381 R10107WO Ryvu Therapeutics S.A. RVU305 382 R10107WO Ryvu Therapeutics S.A. RVU305 383 R10107WO Ryvu Therapeutics S.A. RVU305 384 R10107WO *: reaction performed in anhydrous DMF. **: reaction performed using KI as a catalyst (0.2 eq.) N-(2-Acetylphenyl)-N-[(2-chloroquinolin-7-yl)methyl]acetamid e (Int. P-001) Ryvu Therapeutics S.A. RVU305 385 R10107WO A mixture of K ₂ CO ₃ (0.234 g, 1.70 mmol, 3.0 eq.), 7-(bromomethyl)-2-chloroquinoline (0.145 g, 0.56 mmol, 1.0 eq., Int. A-004) and N-(2-acetylphenyl)acetamide (Int. B-002, 0.100 g, 0.56 mmol, 1.0 eq., ) was stirred overnight at 85 °C. After coming back to RT, the RM was fil- tered and the filtrate was partitioned between water and EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to provide N-(2-acetylphenyl)-N-[(2-chloroquinolin-7-yl)methyl]acetamid e (Int. P-001, 0.144 g, 0.41 mmol, 73%, yellow solid, UPLC purity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.93 – 7.87 (m, 1H), 7.65 (s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.54 – 7.47 (m, 3H), 7.15 – 7.08 (m, 1H), 5.32 (d, J = 15.1 Hz, 1H), 4.39 (d, J = 15.1 Hz, 1H), 2.39 (s, 3H), 1.77 (s, 3H). m/z (ESI): 353.3 [M+H] ⁺ . 4-{N-[(2-chloroquinolin-7-yl)methyl]acetamido}-1-methyl-1H-p yrazole-5-carboxamide (Int. Step 1: NaH (60% in mineral oil, 0.021 g, 0.55 mmol, 1.1 eq.) was added to a solution of methyl 4- acetamido-1-methyl-1H-pyrazole-5-carboxylate (Int. B-010, 0.1 g, 0.50 mmol, 1.0 eq.) in an- hydrous DMF (4.0 mL) at 0 °C and the RM was stirred at that temperature for 5 min. under nitrogen. 7-(Bromomethyl)-2-chloroquinoline (Int. A-004, 0.14 g, 0.50 mmol, 0.1 eq.) was added and the RM was stirred at RT for 2 h. The reaction was quenched with water and the RM was extracted with EtOAc. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield methyl 4-{N-[(2-chloroquinolin-7-yl)methyl]acetamido}- 1-methyl-1H-pyrazole-5-carboxylate (Int. P-002, 0.083 g, 0.22 mmol, 42%, white solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.4 Hz, Ryvu Therapeutics S.A. RVU305 386 R10107WO 1H), 7.72 – 7.69 (m, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 8.4, 1.7 Hz, 1H), 7.46 (s, 1H), 4.94 (s, 2H), 4.02 (s, 3H), 3.73 (s, 3H), 1.89 (s, 3H). m/z (ESI): 373.2 [M+H] ⁺ . The aqueous layer was acidified to pH ≈ 3 with 1 M aq. HCl and extracted with ^{CHCl3/iPrOH 3:1 v/v. The organic layer was dried over anhydrous Na2SO4, filtered and evap-} _{orated under reduced pressure to give 4‐{N‐[(2‐chloroquinolin‐7‐yl)methyl]acetam-} ido}‐1‐methyl‐1H‐pyrazole‐5‐carboxylic acid hydrochloride (Int. P-003, 0.101 g, 0.28 mmol, 54%, white solid, UPLC purity: 96%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.80 (s, 2H), 8.44 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.74 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 8.4, 1.7 Hz, 1H), 7.34 (s, 1H), 4.91 (s, 2H), 4.03 (s, 3H), 1.88 (s, 3H). _m/z (ESI): 359.2 [M+H] ⁺ . Step 2: CDI (0.047 g, 0.29 mmol, 1.1 eq.) was added to a solution of 4‐{N‐[(2‐chloroquinolin‐ 7‐yl)methyl]acetamido}‐1‐methyl‐1H‐pyrazole‐5‐ carboxylic acid hydrochloride (Int. P-003, 0.099 g, 0.26 mmol, 1.0 eq.) in anhydrous DMF (2.0 mL) at RT and the mixture was heated at 60 °C under nitrogen for 1 h. After coming back to RT, ammonia (0.5 M in diox- ane, 1.6 mL, 0.8 mmol, 3.02 eq.) was added and the RM was stirred overnight at RT. The RM was then evaporated under reduced pressure and the residue was partitioned between wa- ter and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic lay- ers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to afford 4-{N-[(2-chloroquinolin-7-yl)methyl]acetamido}-1-methyl-1H-p yrazole-5-carbox- amide (Int. P-004, 0.058 g, 0.162 mmol, 56%, white solid, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.53 (dd, J = 8.4, 1.7 Hz, 1H), 7.22 (s, 1H), 4.95 (s, 2H), 3.89 (s, 3H), 1.96 (s, 3H). m/z (ESI): 358.1 [M+H] ⁺ . 4-{N-[(2-chloroquinolin-7-yl)methyl]-3-(pyridin-4-yl)propana mido}-1-methyl-1H-pyrazole- Step 1: NaH (60% in mineral oil, 0.023 g, 0.6 mmol, 1.15 eq.) was added to a solution of methyl 1- methyl-4-[3-(pyridin-4-yl)propanamido]-1H-pyrazole-3-carboxy late (Int. D-005, 0.166 g, 0.52 mmol, 1.0 eq.) in anhydrous DMF (6.0 mL) at 0 °C and the RM was stirred at that temperature for 15 min. under nitrogen. 7-(Bromomethyl)-2-chloroquinoline (Int. A-004, 0.143 g, 0.524 mmol, 1.0 eq.) was added and the RM was stirred at RT for 2 h.1 M aq. NaOH (20.0 mL) was added to the RM, and stirring was continued at RT overnight. The aqueous mixture was washed with EtOAc and the aqueous layer was acidified to pH ≈ 3 with aq. 1 M HCl. It was then extracted with CHCl ₃ /iPrOH 3:1 v/v and the organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to yield 4- Ryvu Therapeutics S.A. RVU305 387 R10107WO {N-[(2-chloroquinolin-7-yl)methyl]-3-(pyridin-4-yl)propanami do}-1-methyl-1H-pyrazole-3- carboxylic acid (Int. P-005, 0.196 g, 0.43 mmol, 75%, orange solid, UPLC purity: 90%). ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.44 – 8.39 (m, 2H), 8.33 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.50 (dd, J = 8.4, 1.8 Hz, 1H), 7.43 (s, 1H), 7.33 – 7.28 (m, 2H), 5.46 (br s, 1H), 4.59 (br s, 1H), 3.84 (s, 3H), 3.02 (t, J = 6.9 Hz, 2H), 2.65 (t, J = 7.3 Hz, 2H). m/z (ESI): 450.3 [M+H] ⁺ . Step 2: CDI (0.068 g, 0.42 mmol, 1.1 eq.) was added to a solution of 4-{N-[(2-chloroquinolin-7- yl)methyl]-3-(pyridin-4-yl)propanamido}-1-methyl-1H-pyrazole -3-carboxylic acid (Int. P- 005, 0.19 g, 0.38 mmol, 1.0 eq.) in anhydrous DMF (4.0 mL) and the RM was stirred at 80 °C for 1 h. The mixture was cooled to RT and ammonia (0.5 M in dioxane, 2.3 mL, 1.15 mmol, 3.0 eq.) was added. The RM was stirred for 3 h at RT and the volatiles were evapo- rated under reduced pressure. The residue was partitioned between water and AcOEt. The aqueous layer was extracted with AcOEt and 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 (0 to 10% MeOH gradient in DCM) to yield 4-{N-[(2- chloroquinolin-7-yl)methyl]-3-(pyridin-4-yl)propanamido}-1-m ethyl-1H-pyrazole-3-carbox- amide (Int. P-006, 0.165 g, 0.37 mmol, 96%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J = 8.4 Hz, 1H), 8.44 – 8.42 (m, 2H), 7.98 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 7.49 (s, 1H), 7.32 (s, 1H), 7.21 – 7.16 (m, 2H), 5.38 (br s, 1H), 4.49 (br s, 1H), 3.77 (s, 3H), 2.86 (t, J = 7.5 Hz, 2H), 2.52 (t, J = 7.5 Hz, 2H). m/z (ESI): 449.3 [M+H] ⁺ . 4-{N-[(2-chloroquinolin-7-yl)methyl]-3-(pyridin-2-yl)propana mido}-1-methyl-1H-pyrazole- 3-carboxamide (Int. P-007) 4-{N-[(2-chloroquinolin-7-yl)methyl]-3-(pyridin-2-yl)propana mido}-1-methyl-1H-pyrazole- 3-carboxamide (Int. P-007) was prepared from methyl 1-methyl-4-[3-(pyridin-2-yl)pro- panamido]-1H-pyrazole-3-carboxylate (Int. D-006) in a manner similar to the preparation of 4-{N-[(2-chloroquinolin-7-yl)methyl]-3-(pyridin-4-yl)propana mido}-1-methyl-1H-pyrazole- 3-carboxamide (Int. P-006). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 – 8.47 (m, 1H), 8.44 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.67 (td, J = 7.5, 1.8 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 8.4, 1.7 Hz, 1H), 7.48 (s, 1H), 7.30 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.20 (dd, J = 7.5, 4.9 Hz, 1H), 5.42 (br s, 1H), 4.48 (br s, 1H), 3.76 (s, 3H), 2.99 (t, J = 7.6 Hz, 2H), 2.60 (br s, 2H). m/z (ESI): 449.8 [M+H] ⁺ . 4-{N-[(2-chloroquinolin-7-yl)methyl]cyclopropaneamido}-1-met hyl-1H-pyrazole-3-carbox- amide (Int. P-008) Ryvu Therapeutics S.A. RVU305 388 R10107WO CDI (0.328 g, 2.0 mmol, 3.0 eq.) was added to a solution of 4-{N-[(2-chloroquinolin-7-yl)me- thyl]cyclopropaneamido}-1-methyl-1H-pyrazole-3-carboxylic acid (Int. N-027, 0.27 g, 0.67 mmol, 1.0 eq.) in anhydrous DMF (4.0 mL) at RT and the mixture was stirred at 60 °C for 1 h. The RM was cooled to RT, aqueous ammonia (8.08 mL, 4.04 mmol, 6.0 eq.) was added, and the RM was stirred at RT overnight. It was then evaporated under reduced pressure and the residue was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (2x), and the combined organic layers were washed with brine, dried over anhy- drous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was pu- rified by FCC (0 to 5% MeOH gradient in DCM) to yield 4-{N-[(2-chloroquinolin-7-yl)me- thyl]cyclopropaneamido}-1-methyl-1H-pyrazole-3-carboxamide (Int. P-008, 0.139 g, 0.36 mmol, 48%, white solid, UPLC purity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (dd, J = 8.6, 0.8 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.72 – 7.67 (m, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.53 (dd, J = 8.4, 1.7 Hz, 1H), 7.45 (s, 1H), 7.28 (s, 1H), 5.31 (br s, 1H), 4.63 (br s, 1H), 3.78 (s, 3H), 1.55 (tt, J = 8.0, 4.6 Hz, 1H), 0.84 – 0.77 (m, 2H), 0.71 – 0.61 (m, 2H). m/z (ESI): 385.1 [M+H] ⁺ . N-[(2,4-dichloroquinolin-7-yl)methyl]-N-(2-methanesulfonylph enyl)acetamide (Int. P-010) 3-Chloroperbenzoic acid (1.2 g, 4.87 mmol, 1.6 eq.) was added to a solution of N-[(2-chloro- quinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl)acetamide (Int. N-001, 1.233 g, 3.01 mmol, 1.0 eq.) in DCM (30.0 mL) at 0 °C and the RM was stirred at RT overnight. It was then washed with aq. sat. Na ₂ CO ₃ and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give crude 2-chloro-7-{[N-(2-methanesulfonylphenyl)acetamido]methyl}qui n- olin-1-ium-1-olate (Int. P-009, 1.6 g, 3.95 mmol, 80%, beige solid, UPLC purity: 67%), which was used in the next step without further purification. m/z (ESI): 406.1 [M+H] ⁺ . Compound ^{Int. P-009 was suspended in toluene (8.0 mL) and POCl3 (0.75 g, 4.89 mmol, 2.0 eq.) was} _{added dropwise at 0 °C. The reaction was stirred at reflux overnight under nitrogen, and} quenched with aq.1 M NaOH at 0 °C. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N‐[(2,8‐dichloroquinolin‐7‐yl)methyl]‐N‐(2‐me- thanesulfonylphenyl)acetamide (Int. P-010, 0.11 g, 0.26 mmol, 8%, brown solid, UPLC purity: 73%). 85/15 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Ryvu Therapeutics S.A. RVU305 389 R10107WO Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (d, J = 8.5 Hz, 1H), 8.14 (dd, J = 7.9, 1.6 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.66 (td, J = 7.7, 1.3 Hz, 1H), 7.58 (td, J = 7.6, 1.6 Hz, 1H), 7.02 (dd, J = 7.9, 1.3 Hz, 1H), 5.79 (d, J = 15.4 Hz, 1H), 4.77 (d, J = 15.4 Hz, 1H), 3.42 (s, 3H), 1.85 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 8.04 – 8.01 (m, 1H), 7.80 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.47 (td, J = 7.7, 1.7 Hz, 1H), 6.86 (dd, J = 7.8, 1.3 Hz, 1H), 5.50 (d, J = 16.3 Hz, 1H), 5.05 (d, J = 16.3 Hz, 1H), 3.19 (s, 3H), 2.40 (s, 3H). m/z (ESI): 423.0 [M+H] ⁺ . N-[(2-chloroquinolin-7-yl)methyl]-N-(5,6,7,8-tetrahydroquino lin-8-yl)pyridine-3-carbox- Step 1: Acetic acid (0.085 mL, 1.47 mmol, 1.59 eq.) was added to a solution of 1-(2-chloroquinolin- 7-yl)methanamine (Int. A-073, 0.2 g, 0.92 mmol, 1.0 eq.) and 5,6,7,8-tetrahydroquinolin-8- one (0.205 g, 1.39 mmol, 1.5 eq.) in a mixture of anhydrous MeOH (4.0 mL) and anhydrous DCM (2.0 mL) and the mixture was stirred at RT for 30 min. Sodium triacetoxyborohydride (0.395 g, 1.86 mmol, 2.0 eq.) was added portionwise and the RM was stirred for a further 30 min. at RT under nitrogen. At this time, additional sodium triacetoxyborohydride (0.197 g, 0.98 mmol, 1.0 eq.) and the RM was stirred for a further 3 h at RT under nitrogen. The RM was concentrated in vacuo and the crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-chloroquinolin-7-yl)methyl]-5,6,7,8-tetrahydroquinolin -8- amine (Int. P-011, 0.133 g, 0.41 mmol, 34%, brown oil, UPLC purity: 77%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (d, J = 8.6 Hz, 1H), 8.39 (dd, J = 4.8, 1.0 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.98 – 7.93 (m, 1H), 7.72 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.19 (dd, J = 7.6, 4.8 Hz, 2H), 4.13 (d, J = 14.6 Hz, 1H), 4.08 (d, J = 14.6 Hz, 1H), 3.71 (dd, J = 7.1, 5.2 Hz, 1H), 2.75 (m, 2H), 2.05 (dd, J = 12.0, 6.1 Hz, 1H), 2.00 – 1.81 (m, 1H), 1.71 (m, 2H). m/z (ESI): 325.3 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 09, using N-[(2-chloroquinolin-7- yl)methyl]-5,6,7,8-tetrahydroquinolin-8-amine (Int. P-011, 0.13 g, 0.31 mmol, 1.0 eq.) and nicotinoyl chloride hydrochloride (0.1 g, 0.56 mmol, 1.82 eq.) in pyridine (2.0 mL). The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-chloroquino- lin-7-yl)methyl]-N-(5,6,7,8-tetrahydroquinolin-8-yl)pyridine -3-carboxamide (Int. P-012, 0.16 g, 0.37 mmol, 93%, beige oily solid, UPLC purity: 77%). 8/2 mixture of restricted C-N amide Ryvu Therapeutics S.A. RVU305 390 R10107WO rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (dd, J = 2.3, 0.9 Hz, 1H), 8.66 (dd, J = 4.8, 1.7 Hz, 1H), 8.50 (dd, J = 4.6, 1.6 Hz, 1H), 8.43 (d, J = 8.6 Hz, 1H), 8.11 (dt, J = 7.8, 1.9 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.88 (s, 1H), 7.67 (dd, J = 8.5, 1.8 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 9.0, 1.2 Hz, 1H), 7.51 (ddd, J = 7.8, 5.0, 0.6 Hz, 1H), 7.25 (dd, J = 7.7, 4.7 Hz, 1H), 5.03 (dd, J = 11.3, 5.8 Hz, 1H), 4.98 (d, J = 16.4 Hz, 1H), 4.01 (d, J = 16.5 Hz, 1H), 2.84 – 2.73 (m, 1H), 2.70 – 2.56 (m, 1H), 2.37 – 2.23 (m, 1H), 2.02 – 1.90 (m, 1H), 1.90 – 1.78 (m, 1H), 1.70 – 1.52 (m, 1H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (dd, J = 2.2, 0.9 Hz, 1H), 8.82 (dd, J = 4.8, 1.7 Hz, 1H), 8.54 – 8.50 (m, 1H), 8.46 – 8.39 (m, 2H), 8.27 (dt, J = 8.0, 2.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.90 – 7.87 (m, 1H), 7.66 – 7.62 (m, 1H), 7.58 – 7.52 (m, 2H), 7.31 (dd, J = 7.8, 4.7 Hz, 1H), 6.18 (t, J = 4.9 Hz, 1H), 4.74 (d, J = 17.7 Hz, 1H), 4.58 (d, J = 17.8 Hz, 1H), 2.92 (dt, J = 17.3, 5.5 Hz, 1H), 2.86 – 2.74 (m, 1H), 2.02 – 1.90 (m, 1H), 1.90 – 1.80 (m, 1H), 1.80 – 1.69 (m, 1H), 1.62 (t, J = 13.2 Hz, 1H). m/z (ESI): 429.3 [M+H] ⁺ . N-[(2-chloroquinolin-7-yl)methyl]-N-{2H,3H,4H-pyrano[3,2-b]p yridin-4-yl}pyridine-3-car- Step 1: A mixture of 2H,3H,4H-pyrano[3,2-b]pyridin-4-amine (0.104 g, 0.69 mmol, 1.0 eq.), 2-chloro- quinoline-7-carbaldehyde (Int. A-141, 0.158 g, 0.8 mmol, 1.15 eq.), AcOH (0.05 mL, 0.87 mmol, 1.26 eq.) and MeOH (4.5 mL) was stirred at RT for 3 h. NaBH ₃ CN (0.056 g, 0.94 mmol, 1.35 eq.) was added and the RM was stirred at RT for 16 h. It was then concentrated under reduced pressure and the crude material was purified by FCC (0 to 100% AcOEt gradient in hexane) to afford N-[(2-chloroquinolin-7-yl)methyl]-2H,3H,4H-pyrano[3,2-b]pyri din-4- amine (Int. P-013, 0.13 g, 0.37 mmol, 53%, white solid, UPLC purity: 92%). ¹ H NMR (400 ^{MHz, DMSO-d6) δ 8.45 (d, J = 8.6 Hz, 1H), 8.20 – 8.14 (m, 1H), 8.05 (d, J = 8.5 Hz, 1H), 8.04} _{– 8.01 (m, 1H), 7.76 (dd, J = 8.2, 1.1 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.30 – 7.21 (m, 1H),} 7.18 (ddt, J = 7.8, 1.4, 0.7 Hz, 1H), 4.37 (ddd, J = 10.6, 7.6, 2.7 Hz, 1H), 4.31 – 4.18 (m, 4H), 2.29 – 2.13 (m, 1H), 2.13 – 2.01 (m, 1H). m/z (ESI): 326.2 [M+H] ⁺ . Step 2: Step 2 was performed according to General Procedure 09, using N-[(2-chloroquinolin-7- yl)methyl]-2H,3H,4H-pyrano[3,2-b]pyridin-4-amine (Int. P-013, 0.13 g, 0.40 mmol, 1.0 eq.), nicotinoyl chloride hydrochloride (0.135 g, 0.76 mmol, 2.1 eq.) and DMAP (0.013 g, 0.11 mmol, 0.29 eq.) in pyridine (2.0 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(2-chloroquinolin-7-yl)methyl]-N-{2H,3H,4H-pyrano[3,2-b]p yr- idin-4-yl}pyridine-3-carboxamide (Int. P-014, 0.11 g, 0.26 mmol, 63%, yellow solid, UPLC pu- rity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (dd, J = 2.2, 0.8 Hz, 1H), 8.68 (dd, J = 4.9, 1.7 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.26 (dd, J = 4.4, 1.6 Hz, 1H), 8.14 (dt, J = 7.8, 2.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.66 (dd, J = 8.4, 1.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, Ryvu Therapeutics S.A. RVU305 391 R10107WO 1H), 7.52 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 7.27 (dd, J = 8.4, 4.4 Hz, 1H), 7.22 (dd, J = 8.2, 1.5 Hz, 1H), 5.29 (dd, J = 11.2, 6.1 Hz, 1H), 5.03 (d, J = 16.5 Hz, 1H), 4.24 (dt, J = 11.1, 3.2 Hz, 1H), 4.14 (td, J = 11.9, 1.5 Hz, 1H), 3.99 (d, J = 16.7 Hz, 1H), 2.40 – 2.35 (m, 1H), 2.30 – 2.11 (m, 1H). m/z (ESI): 431.9 [M+H] ⁺ . N-[(3-chloro-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesul fonylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide (Int. P-015) Triphenylphosphine (0.163 g, 0.62 mmol, 1.25 eq.) was added to a solution of N-(2-me- thanesulfonylphenyl)-2-(trifluoromethyl)pyrimidine-5-carboxa mide (Int. K-021, 0.2 g, 0.56 mmol, 1.12 eq.) and (3-chloro-2-methylquinoxalin-6-yl)methanol (Int. A-116, 0.109 g, 0.50 mmol, 1.0 eq.) in toluene (5.0 mL). DIAD (0.125 g, 0.62 mmol, 1.25 eq.) was then added dropwise at 0 °C. The RM was stirred for 40 min. at 80 °C, under microwave irradiation. After coming back to RT, the RM was evaporated under reduced pressure and the crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-[(3-chloro-2- methylquinoxalin-6-yl)methyl]-N-(2-methanesulfonylphenyl)-2- (trifluoromethyl)pyrimidine- 5-carboxamide (Int. P-015, 0.085 g, 0.16 mmol, 31%, beige solid, UPLC purity: 98%).8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 2H), 8.08 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.96 (dd, J = 7.9, 1.6 Hz, 1H), 7.95 (dd, J = 8.6, 1.9 Hz, 1H), 7.65 (td, J = 7.6, 1.6 Hz, 1H), 7.59 (td, J = 7.6, 1.5 Hz, 1H), 7.52 (dd, J = 7.8, 1.4 Hz, 1H), 5.81 (d, J = 15.2 Hz, 1H), 4.90 (d, J = 15.3 Hz, 1H), 3.26 (s, 3H), 2.78 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.30. Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 2H), 8.11 – 8.08 (m, 1H), 7.99 – 7.96 (m, 1H), 7.81 (s, 1H), 7.78 (dd, J = 8.7, 1.8 Hz, 1H), 7.69 – 7.61 (m, 2H), 7.27 (dd, J = 7.1, 2.1 Hz, 1H), 5.40 (d, J = 16.0 Hz, 1H), 4.97 (d, J = 15.8 Hz, 1H), 3.29 (s, 3H), 2.75 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.19. m/z (ESI): 536.2 [M+H] ⁺ . N-[(2-chloro-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfo nylpyridin-3-yl)-2-(pyrimidin- Ryvu Therapeutics S.A. RVU305 392 R10107WO Step 1: 4-Methylmorpholin-4-ium-4-olate (0.627 g, 5.35 mmol, 3.0 eq.) was added to a solution of 7-(bromomethyl)-2-chloro-3-fluoroquinoline (Int. A-072, 0.5 g, 1.78 mmol, 1.0 eq.) in diox- ane (6.0 mL) and the RM was stirred at 80 °C for 1 hour. The mixture was partitioned be- tween EtOAc and water, and the organic layer was washed with water and brine, dried over anhydrous MgSO ₄ , filtered, and evaporated under reduced pressure. The obtained crude 2- chloro-3-fluoroquinoline-7-carbaldehyde (Int. P-016, 0.321 g, 1.50 mmol, 84%, white solid, UPLC purity: 98%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.24 (d, J = 0.7 Hz, 1H), 8.64 (d, J = 9.1 Hz, 1H), 8.62 (dd, J = 1.6, 0.8 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.09 (ddd, J = 8.5, 1.6, 0.8 Hz, 1H). _m/z (ESI): 209.9 [M+H] ⁺ . Step 2: 2-Chloro-3-fluoroquinoline-7-carbaldehyde (Int. P-016, 0.32 g, 1.50 mmol, 1.0 eq.) and tri- fluoroacetic acid (0.172 mL, 2.24 mmol, 1.5 eq.) were added to a solution of 2-methanesul- fonylpyridin-3-amine (0.283 g, 1.65 mmol, 1.1 eq.) in DCM (7.5 mL) and the RM was stirred for 1 h at RT. STAB (0.634 g, 2.99 mmol, 2.0 eq.) was added and the RM was stirred at RT overnight. The RM was then poured into a stirred mixture of ice and sat. aq. NaHCO ₃ . The layers were separated, and the aqueous phase was extracted with DCM. The combined or- ganic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-[(2-chloro-3-fluoroquinolin-7-yl)methyl]-2-methanesulfonyl pyridin-3-amine (Int. P- 017, 0.434 g, 1.19 mmol, 79%, white solid, UPLC purity: 100%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.48 (d, J = 9.1 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.94 – 7.92 (m, 1H), 7.89 (dd, J = 4.3, 1.3 Hz, 1H), 7.72 (dd, J = 8.4, 1.8 Hz, 1H), 7.37 (ddd, J = 8.6, 4.2, 0.6 Hz, 1H), 7.26 (t, J = 6.0 Hz, 1H), 7.24 (dd, J = 8.7, 1.3 Hz, 1H), 4.76 (d, J = 6.1 Hz, 2H), 3.37 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -122.33 (d, J = 9.3 Hz). m/z (ESI): 366.1 [M+H] ⁺ . Step 3: Step 3 was performed according to General Procedure 39, using N-[(2-chloro-3-fluoroquin- olin-7-yl)methyl]-2-methanesulfonylpyridin-3-amine (Int. P-017, 0.409 g, 1.12 mmol, 1.0 eq.), 2-(pyrimidin-2-yl)acetic acid (0.309 g, 2.24 mmol, 2.0 eq.), DMAP (0.041 g, 0.33 mmol, 0.3 eq.), pyridine (0.271 mL, 3.35 mmol, 3.0 eq.) and T3P (50 weight % in EtOAc, 2.66 mL, 4.47 mmol, 4.0 eq.) in iPrOAc (4.0 mL) at 50 °C for 2 h. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(2-chloro-3-fluoroquinolin-7-yl)methyl]- N-(2-methanesulfonylpyridin-3-yl)-2-(pyrimidin-2-yl)acetamid e (Int. P-018, 0.265 g, 0.52 mmol, 47%, yellow solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J = 4.9 Hz, 2H), 8.68 (dd, J = 4.7, 1.5 Hz, 1H), 8.50 (d, J = 9.1 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.03 (s, 1H), 7.72 (dd, J = 8.1, 1.5 Hz, 1H), 7.52 (dd, J = 8.1, 4.6 Hz, 1H), 7.41 (t, J = 4.9 Hz, 1H), 7.37 (dd, J = 8.1, 1.5 Hz, 1H), 5.80 (d, J = 15.6 Hz, 1H), 4.39 (d, J = 15.7 Hz, 1H), 3.85 (d, J = 15.9 Hz, 1H), 3.79 (d, J = 15.8 Hz, 1H), 3.54 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 121.95 (d, J = 9.1 Hz). _m/z (ESI): 486.9 [M+H] ⁺ . N-{[2-chloro-3-(methoxymethyl)quinolin-7-yl]methyl}-6-cyclop ropyl-N-(2-methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide (Int. P-020) Ryvu Therapeutics S.A. RVU305 393 R10107WO Step 1: Triphenylphosphine (0.042 g, 0.16 mmol, 1.9 eq.) and carbon tetrabromide (0.053 g, 0.16 mmol, 1.9 eq.) were added to a solution of N-{[2-chloro-3-(hydroxymethyl)quinolin-7-yl]me- thyl}-6-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyridin e-3-carboxamide (Int. O-213, 0.056 g, 0.084 mmol, 1.0 eq.) in DCM (0.6 mL) at 0 °C. The reaction was stirred for 2.5 h, being allowed to slowly reach RT. It was then concentrated under reduced pressure and the crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-{[3- (bromomethyl)-2-chloroquinolin-7-yl]methyl}-6-cyclopropyl-N- (2-methanesulfonylpyridin- 3-yl)pyridine-3-carboxamide (Int. P-019, 0.047 g, 0.06 mmol, 71%, yellow solid, UPLC purity: ^{76%). 1H NMR (400 MHz, DMSO-d} ₆ ^{) δ 8.67 (s, 1H), 8.57 (d, J = 3.6 Hz, 1H), 8.37 (s, 1H),} 8.02 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.78 – 7.66 (m, 2H), 7.64 – 7.56 (m, 2H), 7.15 (d, J = 8.2 Hz, 1H), 5.82 (d, J = 15.1 Hz, 1H), 4.90 (s, 2H), 4.82 (d, J = 15.1 Hz, 1H), 3.33 (s, 3H), 2.07 – 1.97 (m, 1H), 0.98 – 0.90 (m, 2H), 0.87 – 0.80 (m, 2H). m/z (ESI): 584.9 [M+H] ⁺ . Step 2: Sodium methoxide (0.008 g, 0.152 mmol, 2.5 eq.) was added to a solution of N-{[3-(bromo- methyl)-2-chloroquinolin-7-yl]methyl}-6-cyclopropyl-N-(2-met hanesulfonylpyridin-3-yl)pyr- idine-3-carboxamide (Int. P-019, 0.047 g, 0.06 mmol, 1.0 eq.) in anhydrous MeOH (8.0 mL) and the mixture was stirred at 55 °C overnight under nitrogen. After coming back to RT, the RM was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 35% MeCN gradient in DCM) to yield N-{[2-chloro-3-(methoxymethyl)quinolin-7-yl]methyl}-6- cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carb oxamide (Int. P-020, 0.015 g, 0.022 mmol, 56%, white solid, UPLC purity: 78%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 – 8.53 (m, 1H), 8.44 (s, 1H), 8.37 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.61 – 7.50 (m, 2H), 7.15 (d, J = 8.2 Hz, 1H), 5.82 (d, J = 15.1 Hz, 1H), 4.82 (d, J = 15.2 Hz, 1H), 4.62 (s, 2H), 3.45 (s, 3H), 3.33 (s, 3H), 2.07 – 1.95 (m, 1H), 0.98 – 0.88 (m, 2H), 0.88 – 0.81 (m, 2H). m/z (ESI): 537.6 [M+H] ⁺ . Preparation examples of Compounds of Formula (I) Example A-001: N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) acetamide Ryvu Therapeutics S.A. RVU305 394 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) acetamide (Example A- 001), General Procedure 23: A mixture of Cs ₂ CO ₃ (0.078 g, 0.24 mmol, 1.3 eq.), XPhos Pd G3 (0.016 g, 0.02 mmol, 0.1 eq.), tert-butyl carbamate (0.030 g, 0.26 mmol, 1.4 eq.) and N-[(2-chloroquinolin-7-yl)me- thyl]-N-(2-methanesulfonylphenyl)acetamide (Int. N-001, 0.096 g, 0.19 mmol, 1.0 eq.) in an- hydrous dioxane (2.0 mL) was sparged with nitrogen for 10 minutes. The RM was heated under microwave irradiation at 100 °C for 1 h. After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . Water was added to the filtrate and the or- ganic phase was separated. The aqueous layer was extracted with EtOAc (1x). The com- bined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in DCM (4.0 mL) and TFA (1.06 mL, 13.89 mmol, 75.0 eq.) was added. The RM was stirred at RT overnight and the vol- atiles were evaporated under reduced pressure. The residue was partitioned between sat. aq. Na ₂ CO ₃ and DCM. The aqueous phase was extracted with DCM, and the combined or- ganic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to af- ford N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) acetamide (Example A- 001, 0.025 g, 0.07 mmol, 37%, white solid, UPLC long elution purity: 100%).8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (d, J = 7.3 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.72 – 7.54 (m, 3H), 7.23 (s, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.41 (s, 2H), 5.71 (d, J = 14.7 Hz, 1H), 4.20 (d, J = 14.7 Hz, 1H), 3.37 (s, 3H), 1.81 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J = 6.9 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.71 – 7.54 (m, 3H), 7.31 (s, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.79 – 6.75 (m, 1H), 6.46 (s, 2H), 5.34 (d, J = 16.8 Hz, 1H), 4.60 (d, J = 16.8 Hz, 1H), 3.19 (s, 3H), 2.34 (s, 3H). _m/z (ESI): 370.80 [M+H] ⁺ . Compounds prepared according to General Procedure 23: Ryvu Therapeutics S.A. RVU305 395 R10107WO Ryvu Therapeutics S.A. RVU305 396 R10107WO Ryvu Therapeutics S.A. RVU305 397 R10107WO Ryvu Therapeutics S.A. RVU305 398 R10107WO Ryvu Therapeutics S.A. RVU305 399 R10107WO Ryvu Therapeutics S.A. RVU305 400 R10107WO Ryvu Therapeutics S.A. RVU305 401 R10107WO Ryvu Therapeutics S.A. RVU305 402 R10107WO Ryvu Therapeutics S.A. RVU305 403 R10107WO Ryvu Therapeutics S.A. RVU305 404 R10107WO Ryvu Therapeutics S.A. RVU305 405 R10107WO Ryvu Therapeutics S.A. RVU305 406 R10107WO Ryvu Therapeutics S.A. RVU305 407 R10107WO Ryvu Therapeutics S.A. RVU305 408 R10107WO Ryvu Therapeutics S.A. RVU305 409 R10107WO Ryvu Therapeutics S.A. RVU305 410 R10107WO Ryvu Therapeutics S.A. RVU305 411 R10107WO Ryvu Therapeutics S.A. RVU305 412 R10107WO Ryvu Therapeutics S.A. RVU305 413 R10107WO Ryvu Therapeutics S.A. RVU305 414 R10107WO ¹ Purity: UPLC long elution purity *: amination carried out at 70 °C **: Boc deprotection performed by thermal cleavage in 1/1 dioxane:water v/v with micro- wave heating at 120 °C for 2 h ***: reaction carried out using KI as a catalyst (0.2 eq.) Example B-001: N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(ethanesulfonyl)phenyl ]pyridine-3- carboxamide, General Procedure 24 A Biotage ^TM microwave vial was charged with N-[(2-chloroquinolin-7-yl)methyl]-N-[2- (ethanesulfonyl)phenyl]pyridine-3-carboxamide (Int. O-001, 0.18 g, 0.33 mmol, 1.0 eq.), Cs ₂ CO ₃ (0.160 g, 0.49 mmol, 1.5 eq.), tert-butyl carbamate (0.077 g, 0.66 mmol, 2.0 eq.) and anhydrous dioxane (4.5 mL). The RM was sparged with nitrogen for 5 min. Xphos Pd G3 (0.028 g, 0.033 mmol, 0.1 eq.) was added followed by XPhos (0.015 g, 0.033 mmol, 0.1 eq.) and the vial was sealed. The resulting RM was stirred for 1 h at 100 °C in a DrySyn ^® . After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . The filtrate was evaporated under reduced pressure and the residue was dissolved in a mix- ture of DCM (10.0 mL) and TFA (2.5 mL). The RM was stirred for 2 h at RT and evaporated under reduced pressure. The residue was partitioned between DCM and aq. sat. NaHCO ₃ . The aqueous phase was extracted with DCM and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (C18 functionalized silica; 10% to 100% MeCN gradient in water). The fractions containing the pure product were pooled and freeze-dried to yield N-[(2-amino- quinolin-7-yl)methyl]-N-[2-(ethanesulfonyl)phenyl]pyridine-3 -carboxamide (Example B- 001, 0.026 g, 0.06 mmol, 17%, white solid, UPLC long elution purity: 96.40%).7/3 Mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 2.2 Hz, 1H), 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.84 (dd, J = 7.7, 1.4 Hz, 1H), 7.69 (dt, J = 8.0, 1.7 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.0 Hz, 1H), 7.34 (s, 1H), 7.25 (dd, J = 8.1, 5.3 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 9.0 Hz, 1H), 6.44 (s, 2H), 5.67 (d, J = 14.8 Ryvu Therapeutics S.A. RVU305 415 R10107WO Hz, 1H), 4.67 (d, J = 15.4 Hz, 1H), 3.14 – 2.93 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (d, J = 2.2 Hz, 1H), 8.77 – 8.69 (m, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.05 (dd, J = 6.6, 2.4 Hz, 1H), 7.71 – 7.47 (m, 3H), 7.55 (d, J = 8.3 Hz, 1H), 7.39 – 7.31 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.11 (s, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.48 (s, 2H), 5.18 (d, J = 15.8 Hz, 1H), 4.67 (d, J = 15.3 Hz, 1H), 3.34 – 3.22 (m, 2H), 1.15 (t, J = 7.3 Hz, 3H). m/z (ESI): 447.20 [M+H] ⁺ . Examples prepared according to General Procedure 24: Ryvu Therapeutics S.A. RVU305 416 R10107WO Ryvu Therapeutics S.A. RVU305 417 R10107WO Ryvu Therapeutics S.A. RVU305 418 R10107WO Ryvu Therapeutics S.A. RVU305 419 R10107WO Ryvu Therapeutics S.A. RVU305 420 R10107WO Ryvu Therapeutics S.A. RVU305 421 R10107WO Ryvu Therapeutics S.A. RVU305 422 R10107WO Ryvu Therapeutics S.A. RVU305 423 R10107WO Ryvu Therapeutics S.A. RVU305 424 R10107WO Ryvu Therapeutics S.A. RVU305 425 R10107WO Ryvu Therapeutics S.A. RVU305 426 R10107WO Ryvu Therapeutics S.A. RVU305 427 R10107WO Ryvu Therapeutics S.A. RVU305 428 R10107WO Ryvu Therapeutics S.A. RVU305 429 R10107WO Ryvu Therapeutics S.A. RVU305 430 R10107WO Ryvu Therapeutics S.A. RVU305 431 R10107WO Ryvu Therapeutics S.A. RVU305 432 R10107WO Ryvu Therapeutics S.A. RVU305 433 R10107WO Ryvu Therapeutics S.A. RVU305 434 R10107WO Ryvu Therapeutics S.A. RVU305 435 R10107WO Ryvu Therapeutics S.A. RVU305 436 R10107WO Ryvu Therapeutics S.A. RVU305 437 R10107WO Ryvu Therapeutics S.A. RVU305 438 R10107WO Ryvu Therapeutics S.A. RVU305 439 R10107WO Ryvu Therapeutics S.A. RVU305 440 R10107WO Ryvu Therapeutics S.A. RVU305 441 R10107WO Ryvu Therapeutics S.A. RVU305 442 R10107WO Ryvu Therapeutics S.A. RVU305 443 R10107WO Ryvu Therapeutics S.A. RVU305 444 R10107WO Ryvu Therapeutics S.A. RVU305 445 R10107WO Ryvu Therapeutics S.A. RVU305 446 R10107WO Ryvu Therapeutics S.A. RVU305 447 R10107WO Ryvu Therapeutics S.A. RVU305 448 R10107WO Ryvu Therapeutics S.A. RVU305 449 R10107WO Ryvu Therapeutics S.A. RVU305 450 R10107WO Ryvu Therapeutics S.A. RVU305 451 R10107WO Ryvu Therapeutics S.A. RVU305 452 R10107WO Ryvu Therapeutics S.A. RVU305 453 R10107WO Ryvu Therapeutics S.A. RVU305 454 R10107WO Ryvu Therapeutics S.A. RVU305 455 R10107WO Ryvu Therapeutics S.A. RVU305 456 R10107WO Ryvu Therapeutics S.A. RVU305 457 R10107WO Ryvu Therapeutics S.A. RVU305 458 R10107WO Ryvu Therapeutics S.A. RVU305 459 R10107WO Ryvu Therapeutics S.A. RVU305 460 R10107WO Ryvu Therapeutics S.A. RVU305 461 R10107WO ¹ Purity: UPLC long elution purity *: deprotection carried out in neat TFA at 75 °C for 4 h **: 10 min. amination reaction time ***: amination carried out at 70 °C Ryvu Therapeutics S.A. RVU305 462 R10107WO ****: amination carried out using XantPhos Pd G3 in DMF at 80 °C *****: Boc deprotection performed by thermal cleavage in dioxane/water 1:1 v/v with micro- wave heating at 120 °C for 2 h Example C-001: N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)acet- amide, General Procedure 25 A Biotage ^TM microwave vial was charged with N-[(2-chloroquinolin-7-yl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)acetamide (Int. N-006, 0.15 g, 0.37 mmol, 1.0 eq.), Cs ₂ CO ₃ (0.167 g, 0.51 mmol, 1.4 eq.), tert-butyl carbamate (0.057 g, 0.49 mmol, 1.3 eq.) and anhydrous di- oxane (6.0 mL). The RM was sparged with nitrogen for 5 min. XPhos (0.016 g, 0.03 mmol, ^{0.1 eq.) was added followed by Pd(OAc)2 (0.007 g, 0.03 mmol, 0.1 eq.) and the vial was} _{sealed. The resulting RM was stirred for 10 h at 100 °C in a DrySyn®. After coming back to} RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . The filtrate was evaporated under reduced pressure and the residue was dissolved in DCM (3.0 mL) and TFA (0.5 mL) was added. The RM was stirred for 3 h at RT and the volatiles were evapo- rated under reduced pressure. The residue was partitioned between DCM and water, the aqueous phase was basified with aq.1 M NaOH and extracted with DCM/iPrOH 3:1 v/v (3x). The combined organic layers were dried over anhydrous. Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 8% MeOH gra- dient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3- yl)acetamide (Example C-001, 0.083 g, 0.22 mmol, 61%, white solid, UPLC long elution pu- rity: 100%). 9/1 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (dd, J = 4.6, 1.4 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 8.1, 4.6 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.43 (dd, J = 8.1, 1.5 Hz, 1H), 7.18 (s, 1H), 7.04 (dd, J = 8.0, 1.7 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.41 (s, 2H), 5.72 (d, J = 14.8 Hz, 1H), 4.16 (d, J = 14.8 Hz, 1H), 3.51 (s, 3H), 1.81 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 4.7 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.64 (dd, J = 8.1, 4.6 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.44 (s, 2H), 5.33 (d, J = 16.3 Hz, 1H), 4.76 (d, J = 16.2 Hz, 1H), 3.29 (s, 3H), 2.31 (s, 3H). m/z (ESI): 371.50 [M+H] ⁺ . Examples prepared according to General Procedure 25: Ryvu Therapeutics S.A. RVU305 463 R10107WO Ryvu Therapeutics S.A. RVU305 464 R10107WO Ryvu Therapeutics S.A. RVU305 465 R10107WO Ryvu Therapeutics S.A. RVU305 466 R10107WO Ryvu Therapeutics S.A. RVU305 467 R10107WO Ryvu Therapeutics S.A. RVU305 468 R10107WO Ryvu Therapeutics S.A. RVU305 469 R10107WO Ryvu Therapeutics S.A. RVU305 470 R10107WO Ryvu Therapeutics S.A. RVU305 471 R10107WO Ryvu Therapeutics S.A. RVU305 472 R10107WO Ryvu Therapeutics S.A. RVU305 473 R10107WO Ryvu Therapeutics S.A. RVU305 474 R10107WO Ryvu Therapeutics S.A. RVU305 475 R10107WO Ryvu Therapeutics S.A. RVU305 476 R10107WO Ryvu Therapeutics S.A. RVU305 477 R10107WO Ryvu Therapeutics S.A. RVU305 478 R10107WO Ryvu Therapeutics S.A. RVU305 479 R10107WO Ryvu Therapeutics S.A. RVU305 480 R10107WO Ryvu Therapeutics S.A. RVU305 481 R10107WO Ryvu Therapeutics S.A. RVU305 482 R10107WO Ryvu Therapeutics S.A. RVU305 483 R10107WO Ryvu Therapeutics S.A. RVU305 484 R10107WO ¹ Purity: UPLC long elution purity Ryvu Therapeutics S.A. RVU305 485 R10107WO Example D-002: N-[(2-aminoquinolin-7-yl)methyl]-5-chloro-N-(2-methanesulfon ylpyridin- 3-yl)pyridine-3-carboxamide, General Procedure 26 A round bottomed flask was charged with Cs ₂ CO ₃ (0.02 g, 0.06 mmol, 1.2 eq.), 5-chloro-N- (2-methanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Int. K-001, 0.028 g, 0.08 mmol, 1.5 eq.), tert-butyl N-[7-(bromomethyl)quinolin-2-yl]carbamate (Int. A-010, 0.018 g, 0.05 mmol, 1.0 eq.) and anhydrous MeCN (1.0 mL). The RM was stirred at 60 °C for 2 h and parti- tioned between DCM and water. The aqueous phase was extracted with DCM (2x), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was redissolved in a mixture of DCM (1.0 mL) and TFA (0.5 mL) and the RM was stirred at RT for 2 h. The volatiles were evaporated under reduced pressure and the residue was partitioned between DCM and aq. sat. NaHCO ₃ . The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by two consecutive FCCs (first: silica, 0 to 10% MeOH gradient in DCM; second: NH ₂ functionalized silica, 0 to 3% MeOH gradient in DCM) to yield N-[(2- aminoquinolin-7-yl)methyl]-5-chloro-N-(2-methanesulfonylpyri din-3-yl)pyridine-3-carbox- amide (Example D-002, 0.011 g, 0.02 mmol, 45%, white solid, UPLC long elution purity: 96.98%). 8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major conformer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (d, J = 4.9 Hz, 1H), 8.55 (d, J = 2.7 Hz, 1H), 8.45 (s, 1H), 7.91 (s, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.56 (dd, J = 7.9, 5.0 Hz, 1H), 7.29 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.43 (s, 2H), 5.76 (d, J = 14.6 Hz, 1H), 4.68 (d, J = 14.7 Hz, 1H), 3.34 (s, 3H). Minor con- former: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (d, J = 9.9 Hz, 2H), 8.68 (s, 1H), 8.18 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.72 – 7.64 (m, 2H), 7.63 – 7.52 (m, 1H), 7.16 – 7.11 (m, 1H), 7.04 (d, J = 6.2 Hz, 1H), 6.49 (d, J = 8.9 Hz, 1H), 6.46 (s, 2H), 5.15 (d, J = 15.5 Hz, 1H), 4.82 (d, J = 15.4 Hz, 1H), 3.41 (s, 3H). m/z (ESI): 468.14 [M+H] ⁺ . Examples prepared according to General Procedure 26: Ryvu Therapeutics S.A. RVU305 486 R10107WO Ryvu Therapeutics S.A. RVU305 487 R10107WO Ryvu Therapeutics S.A. RVU305 488 R10107WO Ryvu Therapeutics S.A. RVU305 489 R10107WO Ryvu Therapeutics S.A. RVU305 490 R10107WO Ryvu Therapeutics S.A. RVU305 491 R10107WO Ryvu Therapeutics S.A. RVU305 492 R10107WO Ryvu Therapeutics S.A. RVU305 493 R10107WO Ryvu Therapeutics S.A. RVU305 494 R10107WO Ryvu Therapeutics S.A. RVU305 495 R10107WO Ryvu Therapeutics S.A. RVU305 496 R10107WO ¹ Purity: UPLC long elution purity *: Alkylation step performed in anhydrous DMF Example E-001: rac- N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(1-hydroxyethyl)phenyl ]acet- Sodium borohydride (0.010 g, 0.26 mmol, 1.5 eq.) was added in one portion to a solution of N-(2-acetylphenyl)-N-[(2-aminoquinolin-7-yl)methyl]acetamide (Example A-001, 0.06 g, 0.17 mmol, 1.0 eq.) in anhydrous methanol (2.5 mL) at 0 °C. The cooling bath was removed and the RM was stirred at RT for 30 min. The reaction was quenched with aq. sat. NH ₄ Cl. The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by trituration with Et ₂ O and hexane and dried un- der vacuum to yield N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(1-hydroxyethyl)phenyl ]acet- amide (Example E-001, 0.042 g, 0.12 mmol, 71%, white solid) as a stable 5/4 mixture of two distinguishable “diastereoisomer-like” components at RT due to the concomitant presence of amide bond rotamers and a chiral benzylic alcohol (UPLC long elution purity: 53.87% + 43.76%). 5/4 mixture of two “diastereoisomer-like” components in DMSO-d ₆ at RT: Major component: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.38 (td, J = 7.5, 4.7 Hz, 1H), 7.23 (td, J = 7.7, 1.3 Hz, 1H), 7.17 (s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H), 6.38 (s, 2H), 5.12 (d, J = 4.9 Hz, 1H), 5.11 (d, J = 14.3 Hz, 1H), 4.64 (p, J = 6.1 Hz, 1H), 4.54 (d, J = 14.5 Hz, 1H), 1.80 (s, 3H), 1.01 (d, J = 6.3 Hz, 3H). _m/z (ESI): 336.6 [M+H] ⁺ . Minor component: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.41 – 7.34 (m, 1H), 7.22 (d, J = 1.6 Hz, 1H), 7.13 (td, J = 7.5, 1.5 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.38 (s, 2H), 5.70 (d, J = 14.6 Hz, 1H), 5.27 (d, J = 4.3 Hz, 1H), 4.93 – 4.83 (m, 1H), 4.10 (d, J = 14.6 Hz, 1H), 1.74 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H). m/z (ESI): 336.6 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 497 R10107WO Example E-002: N-[(2-aminoquinolin-7-yl)methyl]-N-(1-oxo-2,3-dihydro-1H-iso indol-4- tert-Butyl N-{7-[(N-{2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-i soindol-4-yl}ac- etamido)methyl]quinolin-2-yl}carbamate (Int. Q-001) A mixture of Cs ₂ CO ₃ (0.136 g, 0.42 mmol, 1.3 eq.), XPhos Pd G3 (0.027 g, 0.03 mmol, 0.1 eq.), tert-butyl carbamate (0.053 g, 0.45 mmol, 1.4 eq.), N-[(2-chloroquinolin-7-yl)methyl]- N-{2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-isoindol -4-yl}acetamide (Int. N-002, 0.156 g, 0.32 mmol, 1.0 eq.) and anhydrous dioxane (2.0 mL) was sparged with nitrogen for a 10 minutes. The RM was heated under microwave irradiation at 100 °C for 90 min and filtered through a pad of Celite ^® . The filtrate was partitioned between water and EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concen- trated under reduced pressure. The crude material was purified by FCC (0 to 5 % MeOH gradient in DCM) to yield tert-butyl N-{7-[(N-{2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-di- hydro-1H-isoindol-4-yl}acetamido)methyl]quinolin-2-yl}carbam ate (Int. Q-001, 0.075 g, 0.132 mmol, 38%, white solid, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 8.3, 1.7 Hz, 1H), 7.08 – 7.03 (m, 2H), 6.84 – 6.78 (m, 2H), 4.98 (s, 2H), 4.78 – 4.61 (m, 1H), 4.49 – 4.34 (m, 1H), 4.31 – 4.19 (m, 1H), 3.89 – 3.78 (m, 1H), 3.76 (s, 3H), 1.80 (s, 3H), 1.51 (s, 9H). m/z (ESI): 565.5 [M-H]- . N-[(2-aminoquinolin-7-yl)methyl]-N-(1-oxo-2,3-dihydro-1H-iso indol-4-yl)acetamide (Exam- ple E-002) A solution of tert-butyl N-{7-[(N-{2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-i so- indol-4-yl}acetamido)methyl]quinolin-2-yl}carbamate (Int. Q-001, 0.070 g, 0.11 mmol, 1.0 eq.) in TFA (0.25 mL) and DCM (0.5 mL) in a sealed Biotage ^TM microwave vial was heated at 120 °C overnight in a DrySyn ^® . After coming back to RT, the RM was evaporated under re- duced pressure and the residue was co-evaporated with toluene. The residue was parti- tioned between DCM and sat. aq. Na ₂ CO ₃ and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 20% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(1-oxo-2,3-dihy- dro-1H-isoindol-4-yl)acetamide (Example E-002, 0.015 g, 0.043 mmol, 37%, white solid, UPLC long elution purity: 98.43%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 7.7, 0.6 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.31 (dd, J = 7.8, 1.0 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 7.04 (dd, J = 8.1, 1.7 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.44 (s, 2H), 5.06 (d, J = 12.8 Hz, 1H), 4.81 (d, J = 12.9 Hz, 1H), 4.29 (d, J = 15.6 Hz, 1H), 3.91 (d, J = 15.3 Hz, 1H), 1.81 (s, 3H). m/z (ESI): 347.24 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 498 R10107WO Compounds made in a similar fashion to Example E-002: ¹ Purity: UPLC long elution purity Example E-003: N-[(2-aminoquinolin-7-yl)methyl]-N-[3-(hydroxymethyl)-1-meth yl-1H-py- razol-4-yl]acetamide Methyl 4-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] acetamido}-1-methyl- 1H-pyrazole-3-carboxylate (Int. Q-002) A mixture of Cs ₂ CO ₃ (0.6 g, 1.84 mmol, 1.4 eq.), XPhos Pd G3 (0.11 g, 0.13 mmol, 0.1 eq.), tert-butyl carbamate (0.2 g, 1.71 mmol, 1.30 eq.) and methyl 4-{N-[(2-chloroquinolin-7- yl)methyl]acetamido}-1-methyl-1H-pyrazole-3-carboxylate (Int. N-007, 0.52 g, 1.31 mmol, 1.0 eq.) in anhydrous dioxane (4.0 mL) was sparged with nitrogen for 10 minutes. The RM was heated under microwave irradiation at 100 °C for 1.5 h. After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . Water was added to the filtrate and the organic phase was separated. The aqueous layer was extracted with EtOAc (1x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by two consecutive FCCs (first: 33% to 100% EtOAc gradient in hexane; second: 0 to 10% MeOH gradient in DCM) to yield methyl 4-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)me- thyl]acetamido}-1-methyl-1H-pyrazole-3-carboxylate (Int. Q-002, 0.29 g, 0.639 mmol, 48%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.49 (s, 1H), 7.29 Ryvu Therapeutics S.A. RVU305 499 R10107WO (dd, J = 8.4, 1.7 Hz, 1H), 4.87 (br s, 2H), 3.82 (s, 3H), 3.70 (s, 3H), 1.86 (s, 3H), 1.51 (s, 9H). m/z (ESI): 476.2 [M+Na] ⁺ . N-[7-({N-[3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]acetami do}methyl)quinolin-2- yl]carbamate (Int. Q-003) Finely powdered sodium borohydride (0.1 g, 2.64 mmol, 8.1 eq.) and methyl 4-{N-[(2-{[(tert- butoxy)carbonyl]amino}quinolin-7-yl)methyl]acetamido}-1-meth yl-1H-pyrazole-3-carbox- ylate (Int. Q-002, 0.15 g, 0.33 mmol, 1.0 eq.) were suspended in anhydrous THF (7.0 mL). The resulting mixture was stirred for 15 min. at 65 °C. Methanol (9.0 mL) was then added dropwise over 0.5 h and effervescence was observed. Stirring at 65 °C was maintained for a further 2 h. The reaction was cooled to RT, quenched with sat. aq. NH ₄ Cl (10.0 mL) and stirring was continued for 1 h. The organic layer was separated and the aqueous phase ex- tracted with AcOEt (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield tert-butyl N-[7-({N-[3-(hydroxymethyl)-1-methyl- 1H-pyrazol-4-yl]acetamido}methyl)quinolin-2-yl]carbamate (Int. Q-003, 0.095 g, 0.22 mmol, 65%, white solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.31 (dd, J = 8.3, 1.7 Hz, 1H), 5.03 (t, J = 5.4 Hz, 1H), 4.89 (s, 2H), 4.19 (d, J = 5.4 Hz, 2H), 3.69 (s, 3H), 1.91 (s, 3H), 1.51 (s, 9H). m/z (ESI): 426.3 [M+H] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-[3-(hydroxymethyl)-1-meth yl-1H-pyrazol-4-yl]acetam- ide (Example E-003) TFA (0.4 mL) was added to a solution of tert-butyl N-[7-({N-[3-(hydroxymethyl)-1-methyl- 1H-pyrazol-4-yl]acetamido}methyl)quinolin-2-yl]carbamate (Int. Q-003, 0.093 g, 0.21 mmol, 1.0 eq.) in DCM (3.0 mL). The RM was stirred at RT overnight and evaporated under re- duced pressure. The residue was partitioned between sat. aq. NaHCO ₃ and DCM. The aque- ous layer was extracted with DCM and CHCl ₃ /iPrOH 3:1 v/v. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pres- sure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to afford N-[(2-aminoquinolin-7-yl)methyl]-N-[3-(hydroxymethyl)-1-meth yl-1H-pyrazol-4-yl]acetam- ide (Example E-003, 0.062 g, 0.191 mmol, 92%, white solid, UPLC long elution purity: 99.90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.90 (d, J = 8.9 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.45 (s, 1H), 7.22 (s, 1H), 7.03 (dd, J = 8.2, 1.7 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.58 (s, 2H), 5.02 (t, J = 5.4 Hz, 1H), 4.81 (s, 2H), 4.20 (d, J = 5.3 Hz, 2H), 3.71 (s, 3H), 1.90 (s, 3H). m/z (ESI): 326.20 [M+H] ⁺ . Example E-004: N-[(2,4-diaminoquinazolin-7-yl)methyl]-N-(2-methanesulfonylp henyl)acet- amide Ryvu Therapeutics S.A. RVU305 500 R10107WO N-[(4-cyano-3-fluorophenyl)methyl]-N-(2-methanesulfonylpheny l)acetamide (Int. Q-004) NaH (60% in mineral oil, 0.013 g, 0.34 mmol, 1.05 eq.) was added to a solution of N-(2-me- thanesulfonylphenyl)acetamide (Int. B-001, 0.07 g, 0.33 mmol, 1.0 eq.) in anhydrous DMF (1.5 mL) at 0 °C. The RM was stirred at RT for 30 min. and 4-(bromomethyl)-2-fluoroben- zonitrile (0.072 g, 0.33 mmol, 1.0 eq.) was added. The RM was stirred at RT for 1 h and the reaction was quenched with water. The mixture was extracted with EtOAc (3x) and the combined organic layers were washed with sat. aq. NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ , and evaporated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in hexane) to yield N-[(4-cyano-3-fluorophenyl)methyl]-N-(2-me- thanesulfonylphenyl)acetamide (Int. Q-004, 0.105 g, 0.30 mmol, 92%, white solid, UPLC pu- rity: 100%). 8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 – 8.08 (m, 1H), 7.90 (t, J = 7.4 Hz, 1H), 7.76 – 7.67 (m, 2H), 7.46 (d, J = 11.0 Hz, 1H), 7.34 (dd, J = 8.0, 1.4 Hz, 1H), 7.25 – 7.17 (m, 1H), 5.54 (d, J = 15.8 Hz, 1H), 4.28 (d, J = 15.8 Hz, 1H), 3.38 (s, 3H), 1.81 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (dd, J = 8.1, 1.3 Hz, 1H), 7.93 (t, J = 7.5 Hz, 1H), 7.67 – 7.55 (m, 3H), 7.44 (d, J = 14.0 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 5.32 (d, J = 17.5 Hz, 1H), 4.68 (d, J = 17.4 Hz, 1H), 3.17 (s, 3H), 2.26 (s, 3H). m/z (ESI): 346.7 [M+H] ⁺ . N-[(2,4-diaminoquinazolin-7-yl)methyl]-N-(2-methanesulfonylp henyl)acetamide (Example E-004) A Biotage ^TM microwave vial was charged with N-[(4-cyano-3-fluorophenyl)methyl]-N-(2- methanesulfonylphenyl)acetamide (Int. Q-004, 0.085 g, 0.25 mmol, 1.0 eq.), guanidine hydro- chloride (0.050 g, 0.491 mmol, 2.0 eq.), K ₂ CO ₃ (0.041 g, 0.29 mmol, 1.2 eq.) DIPEA (0.086 mL, 0.49 mmol, 2.0 eq.) and DMA (4.0 mL). The vial was sealed and the RM was stirred at 140 °C for 6 hours in a DrySyn ^® . After coming back to RT, the RM was evaporated under re- duced pressure, and the residue was partitioned between water and EtOAc. The aqueous layer was extracted by EtOAc and the combined organic layers were washed with sat. aq. NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 20% MeOH gradient in DCM). The fractions containing the pure product were pooled and evaporated under reduced pressure. The residue was triturated with Et ₂ O and few drops of iPrOH, then filtered off, washed with Et ₂ O and dried under vacuum to yield N-[(2,4-diaminoquinazolin-7-yl)methyl]-N-(2-me- thanesulfonylphenyl)acetamide (Example E-004, 0.048 g, 0.12 mmol, 50%, light yellow solid, UPLC long elution purity: 98.03%).8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.65 (dd, J = 10.5, 6.7 Hz, 2H), 7.28 (s, 2H), 7.01 – 6.95 (m, 2H), 6.93 Ryvu Therapeutics S.A. RVU305 501 R10107WO (d, J = 8.3 Hz, 1H), 5.99 (s, 2H), 5.63 (d, J = 14.9 Hz, 1H), 4.14 (d, J = 15.0 Hz, 1H), 3.37 (s, 3H), 1.80 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.62 – 7.54 (m, 2H), 7.28 (s, 2H), 7.07 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.01 – 6.96 (m, 1H), 6.02 (s, 2H), 5.27 (d, J = 17.0 Hz, 1H), 4.55 (d, J = 16.9 Hz, 1H), 3.18 (s, 3H), 2.31 (s, 3H). m/z (ESI): 386.50 [M+H] ⁺ . Example E-005: 4-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}-1-methyl-1H-py razole-3- carboxamide 4-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] acetamido}-1-methyl-1H-py- razole-3-carboxylic acid (Int. Q-005) Aq. 1 M NaOH (10.0 mL) was added to a solution of methyl 4-{N-[(2-{[(tert-butoxy)car- bonyl]amino}quinolin-7-yl)methyl]acetamido}-1-methyl-1H-pyra zole-3-carboxylate (Int. Q- 002, 0.22 g, 0.47 mmol, 1.0 eq.) in EtOH (10.0 mL) and the RM was heated at 60 °C for 3 h. After coming back to RT, the RM was acidified with aq. 1 M HCl and the mixture was ex- tracted with CHCl ₃ /iPrOH 3:1 v/v (3x). The combined organic layers were dried over anhy- drous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was pu- rified by FCC (0 to 20% MeOH gradient in DCM) to yield 4-{N-[(2-{[(tert-butoxy)car- bonyl]amino}quinolin-7-yl)methyl]acetamido}-1-methyl-1H-pyra zole-3-carboxylic acid (Int. Q-005, 0.15 g, 0.34 mmol, 71%, white solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.85 (s, 1H), 10.04 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.64 (s, 1H), 7.50 (s, 1H), 7.32 (dd, J = 8.3, 1.6 Hz, 1H), 4.85 (s, 2H), 3.79 (s, 3H), 1.86 (s, 3H), 1.51 (s, 9H). m/z (ESI): 462.3 [M+Na] ⁺ . tert-Butyl N-(7-{[N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)acetamido]met hyl}quinolin-2- yl)carbamate (Int. Q-006) CDI (0.06 g, 0.37 mmol, 1.1 eq.) was added to a solution of 4-{N-[(2-{[(tert-butoxy)car- bonyl]amino}quinolin-7-yl)methyl]acetamido}-1-methyl-1H-pyra zole-3-carboxylic acid (Int. Q-005, 0.15 g, 0.33 mmol, 1.0 eq.) in DMF (3.0 mL) and the mixture was heated at 60 °C for 1 h. After coming back to RT, 0.5 M NH ₃ in dioxane (2.0 mL) was added. The RM was stirred at RT overnight and was evaporated under reduced pressure. The residue was partitioned between water and EtOAc and the aqueous phase was extracted with EtOAc (2x). The com- bined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield tert-butyl N-(7-{[N-(3-carbamoyl-1-methyl-1H-pyrazol-4- yl)acetamido]methyl}quinolin-2-yl)carbamate (Int. Q-006, 0.07 g, 0.16 mmol, 46%, white Ryvu Therapeutics S.A. RVU305 502 R10107WO solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.60 (s, 1H), 7.49 (s, 1H), 7.46 (s, 1H), 7.32 (dd, J = 8.3, 1.7 Hz, 1H), 7.27 (s, 1H), 4.87 (s, 2H), 3.76 (s, 3H), 1.87 (s, 3H), 1.51 (s, 9H). m/z (ESI): 461.3 [M+Na] ⁺ . 4-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}-1-methyl-1H-py razole-3-carboxamide (Ex- ample E-005) TFA (0.29 mL, 3.79 mmol, 25.0 eq.) was added to a solution of tert-butyl N-(7-{[N-(3-car- bamoyl-1-methyl-1H-pyrazol-4-yl)acetamido]methyl}quinolin-2- yl)carbamate (Int. Q-006, 0.07 g, 0.15 mmol, 1.0 eq.) in DCM (3.0 mL). The RM was stirred at RT overnight and evapo- rated under reduced pressure. The residue was partitioned between sat. aq. NaHCO ₃ and DCM and the aqueous layer was extracted with DCM and CHCl ₃ /iPrOH 3:1 v/v. The com- bined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to afford 4-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}-1-methyl-1H-py razole-3- carboxamide (Example E-005, 0.017 g, 0.05 mmol, 33%, white solid, HPLC purity: 98.79%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 7.19 (s, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.39 (s, 2H), 4.80 (br s, 2H), 3.77 (s, 3H), 1.86 (s, 3H). m/z (ESI): 339.3 [M+H] ⁺ . Example E-006: N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(hydroxymethyl)pyridin -3-yl]acet- 3-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] acetamido}pyridine-2-carbox- ylate (Int. Q-007) A suspension of Cs ₂ CO ₃ (0.361 g, 1.11 mmol, 1.4 eq.), BocNH ₂ (0.121 g, 1.03 mmol, 1.30 eq.), methyl 3-{N-[(2-chloroquinolin-7-yl)methyl]acetamido}pyridine-2-car boxylate (Int. N-013, 0.308 g, 0.79 mmol, 1.0 eq.) in anhydrous dioxane (4.0 mL) was sparged with nitrogen for 10 min. and XPhos Pd G3 (0.067 g, 0.08 mmol, 0.1 eq.) was added. The RM was heated under microwave irradiation at 100 °C for 1.5 h. An additional portion of BocNH ₂ (0.121 g, 1.03 mmol, 1.3 eq.) and XPhos Pd G3 (0.067 g, 0.08 mmol, 0.1 eq.) was added and the RM was heated under microwave irradiation at 100 °C for another 1.5 h. After coming back to RT, the RM was diluted with AcOEt and filtered through a pad of Celite ^® . The filtrate was washed with water and the aqueous phase was extracted with AcOEt. The combined or- ganic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (33% to 100% EtOAc gradient in hexane) Ryvu Therapeutics S.A. RVU305 503 R10107WO to yield 3-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] acetamido}pyridine-2- carboxylate (Int. Q-007, 0.05 g, 0.111 mmol, 7%, white solid, UPLC purity: 50%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 8.69 – 8.57 (m, 1H), 8.44 (d, J = 8.9 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.66 – 7.57 (m, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.42 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 5.18 (d, J = 14.3 Hz, 1H), 5.10 (d, J = 14.6 Hz, 1H), 3.68 (s, 3H), 1.83 (s, 3H), 1.51 (t, J = 2.3 Hz, 9H). m/z (ESI): 473.3 [M+Na] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(hydroxymethyl)pyridin -3-yl]acetamide (Example E- 006) Finely powdered NaBH ₄ (0.016 g, 0.42 mmol, 7.9 eq.) and methyl 3-{N-[(2-{[(tert- butoxy)carbonyl]amino}quinolin-7-yl)methyl]acetamido}pyridin e-2-carboxylate (Int. Q-007, 0.048 g, 0.05 mmol, 1.0 eq.) were suspended in THF (3.0 mL) and the RM was stirred for at 65 °C for 15 min. MeOH (4.0 mL) was then added dropwise over 30 min. and effervescence was observed. Stirring at 65 °C was maintained for a further 2 h. After coming back to RT, the reaction and quenched with sat. aq. NH ₄ Cl (10.0 mL) and stirring was continued for 1 h. The organic layer was separated and the aqueous phase extracted with AcOEt (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was dissolved in DCM (2.0 mL) and TFA (0.05 mL) was added. The RM was stirred overnight at RT and evaporated under reduced pressure. The residue was suspended in aq. sat. NaHCO ₃ (final pH ≈ 8), and the mixture was extracted with DCM and CHCl ₃ /iPrOH 3:1 v/v. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-aminoquino- lin-7-yl)methyl]-N-[2-(hydroxymethyl)pyridin-3-yl]acetamide (Example E-006, 0.002 g, 0.006 mmol, 12%, white solid, UPLC long elution purity: 94.90%). ¹ H NMR (400 MHz, Metha- nol-d ₄ ) δ 7.91 (dd, J = 8.9, 0.7 Hz, 1H), 7.76 (dd, J = 4.7, 1.4 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 1.7 Hz, 1H), 7.27 (dd, J = 8.2, 1.7 Hz, 1H), 7.11 (dd, J = 8.4, 4.7 Hz, 1H), 6.97 (dd, J = 8.4, 1.3 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 5.28 (s, 2H), 4.60 (s, 2H), 2.15 (s, 3H). m/z (ESI): 323.20 [M+H] ⁺ . Example E-007: 2-amino-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesul- fonylphenyl)acetamide N-[(2-aminoquinolin-7-yl)methyl]-2-(1,3-dioxo-2,3-dihydro-1H -isoindol-2-yl)-N-(2-me- thanesulfonylphenyl)acetamide (Int. Q-008) A suspension of Cs ₂ CO ₃ (0.044 g, 0.13 mmol, 1.2 eq.), BocNH ₂ (0.019 g, 0.16 mmol, 1.5 eq.), N-[(2-chloroquinolin-7-yl)methyl]-2-(1,3-dioxo-2,3-dihydro-1 H-isoindol-2-yl)-N-(2-me- Ryvu Therapeutics S.A. RVU305 504 R10107WO thanesulfonylphenyl)acetamide (Int. N-014, 0.065 g, 0.11 mmol, 1.0 eq.) in anhydrous diox- ane (4.5 mL) was sparged with nitrogen for 10 min. and XPhos Pd G3 (0.01 g, 0.012 mmol, 0.11 eq.) was added. The RM was heated under microwave irradiation at 100 °C for 1.5 h. After coming back to RT, the RM was diluted with AcOEt and filtered through a pad of Celite ^® . The filtrate was washed with water and the aqueous phase was extracted with Ac- OEt. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The residue was dissolved in a mixture of DCM (2.5 mL) and TFA (0.4 mL) and the RM was stirred at RT for 3 h. The RM was then evaporated under re- duced pressure and the residue was partitioned between sat. aq. NaHCO ₃ and DCM. The aqueous layer was extracted with DCM (3x) and with DCM/iPrOH 3:1. The combined or- ganic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 8% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-2-(1,3-dioxo-2,3-dihydro-1H -isoindol-2-yl)-N-(2-me- thanesulfonylphenyl)acetamide (Int. Q-008, 0.024 g, 0.047 mmol, 50%, light brown solid, UPLC purity: 94.0%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.36 – 8.25 (m, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.88 (s, 2H), 7.74 (d, J = 16.1 Hz, 5H), 7.61 (d, J = 8.1 Hz, 1H), 7.55 (s, 1H), 7.26 – 7.21 (m, 1H), 7.17 (d, J = 8.5 Hz, 1H), 5.83 (d, J = 15.2 Hz, 1H), 4.50 (d, J = 15.1 Hz, 1H), 4.23 (d, J = 17.2 Hz, 1H), 4.16 (d, J = 16.7 Hz, 1H), 3.43 (s, 3H), 1.29 (s, 2H). m/z (ESI): 515.7 [M+H] ⁺ . 2-Amino-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfony lphenyl)acetamide (Exam- ple E-007) Hydrazine monohydrate (0.013 g, 0.26 mmol, 6.0 eq.) was added to a suspension of N-[(2- aminoquinolin-7-yl)methyl]-2-(1,3-dioxo-2,3-dihydro-1H-isoin dol-2-yl)-N-(2-methanesul- fonylphenyl)acetamide (Int. Q-008, 0.024 g, 0.04 mmol, 1.0 eq.) in EtOH (2.5 mL) and the RM was stirred for 3 h at 80 °C. The RM was evaporated under reduced pressure and the crude material was purified by FCC (0 to 20% MeOH gradient in DCM) to yield 2-amino-N- [(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl)ac etamide (Example E-007, 0.007 g, 0.02 mmol, 39%, grey solid, UPLC long elution purity: 96.09%). 8/2 mixture of re- stricted C-N amide rotation isomers in methanol-d ₄ at RT: Major rotamer: ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.20 (dd, J = 7.9, 1.2 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.65 – 7.57 (m, 1H), 7.37 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 5.85 (d, J = 14.6 Hz, 1H), 4.88 (s, 2H), 4.42 (d, J = 14.6 Hz, 1H), 3.29 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.12 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.74 – 7.54 (m, 3H), 7.44 (s, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 7.1 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.30 (d, J = 16.3 Hz, 1H), 4.72 (d, J = 16.6 Hz, 1H), 4.01 (s, 2H), 3.16 (s, 3H). m/z (ESI): 385.26 [M+H] ⁺ . Example E-008: N-[(2-aminoquinolin-7-yl)methyl]-N-{3-cyano-5H,6H,7H-cyclope nta[b]pyri- din-2-yl}acetamide and Example E-009: 2-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}- 5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 505 R10107WO tert-butyl N-{7-[(N-{3-cyano-5H,6H,7H-cyclopenta[b]pyridin-2-yl}acetami do)methyl]quino- lin-2-yl}carbamate (Int. Q-009) A suspension of N-[(2-chloroquinolin-7-yl)methyl]-N-{3-cyano-5H,6H,7H-cyclop enta[b]pyr- idin-2-yl}acetamide (Int. N-016, 0.306 g, 0.77 mmol, 1.0 eq.), BocNH ₂ (0.136 g, 1.16 mmol, 1.5 eq.) and Cs ₂ CO ₃ (0.352 g, 1.08 mmol, 1.4 eq.) in anhydrous dioxane (4.0 mL) was sparged with nitrogen for 10 min. XPhos Pd G3 (0.065 g, 0.08 mmol, 0.1 eq.) was added, and the RM was heated under microwave irradiation at 100 °C for 1 h. After coming back to RT, the RM was poured into stirring water and the mixture was extracted with EtOAc. The or- ganic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in cyclohexane) to yield tert-butyl N-{7-[(N-{3-cyano-5H,6H,7H-cyclopenta[b]pyridin-2- yl}acetamido)methyl]quinolin-2-yl}carbamate (Int. Q-009, 0.248 g, 0.54 mmol, 69%, beige solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.08 (s, 1H), 8.25 (dd, J = 9.1, 2.4 Hz, 1H), 8.18 (s, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.64 (s, 1H), 7.40 (d, J = 8.3 Hz, 1H), 5.18 (s, 2H), 3.01 (t, J = 7.7 Hz, 2H), 2.95 (t, J = 7.7 Hz, 2H), 2.13 (p, J = 7.6 Hz, 2H), 2.01 (s, 3H), 1.51 (s, 9H). m/z (ESI): 480.3 [M+Na] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-{3-cyano-5H,6H,7H-cyclope nta[b]pyridin-2-yl}acetam- ide (Example E-008) and 2-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}-5H,6H,7H-cyclo - penta[b]pyridine-3-carboxamide (Example E-009) tert-Butyl N-{7-[(N-{3-cyano-5H,6H,7H-cyclopenta[b]pyridin-2-yl}acetami do)methyl]quino- lin-2-yl}carbamate (Int. Q-009, 0.248 g, 0.53 mmol, 1.0 eq.) was dissolved in DCM (3.0 mL) and TFA (0.40 mL) was added. The RM was stirred at RT for 4 h and evaporated under re- duced pressure. The residue was partitioned between sat. aq. NaHCO ₃ and DCM, and the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was subjected to FCC (0 to 20% MeOH gradient in DCM) to yield two products: N-[(2-aminoquinolin-7-yl)methyl]-N-{3-cyano-5H,6H,7H-cyclope nta[b]pyridin-2-yl}acetam- ide (Example E-008, 0.030 g, 0.08 mmol, 15%, white solid, UPLC long elution purity: 96.44%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (s, 1H), 7.83 (dd, J = 8.8, 0.8 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.41 (s, 2H), 5.11 (s, 2H), 3.00 (t, J = 7.7 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.12 (p, J = 7.7 Hz, 2H), 1.98 (br s, 3H). m/z (ESI): 358.30 [M+H] ⁺ . 2-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}-5H,6H,7H-cyclo penta[b]pyridine-3-carbox- amide which was further purified by preparative HPLC (FA buffer) to afford Example E-009 as its formate salt (0.014 g, 0.037 mmol, 7%, white solid, HPLC purity: 98.85%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 7.85 (s, 1H), 7.85 – 7.80 (m, 2H), 7.61 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 6.41 (s, 2H), 5.25 (br s, 1H), 4.40 (br s, 1H), 2.94 (t, J = 7.6 Hz, 2H), 2.91 – 2.79 (m, 2H), 2.09 (p, J = 7.6 Hz, 2H), 1.83 (s, 3H). m/z (ESI): 376.27 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 506 R10107WO Example E-010: N-[(2-amino-3-methylquinolin-7-yl)methyl]-N-(2-methanesul- fonylphenyl)acetamide N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylphenyl )acetamide (Int. Q-010) The title compound was prepared according to General Procedure 21 using NaH (60% in mineral oil, 0.128 g, 3.30 mmol, 1.2 eq.), N-(2-methanesulfonylphenyl)acetamide (Int. B-001, 0.595 g, 2.79 mmol, 1.0 eq.) and 1-bromo-4-(bromomethyl)-2-nitrobenzene (0.823 g, 2.79 mmol, 1.0 eq.) in anhydrous DMF (8.0 mL). The crude material was purified by FCC (0 to 20% EtOAc gradient in DCM) to yield N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesul- fonylphenyl)acetamide (Int. Q-010, 0.94 g, 2.2 mmol, 78%, white solid, UPLC purity: 99%). 9/1 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 – 8.11 (m, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.77 – 7.68 (m, 2H), 7.51 (dd, J = 8.3, 2.1 Hz, 1H), 7.19 – 7.15 (m, 1H), 5.52 (d, J = 15.4 Hz, 1H), 4.25 (d, J = 15.4 Hz, 1H), 3.38 (s, 3H), 1.79 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J = 5.5 Hz, 1H), 8.02 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.69 – 7.58 (m, 2H), 7.58 (dd, J = 8.3, 1.8 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 5.28 (d, J = 17.0 Hz, 1H), 4.67 (d, J = 16.9 Hz, 1H), 3.17 (s, 3H), 2.30 (s, 3H). m/z (ESI): 426.9 [M+H] ⁺ . N-[(3-amino-4-bromophenyl)methyl]-N-(2-methanesulfonylphenyl )acetamide (Int. Q-011), General Procedure 27 A mixture of N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylphenyl )acetamide (Int. Q-010, 0.2 g, 0.46 mmol, 1.0 eq.), NH ₄ Cl (0.012 g, 0.23 mmol, 0.5 eq.), iron powder (0.065 g, 1.16 mmol, 2.5 eq.), MeOH (1.5 mL), THF (1.5 mL) and water (1.5 mL) was stirred at 80 °C overnight in a pressure vessel. After coming back to RT, the RM was filtered through a pad of Celite ^® . The filter cake was washed with THF and the filtrate was concentrated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-[(3-amino-4-bromophenyl)methyl]-N-(2-methanesulfonylphenyl )acet- amide (Int. Q-011, 0.161 g, 0.40 mmol, 71%, orange oil, UPLC purity: 81%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.14 – 8.10 (m, 1H), 7.75 – 7.64 (m, 2H), 7.26 (d, J = 8.1 Hz, 1H), 7.03 – 6.98 (m, 1H), 6.70 (d, J = 2.1 Hz, 1H), 6.33 (dd, J = 8.1, 2.1 Hz, 1H), 5.48 (d, J = 14.8 Hz, 1H), 5.29 (s, 2H), 3.93 (d, J = 14.8 Hz, 1H), 3.35 (s, 3H), 1.77 (s, 3H). m/z (ESI): 397.1 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 507 R10107WO N-[(2-amino-3-methylquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)acetamide (Ex- ample E-010) A mixture of potassium acetate (0.116 g, 1.19 mmol, 3.0 eq.), (Bpin) ₂ (0.201 g, 0.79 mmol, 2.0 eq.), N-[(3-amino-4-bromophenyl)methyl]-N-(2-methanesulfonylphenyl )acetamide (Int. Q-011, 0.157 g, 0.40 mmol, 1.0 eq.) and anhydrous dioxane (2.0 mL) in a Biotage ^TM micro- wave vial was sparged with nitrogen for 10 minutes. Pd(dppf)Cl ₂ .DCM (0.033 g, 0.04 mmol, 0.1 eq.) was added, the vial was sealed, and the RM was stirred in a preheated heating block at 100 °C for 5 h. After coming back to room temperature, the RM was filtered through a pad of Celite ^® . The filter cake was washed with methanol and the filtrate was concentrated under reduced pressure. The obtained crude N-{[3-amino-4-(4,4,5,5-tetrame- thyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-N-(2-methanesulf onylphenyl)acetamide (Int. Q-012) was used in the next step without further purification. A mixture of tripotassium phosphate (0.168 g, 0.79 mmol, 2.0 eq.), XPhos Pd G3 (0.033 g, 0.04 mmol, 0.1 eq.), 3-bromo-2-methylprop-2-enenitrile (0.058 g, 0.396 mmol, 1.0 eq.), crude N-{[3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p henyl]methyl}-N-(2-me- thanesulfonylphenyl)acetamide (Int. Q-012, 0.176 g, 0.40 mmol, 1.0 eq.) and dioxane/water 1:1 v/v (3 mL) in a Biotage ^TM microwave vial was sparged with nitrogen for 10 minutes. The vial was sealed and the RM was stirred in a preheated heating block at 90 °C for 2 h. After coming back to RT, the RM was filtered through a pad of Celite ^® . The filtrate was concen- trated under reduced pressure and the crude material was purified by FCC (0 to 10 % MeOH gradient in DCM). The fractions containing the pure product were pooled and concentrated under reduced pressure. The residue was triturated with Et ₂ O and pentane, and dried under vacuum to yield N-[(2-amino-3-methylquinolin-7-yl)methyl]-N-(2-methanesul- fonylphenyl)acetamide (Example E-010, 0.012 g, 0.031 mmol, 8%, brown solid, UPLC long elution purity: 96.72%). ¹ H NMR (400 MHz, DMSO-d ₆ , 80 °C) δ 8.13 (d, J = 5.3 Hz, 1H), 7.80 (s, 1H), 7.73 – 7.55 (m, 3H), 7.36 (s, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.32 (s, 2H), 5.71 (d, J = 8.8 Hz, 1H), 4.30 (d, J = 10.1 Hz, 1H), 3.31 (s, 3H), 2.28 (s, 3H), 1.83 (s, 3H). m/z (ESI): 384.28 [M+H] ⁺ . Example E-011: N-[(2-aminoquinolin-7-yl)methyl]-N-(2-sulfamoylphenyl)acetam ide tert-Butyl N-[7-({N-[2-(benzylsulfanyl)phenyl]acetamido}methyl)quinolin -2-yl]carbamate (Int. Q-013) A suspension of N-[2-(benzylsulfanyl)phenyl]-N-[(2-chloroquinolin-7-yl)methy l]acetamide (Int. N-023, 0.51 g, 1.14 mmol, 1.0 eq.), BocNH ₂ (0.333 g, 2.84 mmol, 2.5 eq.) and Cs ₂ CO ₃ Ryvu Therapeutics S.A. RVU305 508 R10107WO (0.521 g, 1.6 mmol, 1.4 eq.) in anhydrous dioxane (7.5 mL) was sparged with nitrogen for 10 min. XPhos Pd G3 (0.192 g, 0.22 mmol, 0.2 eq.) was added and the reaction mixture was heated under microwave irradiation at 100 °C for 5 h. After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . Water was added to the filtrate and the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 33% EtOAc gradient in cyclohexane) to yield tert-butyl N-[7-({N-[2-(benzylsulfanyl)phenyl]acetamido}methyl)quinolin -2-yl]car- bamate (Int. Q-013, 0.29 g, 0.56 mmol, 47%, beige solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.44 – 7.24 (m, 8H), 7.07 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 5.46 (d, J = 14.7 Hz, 1H), 4.33 (d, J = 13.1 Hz, 1H), 4.28 (d, J = 13.1 Hz, 1H), 4.13 (d, J = 14.7 Hz, 1H), 1.69 (s, 3H), 1.51 (s, 9H). m/z (ESI): 536.4 [M+Na] ⁺ . tert-Butyl N-(7-{[N-(2-sulfamoylphenyl)acetamido]methyl}quinolin-2-yl)c arbamate (Int. Q- 014) A solution of tert-butyl N-[7-({N-[2-(benzylsulfanyl)phenyl]acetamido}methyl)quinolin -2- yl]carbamate (Int. Q-013, 0.18 g, 0.33 mmol, 1.0 eq.) in a mixture of water (0.3 mL) and ace- tic acid (3.3 mL) was cooled to 0 °C and NCS (0.133 g, 1.0 mmol, 3.0 eq.) was added. The RM was stirred at RT for 2 h and cooled to 0 °C. Aq. ammonia (27%; 1.32 mL, 10.0 mmol, 30 eq.) was added dropwise and the RM was allowed to stir at RT for 1 h. The RM was di- luted with water and extracted with DCM (x3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 80% EtOAc gradient in cyclohexane) to yield tert-butyl N-(7-{[N-(2-sulfamoylphenyl)acetamido]methyl}quinolin-2-yl)c arbamate (Int. Q- ^{014, 0.113 g, 0.24 mmol, 69%, white solid, UPLC purity: 96%). 1H NMR (400 MHz, DMSO-d6)} _{δ 10.03 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.02 (dd, J = 7.9, 1.5 Hz, 1H), 7.99 (d, J = 9.0 Hz,} 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.80 (s, 2H), 7.55 (td, J = 7.7, 1.3 Hz, 1H), 7.46 – 7.45 (m, 1H), 7.42 (td, J = 7.6, 1.6 Hz, 1H), 7.33 (dd, J = 8.3, 1.7 Hz, 1H), 6.76 (dd, J = 7.8, 1.3 Hz, 1H), 5.80 (d, J = 15.1 Hz, 1H), 4.18 (d, J = 15.1 Hz, 1H), 1.75 (s, 3H), 1.49 (s, 9H). m/z (ESI): 471.7 [M+H] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-(2-sulfamoylphenyl)acetam ide (Example E-011) tert-Butyl N-(7-{[N-(2-sulfamoylphenyl)acetamido]methyl}quinolin-2-yl)c arbamate (Int. Q- 014, 0.113 g, 0.231 mmol, 1.0 eq.) was dissolved in a mixture of DCM (2.0 mL) and TFA (0.2 mL) and the RM was stirred at RT for 3 h. It was then basified to pH ≈ 8 with sat. aq. Na- HCO ₃ and extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-aminoquino- lin-7-yl)methyl]-N-(2-sulfamoylphenyl)acetamide (Example E-011, 0.047 g, 0.13 mmol, 54%, white solid, UPLC long elution purity: 98.01%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (dd, J = 7.9, 1.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.80 (s, 2H), 7.57 (d, J = 8.2 Hz, 1H), 7.57 (td, J = 7.6, 1.4 Hz, 1H), 7.46 (td, J = 7.6, 1.6 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.05 (dd, J = 8.2, 1.7 Hz, 1H), 6.80 (dd, J = 7.8, 1.3 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.39 (s, 2H), 5.76 (d, J = 15.0 Hz, 1H), 4.10 (d, J = 15.0 Hz, 1H), 1.76 (s, 3H). m/z (ESI): 371.20 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 509 R10107WO Example E-012: N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(hydroxymethyl)phenyl] acetamide tert-Butyl N-[7-({N-[2-(hydroxymethyl)phenyl]acetamido}methyl)quinolin- 2-yl]carbamate (Int. Q-016) A mixture of Cs ₂ CO ₃ (0.298 g, 0.91 mmol, 1.4 eq.), XPhos Pd G3 (0.055 g, 0.06 mmol, 0.1 eq.), tert-butyl carbamate (0.099 g, 0.85 mmol, 1.3 eq.) and methyl 2-{N-[(2-chloroquinolin- 7-yl)methyl]acetamido}benzoate (Int. N-022, 0.256 g, 0.65 mmol, 1.0 eq.) in anhydrous diox- ane (5.0 mL) was sparged with nitrogen for 10 minutes, and the RM was heated under mi- crowave irradiation at 100 °C for 1.5 h. After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . Water was added to the filtrate and the organic phase was separated. The aqueous layer was extracted with EtOAc (2x). The combined or- ganic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concen- trated under reduced pressure. The crude material was purified by FCC (0 to 2% MeOH gra- dient in DCM) to afford methyl 2-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)me- thyl]acetamido}benzoate (Int. Q-015, 0.205 g, 0.46 mmol, 69%, beige solid, UPLC purity: 99%). m/z (ESI): 450.2 [M+H] ⁺ . Finely powdered NaBH ₄ (0.225 g, 5.95 mmol, 30.0 eq.) was suspended in a solution of me- thyl 2-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] acetamido}benzoate (0.09 g, 0.20 mmol, 1.0 eq.) in anhydrous THF (5.0 mL). The RM was stirred at 65 °C for 15 min. under nitrogen, anhydrous MeOH (5.0 mL) was added dropwise over 0.5 h and stirring at 65 °C was maintained for 2 h. After coming back to RT, the reaction was quenched with sat. aq. NH ₄ Cl (5.0 mL) and stirring was continued for 1 h. The organic layer was separated and the aqueous phase was extracted with AcOEt (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude material was purified by FCC (0 to 3% MeOH gradient in DCM) to yield tert-butyl N-[7-({N-[2-(hy- droxymethyl)phenyl]acetamido}methyl)quinolin-2-yl]carbamate (Int. Q-016, 0.072 g, 0.17 mmol, 79%, beige solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 7.8, 1.6 Hz, 1H), 7.48 (d, J = 1.4 Hz, 1H), 7.39 – 7.34 (m, 1H), 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.20 (td, J = 7.6, 1.6 Hz, 1H), 6.84 (dd, J = 7.7, 1.3 Hz, 1H), 5.39 (d, J = 14.6 Hz, 1H), 5.25 (t, J = 5.4 Hz, 1H), 4.45 (d, J = 14.8 Hz, 1H), 4.40 (dd, J = 13.3, 4.7 Hz, 1H), 4.30 (dd, J = 13.6, 5.0 Hz, 1H), 1.75 (s, 3H), 1.50 (s, 9H). m/z (ESI): 444.2 [M+Na] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(hydroxymethyl)phenyl] acetamide (Example E-012) Ryvu Therapeutics S.A. RVU305 510 R10107WO tert-Butyl N-[7-({N-[2-(hydroxymethyl)phenyl]acetamido}methyl)quinolin- 2-yl]carbamate (Int. Q-016, 0.06 g, 0.13 mmol, 1.0 eq.) was dissolved in a mixture of DCM (3.0 mL) and TFA (0.3 mL) and the RM was stirred at RT overnight. The reaction was quenched with sat. aq. NaHCO ₃ and the mixture was extracted with DCM (3x) and CHCl ₃ /iPrOH 3:1 v/v. The com- bined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by preparative TLC (DCM/MeOH 85:15) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(hydroxymethyl)phe- nyl]acetamide (Example E-012, 0.006 g, 0.02 mmol, 13%, white solid, UPLC long elution pu- rity: 92.71%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (d, J = 8.8 Hz, 1H), 7.58 – 7.53 (m, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.21 (td, J = 7.6, 1.5 Hz, 1H), 7.18 (s, 1H), 7.04 (dd, J = 8.2, 1.7 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.39 (s, 2H), 5.31 (d, J = 14.6 Hz, 1H), 4.39 (d, J = 14.0 Hz, 1H), 4.35 (d, J = 15.2 Hz, 1H), 4.29 (d, J = 13.7 Hz, 1H), 1.74 (s, 3H). m/z (ESI): 322.19 [M+H] ⁺ . Example E-013: N-[(2-aminoquinolin-7-yl)methyl]-N-[5-(hydroxymethyl)-1-meth yl-1H-py- razol-4-yl]acetamide Methyl 4-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] acetamido}-1-methyl- 1H-pyrazole-5-carboxylate (Int. Q-017) A Biotage ^TM microwave vial was charged with Cs ₂ CO ₃ (0.13 g, 0.40 mmol, 2.0 eq.), XPhos Pd G3 (0.034 g, 0.04 mmol, 0.2 eq.), tert-butyl carbamate (0.12 g, 1.02 mmol, 5.1 eq.), methyl 4- {N-[(2-chloroquinolin-7-yl)methyl]acetamido}-1-methyl-1H-pyr azole-5-carboxylate (Int. P- 002, 0.081 g, 0.202 mmol, 1.0 eq.) and anhydrous dioxane (4.0 mL), and the mixture was sparged with nitrogen for 10 minutes. The vial was sealed and the RM was heated at 100 °C for 1 h in a DrySyn ^® . After coming back to RT, the RM was diluted with EtOAc and fil- tered through a pad of Celite ^® . Water was added to the filtrate and the organic phase was separated. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under re- duced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to afford methyl 4-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] acetamido}-1- methyl-1H-pyrazole-5-carboxylate (Int. Q-017, 0.048 g, 0.11 mmol, 42%, white solid, UPLC purity: 81%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 7.28 (d, J = 8.3 Hz, 1H), 4.88 (s, 2H), 4.01 (s, 3H), 3.70 (s, 3H), 1.87 (s, 3H), 1.51 (s, 9H). m/z (ESI): 476.2 [M+Na] ⁺ . tert-butyl N-[7-({N-[5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]acetami do}methyl)quino- lin-2-yl]carbamate (Int. Q-018) Ryvu Therapeutics S.A. RVU305 511 R10107WO Finely powdered NaBH ₄ (0.026 g, 0.69 mmol, 8.2 eq.) was suspended in a solution of methyl 4-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] acetamido}-1-methyl-1H-py- razole-5-carboxylate (Int. Q-017, 0.047 g, 0.084 mmol, 1.0 eq.) in anhydrous THF (3.0 mL) and the RM was stirred for 15 min. at 65 °C. Anhydrous methanol (3.0 mL) was then added dropwise over 30 min., effervescence was observed. Stirring at 65 °C was maintained for a further period of 2 h. After coming back to RT, the reaction was quenched with sat. aq. NH ₄ Cl (10.0 mL) and stirring was continued for 1 h. The organic layer was separated and the aqueous phase extracted with AcOEt (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to afford tert-butyl N-[7-({N-[5-(hy- droxymethyl)-1-methyl-1H-pyrazol-4-yl]acetamido}methyl)quino lin-2-yl]carbamate (Int. Q- ^{018, 0.03 g, 0.071 mmol, 63%, white solid, UPLC purity: 75%). 1H NMR (400 MHz, DMSO-d6)} _{δ 10.06 (s, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H),} 7.48 (s, 1H), 7.30 (dd, J = 8.3, 1.7 Hz, 1H), 7.09 (s, 1H), 5.28 (t, J = 5.2 Hz, 1H), 4.86 (s, 2H), 4.19 (d, J = 5.1 Hz, 2H), 3.78 (s, 3H), 1.87 (s, 3H), 1.51 (s, 9H). m/z (ESI): 448.2 [M+Na] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-[5-(hydroxymethyl)-1-meth yl-1H-pyrazol-4-yl]acetam- ide (Example E-013) tert-Butyl N-[7-({N-[5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]acetami do}methyl)quino- lin-2-yl]carbamate (Int. Q-018, 0.03 g, 0.053 mmol, 1.0 eq.) was dissolved in a mixture of DCM (2.0 mL) and TFA (0.2 mL) and the RM was stirred at RT overnight. It was then basi- fied to pH ≈ 8 with sat. aq. NaHCO ₃ and extracted with DCM (3x) and CHCl ₃ /iPrOH 3:1 v/v. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, fil- tered and evaporated under reduced pressure. The crude material was purified by FCC (DCM/MeOH 9:1) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-[5-(hydroxymethyl)-1-me- thyl-1H-pyrazol-4-yl]acetamide (Example E-013, 0.011 g, 0.034 mmol, 63%, white solid, UPLC long elution purity: 97.25%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 7.09 (s, 1H), 7.00 (dd, J = 8.1, 1.7 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.41 (s, 2H), 5.28 (t, J = 5.2 Hz, 1H), 4.78 (s, 2H), 4.19 (d, J = 5.1 Hz, 2H), 3.78 (s, 3H), 1.86 (s, 3H). m/z (ESI): 326.17 [M+H] ⁺ . Example E-014: 2-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}benzamide Ryvu Therapeutics S.A. RVU305 512 R10107WO 2-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] acetamido}benzoic acid (Int. Q-019) Methyl 2-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] acetamido}benzoate (Int. Q-015, 0.095 g, 0.21 mmol, 1.0 eq.) was dissolved in a mixture of MeOH (5.0 mL) and 0.1 M aq. NaOH (8.0 mL). The RM was stirred at RT for 60 h. The volatiles were evaporated under reduced pressure and the residue was acidified with 10% aq. acetic acid. The result- ing precipitate was filtered off, washed with water and dried to afford 2-{N-[(2-{[(tert- butoxy)carbonyl]amino}quinolin-7-yl)methyl]acetamido}benzoic acid (Int. Q-019, 0.084 g, 0.19 mmol, 84%, white solid, UPLC purity: 91%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.25 (s, 1H), 10.04 (s, 1H), 8.26 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.95 (dd, J = 7.0, 2.4 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.53 – 7.42 (m, 3H), 7.35 (dd, J = 8.3, 1.7 Hz, 1H), 6.98 (dd, J = 7.0, 2.1 Hz, 1H), 5.55 (d, J = 14.9 Hz, 1H), 4.23 (d, J = 15.0 Hz, 1H), 1.76 (s, 3H), 1.51 (s, 9H). m/z (ESI): 436.2 [M+H] ⁺ . tert-Butyl N-(7-{[N-(2-carbamoylphenyl)acetamido]methyl}quinolin-2-yl)c arbamate (Int. Q- 020) CDI (0.037 g, 0.23 mmol, 1.5 eq.) was added to a solution of 2-{N-[(2-{[(tert-butoxy)car- bonyl]amino}quinolin-7-yl)methyl]acetamido}benzoic acid (Int. Q-019, 0.072 g, 0.15 mmol, 1.0 eq.) in anhydrous DMF (1.5 mL). RM was stirred at 40 °C for 1 h, ammonium carbonate (0.029 g, 0.30 mmol, 2.0 eq.) was added, and stirring was continued at 40 °C overnight. The RM was then evaporated and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 4% MeOH gradient in DCM followed by 0 to 5% MeOH gradient in EtOAc) to yield tert-butyl N-{7-[(2-methyl-4- oxo-1,4-dihydroquinazolin-1-yl)methyl]quinolin-2-yl}carbamat e (Int. Q-020, 0.03 g, 0.07 mmol, 47%, white solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.26 (d, J = 9.1 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.96 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.57 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 5.66 (d, J = 14.9 Hz, 1H), 4.17 (d, J = 15.0 Hz, 1H), 1.82 (s, 3H), 1.51 (s, 9H). m/z (ESI): 435.1 [M+H] ⁺ . 2-{N-[(2-aminoquinolin-7-yl)methyl]acetamido}benzamide (Example E-014) tert-Butyl N-(7-{[N-(2-carbamoylphenyl)acetamido]methyl}quinolin-2-yl)c arbamate (Int. Q- 020, 0.03 g, 0.065 mmol, 1.0 eq.) was dissolved in a mixture of DCM (2.0 mL) and TFA (0.2 mL) and the RM was stirred overnight at RT. It was then basified to pH ≈ 8 with sat. aq. Na- HCO ₃ and extracted with DCM (3x) and CHCl ₃ /iPrOH 3:1 v/v. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under re- duced pressure. The crude material was purified by FCC (DCM/MeOH 9:1) to yield 2-{N- [(2-aminoquinolin-7-yl)methyl]acetamido}benzamide (Example E-014, 0.01 g, 0.03 mmol, 42%, white solid, UPLC long elution purity: 91.66%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.62 – 7.53 (m, 3H), 7.40 (t, J = 7.5 Hz, 1H), 7.32 (td, J = 7.7, 1.7 Hz, 1H), 7.23 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.51 (s, 2H), 5.62 (d, J = 14.9 Hz, 1H), 4.07 (d, J = 15.0 Hz, 1H), 1.81 (s, 3H). m/z (ESI): 335.19 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 513 R10107WO Example E-015: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesul- fonylphenyl)acetamide N-[(4-ethenyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylphen yl)acetamide (Int. Q-022), General Procedure 28 A mixture of Cs ₂ CO ₃ (0.919 g, 2.82 mmol, 3.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-diox- aborolane (0.289 g, 1.88 mmol, 2.0 eq.) and N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-me- thanesulfonylphenyl)acetamide (Int. Q-010, 0.406 g, 0.94 mmol, 1.0 eq.) in a mixture of diox- ane (6.0 mL) and water (2.0 mL) in a Biotage ^TM microwave vial was sparged with nitrogen for a few minutes. Bis(triphenylphosphine)palladium(II)chloride (0.066 g, 0.09 mmol, 0.1 eq.) was added, the vial was sealed, and the RM was stirred in a preheated heating block at 80 °C for 4 h and at RT overnight. The RM mixture was filtered through a pad of Celite ^® . The filtrate was partitioned between water and EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 30% gradient of EtOAc in DCM) to yield N-[(4-ethenyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylphen yl)acetamide (Int. Q- 022, 0.331 g, 0.88 mmol, 91%, orange solid, UPLC purity: 97%). 85/15 mixture of restricted C-N amide rotation isomers in DMSO- d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (dd, J = 6.0, 3.5 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.75 – 7.67 (m, 2H), 7.60 (dd, J = 8.0, 1.8 Hz, 1H), 7.10 (dd, J = 5.8, 3.3 Hz, 1H), 7.01 (dd, J = 17.4, 11.0 Hz, 1H), 5.92 (dd, J = 17.3, 1.0 Hz, 1H), 5.57 (d, J = 15.5 Hz, 1H), 5.53 (dd, J = 11.0, 1.0 Hz, 1H), 4.26 (d, J = 15.2 Hz, 1H), 3.38 (s, 3H), 1.79 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (dd, J = 7.7, 1.5 Hz, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.64 (dd, J = 8.0, 1.8 Hz, 1H), 7.56 – 7.47 (m, 2H), 7.13 – 7.06 (m, 1H), 7.04 – 6.93 (m, 1H), 5.93 (d, J = 17.7 Hz, 1H), 5.46 – 5.36 (m, 1H), 5.31 (d, J = 16.9 Hz, 1H), 4.69 (d, J = 16.8 Hz, 1H), 3.17 (s, 3H), 2.31 (s, 3H). m/z (ESI): 374.9 [M+H] ⁺ . N-[(4-formyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpheny l)acetamide (Int. Q-023), General Procedure 29 N-[(4-ethenyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylphen yl)acetamide (Int. Q-022, 0.275 g, 0.712 mmol, 1.0 eq.) was dissolved in a mixture of dioxane (11.0 mL) and water (2.2 Ryvu Therapeutics S.A. RVU305 514 R10107WO mL), and 4% aq. OsO ₄ (0.07 mL, 0.28 mmol, 0.7 eq.) was added. After stirring for 5 min., so- dium periodate (0.610 g, 2.85 mmol, 4.0 eq.) was added. The RM was stirred for 30 min., di- luted with brine and extracted with EtOAc (2x). The combined organic layers were washed with a 15% Na ₂ SO ₃ aq. solution and brine, dried over anhydrous Na ₂ SO ₄ , filtered and con- centrated under reduced pressure. The obtained crude N-[(4-formyl-3-nitrophenyl)methyl]- N-(2-methanesulfonylphenyl)acetamide (Int. Q-023, 0.234 g, 0.62 mmol, 74%, brown solid, UPLC purity: 85%) was used in the next step without further purification. 85/15 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.23 (s, 1H), 8.16 (dd, J = 6.0, 3.5 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.74 – 7.69 (m, 2H), 7.22 – 7.14 (m, 1H), 5.60 (d, J = 15.7 Hz, 1H), 4.38 (d, J = 15.6 Hz, 1H), 3.40 (s, 3H), 1.81 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 8.11 (s, 1H), 8.05 – 8.01 (m, 1H), 7.95 – 7.87 (m, 1H), 7.76 (dd, J = 7.9, 1.3 Hz, 1H), 7.65 – 7.55 (m, 2H), 7.17 – 7.12 (m, 1H), 5.40 (d, J = 17.4 Hz, 1H), 4.80 (d, J = 17.4 Hz, 1H), 3.18 (s, 3H), 2.30 (s, 3H). m/z (ESI): 376.6 [M+H] ⁺ . N-[(3-amino-4-formylphenyl)methyl]-N-(2-methanesulfonylpheny l)acetamide (Int. Q-024), General Procedure 30 An aq. HCl solution was prepared by addition of conc. HCl (0.25 mL) to water (13.0 mL). Iron powder (0.258 g, 4.62 mmol, 10.0 eq.) and the aforementioned HCl solution (0.5 mL) were added to a suspension of N-[(4-formyl-3-nitrophenyl)methyl]-N-(2-methanesul- fonylphenyl)acetamide (Int. Q-023, 0.174 g, 0.46 mmol, 1.0 eq.) in EtOH (3.5 mL) and the RM was refluxed for 90 min. After cooling back to RT, the RM was diluted with EtOAc, dried ^{over anhydrous Na SO , and f ® 2 4 iltered through a pad of Celite . The filter cake was washed} _{with EtOAc and the filtrate was concentrated under reduced pressure (bath temp. 25 °C).} The residue was redissolved in DCM, filtered through a microfilter and concentrated under reduced pressure. The obtained crude N-[(3-amino-4-formylphenyl)methyl]-N-(2-me- thanesulfonylphenyl)acetamide (Int. Q-024, 0.144 g, 0.416 mmol, 90%, brown foam, UPLC purity: 93%) was used in the next step without further purification. 75/25 mixture of re- stricted C-N amide rotation isomers in DMSO- d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.15 – 8.10 (m, 1H), 7.76 – 7.65 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.14 – 7.08 (m, 3H), 6.65 (d, J = 1.5 Hz, 1H), 6.53 (dd, J = 8.0, 1.6 Hz, 1H), 5.51 (d, J = 15.3 Hz, 1H), 4.03 (d, J = 15.4 Hz, 1H), 3.37 (s, 3H), 1.80 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.81 (s, 1H), 8.04 (dd, J = 7.8, 1.7 Hz, 1H), 7.66 – 7.57 (m, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.23 – 7.16 (m, 3H), 6.83 (s, 1H), 6.61 (dd, J = 8.1, 1.3 Hz, 1H), 5.18 (d, J = 17.7 Hz, 1H), 4.40 (d, J = 17.7 Hz, 1H), 3.18 (s, 3H), 2.25 (s, 3H). m/z (ESI): 347.3 [M+H] ⁺ . Diethyl [chloro(cyano)methyl]phosphonate (Int. Q-021), General Procedure 31 LiHMDS 1 M in THF (3.72 mL, 3.72 mmol, 1.1 eq.) was added to a solution of diethyl (cy- anomethyl)phosphonate (0.6 g, 3.39 mmol, 1.0 eq.) in anhydrous THF (18.0 mL) at 0 °C and the resulting RM was stirred at that temperature for 30 min under nitrogen. The RM was then cooled to -78 °C (dry ice/acetone bath) and NCS (0.543 g, 4.06 mmol, 1.2 eq.) was added in one portion. The RM was then allowed to come back slowly to RT over a pe- riod of 3 h under nitrogen. The reaction was quenched with aq. 2 M HCl and extracted with DCM (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 50% Ryvu Therapeutics S.A. RVU305 515 R10107WO EtOAc gradient in cyclohexane, ELSD detection) to yield diethyl [chloro(cyano)methyl]phos- phonate (Int. Q-021, 0.231 g, 1.09 mmol, 32%) as an orange oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.21 (d, J = 17.3 Hz, 1H), 4.28 (p, J = 7.5 Hz, 4H), 1.33 (t, J = 7.0 Hz, 6H). N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)acetamide (Exam- ple E-015), General Procedure 32 To a suspension of NaH 60% in mineral oil (0.016 g, 0.41 mmol, 1.5 eq.) in THF (0.5 mL) un- der nitrogen at 0 °C, was added a solution of diethyl [chloro(cyano)methyl]phosphonate (Int. Q-021, 0.080 g, 0.38 mmol, 1.4 eq.) in THF (0.5 mL). The resulting RM was stirred for 15 min at 0 °C, then treated with solution of N-[(3-amino-4-formylphenyl)methyl]-N-(2- methanesulfonylphenyl)acetamide (Int. Q-024, 0.094 g, 0.27 mmol, 1.0 eq.) in THF (0.7 mL). After 5 min, the cooling bath was removed and the RM was stirred at RT for 1 h. The reac- tion was carefully quenched with water at 0 °C and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to provide N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N- (2-methanesulfonylphenyl)acetamide (Example E-015, 0.043 g, 0.106 mmol, 38%, brown solid, UPLC long elution purity: 97.89%). 8/2 mixture of restricted C-N amide rotation iso- mers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (s, 1H), 8.13 (dd, J = 7.7, 1.8 Hz, 1H), 7.72 – 7.59 (m, 2H), 7.63 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 8.3, 1.7 Hz, 1H), 6.93 (dd, J = 7.6, 1.5 Hz, 1H), 6.74 (s, 2H), 5.70 (d, J = 14.9 Hz, 1H), 4.22 (d, J = 14.9 Hz, 1H), 3.37 (s, 3H), 1.80 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 8.02 (dd, J = 6.5, 2.8 Hz, 1H), 7.65 – 7.53 (m, 3H), 7.35 (s, 1H), 7.23 (dd, J = 8.3, 1.4 Hz, 1H), 7.00 (dd, J = 6.2, 2.6 Hz, 1H), 6.78 (s, 2H), 5.34 (d, J = 16.8 Hz, 1H), 4.62 (d, J = 16.7 Hz, 1H), 3.18 (s, 3H), 2.33 (s, 3H). m/z (ESI): 404.18 [M+H] ⁺ . Example E-016: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin- 3-yl)pyridine-3-carboxamide N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridi n-3-yl)pyridine-3-carbox- amide (Int. Q-025) N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridi n-3-yl)pyridine-3-carbox- amide (Int. Q-025, 1.60 g, 3.26 mmol, 60%, yellow solid, UPLC purity: 95%) was prepared ac- cording to General Procedure 22, using N-(2-methanesulfonylpyridin-3-yl)pyridine-3-car- boxamide (Int. C-0031.5 g, 5.19 mmol, 1.0 eq.), 1-bromo-4-(bromomethyl)-2-nitrobenzene Ryvu Therapeutics S.A. RVU305 516 R10107WO ^{(2.297 g, 7.79 mmol, 1.5 eq.) and Cs2CO3 (2.03 g, 6.23 mmol, 1.2 eq.) in anhydrous MeCN} _{(35.0 mL) at 65 °C. The crude material was purified by FCC (0 to 3% MeOH gradient in} DCM) to yield N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridi n-3-yl)pyri- dine-3-carboxamide (Int. Q-025, 1.603 g, 3.26 mmol, 60%, yellow solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 4.6 Hz, 1H), 8.55 (s, 1H), 8.47 (d, J = 4.8 Hz, 1H), 8.03 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.68 (dd, J = 8.1, 4.7 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 8.0, 5.0 Hz, 1H), 5.59 (d, J = 15.4 Hz, 1H), 4.72 (d, J = 15.4 Hz, 1H), 3.35 (s, 3H). m/z (ESI): 492.3 [M+H] ⁺ . N-[(4-ethenyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyri din-3-yl)pyridine-3-carbox- amide (Int. Q-026) The title compound was prepared according to General Procedure 28 using N-[(4-bromo-3- nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)pyridin e-3-carboxamide (Int. Q-025, 1.603 g, 3.1 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.955 g, 6.20 mmol, 2.0 eq.), Cs ₂ CO ₃ (3.030 g, 9.3 mmol, 3.0 eq.) and bis(triphenylphosphine)palla- dium(II)chloride (0.218 g, 0.31 mmol, 0.1 eq.) in dioxane/water 3:1 v/v (40.0 mL). The crude material was purified by FCC (0 to 3% MeOH gradient in DCM) to yield N-[(4-ethenyl-3-ni- trophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)pyridine- 3-carboxamide (Int. Q-026, 1.267 g, 2.89 mmol, 88%, yellow solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J = 4.5 Hz, 1H), 8.55 (s, 1H), 8.47 (d, J = 4.2 Hz, 1H), 7.95 (s, 1H), 7.89 (dd, J = 8.2, 1.4 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.65 (dd, J = 8.1, 4.6 Hz, 1H), 7.29 (dd, J = 7.7, 5.0 Hz, 1H), 6.99 (dd, J = 17.3, 11.0 Hz, 1H), 5.92 (d, J = 17.3 Hz, 1H), 5.65 (d, J = 15.2 Hz, 1H), 5.53 (d, J = 11.1 Hz, 1H), 4.74 (d, J = 15.2 Hz, 1H), 3.32 (s, 3H). m/z (ESI): 439.6 [M+H] ⁺ . N-[(4-formyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)pyridine-3-carbox- amide (Int. Q-027) The title compound was prepared according to General Procedure 29 using N-[(4-ethenyl- 3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)pyrid ine-3-carboxamide (Int. Q- 026, 0.667 g, 1.4 mmol, 1.0 eq.), 4% aq. OsO ₄ (0.813 mL, 0.13 mmol, 0.09 eq.) and NaIO ₄ (1.220 g, 5.72 mmol, 4.0 eq.) in a mixture of dioxane (15.0 mL) and water (2.4 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(4-formyl- 3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)pyrid ine-3-carboxamide (Int. Q- ^{027, 0.366 g, 0.83 mmol, 55%, beige solid, UPLC purity: 83%). 1H NMR (400 MHz, DMSO-d6)} _{δ 10.23 (s, 1H), 8.63 (d, J = 4.7 Hz, 1H), 8.57 (s, 1H), 8.48 (d, J = 4.0 Hz, 1H), 8.16 (s, 1H),} 7.98 (dd, J = 8.0, 0.9 Hz, 1H), 7.92 (s, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 8.2, 4.3 Hz, 1H), 7.30 (dd, J = 7.9, 5.0 Hz, 1H), 5.68 (d, J = 15.6 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 3.32 (s, 3H). m/z (ESI): 441.6 [M+H] ⁺ . N-[(3-amino-4-formylphenyl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)pyridine-3-carbox- amide (Int. Q-028) The title compound was prepared according to General Procedure 30 using N-[(4-formyl-3- nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)pyridin e-3-carboxamide (Int. Q-027, 0.33 g, 0.71 mmol, 1.0 eq.), iron powder (0.4 g, 7.16 mmol, 10.0 eq.) and 1 M aq. HCl (0.142 mL, 0.14 mmol, 0.2 eq.) in a mixture of EtOH (7.0 mL) and water (1.0 mL). The obtained crude N-[(3-amino-4-formylphenyl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)pyridine-3- Ryvu Therapeutics S.A. RVU305 517 R10107WO carboxamide (Int. Q-028, 0.273 g, 0.665 mmol, 92%, brown solid, UPLC purity: 98%) was used in the next step without further purification. 8/2 mixture of restricted C-N amide rota- tion isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 8.60 (dd, J = 4.7, 1.1 Hz, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.48 (dd, J = 4.9, 1.6 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.64 (dd, J = 8.1, 4.5 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 8.0, 4.9 Hz, 1H), 7.17 (s, 2H), 6.77 (s, 1H), 6.61 (d, J = 8.0 Hz, 1H), 5.65 (d, J = 15.5 Hz, 1H), 4.46 (d, J = 15.5 Hz, 1H), 3.38 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.77 (s, 1H), 8.88 (s, 1H), 8.78 – 8.68 (m, 2H), 8.07 (d, J = 6.6 Hz, 1H), 7.67 – 7.60 (m, 1H), 7.59 (d, J = 3.2 Hz, 1H), 7.57 (dd, J = 3.4, 1.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.17 (s, 2H), 6.69 (s, 1H), 6.49 (d, J = 7.5 Hz, 1H), 4.99 (d, J = 16.8 Hz, 1H), 4.62 (d, J = 16.5 Hz, 1H), 3.44 (s, 3H). m/z (ESI): 411.5 [M+H] ⁺ . N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyridine-3- carboxamide (Example E-016). A solution of diethyl [chloro(cyano)methyl]phosphonate (Int. Q-021, 0.215 g, 0.92 mmol, 1.4 eq.) in anhydrous THF (1.0 mL) was added to a suspension of NaH (60% in mineral oil, 0.038 g, 0.99 mmol, 1.5 eq.) in anhydrous THF (2.0 mL) at 0 °C under nitrogen. The result- ing mixture was stirred at 0 °C for 15 min. and a solution of N-[(3-amino-4- formylphenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)pyridi ne-3-carboxamide (Int. Q- 028, 0.273 g, 0.65 mmol, 1.0 eq.) in anhydrous THF (3.0 mL) was added dropwise. The RM was stirred 1 h, being allowed to come back to RT and the reaction was quenched by addi- tion of water. The phases were separated and the aqueous phase was extracted with EtOAc (x2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by two consecutive FCCs (first: silica, 0 to 5% MeOH gradient in DCM; second: C18 functionalized silica, 5% to 50% MeCN gradient in water) to yield N-[(2-amino-3-chloroquinolin-7-yl)me- thyl]-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-carboxamid e (Example E-016, 0.146 g, 0.31 mmol, 47%, off-white solid, UPLC long elution purity: 99.1%).8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.54 (s, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.44 (d, J = 4.8 Hz, 1H), 8.18 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.50 (dd, J = 7.9, 4.4 Hz, 1H), 7.33 (s, 1H), 7.29 – 7.25 (m, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.75 (s, 2H), 5.79 (d, J = 14.8 Hz, 1H), 4.68 (d, J = 14.7 Hz, 1H), 3.33 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 – 8.85 (m, 1H), 8.77 – 8.69 (m, 1H), 8.68 – 8.62 (m, 1H), 8.18 (s, 1H), 8.13 – 8.05 (m, 1H), 7.69 – 7.54 (m, 4H), 7.22 – 7.16 (m, 1H), 7.15 – 7.05 (m, 1H), 6.75 (s, 2H), 5.15 (d, J = 15.4 Hz, 1H), 4.82 (d, J = 15.4 Hz, 1H), 3.33 (s, 3H). m/z (ESI): 468.18 [M+H] ⁺ . Example E-017: N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶- benzothiophen-7-yl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 N-[(4-bromo-3-nitrophenyl)methyl]-N-(1,1-dioxo-2,3-dihydro-1 λ⁶-benzothiophen-7-yl)pyr- idine-3-carboxamide (Int. Q-029) The title compound was prepared according to General Procedure 22 using N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide (Int. C-004, 0.4 g, 1.36 mmol, 1.0 eq.), 1-bromo-4-(bromomethyl)-2-nitrobenzene (0.6 g, 2.03 mmol, 1.5 eq.) and Cs ₂ CO ₃ (0.53 g, 1.63 mmol, 1.2 eq.) in anhydrous MeCN (7.0 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(4-bromo-3-nitrophenyl)methyl]-N- (1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3- carboxamide (Int. Q-029, 0.53 g, 1.06 mmol, 71%, brown solid, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 8.3, 2.1 Hz, 1H), 7.42 (d, J = 4.1 Hz, 2H), 7.29 (dd, J = 8.0, 4.9 Hz, 1H), 7.09 – 6.97 (m, 1H), 5.71 (d, J = 15.4 Hz, 1H), 4.73 (d, J = 15.4 Hz, 1H), 3.84 – 3.65 (m, 2H), 3.38 (t, J = 7.1 Hz, 2H). m/z (ESI): 503.2 [M+H] ⁺ . N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(4-et henyl-3-nitrophenyl)me- thyl]pyridine-3-carboxamide (Int. Q-030) The title compound was prepared according to General Procedure 28 using N-[(4-bromo-3- nitrophenyl)methyl]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothi ophen-7-yl)pyridine-3-carbox- amide (Int. Q-029, 0.53 g, 0.97 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxabo- rolane (0.299 g, 1.94 mmol, 2.0 eq.), bis(triphenylphosphine)palladium(II)chloride (0.07 g, 0.1 mmol, 0.1 eq.) and Cs ₂ CO ₃ (0.95 g, 2.92 mmol, 3.0 eq.) in a mixture of dioxane (10.0 mL) and water (3.0 mL). The crude material was purified by FCC (0 to 3 % MeOH gradient in DCM) to yield N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(4-et henyl-3-nitro- phenyl)methyl]pyridine-3-carboxamide (Int. Q-030, 0.302 g, 0.67 mmol, 68%, yellow solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (s, 1H), 8.47 (d, J = 4.9 Hz, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 8.4, 1.8 Hz, 1H), 7.45 – 7.36 (m, 2H), 7.29 (dd, J = 7.2, 4.9 Hz, 1H), 6.98 (dd, J = 17.4, 11.0 Hz, 1H), 6.97 – 6.92 (m, 1H), 5.91 (dd, J = 17.3, 1.0 Hz, 1H), 5.77 (d, J = 15.2 Hz, 1H), 5.52 (dd, J = 11.0, 1.0 Hz, 1H), 4.74 (d, J = 15.3 Hz, 1H), 3.85 – 3.67 (m, 2H), 3.39 (t, J = 7.0 Hz, 2H). m/z (ESI): 450.6 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 519 R10107WO N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(4-fo rmyl-3-nitrophenyl)methyl]pyri- dine-3-carboxamide (Int. Q-031) The title compound was prepared according to General Procedure 29 using N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(4-ethenyl-3-nitro phenyl)methyl]pyridine-3-car- boxamide (Int. Q-030, 0.302 g, 0.66 mmol, 1.0 eq.), OsO ₄ (4% aqueous, 0.43 mL, 0.07 mmol, 0.1 eq.) and sodium periodate (0.563 g, 2.63 mmol, 4.0 eq.) in a mixture of dioxane (7.5 mL) and water (1.2 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to give N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(4-fo rmyl-3-nitro- phenyl)methyl]pyridine-3-carboxamide (Int. Q-031, 0.26 g, 0.576 mmol, 83%, white solid, UPLC purity: 70%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.49 (d, J = 4.8 Hz, 1H), 8.10 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.85 (dd, J = 7.8, 1.5 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.46 – 7.37 (m, 2H), 7.30 (dd, J = 8.0, 4.8 Hz, 1H), 7.11 – 7.01 (m, 1H), 5.78 (d, J = 15.6 Hz, 1H), 4.86 (d, J = 15.7 Hz, 1H), 3.84 – 3.66 (m, 2H), 3.38 (t, J = 7.1 Hz, 2H). m/z (ESI): 452.5 [M+H] ⁺ . N-[(3-amino-4-formylphenyl)methyl]-N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7- yl)pyridine-3-carboxamide (Int. Q-032) The title compound was prepared according to General Procedure 30 using N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(4-formyl-3-nitrop henyl)methyl]pyridine-3-car- boxamide (Int. Q-031, 0.26 g, 0.55 mmol, 1.0 eq.), iron powder (0.306 g, 5.47 mmol, 10.0 eq.) and aq.1 M HCl (1.0 mL) in EtOH (5.5 mL). The obtained crude N-[(3-amino-4- formylphenyl)methyl]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzoth iophen-7-yl)pyridine-3-carbox- amide (Int. Q-032, 0.24 g, 0.569 mmol, 98%, beige solid, UPLC purity: 94%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.81 (s, 1H), 8.70 – 8.62 (m, 1H), 8.55 – 8.46 (m, 1H), 7.75 – 7.63 (m, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.47 – 7.38 (m, 2H), 7.36 – 7.27 (m, 1H), 7.20 (s, 2H), 6.94 (s, 1H), 6.77 (s, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 16.7 Hz, 1H), 4.54 (d, J = 15.6 Hz, 1H), 3.91 – 3.67 (m, 2H), 3.57 – 3.25 (m, 2H). m/z (ESI): 422.6 [M+H] ⁺ . Diethyl [cyano(fluoro)methyl]phosphonate (Int. Q-033) LiHMDS (1 M in THF, 6.2 mL, 6.2 mmol, 1.1 eq.) was added dropwise over 5 min. to a stirred solution of diethyl (cyanomethyl)phosphonate (1.0 g, 5.65 mmol, 1.0 eq.) in anhydrous THF (7.0 mL) at 0 °C under argon. After stirring for 25 min. at 0 °C, a solution of SelectFluor ^TM (2.2 g, 6.21 mmol, 1.1 eq.) in MeCN (9.5 mL) was added dropwise at the same temperature. The RM was stirred at RT for 1.5 h and the reaction was quenched by addition of conc. HCl (1.6 mL). The solvent was evaporated under reduced pressure and the residue was sus- pended in aq. sat. NaHCO ₃ . The suspension was extracted with EtOAc (3x) and the com- bined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by two consecutive FCCs (first: 0 to 100% CHCl ₃ gradient in hexane, second: 0 to 20% EtOAc in hexane) to yield diethyl [cyano(fluoro)methyl]phosphonate (Int. Q-033, 0.21 g, 1.076 mmol, 18%, colorless oil, NMR purity: 95%). ¹ H NMR (400 MHz, Chloroform-d) δ 5.34 (dd, J = 46.3, 12.8 Hz, 1H), 4.38 (m, 4H), 1.46 (td, J = 7.1, 2.8 Hz, 6H). N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide (Example E-017) Ryvu Therapeutics S.A. RVU305 520 R10107WO The title compound was prepared according to General Procedure 32 using N-[(3-amino-4- formylphenyl)methyl]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzoth iophen-7-yl)pyridine-3-carbox- amide (Int. Q-032, 0.12 g, 0.27 mmol, 1.0 eq.), diethyl [cyano(fluoro)methyl]phosphonate (Int. Q-033, 0.08 g, 0.39 mmol, 1.5 eq.) and NaH (60% in mineral oil, 0.02 g, 0.52 mmol, 1.9 eq.) in THF (1.0 mL). The crude material was purified by two consecutive FCCs (first: 15 ^m silica, 0 to 10% MeOH gradient in DCM; second: NH ₂ functionalized silica, 0 to 2% MeOH gradient in DCM) to yield N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-d ihy- dro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide (Example E-017, 0.017 g, 0.04 mmol, 14%, pale yellow solid, UPLC long elution purity: 99.06%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 8.45 (d, J = 4.8 Hz, 1H), 7.83 (d, J = 11.8 Hz, 1H), 7.82 – 7.76 (m, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.30 (m, 4H), 7.21 (d, J = 8.4 Hz, 1H), 6.94 (s, 2H), 6.64 (d, J = 7.7 Hz, 1H), 5.93 (d, J = 14.8 Hz, 1H), 4.70 (d, J = 14.8 Hz, 1H), 3.89 – 3.63 (m, 2H), 3.39 (t, J = 7.5 Hz, 2H). m/z (ESI): 463.10 [M+H] ⁺ . Example E-018: rac-N-[(2-aminoquinolin-7-yl)methyl]-N-{3-[(1R)-1-hydroxyeth yl]-1-me- (Int. Q-034) 1 M aq. NaOH (15.0 mL) was added to a solution of methyl 4-{N-[(2-chloroquinolin-7- yl)methyl]acetamido}-1-methyl-1H-pyrazole-3-carboxylate (Int. N-007, 0.33 g, 0.80 mmol, 1.0 eq.) in ethanol (15.0 mL). The RM was stirred at 60 °C for 3 h, concentrated under re- duced pressure and acidified with 1 M aq. HCl. The aqueous mixture was extracted CHCl ₃ /iPrOH 3:1 v/v and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to afford 4-{N-[(2-chloroquinolin-7-yl)methyl]acetam- ido}-1-methyl-1H-pyrazole-3-carboxylic acid (Int. Q-034, 0.3 g, 0.836 mmol, 95%, white solid, UPLC purity: 91%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 8.44 (dd, J = 8.6, 0.8 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 8.4, 1.7 Hz, 1H), 4.92 (br s, 2H), 3.81 (s, 3H), 1.89 (s, 3H). m/z (ESI): 359.2 [M+H] ⁺ . 4-{N-[(2-chloroquinolin-7-yl)methyl]acetamido}-N-methoxy-N,1 -dimethyl-1H-pyrazole-3- carboxamide (Int. Q-035) Ryvu Therapeutics S.A. RVU305 521 R10107WO TEA (0.29 mL, 2.08 mmol, 2.7 eq.) and T3P (50 wt. % in EtOAc, 0.98 mL, 1.68 mmol, 2.2 eq.) were added to a solution of 4-{N-[(2-chloroquinolin-7-yl)methyl]acetamido}-1-methyl-1H- pyrazole-3-carboxylic acid (Int. Q-034, 0.3 g, 0.76 mmol, 1.0 eq.) in THF (7.0 mL) at 0 °C. The RM was stirred at this temperature for 10 min. under argon and methoxy(methyl)amine hydrochloride (0.104 g, 1.07 mmol, 1.4 eq.) was added. The RM was stirred overnight at RT under argon and partitioned between water and AcOEt. The aqueous layer was extracted with AcOEt and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH in DCM) to yield 4-{N-[(2-chloroquinolin-7-yl)methyl]acetamido}-N-methoxy-N,1 - dimethyl-1H-pyrazole-3-carboxamide (Int. Q-035, 0.295 g, 0.73 mmol, 89%, white solid, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.4, 1.7 Hz, 1H), 4.88 (s, 2H), 3.81 (s, 3H), 3.57 (s, 3H), 3.10 (s, 3H), 1.95 (s, 3H). m/z (ESI): 402.1 [M+H] ⁺ . N-(3-acetyl-1-methyl-1H-pyrazol-4-yl)-N-[(2-chloroquinolin-7 -yl)methyl]acetamide (Int. Q- 036) To a solution of 4-{N-[(2-chloroquinolin-7-yl)methyl]acetamido}-N-methoxy-N,1 -dimethyl- 1H-pyrazole-3-carboxamide (Int. Q-035, 0.1 g, 0.23 mmol, 1.0 eq.) in anhydrous THF (4.0 mL) was added MeMgBr (3 M in THF, 0.39 mL, 1.17 mmol, 5.1 eq.) under argon at -78 °C. The RM was stirred at this temperature for 2h and allowed to come back to RT. The reac- tion was quenched with aq. sat. NH ₄ Cl And the mixture was extracted with AcOEt. The or- ganic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pres- sure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N- (3-acetyl-1-methyl-1H-pyrazol-4-yl)-N-[(2-chloroquinolin-7-y l)methyl]acetamide (Int. Q- 036, 0.078 g, 0.219 mmol, 85%, white solid, UPLC purity: 89%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.57 (dd, J = 8.4, 1.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.89 (s, 2H), 3.85 (s, 3H), 2.44 (s, 3H), 1.86 (s, 3H). m/z (ESI): 357.2 [M+H] ⁺ . N-(7-{[N-(3-acetyl-1-methyl-1H-pyrazol-4-yl)acetamido]methyl }quinolin-2-yl)carbamate (Int. Q-037) In a Biotage ^TM microwave vial, a mixture of Cs ₂ CO ₃ (0.21 g, 0.64 mmol, 2.0 eq.), XPhos Pd G3 (0.034 g, 0.04 mmol, 0.2 eq.), tert-butyl carbamate (0.189 g, 1.61 mmol, 5.0 eq.) and N-(3- acetyl-1-methyl-1H-pyrazol-4-yl)-N-[(2-chloroquinolin-7-yl)m ethyl]acetamide (Int. Q-036, 0.126 g, 0.32 mmol, 1.0 eq.) in anhydrous dioxane (3.0 mL) was sparged with nitrogen for 10 minutes. The vial was sealed and the RM was heated at 100 °C for 2 h in a DrySyn ^® . After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . Water was added to the filtrate and the organic phase was separated. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude mate- rial was purified by FCC (0 to 50% EtOAc gradient in hexane) to afford tert-butyl N-(7-{[N- (3-acetyl-1-methyl-1H-pyrazol-4-yl)acetamido]methyl}quinolin -2-yl)carbamate (Int. Q-037, 0.054 g, 0.12 mmol, 36%, white solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.71 Ryvu Therapeutics S.A. RVU305 522 R10107WO (s, 1H), 7.46 (s, 1H), 7.28 (dd, J = 8.3, 1.7 Hz, 1H), 4.83 (s, 2H), 3.83 (s, 3H), 2.43 (s, 3H), 1.83 (s, 3H), 1.51 (s, 9H). m/z (ESI): 460.2 [M+Na] ⁺ . tert-Butyl N-[7-({N-[3-(1-hydroxyethyl)-1-methyl-1H-pyrazol-4-yl]acetam ido}methyl)quino- lin-2-yl]carbamate (Int. Q-038) NaBH ₄ (0.013 g, 0.34 mmol, 3.0 eq.) was added to a solution of tert-butyl N-(7-{[N-(3-ace- tyl-1-methyl-1H-pyrazol-4-yl)acetamido]methyl}quinolin-2-yl) carbamate (Int. Q-037, 0.054 g, 0.12 mmol, 1.0 eq.) in anhydrous MeOH (2.0 mL) at 0 °C. The RM was stirred at RT for 1.5 h and the reaction was quenched with sat. aq. NH ₄ Cl. The aqueous mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to af- ford tert-butyl N-[7-({N-[3-(1-hydroxyethyl)-1-methyl-1H-pyrazol-4-yl]acetam ido}me- thyl)quinolin-2-yl]carbamate (Int. Q-038, 0.045 g, 0.10 mmol, 83%, white solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 8.27 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 7.31 (dd, J = 8.4, 1.7 Hz, 1H), 5.07 (d, J = 5.3 Hz, 1H), 5.02 (br s, 1H), 4.78 (br s, 1H), 4.63 – 4.50 (m, 1H), 3.68 (s, 3H), 1.90 (s, 3H), 1.51 (s, 9H), 1.29 (d, J = 6.5 Hz, 3H). m/z (ESI): 462.2 [M+Na] ⁺ . rac-N-[(2-aminoquinolin-7-yl)methyl]-N-[3-(1-hydroxyethyl)-1 -methyl-1H-pyrazol-4-yl]ac- etamide (Example E-018) tert-Butyl N-[7-({N-[3-(1-hydroxyethyl)-1-methyl-1H-pyrazol-4-yl]acetam ido}methyl)quino- lin-2-yl]carbamate (Int. Q-038, 0.073 g, 0.15 mmol, 1.0 eq.) was dissolved in a mixture of DCM (3.0 mL) and TFA (0.3 mL) and the RM was stirred overnight at RT. It was then basi- fied to pH ≈ 8 with sat. aq. NaHCO ₃ and extracted with DCM (3x) and CHCl ₃ /iPrOH 3:1 v/v. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield rac-N-[(2-aminoquinolin-7-yl)methyl]-N-[3-(1-hydroxy- ethyl)-1-methyl-1H-pyrazol-4-yl]acetamide (Example E-018, 0.029 g, 0.085 mmol, 55%, white solid, UPLC long elution purity: 96.53%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.20 (d, J = 1.7 Hz, 1H), 7.01 (dd, J = 8.2, 1.7 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.42 (s, 2H), 5.04 (d, J = 5.3 Hz, 1H), 4.94 (br s, 1H), 4.69 (br s, 1H), 4.62 – 4.50 (m, 1H), 3.69 (s, 3H), 1.89 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H). m/z (ESI): 340.23 [M+H] ⁺ . Example E-019: N-[(2-aminoquinolin-7-yl)methyl]-N-(3-carbamoyl-1-methyl-1H- pyrazol-4- yl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 523 R10107WO Methyl 4-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] pyridine-3-amido}-1- methyl-1H-pyrazole-3-carboxylate (Int. Q-039) A mixture of Cs ₂ CO ₃ (0.434 g, 1.33 mmol, 2.1 eq.), XPhos Pd G3 (0.131 g, 0.16 mmol, 0.25 eq.), tert-butyl carbamate (0.511 g, 4.36 mmol, 7.0 eq.) and methyl 4-{N-[(2-chloroquinolin- 7-yl)methyl]pyridine-3-amido}-1-methyl-1H-pyrazole-3-carboxy late (Int. N-025, 0.295 g, 0.62 mmol, 1.0 eq.) in anhydrous dioxane (8.0 mL) was sparged with nitrogen for 10 minutes. The vial was sealed and the RM was heated at 110 °C under microwave irradia- tion for 1.5 h. After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . Water was added to the filtrate and the organic phase was separated. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 7% MeOH gradient in DCM) to yield methyl 4- {N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl]py ridine-3-amido}-1-methyl-1H- pyrazole-3-carboxylate (Int. Q-039, 0.25 g, 0.484 mmol, 70%, light yellow solid, UPLC purity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 8.52 (d, J = 1.3 Hz, 1H), 8.49 (dd, J = 4.9, 1.1 Hz, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.73 (dt, J = 7.6, 1.6 Hz, 1H), 7.63 (s, 1H), 7.44 (dd, J = 8.3, 1.6 Hz, 1H), 7.32 (dd, J = 7.9, 4.8 Hz, 1H), 5.21 (br s, 1H), 4.99 (br s, 1H), 3.75 (s, 3H), 3.61 (s, 3H), 1.51 (s, 9H). m/z (ESI): 539.3 [M+Na] ⁺ . 4-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] pyridine-3-amido}-1-methyl- 1H-pyrazole-3-carboxylic acid (Int. Q-040) LiOH monohydrate (0.094 g, 2.2 mmol, 5.1 eq.) was added to a solution of methyl 4-{N-[(2- {[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl]pyridine- 3-amido}-1-methyl-1H-pyra- zole-3-carboxylate (Int. Q-039, 0.25 g, 0.44 mmol, 1.0 eq.) in a mixture of THF (5.0 mL) and water (2.5 mL). The RM was stirred 4 h at RT. THF was evaporated under reduced pressure, the RM was diluted with water and acidified to pH ≈ 5 with 5% aq. KHSO ₄ . The aqueous mixture was extracted with DCM/iPrOH 3:1 (4x) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield 4-{N- [(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl]pyrid ine-3-amido}-1-methyl-1H-py- razole-3-carboxylic acid (Int. Q-040, 0.187 g, 0.37 mmol, 81%, light yellow solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.49 (dd, J = 4.9, 1.4 Hz, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.71 (dt, J = 7.9, 1.6 Hz, 1H), 7.64 (s, 1H), 7.47 (dd, J = 8.3, 1.1 Hz, 1H), 7.33 (dd, J = 7.9, 4.8 Hz, 1H), 5.43 (br s, 1H), 4.74 (br s, 1H), 3.71 (s, 3H), 1.51 (s, 9H). m/z (ESI): 503.2 [M+H] ⁺ . N-(7-{[N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-1-(pyridin-3 -yl)formamido]methyl}quino- lin-2-yl)carbamate (Int. Q-041) In a pressure vessel, CDI (0.064 g, 0.39 mmol, 1.1 eq.) was added to a solution of 4-{N-[(2- {[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl]pyridine- 3-amido}-1-methyl-1H-pyra- zole-3-carboxylic acid (Int. Q-040, 0.187 g, 0.35 mmol, 1.0 eq.) in anhydrous DMF (2.5 mL). The RM was stirred at 60 °C for 1 h, ammonia (0.5 M solution in dioxane, 2.5 mL, 1.25 mmol, 3.54 eq.) was added, and stirring was continued at RT overnight. The RM was then evaporated and the residue was partitioned between EtOAc and water. The organic layer Ryvu Therapeutics S.A. RVU305 524 R10107WO was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under re- duced pressure. The crude material was purified by FCC (0 to 6% MeOH gradient in DCM) to yield tert-butyl N-(7-{[N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-1-(pyridin-3 - yl)formamido]methyl}quinolin-2-yl)carbamate (Int. Q-041, 0.141 g, 0.281 mmol, 76%, yellow solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.08 (s, 1H), 8.51 (d, J = 1.7 Hz, 1H), 8.48 (dd, J = 4.9, 1.7 Hz, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.73 (dt, J = 8.2, 1.9 Hz, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.48 (dd, J = 8.3, 1.1 Hz, 1H), 7.34 – 7.29 (m, 2H), 7.19 (s, 1H), 5.54 (br s, 1H), 4.64 (br s, 1H), 3.65 (s, 3H), 1.51 (s, 9H). m/z (ESI): 502.2 [M+H] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-(3-carbamoyl-1-methyl-1H- pyrazol-4-yl)pyridine-3- carboxamide (Example E-019) tert-Butyl N-(7-{[N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-1-(pyridin-3 - yl)formamido]methyl}quinolin-2-yl)carbamate (Int. Q-041, 0.141 g, 0.27 mmol, 1.0 eq.) was dissolved in a mixture of DCM (5.0 mL) and TFA (1.0 mL) and the RM was stirred 2.5 h at RT. It was then basified to pH ≈ 8 with sat. aq. NaHCO ₃ and extracted with DCM (3x) and CHCl ₃ /iPrOH 3:1 v/v. The combined organic layers were washed with brine, dried over anhy- drous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was pu- rified by FCC (0 to 4% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]- N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxami de (Example E-019, 0.063 g, 0.157 mmol, 58%, white solid, UPLC long elution purity: 99.14%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (s, 1H), 8.47 (d, J = 4.7 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.37 – 7.27 (m, 3H), 7.21 (s, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.41 (s, 2H), 5.54 (br s, 1H), 4.48 (br s, 1H), 3.65 (s, 3H). m/z (ESI): 402.4 [M+H] ⁺ . Example E-020: N-[(2-amino-3-cyanoquinolin-7-yl)methyl]-N-(2-methanesul- fonylphenyl)acetamide A Biotage ^TM microwave vial was charged with N-[(3-amino-4-formylphenyl)methyl]-N-(2- methanesulfonylphenyl)acetamide (Int. Q-024, 0.02 g, 0.058 mmol, 1.0 eq.), malononitrile (0.004 g, 0.061 mmol, 1.05 eq.) and TEA (0.024 mL, 0.18 mmol, 3.0 eq.) and absolute EtOH. The vial was sealed and the RM was sonicated in an ultrasound bath for 3 h (bath tempera- ture ≈ 45 °C). The volatiles were evaporated under reduced pressure and the crude mate- rial was purified by FCC (0 to 2% MeOH gradient in DCM) to yield N-[(2-amino-3-cyano- quinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl)acetamide (Example E-020, 0.015 g, 0.04 mmol, 65%, beige solid, UPLC long elution purity: 99.33%).85/15 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.66 (s, 1H), 8.13 (dd, J = 7.4, 2.1 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.69 – 7.61 (m, 2H), 7.30 (d, J = 1.4 Hz, 1H), 7.21 (dd, J = 8.3, 1.7 Hz, 1H), 6.98 (dd, J = 7.3, 1.9 Hz, 1H), 6.96 (s, Ryvu Therapeutics S.A. RVU305 525 R10107WO 2H), 5.68 (d, J = 15.1 Hz, 1H), 4.24 (d, J = 15.1 Hz, 1H), 3.38 (s, 3H), 1.81 (s, 3H). Minor rota- mer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 8.02 (dd, J = 7.2, 2.0 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.65 – 7.54 (m, 2H), 7.37 (s, 1H), 7.31 – 7.28 (m, 1H), 7.04 (dd, J = 7.4, 1.8 Hz, 1H), 7.01 (s, 2H), 5.35 (d, J = 17.1 Hz, 1H), 4.66 (d, J = 17.1 Hz, 1H), 3.18 (s, 3H), 2.31 (s, 3H). m/z (ESI): 417.20 [M+Na] ⁺ . Example E-021: (2R)-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylph enyl)ox- olane-2-carboxamide and Example E-022: (2S)-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-me- thanesulfonylphenyl)oxolane-2-carboxamide (2R)-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylph enyl)oxolane-2-carbox- amide (Example E-021) and (2S)-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesul- fonylphenyl)oxolane-2-carboxamide (Example E-022) were obtained from rac-N-[(2-amino- quinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl)oxolane-2-c arboxamide (Example C- 003) by purification by chiral HPLC (column: CHIRALPAK ^® AY-H; mobile phase: isocratic hexane/EtOH 90:10 v/v (+0.1% n-butylamine); flow rate: 19 mL/min.; elution time: 140 min.). R and S configurations were attributed arbitrarily. (2R)-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylph enyl)oxolane-2-carbox- amide (Example E-021, 8 mg, at RT; two diastereoisomers are visible in LC due to the pres- ence of atropisomers (N-phenyl restricted rotation) and the tetrahydrofuran chiral center: UPLC long elution purity: two diastereoisomers 62.10% + 36.64% = 98.74%, chiral HPLC: one peak visible due to the long timeframe of elution and the dynamic equilibrium existing between the 2 atropisomers, chiral purity: 100%). In DMSO-d ₆ at RT, the compound exists as a 45/36/6/13 mixture of 4 components resulting from 2 diastereoisomers (N-phenyl re- stricted rotation atropisomers in dynamic equilibrium + the defined tetrahydrofuran chiral center) with two C-N amide rotation isomers, only the major component described: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (dd, J = 1.3, 7.9 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.72 – 7.50 (m, 3H), 7.18 (s, 1H), 7.02 (dd, J = 1.7, 8.1 Hz, 1H), 6.79 (dd, J = 1.3, 7.8 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.43 (s, 2H), 5.79 – 5.70 (m, 1H), 4.14 (d, J = 14.8 Hz, 1H), 4.07 (dd, J = 5.6, 12.9 Hz, 1H), 4.02 – 3.81 (m, 1H), 3.75 – 3.65 (m, 1H), 3.35 (s, 3H), 2.32 – 2.12 (m, 1H), 2.04 – 1.90 (m, 1H), 1.90 – 1.75 (m, 1H), 1.75 – 1.62 (m, 1H). m/z (ESI): 426.26 [M+H] ⁺ . (2S)-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylph enyl)oxolane-2-carbox- amide (Example E-022, 13 mg, at RT; two diastereoisomers are visible in LC due to the presence of atropisomers (N-phenyl restricted rotation) and the tetrahydrofuran chiral cen- ter: UPLC long elution purity: two diastereoisomers 62.43% + 36.88% = 99.31%, chiral HPLC: one peak visible due to the long timeframe of elution and the dynamic equilibrium Ryvu Therapeutics S.A. RVU305 526 R10107WO existing between the 2 atropisomers, chiral purity: 100%). In DMSO-d ₆ at RT, the compound exists as a 44/38/6/12 mixture of 4 components resulting from 2 diastereoisomers (N-phe- nyl restricted rotation atropisomers in dynamic equilibrium + the defined tetrahydrofuran chiral center) with two C-N amide rotation isomers, only the major component described: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (dd, J = 7.9, 1.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.73 – 7.51 (m, 3H), 7.18 (d, J = 1.5 Hz, 1H), 7.02 (dd, J = 8.2, 1.7 Hz, 1H), 6.79 (dd, J = 7.8, 1.3 Hz, 1H), 6.74 (dt, J = 8.8, 1.6 Hz, 1H), 6.43 (s, 2H), 5.73 (d, J = 13.9 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.07 (dd, J = 13.0, 5.6 Hz, 1H), 4.03 – 3.80 (m, 1H), 3.75 – 3.65 (m, 1H), 3.32 (s, 3H), 2.24 – 2.11 (m, 1H), 2.05 – 1.90 (m, 2H), 1.90 – 1.75 (m, 1H).m/z (ESI): 426.25 [M+H] ⁺ . Example E-023: 2-amino-7-{[N-(2-methanesulfonylphenyl)acetamido]methyl}quin oline-3- carboxamide Sodium ethoxide (21% w/w solution in EtOH, 0.017 mL, 0.07 mmol, 1.25 eq.) was added to a solution of N-[(3-amino-4-formylphenyl)methyl]-N-(2-methanesulfonylpheny l)acetamide (Int. Q-024, 0.02 g, 0.06 mmol, 1.0 eq.) and 2-cyanoacetamide (0.005 g, 0.06 mmol, 1.0 eq.) in absolute EtOH (1.0 mL). The RM was heated under reflux for 30 minutes under nitrogen and the solvent was evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH in DCM) to yield 2-amino-7-{[N-(2-methanesulfonylphenyl)acetam- ido]methyl}quinoline-3-carboxamide (Example E-023, 0.016 g, 0.04 mmol, 66%, yellowish solid, UPLC long elution purity: 98.36%). 85/15 mixture of restricted C-N amide rotation iso- mers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 8.21 (s, 1H), 8.13 (dd, J = 7.6, 1.9 Hz, 1H), 7.69 – 7.59 (m, 2H), 7.64 (d, J = 8.1 Hz, 1H), 7.59 – 7.55 (m, 1H), 7.24 (s, 1H), 7.23 – 7.20 (m, 2H), 7.14 (dd, J = 8.2, 1.7 Hz, 1H), 6.95 (dd, J = 7.6, 1.6 Hz, 1H), 5.71 (d, J = 15.0 Hz, 1H), 4.22 (d, J = 15.0 Hz, 1H), 3.38 (s, 3H), 1.81 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.16 (s, 1H), 8.02 (dd, J = 7.0, 2.3 Hz, 1H), 7.72 – 7.52 (m, 4H), 7.32 (s, 1H), 7.28 – 7.17 (m, 3H), 7.01 (dd, J = 7.0, 2.1 Hz, 1H), 5.35 (d, J = 16.9 Hz, 1H), 4.63 (d, J = 16.8 Hz, 1H), 3.18 (s, 3H), 2.33 (s, 3H). m/z (ESI): 413.25 [M+H] ⁺ . Example E-024: N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)- tert-Butyl N-(7-{[N-(2-methanesulfonylpyridin-3-yl)-1-{4H,5H,6H-pyrrolo [1,2-b]pyrazol-2- yl}formamido]methyl}quinolin-2-yl)carbamate (Int. Q-042) Ryvu Therapeutics S.A. RVU305 527 R10107WO In a Biotage ^TM microwave vial, a mixture of Cs ₂ CO ₃ (0.128 g, 0.39 mmol, 2.0 eq.), XPhos Pd G3 (0.131 g, 0.155 mmol, 0.25 eq.), tert-butyl carbamate (0.115 g, 0.98 mmol, 5.0 eq.) and N- [(2-chloroquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin- 3-yl)-4H,5H,6H-pyrrolo[1,2- b]pyrazole-2-carboxamide (Int. N-031, 0.104 g, 0.20 mmol, 1.0 eq.) in anhydrous dioxane (2.0 mL) was sparged with nitrogen for 10 minutes. The vial was sealed and the RM was heated at 110 °C for 1.5 h in a DrySyn ^® . After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . Water was added to the filtrate and the organic phase was separated. The aqueous layer was extracted with EtOAc (2x). The combined or- ganic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concen- trated under reduced pressure. The crude material was purified by FCC (66% to 100% EtOAc gradient in hexane) to yield tert-butyl N-(7-{[N-(2-methanesulfonylpyridin-3-yl)-1- {4H,5H,6H-pyrrolo[1,2-b]pyrazol-2-yl}formamido]methyl}quinol in-2-yl)carbamate (Int. Q- 042, 0.06 g, 0.11 mmol, 47%, white solid, UPLC purity: 86%).8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.08 (s, 1H), 8.64 (dd, J = 4.6, 1.5 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.57 (s, 1H), 7.52 (dd, J = 8.1, 4.5 Hz, 1H), 7.41 (dd, J = 8.2, 1.4 Hz, 1H), 7.28 (dd, J = 8.1, 1.2 Hz, 1H), 6.32 (s, 1H), 5.90 (d, J = 15.1 Hz, 1H), 4.45 (d, J = 15.1 Hz, 1H), 3.84 – 3.66 (m, 2H), 3.22 (s, 3H), 2.76 (t, J = 7.4 Hz, 2H), 2.41 (p, J = 7.3 Hz, 2H), 1.50 (s, 9H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.08 (s, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.29 (d, J = 12.4 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.90 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.59 – 7.49 (m, 1H), 7.50 – 7.44 (m, 1H), 7.38 (d, J = 7.5 Hz, 1H), 6.57 (d, J = 13.7 Hz, 2H), 4.95 (d, J = 16.1 Hz, 1H), 4.29 – 4.09 (m, 2H), 3.32 (s, 3H), 2.92 (t, J = 7.1 Hz, 2H), 2.64 – 2.54 (m, 2H), 1.50 (s, 9H). m/z (ESI): 585.2 [M+Na] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-4H,5H,6H-pyrrolo[1,2- b]pyrazole-2-carboxamide (Example E-024) tert-Butyl N-(7-{[N-(2-methanesulfonylpyridin-3-yl)-1-{4H,5H,6H-pyrrolo [1,2-b]pyrazol-2- yl}formamido]methyl}quinolin-2-yl)carbamate (Int. Q-042, 0.044 g, 0.07 mmol, 1.0 eq.) was suspended in a mixture of water (10.0 mL) and MeOH (2.0 mL). The RM was refluxed for 2 days and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesul- fonylpyridin-3-yl)-4H,5H,6H-pyrrolo[1,2-b]pyrazole-2-carboxa mide (Example E-024, 0.012 g, 0.03 mmol, 37%, white solid, UPLC long elution purity: 99.91%).8/2 mixture of restricted C- ^{N amide rotation isomers in DMSO-d 1 6 at RT: Major rotamer: H NMR (400 MHz, DMSO-d6)} _{δ 8.63 (dd, J = 4.6, 1.5 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.52 (dd, J} = 8.1, 4.6 Hz, 1H), 7.27 – 7.25 (m, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.2, 1.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.41 (s, 2H), 6.30 (s, 1H), 5.87 (d, J = 15.0 Hz, 1H), 4.32 (d, J = 15.0 Hz, 1H), 3.84 – 3.69 (m, 2H), 3.23 (s, 3H), 2.75 (t, J = 7.3 Hz, 2H), 2.41 (p, J = 7.3 Hz, 2H). Minor rota- mer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (dd, J = 4.6, 1.5 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.61 – 7.55 (m, 1H), 7.55 (s, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.13 – 7.08 (m, 2H), 6.72 (d, J = 8.7 Hz, 1H), 6.52 (d, J = 14.1 Hz, 2H), 6.41 (s, 2H), 4.81 (d, J = 15.7 Hz, 1H), 4.24 – 4.14 (m, 2H), 3.31 (s, 3H), 2.92 (t, J = 7.2 Hz, 2H), 2.60 (dd, J = 13.8, 7.0 Hz, 2H). m/z (ESI): 463.24 [M+H] ⁺ . Example E-025: N-{[2-amino-3-(hydroxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesul- fonylphenyl)acetamide Ryvu Therapeutics S.A. RVU305 528 R10107WO Sodium ethoxide (21% w/w solution in EtOH, 0.028 mL, 0.12 mmol, 1.25 eq.) was added to a solution of N-[(3-amino-4-formylphenyl)methyl]-N-(2-methanesulfonylpheny l)acetamide (Int. Q-024, 0.033 g, 0.09 mmol, 1.0 eq.) and ethyl 2-cyanoacetate (0.011 g, 0.09 mmol, 1.0 eq.) in absolute EtOH (2.0 mL). The RM was heated to reflux for 1 hour under nitrogen and the solvent was evaporated under reduced pressure. The crude material was purified by FCC (0 to 2.5% MeOH gradient in DCM) to yield ethyl 2- amino-7-{[N-(2-methanesulfonylphenyl)acetamido]methyl}quinol ine-3-carboxylate (Int. Q- 043, 0.017 g, 0.04 mmol, 35%, beige solid, UPLC purity: 85%). m/z (ESI): 442.5 [M+H] ⁺ . Int. Q-043 was dissolved in anhydrous THF (1.0 mL) and finely powdered NaBH ₄ (0.037 g, 0.98 mmol, 30.0 eq.) was added. The resulting mixture was stirred for 15 min. at 70 °C under ni- trogen, MeOH (0.2 mL) was added dropwise over 30 min. and stirring at 70 °C was main- tained for a further 1 h. After coming back to RT, the reaction was quenched with sat. aq. NH ₄ Cl solution and extracted with EtOAc (x2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 8% MeOH gradient in DCM) to yield N-{[2-amino-3-(hydroxyme- thyl)quinolin-7-yl]methyl}-N-(2-methanesulfonylphenyl)acetam ide (Example E-025, 0.002 g, 0.005 mmol, 15%, white solid, UPLC long elution purity: 97.38%).4/1 mixture of restricted C-N amide rotation isomers in DMSO- d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.71 – 7.53 (m, 3H), 7.26 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 6.22 (s, 2H), 5.72 (d, J = 14.8 Hz, 1H), 5.39 (t, J = 5.3 Hz, 1H), 4.49 (d, J = 5.3 Hz, 2H), 4.21 (d, J = 14.8 Hz, 1H), 3.37 (s, 3H), 1.80 (s, 3H). Minor rota- mer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J = 6.9 Hz, 1H), 7.90 (s, 1H), 7.73 – 7.53 (m, 3H), 7.34 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 6.9 Hz, 1H), 6.26 (s, 2H), 5.39 (t, J = 5.0 Hz, 1H), 5.35 (d, J = 17.8 Hz, 1H), 4.61 (d, J = 16.8 Hz, 1H), 4.49 (d, J = 5.3 Hz, 2H), 3.18 (s, 3H), 2.34 (s, 3H). m/z (ESI): 400.23 [M+H] ⁺ . Example E-026: N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -6-oxo- 1,6-dihydropyridine-2-carboxamide Tert-butyl N-(7-{[N-(2-methanesulfonylphenyl)-1-(6-methoxypyridin-2-yl) formamido]me- thyl}quinolin-2-yl)carbamate (Int. Q-044) Ryvu Therapeutics S.A. RVU305 529 R10107WO A mixture of Cs ₂ CO ₃ (0.125 g, 0.38 mmol, 1.4 eq.), XPhos Pd G3 (0.023 g, 0.03 mmol, 0.1 eq.), tert-butyl carbamate (0.042 g, 0.36 mmol, 1.3 eq.) and N-[(2-chloroquinolin-7-yl)me- thyl]-N-(2-methanesulfonylphenyl)-6-methoxypyridine-2-carbox amide (Int. N-036, 0.136 g, 0.27 mmol, 1.0 eq.) in anhydrous dioxane (4.0 mL) was sparged with nitrogen for 10 minutes, and the RM was heated under microwave irradiation at 100 °C for 1.5 h. After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . Water was added to the filtrate, the organic phase was separated and the aqueous layer was extracted with EtOAc (1x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude mate- rial was purified by FCC (0 to 2% MeOH gradient in DCM) to yield tert-butyl N-(7-{[N-(2- methanesulfonylphenyl)-1-(6-methoxypyridin-2-yl)formamido]me thyl}quinolin-2-yl)carba- mate (Int. Q-044, 0.12 g, 0.213 mmol, 78%, beige solid, UPLC purity: 97%). 75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.99 (dd, J = 6.2, 3.7 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.64 (s, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.44 (dd, J = 8.3, 1.7 Hz, 1H), 7.03 – 6.94 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 5.91 (d, J = 15.1 Hz, 1H), 4.63 (d, J = 15.1 Hz, 1H), 3.20 (s, 3H), 3.17 (s, 3H), 1.50 (s, 9H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 7.3, 1.9 Hz, 1H), 8.01 (d, J = 9.6 Hz, 1H), 8.04 – 7.96 (m, 1H), 7.93 (t, J = 8.1 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.64 – 7.56 (m, 1H), 7.58 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.63 – 7.41 (m, 2H), 7.43 (d, J = 7.4 Hz, 1H), 5.60 (d, J = 16.1 Hz, 1H), 4.74 (d, J = 16.2 Hz, 1H), 3.87 (s, 3H), 3.36 (s, 3H), 1.50 (s, 9H). m/z (ESI): 585.2 [M+Na] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -6-oxo-1,6-dihydropyridine- 2-carboxamide (Example E-026) Finely powdered tert-butyl N-(7-{[N-(2-methanesulfonylphenyl)-1-(6-methoxypyridin-2- yl)formamido]methyl}quinolin-2-yl)carbamate (Int. Q-044, 0.1 g, 0.18 mmol, 1.0 eq.) was mixed with pyridine hydrochloride (0.513 g, 4.44 mmol, 25.0 eq.) and the RM was stirred at 160 °C for 30 minutes. After coming back to RT, the RM was partitioned between sat. aq. NaHCO ₃ and DCM, and the aqueous layer was extracted with DCM (2x). The combined or- ganic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl) -6-oxo- 1,6-dihydropyridine-2-carboxamide (Example E-026, 0.025 g, 0.06 mmol, 31%, white solid, UPLC long elution purity: 97.24%).65/35 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.59 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 8.1 Hz, 1H), 7.45 – 7.37 (m, 1H), 7.30 (s, 1H), 7.19 – 7.03 (m, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.52 – 6.31 (m, 3H), 5.81 (d, J = 14.9 Hz, 1H), 4.53 (d, J = 14.9 Hz, 1H), 3.43 (s, 3H), 3.36 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.80 (s, 1H), 8.08 (d, J = 7.6 Hz, 1H), 8.06 – 7.98 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.70 – 7.64 (m, 1H), 7.63 – 7.51 (m, 1H), 7.21 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.70 – 6.64 (m, 1H), 6.59 (t, J = 8.3 Hz, 1H), 6.51 – 6.29 (m, 3H), 5.45 (d, J = 15.4 Hz, 1H), 4.64 (d, J = 15.4 Hz, 1H), 3.27 (s, 3H). _m/z (ESI): 449.17 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 530 R10107WO Example E-027: (R _a )-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-fluoro-6-metha nesul- fonylphenyl)acetamide and Example E-028: (S _a )-N-[(2-aminoquinolin-7-yl)methyl]-N-(2- fluoro-6-methanesulfonylphenyl)acetamide Example C-012 exists as a stable 1/1 mixture of atropisomers at RT due to the restricted rotation of the N-phenyl bond. The racemic mixture was separated by chiral preparative chi- ral HPLC (column: CHIRALPAK ^® AD-H; mobile phase: isocratic hexane/iPrOH 80:20 v/v; flow rate: 19 mL/min.; elution time: 170 min., (R _a ) and (S _a ) were arbitrarily assigned) to pro- vide: Peak 1: (R _a )-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-fluoro-6-metha nesulfonylphenyl)acet- amide (Example E-027, 84.2% enantiomeric purity, UPLC long elution purity: 100%): 75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (d, J = 8.0 Hz, 1H), 7.85 (dd, J = 9.0, 2.6 Hz, 1H), 7.71 (td, J = 8.2, 5.1 Hz, 1H), 7.60 (td, J = 9.0, 1.3 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.52 (s, 2H), 5.58 (d, J = 14.3 Hz, 1H), 4.30 (d, J = 14.3 Hz, 1H), 3.39 (s, 3H), 1.82 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 – 7.83 (m, 2H), 7.61 – 7.56 (m, 1H), 7.56 – 7.46 (m, 2H), 7.29 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.52 (s, 2H), 5.25 (d, J = 15.2 Hz, 1H), 4.77 (d, J = 15.2 Hz, 1H), 3.19 (s, 3H), 2.39 (s, 3H). m/z (ESI): 388.18 [M+H] ⁺ . Peak 2: (S _a )-N-[(2-aminoquinolin-7-yl)methyl]-N-(2-fluoro-6-metha nesulfonylphenyl)acet- amide (Example E-028, 83.3% enantiomeric purity, UPLC long elution purity: 97.54%): 75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ : Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (dd, J = 8.0, 1.2 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.71 (td, J = 8.1, 5.0 Hz, 1H), 7.59 (td, J = 8.5, 1.4 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.19 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.41 (s, 2H), 5.58 (d, J = 14.3 Hz, 1H), 4.30 (d, J = 14.3 Hz, 1H), 3.39 (s, 3H), 1.81 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 – 7.80 (m, 2H), 7.63 – 7.56 (m, 1H), 7.51 (t, J = 8.2 Hz, 2H), 7.27 (s, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.45 (s, 2H), 5.25 (d, J = 15.2 Hz, 1H), 4.77 (d, J = 15.2 Hz, 1H), 3.19 (s, 3H), 2.39 (s, 3H). m/z (ESI): 388.19 [M+H] ⁺ . Example E-029: N-[(2,4-diamino-5-fluoroquinazolin-7-yl)methyl]-N-(1,1-dioxo -2,3-dihydro- 1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 531 R10107WO 2,6-Difluoro-4-(hydroxymethyl)benzonitrile (Int. Q-045) ^{NaBH4 (0.113 g, 2.99 mmol, 1.0 eq.) was added to a solution of 2,6-difluoro-4-formylbenzo-} _{nitrile (0.5 g, 2.99 mmol, 1.0 eq.) in absolute ethanol (9.0 mL) at 0 °C and the RM was} stirred at this temperature for 2 h. The reaction was quenched at 0 °C by dropwise addi- tion of water followed by aq.2 M HCl and the mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (x2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under re- duced pressure to yield 2,6-difluoro-4-(hydroxymethyl)benzonitrile (Int. Q-045, 0.5 g, 2.96 mmol, 98%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.36 (d, J = 9.6 Hz, 2H), 5.72 (t, J = 5.7 Hz, 1H), 4.62 (d, J = 5.8 Hz, 2H). m/z (ESI): 170.1 [M+H] ⁺ . 4-(Bromomethyl)-2,6-difluorobenzonitrile (Int. Q-046) CBr ₄ (0.61 g, 1.84 mmol, 1.3 eq.) and triphenylphosphine (0.423 g, 1.61 mmol, 1.1 eq.) were successively added to a solution of 2,6-difluoro-4-(hydroxymethyl)benzonitrile (Int. Q-045, 0.25 g, 1.46 mmol, 1.0 eq.) in THF (10.0 mL) at 0 °C and the RM was stirred overnight at RT under nitrogen. It was then filtered and the filtrate was partitioned between sat. aq. NH ₄ CI and EtOAc. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 20% EtOAc gra- dient in hexane) to yield 4-(bromomethyl)-2,6-difluorobenzonitrile (Int. Q-046, 0.25 g, 1.08 mmol, 72%, colorless oil, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.65 – 7.52 (m, 2H), 4.76 (s, 2H). m/z (ESI): 295.0 [M+MeCN+Na] ⁺ . N-[(4-cyano-3,5-difluorophenyl)methyl]-N-(1,1-dioxo-2,3-dihy dro-1λ⁶-benzothiophen-7- yl)pyridine-3-carboxamide (Int. Q-047) N-[(4-cyano-3,5-difluorophenyl)methyl]-N-(1,1-dioxo-2,3-dihy dro-1λ⁶-benzothiophen-7- yl)pyridine-3-carboxamide (Int. Q-047, 0.109 g, 0.25 mmol, 72%, orange solid, UPLC purity: 98%) was prepared according to General Procedure 22, using N-(1,1-dioxo-2,3-dihydro- 1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide (Int. C-004, 0.098 g, 0.34 mmol, 1.0 eq.), 4-(bromomethyl)-2,6-difluorobenzonitrile (Int. Q-046, 0.081 g, 0.34 mmol, 1.0 eq.) and Cs ₂ CO ₃ (0.133 g, 0.41 mmol, 1.2 eq.) in anhydrous MeCN (1.5 mL) at reflux. The crude mate- rial was purified by consecutive triturations with DCM and hexane to yield N-[(4-cyano-3,5- Ryvu Therapeutics S.A. RVU305 532 R10107WO difluorophenyl)methyl]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzo thiophen-7-yl)pyridine-3-car- boxamide (Int. Q-047, 0.109 g, 0.25 mmol, 72%, orange solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 8.48 (d, J = 4.8 Hz, 1H), 7.85 (dt, J = 7.9, 1.5 Hz, 1H), 7.51 – 7.41 (m, 4H), 7.33 – 7.23 (m, 2H), 5.62 (d, J = 16.1 Hz, 1H), 4.81 (d, J = 16.1 Hz, 1H), 3.81 – 3.63 (m, 2H), 3.37 (t, J = 6.9 Hz, 2H). m/z (ESI): 440.4 [M+H] ⁺ . N-[(2,4-diamino-5-fluoroquinazolin-7-yl)methyl]-N-(1,1-dioxo -2,3-dihydro-1λ⁶-benzothio- phen-7-yl)pyridine-3-carboxamide (Example E-029) DIPEA (0.083 mL, 0.48 mmol, 2.0 eq.) was added to a mixture of N-[(4-cyano-3,5-difluoro- phenyl)methyl]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen -7-yl)pyridine-3-carboxamide (Int. Q-047, 0.107 g, 0.24 mmol, 1.0 eq.), guanidine hydrochloride (0.046 g, 0.48 mmol, 2.0 ^{eq.) and K2CO3 (0.04 g, 0.289 mmol, 1.2 eq.) in DMA (5.0 mL). The RM was stirred at 140} _{°C overnight under nitrogen and, after coming back to RT, was partitioned between water} and EtOAc. The aqueous layer was extracted with CHCl ₃ /iPrOH 3:1 v/v (x2) and the com- bined organic layers were washed with sat. aq. NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ , fil- tered and evaporated under reduced pressure. The crude material was purified by 2 consec- utive FCCs (first: silica, 0 to 20% MeOH gradient in DCM; second: NH ₂ functionalized silica, 0 to 5% MeOH gradient in DCM) to yield N-[(2,4-diamino-5-fluoroquinazolin-7-yl)methyl]- N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine- 3-carboxamide (Example E-029, 0.019 g, 0.04 mmol, 16%, white solid, UPLC long elution purity: 97.63%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (s, 1H), 8.47 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.46 – 7.17 (m, 4H), 6.89 – 6.70 (m, 4H), 6.20 (s, 2H), 5.78 (d, J = 14.9 Hz, 1H), 4.63 (d, J = 15.0 Hz, 1H), 3.90 – 3.64 (m, 2H), 3.48 – 3.34 (m, 2H). m/z (ESI): 479.5 [M+H] ⁺ . Example E-030: N-[(2-amino-8-chloroquinolin-7-yl)methyl]-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide N-[(2-azido-8-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-carbox- amide (Int. Q-048) A solution of N-[(2,8-dichloroquinolin-7-yl)methyl]-N-(2-methanesulfonylph enyl)pyridine-3- carboxamide (Int. O-032, 0.09 g, 0.17 mmol, 1.0 eq.) and sodium azide (0.014 g, 0.21 mmol, 1.2 eq.) in DMSO (1.0 mL) was heated at 90 °C overnight under nitrogen. The RM was then diluted with water and extracted with DCM (2x). The combined organic layers were washed with brine (x2), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pres- sure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N- [(2-azido-8-chloroquinolin-7-yl)methyl]-N-(2-methanesulfonyl phenyl)pyridine-3-carbox- amide (Int. Q-048, 0.056 g, 0.11 mmol, 56%, beige solid, UPLC purity: 86%).7/3 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (d, J = 1.8 Hz, 1H), 8.47 (dd, J = 5.0, 1.4 Hz, 1H), 8.37 (d, J = 9.5 Hz, 1H), Ryvu Therapeutics S.A. RVU305 533 R10107WO 8.25 (d, J = 8.3 Hz, 1H), 8.19 (d, J = 9.4 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.99 – 7.96 (m, 1H), 7.78 (dt, J = 8.0, 1.8 Hz, 1H), 7.56 – 7.52 (m, 2H), 7.45 – 7.41 (m, 1H), 7.30 (ddd, J = 7.9, 4.9, 0.6 Hz, 1H), 5.95 (d, J = 15.8 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 3.29 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (d, J = 1.7 Hz, 1H), 8.78 (dd, J = 4.7, 1.1 Hz, 1H), 8.29 (d, J = 9.6 Hz, 1H), 8.24 – 8.21 (m, 1H), 8.17 (d, J = 9.4 Hz, 1H), 8.13 – 8.07 (m, 1H), 7.65 (dt, J = 8.2, 2.2 Hz, 1H), 7.60 (td, J = 7.7, 1.1 Hz, 1H), 7.47 (td, J = 7.8, 1.7 Hz, 2H), 6.95 (dd, J = 7.8, 1.0 Hz, 2H), 5.39 (d, J = 15.6 Hz, 1H), 5.16 (d, J = 15.0 Hz, 1H), 3.30 (s, 3H). m/z (ESI): 494.0 [M+H] ⁺ . N-[(2-amino-8-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-carbox- amide (Example E-030) A mixture of N-[(2-azido-8-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylphenyl)pyri- dine-3-carboxamide (Int. Q-048, 0.056 g, 0.1 mmol, 1.0 eq.) and zinc dust (0.04 g, 0.61 mmol, 6.1 eq.) in acetic acid (1.0 mL) was stirred at 65 °C overnight. After coming back to RT, the RM was neutralized with aq. sat. NaHCO ₃ and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (NH ₂ functionalized silica, 0 to 2% MeOH gradient in DCM) to yield N-[(2-amino-8-chloroquinolin-7-yl)methyl]- N-(2-methanesulfonylphenyl)pyridine-3-carboxamide (Example E-030, 0.018 g, 0.04 mmol, 40%, yellow solid, UPLC long elution purity: 99.09%).7/3 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 8.44 (d, J = 4.8 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 – 7.45 (m, 2H), 7.39 (d, J = 8.1 Hz, 1H), 7.27 (dd, J = 7.5, 5.2 Hz, 1H), 7.22 – 7.15 (m, 1H), 6.89 – 6.70 (m, 3H), 5.90 (d, J = 15.2 Hz, 1H), 4.81 (d, J = 15.2 Hz, 1H), 3.23 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.67 – 7.55 (m, 2H), 7.54 – 7.44 (m, 2H), 6.97 (d, J = 8.1 Hz, 1H), 6.89 – 6.73 (m, 4H), 5.21 (d, J = 14.9 Hz, 1H), 5.03 (d, J = 15.0 Hz, 1H), 3.28 (s, 3H). m/z (ESI): 467.10 [M+H] ⁺ . Example E-031: N-{[2-amino-3-(hydroxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesul- fonylphenyl)pyridine-3-carboxamide (2-amino-7-{[N-(2-methanesulfonylphenyl)-1-(pyridin-3-yl)for mamido]methyl}quinolin-3- yl)methyl acetate (Int. Q-049). A Biotage ^TM microwave vial was charged with (2-chloro-7-{[N-(2-methanesulfonylphenyl)- 1-(pyridin-3-yl)formamido]methyl}quinolin-3-yl)methyl acetate (Int. O-059, 0.148 g, 0.27 mmol, 1.0 eq.), Cs ₂ CO ₃ (0.13 g, 0.40 mmol, 1.5 eq.), tert-butyl carbamate (0.062 g, 0.53 mmol, 2.0 eq.) and anhydrous dioxane (2.8 mL). The RM was sparged with argon for 10 min. XPhos Pd G3 (0.034 g, 0.04 mmol, 0.15 eq.) was added followed by XPhos (0.019 g, 0.04 Ryvu Therapeutics S.A. RVU305 534 R10107WO mmol, 0.15 eq.) and the vial was sealed. The resulting RM was stirred for 1 h at 110 °C in a DrySyn ^® . After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . Water was added to the filtrate, the organic phase was separated and the aque- ous layer was extracted with EtOAc (1x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by two consecutive FCCs (first: silica, 0 to 3% MeOH gradient in DCM; second: C18 functionalized silica, 5% to 50% MeCN gradient in water) to yield (2- amino-7-{[N-(2-methanesulfonylphenyl)-1-(pyridin-3-yl)formam ido]methyl}quinolin-3- yl)methyl acetate (Int. Q-049, 0.035 g, 0.07 mmol, 26%, white solid, UPLC purity: 98%). Ma- jor rotamer: NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (d, J = 2.2 Hz, 1H), 8.42 (dd, J = 4.9, 1.7 Hz, 1H), 7.97 (s, 1H), 7.92 (dd, J = 7.5, 2.0 Hz, 1H), 7.68 (dt, J = 7.4, 1.8 Hz, 1H), 7.65 – 7.57 (m, 1H), 7.56 – 7.46 (m, 2H), 7.39 (s, 1H), 7.29 – 7.23 (m, 2H), 7.19 (d, J = 7.0 Hz, 1H), 6.43 (s, 2H), 5.75 (d, J = 14.9 Hz, 1H), 5.07 (s, 2H), 4.64 (d, J = 14.9 Hz, 1H), 3.16 (s, 3H), 2.12 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.73 (d, J = 4.9 Hz, 1H), 8.12 (dt, J = 7.9, 1.7 Hz, 1H), 8.09 (dd, J = 6.1, 3.3 Hz, 1H), 7.72 – 7.65 (m, 2H), 7.65 – 7.58 (m, 2H), 7.21 – 7.16 (m, 2H), 7.14 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.43 (s, 2H), 5.19 (d, J = 16.0 Hz, 1H), 5.05 (s, 2H), 4.70 (d, J = 16.1 Hz, 1H), 3.26 (s, 3H), 2.11 (s, 3H). m/z (ESI): 505.2 [M+H] ⁺ . N-{[2-amino-3-(hydroxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesulfonylphenyl)pyri- dine-3-carboxamide (Example E-031) LiOH monohydrate (0.002 g, 0.09 mmol, 3.12 eq.) was added to a solution of (2-amino-7- {[N-(2-methanesulfonylphenyl)-1-(pyridin-3-yl)formamido]meth yl}quinolin-3-yl)methyl ace- tate (Int. Q-049, 0.015 g, 0.03 mmol, 1.0 eq.) in a mixture of THF (1.0 mL) and water (0.25 mL) and the RM was stirred at RT for 2 h. It was then diluted with water and neutralized by addition of aq.1 M HCl. The mixture was extracted with EtOAc (3x) and the combined or- ganic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by preparative HPLC to yield N-{[2-amino-3-(hydroxymethyl)quinolin-7-yl]me- thyl}-N-(2-methanesulfonylphenyl)pyridine-3-carboxamide as its formate salt (Example E- 031, 0.007 g, 0.015 mmol, 51%, white solid, UPLC long elution purity: 99.81%). 7/3 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, J = 2.2 Hz, 1H), 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 8.17 (s, 1H), 7.92 (dd, J = 7.6, 1.9 Hz, 1H), 7.88 (s, 1H), 7.68 (ddd, J = 7.9, 2.0, 1.9 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.65 – 7.58 (m, 1H), 7.51 (ddd, J = 9.7, 7.5, 1.7 Hz, 1H), 7.38 (s, 1H), 7.25 (t, J = 8.1 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.20 (dd, J = 7.9, 1.3 Hz, 1H), 6.21 (s, 2H), 5.74 (d, J = 14.8 Hz, 1H), 5.39 (s, 1H), 4.64 (d, J = 15.0 Hz, 1H), 4.48 (s, 2H), 3.14 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.73 (dd, J = 5.0, 1.5 Hz, 1H), 8.17 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.10 – 8.05 (m, 1H), 7.85 (s, 1H), 7.64 – 7.57 (m, 2H), 7.56 – 7.46 (m, 2H), 7.17 (s, 1H), 7.15 – 7.09 (m, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.25 (s, 2H), 5.39 (s, 1H), 5.18 (d, J = 15.9 Hz, 1H), 4.69 (d, J = 16.4 Hz, 1H), 4.47 (s, 2H), 3.25 (s, 3H). _m/z (ESI): 463.10 [M+H] ⁺ . Example E-032: N-[(2-aminoquinolin-7-yl)methyl]-N-[2-methanesulfonyl-4-(tri fluorome- thyl)phenyl]pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 535 R10107WO - thyl)quinolin-2-yl]carbamate (Int. Q-050), General Procedure 33 Triphenylphosphine (0.46 g, 1.75 mmol, 2.013 eq.) was added to a solution of N-[2-me- thanesulfonyl-4-(trifluoromethyl)phenyl]pyridine-3-carboxami de (Int. M-051, 0.3 g, 0.87 mmol, 1.0 eq.) and tert-butyl N-[7-(hydroxymethyl)quinolin-2-yl]carbamate (Int. A-007, 0.370 g, 1.32 mmol, 1.52 eq.) in anhydrous THF (9.0 mL). DIAD (0.355 g, 1.76 mmol, 2.01 eq.) was added dropwise and the RM was stirred for 16 h at RT under nitrogen. The mixture was concentrated in vacuo and the crude material was purified by FCC (silica 15 ^m, 0 to 10% MeOH gradient in DCM). The fractions containing the title product were pooled, evapo- rated to dryness and the residue was taken up in MeOH. The solution was passed down a SCX cartridge, washing with MeOH and eluting with 2 M ammonia in MeOH. The fractions containing the pure title product were pooled and evaporated to dryness to yield tert-butyl N-[7-({N-[2-methanesulfonyl-4-(trifluoromethyl)phenyl]-1-(py ridin-3-yl)formamido}me- thyl)quinolin-2-yl]carbamate (Int. Q-050, 0.27 g, 0.45 mmol, 50%, beige solid, UPLC purity: 97%). 6/4 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rota- mer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.08 (s, 1H), 8.48 (d, J = 1.5 Hz, 1H), 8.45 (dd, J = 4.7, 1.2 Hz, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.24 – 8.22 (m, 1H), 8.02 (d, J = 9.0 Hz, 1H), 8.01 – 7.97 (m, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.72 – 7.66 (m, 2H), 7.55 – 7.50 (m, 2H), 7.28 (dd, J = 8.0, 4.9 Hz, 1H), 5.77 (d, J = 15.0 Hz, 1H), 4.81 (d, J = 15.0 Hz, 1H), 3.24 (s, 3H), 1.49 (s, 9H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 8.92 (s, 1H), 8.73 (d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 8.05 – 7.95 (m, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.59 (dd, J = 7.5, 5.3 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.48 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 5.30 (d, J = 16.2 Hz, 1H), 4.90 (d, J = 16.4 Hz, 1H), 3.38 (s, 3H), 1.49 (s, 9H). m/z (ESI): 623.3 [M+Na] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-[2-methanesulfonyl-4-(tri fluoromethyl)phenyl]pyri- dine-3-carboxamide (Example E-032) TFA (1.7 mL, 22.2 mmol, 51 eq.) was added to a solution of tert-butyl N-[7-({N-[2-me- thanesulfonyl-4-(trifluoromethyl)phenyl]-1-(pyridin-3-yl)for mamido}methyl)quinolin-2- yl]carbamate (Int. Q-050, 0.27 g, 0.45 mmol, 1.0 eq.) in DCM (4.4 mL). The RM was stirred for 1.5 h at RT and the volatiles were evaporated under reduced pressure. The residue was partitioned between sat. aq. NaHCO ₃ and DCM. The aqueous phase was extracted with DCM, and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and con- centrated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-[2-methanesulfonyl-4-(tri - fluoromethyl)phenyl]pyridine-3-carboxamide (Example E-032, 0.214 g, 0.43 mmol, 98%, white solid, UPLC long elution purity: 99.72%). 55/45 mixture of restricted C-N amide rota- tion isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 8.12 (t, J = 9.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 8.7 Hz, 1H), 7.38 (s, 1H), 7.28 Ryvu Therapeutics S.A. RVU305 536 R10107WO (dd, J = 8.0, 4.8 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 6.73 (t, J = 8.2 Hz, 1H), 6.43 (s, 2H), 5.71 (d, J = 15.0 Hz, 1H), 4.71 (d, J = 15.0 Hz, 1H), 3.25 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.73 (d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.12 (t, J = 9.0 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.47 (s, 2H), 5.22 (d, J = 16.3 Hz, 1H), 4.77 (d, J = 16.2 Hz, 1H), 3.37 (s, 3H). m/z (ESI): 501.4 [M+H] ⁺ . Example E-033: N-[(2-aminoquinolin-7-yl)methyl]-N-(3-methanesulfonylpyridin -4-yl)pyri- dine-3-carboxamide Triphenylphosphine (0.07 g, 0.27 mmol, 1.5 eq.) was added to a solution of N-(3-me- thanesulfonylpyridin-4-yl)pyridine-3-carboxamide (Int. M-055, 0.05 g, 0.18 mmol, 1.0 eq.) and tert-butyl N-[7-(hydroxymethyl)quinolin-2-yl]carbamate (Int. A-007, 0.064 g, 0.23 mmol, 1.294 eq.) in anhydrous toluene (2.0 mL). DIAD (0.054 g, 0.26 mmol, 1.5 eq.) was added dropwise and the RM was stirred for 30 min. at 80 °C under microwave irradiation. After coming back to RT, the RM was evaporated under reduced pressure. The residue was taken up in DCM (1.0 mL), TFA was added (0.03 mL) and the RM was stirred overnight at RT. It was then evaporated under reduced pressure and the residue was partitioned between CHCl ₃ /iPrOH 3:1 v/v and sat. aq. NaHCO ₃ . The aqueous phase was extracted with CHCl ₃ /iPrOH 3:1 v/v and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(3-me- thanesulfonylpyridin-4-yl)pyridine-3-carboxamide (Example E-033, 0.008 g, 0.02 mmol, 10%, white solid, UPLC long elution purity: 99.25%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (s, 1H), 8.75 (d, J = 5.3 Hz, 1H), 8.71 – 8.65 (m, 1H), 8.63 – 8.54 (m, 1H), 7.95 – 7.85 (m, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.47 – 7.37 (m, 1H), 7.36 (d, J = 5.3 Hz, 1H), 7.33 (s, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.17 (s, 2H), 5.13 (br s, 2H), 3.23 (s, 3H). m/z (ESI): 434.70 [M+H] ⁺ . Example E-034: N-[(2-aminoquinolin-7-yl)methyl]-N-(2-trifluoromethanesul- fonylphenyl)pyridine-3-carboxamide Triphenylphosphine (0.235 g, 0.90 mmol, 1.6 eq.) was added to a solution of N‐(2‐trifluo- romethanesulfonylphenyl)pyridine‐3‐carboxamide (Int. C-016, 0.188 g, 0.57 mmol, 1.00 Ryvu Therapeutics S.A. RVU305 537 R10107WO eq.) and tert-butyl N-[7-(hydroxymethyl)quinolin-2-yl]carbamate (Int. A-007, 0.208 g, 0.75 mmol, 1.32 eq.) in anhydrous toluene (5.8 mL). DIAD (0.180 g, 0.89 mmol, 1.56 eq.) was added dropwise and the RM was stirred for 30 min. at 80 °C under microwave irradiation. After coming back to RT, the RM was evaporated under reduced pressure and the crude material was purified by FCC (0 to 80% EtOAc gradient in hexane). The fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was dissolved in a mixture of DCM (7.6 mL) and TFA (2.55 mL) and the RM was stirred for 2 h at RT. It was then evaporated under reduced pressure and the residue was taken up in MeOH. The solution was passed through a SCX cartridge, washing with MeOH and eluting with 2 M ammonia in MeOH. The fractions containing the title compound were pooled and evapo- rated under reduced pressure. The crude material was purified by FCC (silica 15 ^m; 0 to 5% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(2-trifluoro- methanesulfonylphenyl)pyridine-3-carboxamide (Example E-034, 0.099 g, 0.19 mmol, 35%, white solid, UPLC long elution purity: 97.84%). 65/35 mixture of restricted C-N amide rota- tion isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (dd, J = 4.7, 1.3 Hz, 1H), 8.39 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.93 (dd, J = 7.7, 1.2 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.67 – 7.58 (m, 3H), 7.34 (s, 1H), 7.29 (dd, J = 7.9, 4.9 Hz, 1H), 7.23 (dd, J = 8.0, 1.3 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 6.43 (s, 2H), 5.75 (d, J = 15.1 Hz, 1H), 4.49 (d, J = 15.1 Hz, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -77.19. Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.87 (s, 1H), 8.74 (d, J = 4.9 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 8.01 – 7.91 (m, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.72 – 7.57 (m, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 5.8 Hz, 1H), 7.07 (s, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 9.0 Hz, 1H), 6.46 (s, 2H), 5.23 (d, J = 15.9 Hz, 1H), 4.74 (d, J = 15.9 Hz, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -76.84. _m/z (ESI): 487.40 [M+H] ⁺ . Example E-035: N-[(2-aminoquinolin-7-yl)(²H₂)methyl]-N-(2-methanesulfony lphenyl)pyri- dine-3-carboxamide N-[(2-chloroquinolin-7-yl)(²H₂)methyl]-N-(2-methanesulfon ylphenyl)pyridine-3-carbox- amide (Int. Q-051) Triphenylphosphine (0.315 g, 1.20 mmol, 1.2 eq.) was added to a solution of (Int. A-015, 2- chloroquinolin-7-yl)(²H₂)methanol (0.2 g, 1.00 mmol, 1.0 eq.) and N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int. C-002, 0.364 g, 1.30 mmol, 1.3 eq.) in anhydrous THF (6.0 mL). The mixture was cooled to 0 °C and DIAD (0.243 g, 1.20 mmol, 1.2 eq.) was added dropwise. The RM was stirred 10 min at 0 °C and overnight at RT. It was then evap- orated under reduced pressure and the crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(2-chloroquinolin-7-yl)(²H₂)methyl]-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int. Q-051, 0.133 g, 0.29 mmol, 29%, white solid, UPLC purity: 99%).8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major Ryvu Therapeutics S.A. RVU305 538 R10107WO rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.43 (dd, J = 4.9, 1.7 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 7.5, 2.0 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.76 (dd, J = 8.4, 1.7 Hz, 1H), 7.72 (dt, J = 8.0, 2.0 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.65 – 7.57 (m, 1H), 7.54 (td, J = 7.6, 1.9 Hz, 1H), 7.29 (dd, J = 7.4, 1.9 Hz, 1H), 7.26 (dd, J = 8.0, 4.7 Hz, 1H), 3.19 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 4.9 Hz, 1H), 8.45 – 8.41 (m, 1H), 8.14 (dt, J = 7.9, 1.8 Hz, 2H), 8.11 – 8.08 (m, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.71 – 7.66 (m, 1H), 7.66 – 7.49 (m, 4H), 7.33 – 7.22 (m, 1H), 3.28 (s, 3H). m/z (ESI): 455.0 [M+H] ⁺ . N-[(2-aminoquinolin-7-yl)(²H₂)methyl]-N-(2-methanesulfony lphenyl)pyridine-3-carbox- amide (Example E-035) The title compound was prepared according to General Procedure 25, using N-[(2-chloro- quinolin-7-yl)(²H₂)methyl]-N-(2-methanesulfonylphenyl)pyr idine-3-carboxamide (Int. Q- 051, 0.13 g, 0.28 mmol, 1.0 eq.), Cs ₂ CO ₃ (0.28 g, 0.86 mmol, 3.03 eq.), tert-butyl carbamate (0.5 g, 4.27 mmol, 15.05 eq.), XPhos (0.027 g, 0.06 mmol, 0.2 eq.) and Pd(OAc) ₂ (0.006 g, 0.03 mmol, 0.1 eq.), followed by treatment in a mixture of DCM (1.5 mL) and TFA (0.2 mL). The crude material was purified by two consecutive FCCs (first: silica, 0 to 15% MeOH gra- dient in DCM; second: NH ₂ functionalized silica, 0 to 5% MeOH gradient in DCM) to yield N- [(2-aminoquinolin-7-yl)(²H₂)methyl]-N-(2-methanesulfonylp henyl)pyridine-3-carboxamide (Example E-035, 0.040 g, 0.092 mmol, 32%, white solid, UPLC long elution purity: 99.32%). 7/3 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (d, J = 2.9 Hz, 1H), 8.45 – 8.39 (m, 1H), 7.96 – 7.91 (m, 1H), 7.91 – 7.86 (m, 1H), 7.72 – 7.66 (m, 1H), 7.66 – 7.58 (m, 1H), 7.58 – 7.45 (m, 2H), 7.35 (d, J = 3.3 Hz, 1H), 7.29 – 7.18 (m, 3H), 6.78 – 6.72 (m, 1H), 6.43 (s, 2H), 3.16 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (d, J = 3.3 Hz, 1H), 8.78 – 8.69 (m, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.10 (dd, J = 6.8, 2.9 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.66 – 7.58 (m, 2H), 7.58 – 7.45 (m, 1H), 7.24 – 7.19 (m, 1H), 7.18 – 7.14 (m, 1H), 7.15 (s, 1H), 6.99 (dd, J = 7.8, 3.1 Hz, 1H), 6.75 – 6.70 (m, 1H), 6.48 (s, 2H), 3.26 (s, 3H). m/z (ESI): 435.30 [M+H] ⁺ . Example E-036: N-[(2-aminoquinolin-7-yl)methyl]-N-(4-cyano-2-methanesul- fonylphenyl)pyridine-3-carboxamide tert-butyl N-(7-{[N-(4-bromo-2-methanesulfonylphenyl)-1-(pyridin-3-yl)f ormamido]me- thyl}quinolin-2-yl)carbamate (Int. Q-052) The title compound was prepared according to General Procedure 22, using N-(4-bromo-2- methanesulfonylphenyl)pyridine-3-carboxamide (Int. C-010, 0.155 g, 0.42 mmol, 1.0 eq.), tert-butyl N-[7-(bromomethyl)quinolin-2-yl]carbamate (Int. A-010, 0.22 g, 0.63 mmol, 1.5 eq.), Cs ₂ CO ₃ (0.205 g, 0.63 mmol, 1.5 eq.), NaI (0.006 g, 0.04 mmol, 0.1 eq.) in DMF (4.2 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield tert- butyl N-(7-{[N-(4-bromo-2-methanesulfonylphenyl)-1-(pyridin-3-yl)f ormamido]me- thyl}quinolin-2-yl)carbamate (Int. Q-052, 0.075 g, 0.12 mmol, 23%, beige solid, UPLC purity: Ryvu Therapeutics S.A. RVU305 539 R10107WO 78%). 6/4 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rota- mer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.47 (dd, J = 4.9, 1.6 Hz, 1H), 8.30 (d, J = 9.0 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.78 (dd, J = 8.5, 2.4 Hz, 1H), 7.69 (dt, J = 8.2, 2.1 Hz, 1H), 7.67 (s, 1H), 7.52 (dd, J = 8.3, 1.7 Hz, 1H), 7.30 (dd, J = 7.9, 4.8 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 5.75 (d, J = 15.0 Hz, 1H), 4.72 (d, J = 14.9 Hz, 1H), 3.22 (s, 3H), 1.50 (s, 9H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.73 (dd, J = 4.9, 1.1 Hz, 1H), 8.26 (d, J = 8.9 Hz, 1H), 8.21 (d, J = 2.5 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.64 – 7.57 (m, 2H), 7.44 (s, 1H), 7.39 (dd, J = 8.4, 1.7 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 5.24 (d, J = 16.0 Hz, 1H), 4.82 (d, J = 16.2 Hz, 1H), 3.37 (s, 3H), 1.50 (s, 9H). m/z (ESI): 634.8 [M+Na] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-(4-cyano-2-methanesulfony lphenyl)pyridine-3-carbox- amide (Example E-036) A Biotage ^TM microwave vial was charged with tert-butyl N-(7-{[N-(4-bromo-2-methanesul- fonylphenyl)-1-(pyridin-3-yl)formamido]methyl}quinolin-2-yl) carbamate (Int. Q-052, 0.09 g, 0.13 mmol, 1.0 eq.), TEA (0.04 mL, 0.29 mmol, 2.17 eq.) and anhydrous DMF (1.3 mL). The suspension was sparged with nitrogen for 10 min. and zinc cyanide (0.05 g, 0.43 mmol, 3.2 ^{eq.) was added followed by Pd(dppf)Cl2 (0.005 g, 0.01 mmol, 0.05 eq.). The vial was sealed} _{and the RM was heated at 150 °C under microwave irradiation for 20 min. It was then par-} titioned between water and EtOAc and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by two consecu- tive FCCs (first: silica, 0 to 10% MeOH gradient in DCM; second: C18 functionalized silica, 10% to 100% MeCN gradient in water) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(4-cy- ano-2-methanesulfonylphenyl)pyridine-3-carboxamide (Example E-036, 0.014 g, 0.031 mmol, 23%, white solid, UPLC long elution purity: 99.40%).6/4 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 8.47 (d, J = 4.3 Hz, 1H), 8.44 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.28 (dd, J = 8.0, 4.9 Hz, 1H), 7.20 (d, J = 6.5 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.44 (s, 2H), 5.66 (d, J = 14.9 Hz, 1H), 4.79 (d, J = 14.7 Hz, 1H), 3.19 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.74 (d, J = 4.9 Hz, 1H), 8.54 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.64 – 7.58 (m, 1H), 7.57 – 7.47 (m, 2H), 7.20 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.48 (s, 2H), 5.21 (d, J = 16.1 Hz, 1H), 4.80 (d, J = 16.5 Hz, 1H), 3.35 (s, 3H). m/z (ESI): 458.2 [M+H] ⁺ . Example E-037: N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(2-methanesulfony lpyridin- 3-yl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 540 R10107WO The title compound was prepared according to General Procedure 31, using diethyl (cy- anomethyl)phosphonate (1.25 g, 7.06 mmol, 1.0 eq.), LiHMDS (1 M in THF, 7.8 mL, 7.8 mmol, 1.10 eq.) and NBS (1.51 g, 8.48 mmol, 1.2 eq.). The crude material was purified by FCC (0 to 50% EtOAc gradient in cyclohexane, ELSD detection) to yield diethyl [bromo(cy- ano)methyl]phosphonate (Int. Q-053, 1.08 g, 4.22 mmol, 48%, yellow oil, NMR purity: 88%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.93 (d, J = 16.4 Hz, 1H), 4.31 – 4.19 (m, 4H), 1.33 (td, J = 7.1, 1.9 Hz, 6H). N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(2-methanesulfony lpyridin-3-yl)pyridine-3- carboxamide (Example E-037) The title compound was prepared according to General Procedure 32, using N-[(3-amino-4- formylphenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)pyridi ne-3-carboxamide (Int. Q- 028, 0.12 g, 0.29 mmol, 1.0 eq.), NaH (60% in mineral oil, 0.02 g, 0.52 mmol, 1.8 eq.) and di- ethyl [bromo(cyano)methyl]phosphonate (Int. Q-053, 0.13 g, 0.41 mmol, 1.4 eq.) in anhy- drous THF (0.5 mL). The crude material was purified by two consecutive FCCs (first: silica 15 ^m, 0 to 10% MeOH gradient in DCM; second: C18 functionalized silica, 10% to 100% MeCN gradient in water) to yield N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide (Example E-037, 0.007 g, 0.014 mmol, 5%, yellow solid, UPLC long elution purity: 97.20%).8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (m, 2H), 8.46 (d, J = 4.8 Hz, 1H), 8.38 (s, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 7.8, 4.5 Hz, 1H), 7.34 (s, 1H), 7.26 (dd, J = 12.3, 5.9 Hz, 2H), 6.69 (s, 2H), 5.80 (d, J = 14.8 Hz, 1H), 4.69 (d, J = 14.7 Hz, 1H), 3.35 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.94 – 8.86 (m, 1H), 8.77 – 8.71 (m, 1H), 8.70 – 8.63 (m, 1H), 8.41 – 8.33 (m, 1H), 8.16 – 8.05 (m, 1H), 7.70 – 7.56 (m, 4H), 7.22 – 7.18 (m, 1H), 7.11 (m, 1H), 6.69 (s, 2H), 5.16 (d, J = 15.6 Hz, 1H), 4.84 (d, J = 15.5 Hz, 1H), 3.40 (s, 3H). m/z (ESI): 514.07 [M+H] ⁺ . Example E-038: N-[(2-aminoquinolin-7-yl)methyl]-N-[5-carbamoyl-1-(difluorom ethyl)-1H- pyrazol-4-yl]pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 541 R10107WO (difluoromethyl)-1H-pyrazole-5-carboxylate (Int. Q-054) The title compound was prepared according to General Procedure 26, using ethyl 1-(difluo- romethyl)-4-(pyridine-3-amido)-1H-pyrazole-5-carboxylate (Int. M-082, 0.235 g, 0.74 mmol, 1.0 eq.), Cs ₂ CO ₃ (0.315 g, 0.97 mmol, 1.3 eq.) and tert-butyl N-[7-(bromomethyl)quinolin-2- yl]carbamate (0.323 g, 0.89 mmol, 1.2 eq.) in MeCN (8.0 mL). The crude material was puri- fied by FCC (0 to 50% EtOAc gradient in hexane) to yield ethyl 4-{N-[(2-{[(tert-butoxy)car- bonyl]amino}quinolin-7-yl)methyl]pyridine-3-amido}-1-(difluo romethyl)-1H-pyrazole-5-car- boxylate (Int. Q-054, 0.236 g, 0.42 mmol, 54%, orange solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 8.56 (s, 1H), 8.53 (dd, J = 4.9, 1.5 Hz, 1H), 8.28 (d, J = 9.1 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.82 (t, J = 58.1 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.35 (dd, J = 7.9, 5.1 Hz, 1H), 5.17 (s, 2H), 4.06 (q, J = 7.1 Hz, 2H), 1.51 (s, 9H), 1.17 (t, J = 7.1 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -96.98 (d, J = 57.5 Hz). m/z (ESI): 565.1 [M-H]- . Ethyl 4-{N-[(2-{[(tert-butoxy)carbonyl]amino}quinolin-7-yl)methyl] pyridine-3-amido}-1- (difluoromethyl)-1H-pyrazole-5-carboxylate (Int. Q-055) 1 M NaOH (20.0 mL) was added to a solution of ethyl 4-{N-[(2-{[(tert-butoxy)car- bonyl]amino}quinolin-7-yl)methyl]pyridine-3-amido}-1-(difluo romethyl)-1H-pyrazole-5-car- boxylate (Int. Q-054, 0.213 g, 0.36 mmol, 1.0 eq.) in EtOH (20.0 mL) and the RM was stirred at RT for 1 h. The volatiles were evaporated under reduced pressure. The mixture was acidi- fied with aq. 1 M HCl, extracted with CHCl ₃ /iPrOH 3:1 v/v and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to yield crude 4-{N-[(2-{[(tert-butoxy)car- bonyl]amino}quinolin-7-yl)methyl]pyridine-3-amido}-1-(difluo romethyl)-1H-pyrazole-5-car- boxylic acid (Int. Q-055, 0.178 g, 0.33 mmol, 98%, orange solid, UPLC purity: 96%) which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 8.56 – 8.54 (m, 1H), 8.53 (d, J = 4.9 Hz, 1H), 8.32 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.94 (t, J = 59.2 Hz, 1H), 7.93 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.70 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 7.8, 5.2 Hz, 1H), 5.12 (br s, 2H), 1.51 (s, 9H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -97.01 (dd, J = 115.0, 58.5 Hz). m/z (ESI): 537.1 [M-H]- . N-[(2-aminoquinolin-7-yl)methyl]-N-[5-carbamoyl-1-(difluorom ethyl)-1H-pyrazol-4-yl]pyri- dine-3-carboxamide (Example E-038) Ryvu Therapeutics S.A. RVU305 542 R10107WO CDI (0.039 g, 0.24 mmol, 1.11 eq.) was added to a solution of 4-{N-[(2-{[(tert-butoxy)car- bonyl]amino}quinolin-7-yl)methyl]pyridine-3-amido}-1-(difluo romethyl)-1H-pyrazole-5-car- boxylic acid (Int. Q-055, 0.128 g, 0.22 mmol, 1.0 eq.) in anhydrous DMF (4.0 mL) at RT and the mixture was stirred at 60 °C under argon for 1 h. After coming back to RT, ammonia (0.5 M in dioxane, 1.3 mL, 0.65 mmol, 3.1 eq.) was added. The RM was stirred at RT under argon overnight before being evaporated under reduced pressure. The residue was parti- tioned between water and DCM and the aqueous layer was extracted with EtOAc. The or- ganic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield tert-butyl N-[7-({N-[5-carbamoyl-1-(difluoromethyl)-1H-pyrazol-4-yl]-1- (pyr- idin-3-yl)formamido}methyl)quinolin-2-yl]carbamate (0.044 g, 0.08 mmol, 33%, yellow solid, UPLC purity: 86%). m/z (ESI): 538.4 [M+H] ⁺ . The obtained material was dissolved in a mix- ture of DCM (3.0 mL) and TFA (0.05 mL) and the RM was stirred overnight at RT before be- ing evaporated under reduced pressure. The residue was partitioned between sat. aq. Na- HCO ₃ and CHCl ₃ /iPrOH 3:1 v/v. The aqueous layer was extracted with CHCl ₃ /iPrOH 3:1 v/v (2x) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 20% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-[5-carbamoyl-1-(difluorom e- thyl)-1H-pyrazol-4-yl]pyridine-3-carboxamide (Example E-038, 0.023 g, 0.05 mmol, 75%, white solid, UPLC long elution purity: 97.10%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 8.54 (d, J = 3.6 Hz, 1H), 8.28 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.83 (t, J = 57.9 Hz, 1H), 7.77 (d, J = 6.7 Hz, 1H), 7.69 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.38 (s, 1H), 7.36 – 7.27 (m, 2H), 7.16 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.46 (s, 2H), 5.09 (s, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -95.97 (d, J = 58.1 Hz). _m/z (ESI): 438.2 [M+H] ⁺ . Example E-039: N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-6- (trifluoromethyl)pyridazine-3-carboxamide The title compound was prepared according to General Procedure 33, using N-(2-me- thanesulfonylpyridin-3-yl)-6-(trifluoromethyl)pyridazine-3-c arboxamide (Int. K-017, 0.059 g, 0.16 mmol, 1.0 eq.), (2-aminoquinolin-7-yl)methanol (Int. A-008, 0.075 g, 0.41 mmol, 2.53 eq.), triphenylphosphine (0.108 g, 0.41 mmol, 2.53 eq.) and DIAD (0.085 g, 0.42 mmol, 2.57 eq.) in anhydrous THF (1.7 mL). The crude material was purified by preparative HPLC (am- monia buffer) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)- 6-(trifluoromethyl)pyridazine-3-carboxamide (Example E-039, 0.025 g, 0.05 mmol, 31%, white solid, UPLC long elution purity: 100%). 85/15 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (dd, J = 4.5, 1.5 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.32 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), Ryvu Therapeutics S.A. RVU305 543 R10107WO 7.72 (dd, J = 8.2, 1.5 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.64 (dd, J = 8.2, 4.5 Hz, 1H), 7.39 (s, 1H), 7.19 (dd, J = 8.2, 1.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 6.46 (s, 2H), 5.87 (d, J = 15.0 Hz, 1H), 4.64 (d, J = 15.1 Hz, 1H), 3.28 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (dd, J = 4.6, 1.5 Hz, 1H), 8.55 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.71 – 7.67 (m, 1H), 7.60 – 7.57 (m, 2H), 7.33 (s, 1H), 7.22 – 7.19 (m, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.46 (s, 2H), 5.26 (d, J = 15.5 Hz, 1H), 4.75 (d, J = 15.5 Hz, 1H), 3.42 (s, 3H). _m/z (ESI): 503.15 [M+H] ⁺ . Example E-040: N-{[2-amino-3-(²H₃)methylquinolin-7-yl]methyl}-N-(2-metha nesul- fonylpyridin-3-yl)pyridine-3-carboxamide cyano LiHMDS (1 M solution in THF 5.81 mL, 5.81 mmol, 1.0 eq.) was added to a solution of di- ethyl (cyanomethyl)phosphonate (1.0 g, 5.64 mmol, 1.03 eq.) in anhydrous THF (15.0 mL) at 0 °C under argon. The RM was stirred at this temperature for 30 min. before Iodo(²H₃)me- thane (0.859 g, 5.93 mmol, 1.05 eq.) was added at -78 °C. The RM was then stirred at -15 °C for 3 h. The reaction was quenched by addition of sat. aq. NH ₄ Cl. The phases were sep- arated and the aqueous phase was extracted with DCM (2x). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield diethyl [1-cyano(2,2,2-²H₃)ethyl]phosphonate (Int. Q-056, 0.356 g, 1.83 mmol, 32%, colorless oil, NMR purity: 100%). ¹ H NMR (400 MHz, Chloroform-d) δ 4.37 – 4.20 (m, 4H), 2.98 (d, J = 23.4 Hz, 1H), 1.49 – 1.40 (m, 6H). N-{[2-amino-3-(²H₃)methylquinolin-7-yl]methyl}-N-(2-metha nesulfonylpyridin-3-yl)pyri- dine-3-carboxamide (Example E-040), General Procedure 34 EtONa (21% solution in EtOH, 0.124 mL, 0.53 mmol, 1.5 eq.) was added to a solution of N- [(3-amino-4-formylphenyl)methyl]-N-(2-methanesulfonylpyridin -3-yl)pyridine-3-carbox- amide (Int. Q-028, 0.145 g, 0.35 mmol, 1.0 eq.) and diethyl [1-cyano(2,2,2-²H₃)ethyl]phos- phonate (Int. Q-056, 0.072 g, 0.37 mmol, 1.05 eq.) in absolute EtOH (3.0 mL) in a Biotage ^TM microwave vial under argon. The vial was sealed and the RM was stirred at 80 °C for 2 h. After coming back to RT, the volatiles were evaporated under reduced pressure and the res- idue was partitioned between sat. aq. NH ₄ Cl and DCM. The aqueous phase was extracted with DCM (2x) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered Ryvu Therapeutics S.A. RVU305 544 R10107WO and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM). The fractions containing the pure desired product were pooled and evaporated under reduced pressure. The residue was triturated with HPLC grade hexane for 1 h and the resulting white powder was filtered off. It was taken up in MeOH and the solu- tion was filtered through a syringe microfilter into water. The solution was freeze-dried to yield N-{[2-amino-3-(²H₃)methylquinolin-7-yl]methyl}-N-(2-metha nesulfonylpyridin-3- yl)pyridine-3-carboxamide (Example E-040, 0.02 g, 0.044 mmol, 12%, beige solid, UPLC long elution purity: 99.26%). 8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 – 8.50 (m, 2H), 8.46 (d, J = 4.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.59 – 7.52 (m, 2H), 7.49 (dd, J = 7.8, 5.1 Hz, 1H), 7.28 (m, 2H), 7.15 (d, J = 7.9 Hz, 1H), 6.27 (s, 2H), 5.81 (d, J = 14.6 Hz, 1H), 4.67 (d, J = 14.6 Hz, 1H), 3.34 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 – 8.87 (m, 1H), 8.78 – 8.71 (m, 1H), 8.69 – 8.62 (m, 1H), 8.16 – 8.06 (m, 1H), 7.71 – 7.68 (m, 1H), 7.67 – 7.58 (m, 3H), 7.58 – 7.51 (m, 1H), 7.19 – 7.12 (m, 1H), 7.04 – 6.92 (m, 1H), 6.30 (s, 2H), 5.15 (d, J = 14.8 Hz, 1H), 4.81 (d, J = 15.5 Hz, 1H), 3.34 (s, 3H). m/z (ESI): 451.26 [M+H] ⁺ . Example E-041: N-[(2-amino-3-methylquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin- 3-yl)pyridine-3-carboxamide The title compound was prepared according to General Procedure 34, using N-[(3-amino-4- formylphenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)pyridi ne-3-carboxamide (Int. Q- 028, 0.26 g, 0.63 mmol, 1.0 eq.), diethyl (1-cyanoethyl)phosphonate (0.13 g, 0.68 mmol, 1.1 eq.) and EtONa (21% solution in EtOH, 0.22 mL, 0.94 mmol, 1.5 eq.) in absolute EtOH (5.0 mL). The crude material was purified by FCC (silica 15 ^m, 0 to 20% MeOH gradient in DCM). The fractions containing the desired product were pooled, evaporated under reduced pressure and the residue was taken up DCM. The solution was washed with sat. aq. Na- HCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by FCC (NH ₂ functionalized silica, 0 to 2% MeOH gradient in DCM) to yield N-[(2-amino-3-methylquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pyri- dine-3-carboxamide (Example E-041, 0.021 g, 0.047 mmol, 7%, white solid, UPLC long elu- tion purity: 99.87%). 75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (s, 1H), 8.52 (d, J = 4.3 Hz, 1H), 8.44 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.47 (dd, J = 8.2, 4.5 Hz, 1H), 7.27 (s, 1H), 7.29 – 7.24 (m, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.27 (s, 2H), 5.81 (d, J = 14.6 Hz, 1H), 4.66 (d, J = 14.6 Hz, 1H), 3.33 (s, 3H), 2.19 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 – 8.84 (m, 1H), 8.80 – 8.69 (m, 1H), 8.69 – 8.60 (m, 1H), 8.15 – 8.06 (m, 1H), 7.70 – 7.65 (m, 1H), 7.66 – 7.56 (m, 1H), 7.56 – 7.44 (m, 3H), 7.18 – 7.09 (m, 1H), 7.03 – 6.94 (m, 1H), 6.27 (s, 2H), 5.13 (d, J = 13.8 Hz, 1H), 4.80 (d, J = 16.1 Hz, 1H), 3.38 (s, 3H), 2.19 (s, 3H). m/z (ESI): 448.24 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 545 R10107WO Example E-042: N-[(2-amino-4-cyanoquinolin-7-yl)methyl]-N-(2-methanesul- fonylphenyl)pyridine-3-carboxamide 2-{[(tert-butoxy)carbonyl]amino}-7-{[N-(2-methanesulfonylphe nyl)-1-(pyridin-3- yl)formamido]methyl}quinoline-4-carboxylate (Int. Q-057) A mixture of Cs ₂ CO ₃ (0.6 g, 1.84 mmol, 2.81 eq.), XPhos Pd G3 (0.06 g, 0.07 mmol, 0.11 eq.), tert-butyl carbamate (0.25 g, 2.13 mmol, 3.25 eq.) and methyl 2-chloro-7-{[N-(2-me- thanesulfonylphenyl)-1-(pyridin-3-yl)formamido]methyl}quinol ine-4-carboxylate (Int. O-058, 0.352 g, 0.66 mmol, 1.0 eq.) in anhydrous dioxane (4.5 mL) was sparged with nitrogen for 10 minutes. The RM was heated under microwave irradiation at 100 °C for 2 h. After coming back to RT, the RM was partitioned between water and iPrOH/DCM 1:3 v/v. The aqueous layer was further extracted with iPrOH/DCM 1:3 v/v and the combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield methyl 2-{[(tert- butoxy)carbonyl]amino}-7-{[N-(2-methanesulfonylphenyl)-1-(py ridin-3-yl)formamido]me- thyl}quinoline-4-carboxylate (Int. Q-057, 0.396 g, 0.67 mmol, 96%, orange solid, UPLC purity: 94%). 75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major ro- tamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.41 (s, 1H), 8.55 (s, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.43 (dd, J = 4.9, 1.7 Hz, 1H), 7.94 (dd, J = 7.5, 2.0 Hz, 1H), 7.76 (s, 1H), 7.69 (dt, J = 7.9, 2.0 Hz, 1H), 7.65 (dd, J = 8.8, 1.8 Hz, 1H), 7.58 – 7.48 (m, 2H), 7.26 (dd, J = 7.8, 4.8 Hz, 1H), 7.23 (dd, J = 7.7, 1.6 Hz, 1H), 5.82 (d, J = 15.1 Hz, 1H), 4.73 (d, J = 15.0 ^{Hz, 1H), 4.01 (s, 3H), 3.20 (s, 3H), 1.52 (s, 9H). Minor rotamer: 1H NMR (400 MHz, DMSO-d6)} _{δ 10.43 (s, 1H), 8.93 (s, 1H), 8.72 (d, J = 4.9 Hz, 1H), 8.54 (s, 1H), 8.45 (d, J = 8.7 Hz, 1H),} 8.14 (dt, J = 8.1, 1.5 Hz, 1H), 8.10 (dd, J = 7.2, 1.9 Hz, 1H), 7.64 – 7.61 (m, 1H), 7.59 (dd, J = 7.9, 5.0 Hz, 1H), 7.57 – 7.48 (m, 3H), 7.24 – 7.18 (m, 1H), 5.27 (d, J = 16.3 Hz, 1H), 4.84 (d, J = 16.3 Hz, 1H), 4.00 (s, 3H), 3.28 (s, 3H), 1.52 (s, 9H). m/z (ESI): 591.4 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 546 R10107WO 2-{[(tert-butoxy)carbonyl]amino}-7-{[N-(2-methanesulfonylphe nyl)-1-(pyridin-3- yl)formamido]methyl}quinoline-4-carboxylic acid (Int. Q-058) Aqueous 1 M NaOH (23.0 mL) was added to a solution of methyl 2-{[(tert-butoxy)car- bonyl]amino}-7-{[N-(2-methanesulfonylphenyl)-1-(pyridin-3-yl )formamido]methyl}quino- line-4-carboxylate (0.285 g, 0.45 mmol, 1.0 eq.) in methanol (15.0 mL) at 0 °C. The RM was stirred at this temperature for 1 h, then acidified to pH ≈ 5 with aq.1 M HCl and the mixture was extracted with iPrOH/DCM 1:3 v/v (3x). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The obtained crude 2- {[(tert-butoxy)carbonyl]amino}-7-{[N-(2-methanesulfonylpheny l)-1-(pyridin-3- yl)formamido]methyl}quinoline-4-carboxylic acid (Int. Q-058, 0.252 g, 0.44 mmol, 90%, yel- low solid, UPLC purity: 93%) was used in the next step without further purification. m/z (ESI): 575.1 [M-H]- . tert-butyl N-(4-carbamoyl-7-{[N-(2-methanesulfonylphenyl)-1-(pyridin-3- yl)formamido]me- thyl}quinolin-2-yl)carbamate (Int. Q-059) CDI (0.074 g, 0.46 mmol, 1.12 eq.) was added to a solution of 2-{[(tert-butoxy)car- bonyl]amino}-7-{[N-(2-methanesulfonylphenyl)-1-(pyridin-3-yl )formamido]methyl}quino- line-4-carboxylic acid (Int. Q-058, 0.252 g, 0.41 mmol, 1.0 eq.) in anhydrous DMF at RT and the mixture was stirred at 60 °C under argon for 1 h. After coming back to RT, ammonia (0.5 M in dioxane, 2.5 mL, 1.25 mmol, 3.1 eq.) was added. The RM was stirred at RT under argon for 22 h before being evaporated under reduced pressure. The residue was parti- tioned between water and DCM and the aqueous layer was extracted with iPrOH:DCM 1:3 v/v. The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , fil- tered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield tert-butyl N-(4-carbamoyl-7-{[N-(2-methanesul- fonylphenyl)-1-(pyridin-3-yl)formamido]methyl}quinolin-2-yl) carbamate (Int. Q-059, 0.163 g, 0.28 mmol, 68%, off-white solid, UPLC purity: 97%). 75/25 mixture of restricted C-N am- ide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 8.48 (dd, J = 2.2, 0.9 Hz, 1H), 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.94 (dd, J = 7.4, 2.1 Hz, 1H), 7.88 (s, 1H), 7.69 (s, 1H), 7.68 (dt, J = 8.4, 1.9 Hz, 1H), 7.57 (dd, J = 8.6, 1.8 Hz, 1H), 7.54 – 7.49 (m, 2H), 7.25 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.18 (dd, J = 7.3, 2.0 Hz, 1H), 5.82 (d, J = 15.0 Hz, 1H), 4.68 (d, J = 15.0 Hz, 1H), 3.21 (s, 3H), 1.50 (s, 9H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 8.92 (d, J = 1.7 Hz, 1H), 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 8.22 (s, 1H), 8.13 (dt, J = 7.7, 1.7 Hz, 1H), 8.10 – 8.07 (m, 1H), 8.08 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.90 – 7.86 (m, 1H), 7.65 – 7.60 (m, 2H), 7.60 – 7.55 (m, 1H), 7.44 (s, 1H), 7.44 – 7.41 (m, 1H), 7.21 – 7.14 (m, 1H), 5.24 (d, J = 16.3 Hz, 1H), 4.81 (d, J = 16.3 Hz, 1H), 3.27 (s, 3H), 1.50 (s, 9H). m/z (ESI): 598.2 [M+Na] ⁺ . tert-Butyl N-(4-cyano-7-{[N-(2-methanesulfonylphenyl)-1-(pyridin-3-yl)f ormamido]me- thyl}quinolin-2-yl)carbamate (Int. Q-060) TEA (0.084 mL, 0.61 mmol, 2.21 eq.) and TFAA (0.115 g, 0.55 mmol, 2.0 eq.) were succes- sively added to a solution of tert-butyl N-(4-carbamoyl-7-{[N-(2-methanesulfonylphenyl)-1- (pyridin-3-yl)formamido]methyl}quinolin-2-yl)carbamate (Int. Q-059, 0.162 g, 0.27 mmol, 1.0 Ryvu Therapeutics S.A. RVU305 547 R10107WO eq.) in anhydrous DCM (1.5 mL) at 0 °C under argon. The RM was stirred at RT for 50 min., diluted with DCM and then basified to pH ≈ 8 with sat. aq. NaHCO ₃ . The phase were sepa- rated and the organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 1.5% MeOH gradient in DCM then isocratic) to yield tert-butyl N-(4-cyano-7-{[N-(2-methanesul- fonylphenyl)-1-(pyridin-3-yl)formamido]methyl}quinolin-2-yl) carbamate (Int. Q-060, 0.153 g, 0.27 mmol, 96%, yellow solid, UPLC purity: 96%). 75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H), 8.48 (s, 1H), 8.48 (d, J = 1.1 Hz, 1H), 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.93 (dd, J = 7.4, 2.1 Hz, 1H), 7.81 (s, 1H), 7.78 (dd, J = 8.5, 1.7 Hz, 1H), 7.68 (dt, J = 8.0, 2.0 Hz, 1H), 7.57 – 7.48 (m, 2H), 7.25 (dd, J = 8.0, 4.8 Hz, 1H), 7.23 (dd, J = 7.5, 1.6 Hz, 1H), 5.81 (d, J = 15.1 Hz, 1H), 4.76 (d, J = 15.1 Hz, 1H), 3.18 (s, 3H), 1.51 (s, 9H). Minor rota- mer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.91 (s, 1H), 8.71 (d, J = 5.3 Hz, 1H), 8.46 (s, 1H), 8.12 (dt, J = 7.7, 1.7 Hz, 1H), 8.09 (dd, J = 7.4, 2.2 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.66 – 7.61 (m, 2H), 7.60 – 7.46 (m, 3H), 7.25 – 7.17 (m, 1H), 5.28 (d, J = 16.3 Hz, 1H), 4.87 (d, J = 16.2 Hz, 1H), 3.27 (s, 3H), 1.51 (s, 9H). m/z (ESI): 580.2 [M+Na] ⁺ . N-[(2-amino-4-cyanoquinolin-7-yl)methyl]-N-(2-methanesulfony lphenyl)pyridine-3-carbox- amide (Example E-042) TFA (0.6 mL, 7.90 mmol, 30.0 eq.) was added to a solution of tert-butyl N-(4-cyano-7-{[N- (2-methanesulfonylphenyl)-1-(pyridin-3-yl)formamido]methyl}q uinolin-2-yl)carbamate (Int. Q-060, 0.153 g, 0.26 mmol, 1.0 eq.) in DCM (2.5 mL). The RM was stirred at RT for 1 h and evaporated under reduced pressure. The residue was partitioned between DCM and sat. aq. NaHCO ₃ and the aqueous layer was extracted with DCM (3x). The combined organic layers were washed with brine (2x), dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 6% MeOH gradient in DCM) to yield N-[(2-amino-4-cyanoquinolin-7-yl)methyl]-N-(2-methanesulfony lphenyl)pyridine-3- carboxamide (Example E-042, 0.099 g, 0.22 mmol, 82%, white solid, UPLC long elution pu- rity: 100%). 75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Ma- jor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (dd, J = 2.3, 0.9 Hz, 1H), 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 7.93 (dd, J = 7.6, 1.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.68 (dt, J = 8.0, 2.1 Hz, 1H), 7.57 – 7.49 (m, 2H), 7.48 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 8.3, 1.7 Hz, 1H), 7.27 – 7.21 (m, 3H), 6.93 (s, 2H), 5.75 (d, J = 15.0 Hz, 1H), 4.64 (d, J = 15.1 Hz, 1H), 3.19 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J = 1.6 Hz, 1H), 8.71 (dd, J = 4.9, 1.5 Hz, 1H), 8.13 – 8.07 (m, 2H), 7.72 – 7.66 (m, 1H), 7.66 – 7.57 (m, 3H), 7.31 – 7.16 (m, 4H), 6.97 (s, 2H), 5.20 (d, J = 16.2 Hz, 1H), 4.74 (d, J = 16.3 Hz, 1H), 3.26 (s, 3H). m/z (ESI): 458.50 [M+H] ⁺ . Example E-043: 2-amino-7-{[N-(2-methanesulfonylphenyl)-1-(pyridin-3-yl)form amido]me- thyl}quinoline-4-carboxamide Ryvu Therapeutics S.A. RVU305 548 R10107WO TFA (0.156 mL, 2.04 mmol, 30 eq.) was added to a solution of tert-butyl N-(4-carbamoyl-7- {[N-(2-methanesulfonylphenyl)-1-(pyridin-3-yl)formamido]meth yl}quinolin-2-yl)carbamate (Int. Q-059, 0.042 g, 0.07 mmol, 1.0 eq.) in DCM (0.7 mL). The RM was stirred at RT for 2.5 h and evaporated under reduced pressure. The residue was partitioned between iPrOH:DCM 1:3 v/v and sat. aq. NaHCO ₃ and the aqueous layer was extracted with iPrOH:DCM 1:3 v/v (3x). The combined organic layers were washed with brine (2x), dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (NH ₂ functionalized silica, 0 to 8% MeOH gradient in DCM) to yield 2-amino-7-{[N-(2- methanesulfonylphenyl)-1-(pyridin-3-yl)formamido]methyl}quin oline-4-carboxamide (Ex- ample E-043, 0.02 g, 0.042 mmol, 62%, white solid, UPLC long elution purity: 99.90%). 7/3 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (dd, J = 2.3, 0.6 Hz, 1H), 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 8.15 – 8.06 (m, 1H), 7.93 (dd, J = 7.5, 2.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.67 (dt, J = 7.9, 2.0 Hz, 1H), 7.56 – 7.47 (m, 2H), 7.38 (d, J = 1.8 Hz, 1H), 7.25 (dd, J = 8.2, 0.9 Hz, 1H), 7.25 – 7.22 (m, 1H), 7.18 (dd, J = 7.5, 1.4 Hz, 1H), 6.77 (s, 1H), 6.57 (s, 2H), 5.77 (d, J = 15.0 ^{Hz, 1H), 4.57 (d, J = 15.0 Hz, 1H), 3.20 (s, 3H). Minor rotamer: 1H NMR (400 MHz, DMSO-d6)} _{δ 8.91 (d, J = 1.3 Hz, 1H), 8.72 (dd, J = 4.9, 1.4 Hz, 1H), 8.16 – 8.06 (m, 3H), 7.77 (d, J = 8.4} Hz, 1H), 7.65 – 7.57 (m, 4H), 7.21 – 7.14 (m, 2H), 7.07 (dd, J = 8.7, 1.6 Hz, 1H), 6.75 (s, 1H), 6.61 (s, 2H), 5.17 (d, J = 16.2 Hz, 1H), 4.68 (d, J = 16.2 Hz, 1H), 3.26 (s, 3H). m/z (ESI): 476.23 [M+H] ⁺ . Example E-044: N-{[2-amino-4-(hydroxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesul- fonylphenyl)pyridine-3-carboxamide tert-Butyl N-[4-(hydroxymethyl)-7-{[N-(2-methanesulfonylphenyl)-1-(pyri din-3- yl)formamido]methyl}quinolin-2-yl]carbamate (Int. Q-061) A solution of methyl 2-{[(tert-butoxy)carbonyl]amino}-7-{[N-(2-methanesulfonylphe nyl)-1- (pyridin-3-yl)formamido]methyl}quinoline-4-carboxylate (Int. Q-057, 0.1 g, 0.16 mmol, 1.0 eq.) in absolute EtOH (1.0 mL) was treated with CaCl ₂ (0.03 g, 0.27 mmol, 1.7 eq.) and NaBH ₄ (0.024 g, 0.64 mmol, 4.0 eq.) at 0 °C under argon. The RM was stirred at RT for 1 h and the reaction was quenched by addition of sat. aq. NH ₄ Cl. The mixture was extracted with EtOAc (2x) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered Ryvu Therapeutics S.A. RVU305 549 R10107WO and evaporated under reduced pressure. The crude material was purified by FCC (5 to 10% MeOH gradient in DCM) to yield tert-butyl N-[4-(hydroxymethyl)-7-{[N-(2-methanesul- fonylphenyl)-1-(pyridin-3-yl)formamido]methyl}quinolin-2-yl] carbamate (Int. Q-061, 0.023 g, 0.041 mmol, 24%, yellow solid, UPLC purity: 94%). 75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 8.46 (dd, J = 2.2, 0.7 Hz, 1H), 8.42 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (s, 1H), 7.92 (dd, J = 7.5, 2.0 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.69 – 7.64 (m, 2H), 7.56 – 7.47 (m, 3H), 7.24 (dd, J = 7.9, 4.8 Hz, 1H), 7.19 (dd, J = 7.5, 1.5 Hz, 1H), 5.78 (d, J = 15.0 Hz, 1H), 5.57 (t, J = 5.7 Hz, 1H), 4.98 (d, J = 5.6 Hz, 2H), 4.69 (d, J = 15.0 Hz, 1H), 3.15 (s, 3H), 1.49 (d, J = 2.2 Hz, 9H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.72 (d, J = 4.4 Hz, 1H), 8.17 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.08 (dd, J = 6.7, 2.6 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.64 – 7.55 (m, 3H), 7.43 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.21 – 7.15 (m, 1H), 5.57 (t, J = 5.7 Hz, 1H), 5.24 (d, J = 16.2 Hz, 1H), 4.94 (d, J = 5.9 Hz, 2H), 4.79 (d, J = 16.3 Hz, 1H), 3.26 (s, 3H), 1.49 (d, J = 2.2 Hz, 9H). m/z (ESI): 585.2 [M+Na] ⁺ . N-{[2-amino-4-(hydroxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesulfonylphenyl)pyri- dine-3-carboxamide (Example E-044) TFA (0.173 mL, 2.25 mmol, 60 eq.) was added to a solution of tert-butyl N-[4-(hydroxyme- thyl)-7-{[N-(2-methanesulfonylphenyl)-1-(pyridin-3-yl)formam ido]methyl}quinolin-2-yl]car- bamate (Int. Q-061, 0.023 g, 0.04 mmol, 1.0 eq.) in DCM (0.4 mL). The RM was stirred at RT overnight and evaporated under reduced pressure. The residue was partitioned between iPrOH:DCM 1:3 v/v and sat. aq. NaHCO ₃ , and the aqueous layer was extracted with iPrOH:DCM 1:3 v/v (3x). The combined organic layers were washed with brine (2x), dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (C18 functionalized silica, 10% to 100% MeCN gradient in water) to yield N-{[2-amino-4-(hydroxymethyl)quinolin-7-yl]methyl}-N-(2-meth anesul- fonylphenyl)pyridine-3-carboxamide (Example E-044, 0.005 g, 0.011 mmol, 27%, white solid, UPLC long elution purity: 95.39%). 65/35 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 8.41 (d, J = 3.2 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.73 – 7.47 (m, 4H), 7.37 (s, 1H), 7.30 – 7.13 (m, 3H), 6.88 (s, 1H), 6.47 (s, 2H), 5.72 (d, J = 14.9 Hz, 1H), 5.50 – 5.37 (m, 1H), 4.84 (d, J = 5.5 Hz, 2H), 4.59 (d, J = 14.8 Hz, 1H), 3.15 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.72 (d, J = 2.9 Hz, 1H), 8.12 (d, J = 7.0 Hz, 1H), 8.09 (d, J = 7.3 Hz, 1H), 7.75 – 7.46 (m, 3H), 7.30 – 7.09 (m, 3H), 6.98 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.47 (s, 2H), 5.47 – 5.33 (m, 1H), 5.17 (d, J = 16.0 Hz, 1H), 4.82 – 4.76 (m, 2H), 4.66 (d, J = 16.4 Hz, 1H), 3.25 (s, 3H). m/z (ESI): 463.18 [M+H] ⁺ . Example E-045: N-[(2-amino-5-bromoquinolin-7-yl)methyl]-N-(2-methanesulfony lpyridin- 3-yl)pyridine-3-carboxamide, General Procedure 35 Ryvu Therapeutics S.A. RVU305 550 R10107WO A mixture of N-[(5-bromo-2-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3- yl)pyridine-3-carboxamide (Int. O-061, 0.103 g, 0.12 mmol, 1.0 eq.), ammonium chloride (0.013 mg, 0.24 mmol, 2 eq.) and sodium azide (0.015 g, 0.24 mmol, 2 eq.) in anhydrous DMF (1.0 mL) was stirred at 110 °C for 3 h under argon. After coming back to RT, the RM was taken up in EtOAc and the solution was washed with water (4x) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to yield crude N-[(2-az- ido-5-bromoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)pyridine-3-carbox- amide (Int. Q-062, 0.085 mg, 0.11 mmol, 94%, brown oil, UPLC purity: 70%). m/z (ESI): 539.2 [M+H] ⁺ . The residue was dissolved in a mixture of MeOH (7.0 mL) and water (3.0 mL), and Bu ₃ P (0.133 g, 0.66 mmol, 6 eq.) was added. The RM was refluxed for 4 h and cooled to RT. It was then partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) and the fractions containing the desired compound were passed through an SCX column, washing with MeOH and eluting with 2 M NH ₃ in MeOH. The frac- tions containing the title compound were pooled and evaporated under reduced pressure to yield N-[(2-amino-5-bromoquinolin-7-yl)methyl]-N-(2-methanesulfony lpyridin-3-yl)pyri- dine-3-carboxamide (Example E-045, 0.020 g, 0.04 mmol, 31% overall yield, white solid, UPLC long elution purity: 96.21%).85/15 mixture of C-N restricted rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (d, J = 4.0 Hz, 1H), 8.53 (s, 1H), 8.45 (d, J = 3.9 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.76 – 7.68 (m, 2H), 7.57 (dd, J = 7.6, 4.5 Hz, 1H), 7.46 (s, 1H), 7.29 (s, 1H), 7.30 – 7.19 (m, 1H), 6.85 (d, J = 9.1 Hz, 1H), 6.72 (s, 2H), 5.69 (d, J = 14.8 Hz, 1H), 4.69 (d, J = 14.8 Hz, 1H), 3.31 (s, 3H). Minor rotamer: ¹ H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.73 (s, 1H), 8.68 (s, 1H), 8.14 – 8.05 (m, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.81 – 7.68 (m, 2H), 7.57 (dd, J = 8.2, 4.7 Hz, 1H), 7.29 (s, 1H), 7.22 (s, 1H), 6.85 (d, J = 9.1 Hz, 1H), 6.72 (s, 2H), 5.14 (d, J = 15.1 Hz, 1H), 4.84 (d, J = 16.7 Hz, 1H), 3.37 (s, 3H). m/z (ESI): 514.11 [M+H] ⁺ . Example E-046: N-[(2-aminoquinolin-7-yl)methyl]-2-cyclopropoxy-N-(2-methane sul- fonylpyridin-3-yl)acetamide Ryvu Therapeutics S.A. RVU305 551 R10107WO The title compound was prepared according to General Procedure 35, using N‐[(2‐chloro- quinolin‐7‐yl)methyl]‐2‐cyclopropoxy‐N‐(2‐meth anesulfonylpyridin‐3‐yl)acetam- ide (Int. O-062, 0.163 g, 0.35 mmol, 1.0 eq.), NH ₄ Cl (0.037 g, 0.77 mmol, 2.21 eq.) and so- dium azide (0.045 g, 0.71 mmol, 2.04 eq.) in anhydrous DMF (2.0 mL), followed by treatment with PBu ₃ (250 ^L, 1.01 mmol, 6.38 eq.) in a mixture of MeOH (8.8 mL) and water (3.7 mL). The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) and the fractions containing the desired compound were passed through an SCX column, washing with MeOH and eluting with 2 M NH ₃ in MeOH. The fractions containing the title compound were pooled and evaporated under reduced pressure to yield N-[(2-aminoquinolin-7-yl)methyl]- 2-cyclopropoxy-N-(2-methanesulfonylpyridin-3-yl)acetamide (Example E-046, 0.059 g, 0.14 ^{mmol, 39%, white solid UPLC long elution purity: 98.14%). 1H NMR (400 MHz, Methanol-d4)} _{δ 8.64 (dd, J = 4.7, 1.5 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.48 (dd, J} = 8.1, 4.6 Hz, 1H), 7.32 (dd, J = 8.0, 1.5 Hz, 1H), 7.25 (s, 1H), 7.18 (dd, J = 8.2, 1.7 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 5.91 (d, J = 14.7 Hz, 1H), 4.29 (d, J = 14.7 Hz, 1H), 3.98 (d, J = 14.7 Hz, 1H), 3.90 (d, J = 14.7 Hz, 1H), 3.46 (s, 3H), 3.37 (tt, J = 5.9, 2.9 Hz, 1H), 0.51 – 0.34 (m, 4H). m/z (ESI): 427.23 [M+H] ⁺ . Further Examples prepared according to General Procedure 35: Ryvu Therapeutics S.A. RVU305 552 R10107WO Ryvu Therapeutics S.A. RVU305 553 R10107WO Ryvu Therapeutics S.A. RVU305 554 R10107WO Ryvu Therapeutics S.A. RVU305 555 R10107WO Ryvu Therapeutics S.A. RVU305 556 R10107WO Ryvu Therapeutics S.A. RVU305 557 R10107WO Ryvu Therapeutics S.A. RVU305 558 R10107WO Ryvu Therapeutics S.A. RVU305 559 R10107WO Ryvu Therapeutics S.A. RVU305 560 R10107WO Ryvu Therapeutics S.A. RVU305 561 R10107WO Ryvu Therapeutics S.A. RVU305 562 R10107WO Ryvu Therapeutics S.A. RVU305 563 R10107WO ¹ Purity: UPLC long elution purity Example E-047: N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzothiazol-7-yl)py ridine-3-car- boxamide, General Procedure 36 A Biotage ^TM microwave vial was charged with N-(1,3-benzothiazol-7-yl)-N-[(2-chloroquino- lin-7-yl)methyl]pyridine-3-carboxamide (Int. N-041, 0.178 g, 0.41 mmol, 1.0 eq.), Cs ₂ CO ₃ (0.329 g, 1.0 mmol, 2.5 eq.), tert-butyl carbamate (0.166 g, 1.42 mmol, 3.5 eq.) and anhy- drous dioxane (5.0 mL). The RM was sparged with nitrogen for 10 min. BINAP (0.045 g, 0.07 ^{mmol, 0.18 eq.) was added followed by Pd2(dba)3 (0.033 g, 0.036 mmol, 0.09 eq.) and the} _{vial was sealed. The resulting RM was stirred at 110 °C in a DrySyn® for 24 h, during which} time the Boc group was also cleaved. After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . The filtrate was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was Ryvu Therapeutics S.A. RVU305 564 R10107WO purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)me- thyl]-N-(1,3-benzothiazol-7-yl)pyridine-3-carboxamide (Example E-047, 0.08 g, 0.19 mmol, 47%, off white solid, UPLC long elution purity: 99.87%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.49 (s, 1H), 8.37 (d, J = 4.5 Hz, 1H), 7.92 (dd, J = 7.7, 1.4 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 7.21 – 7.13 (m, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.43 (s, 2H), 5.25 (s, 2H). _m/z (ESI): 412.24 [M+H] ⁺ . Example E-048: N-[(2-aminoquinolin-7-yl)methyl]-N-(1H-indazol-7-yl)pyridine -3-carbox- amide N-[(2-aminoquinolin-7-yl)methyl]-N-(1-{[2-(trimethylsilyl)et hoxy]methyl}-1H-indazol-7- yl)pyridine-3-carboxamide (Int. Q-063) The title compound was prepared according to General Procedure 36, using N-[(2-chloro- quinolin-7-yl)methyl]-N-(1-{[2-(trimethylsilyl)ethoxy]methyl }-1H-indazol-7-yl)pyridine-3- carboxamide (Int. N-045, 0.156 g, 0.27 mmol, 1.0 eq.), tert-butyl carbamate (0.110 g, 0.94 mmol, 3.5 eq.), Pd ₂ (dba) ₃ (0.022 g, 0.024 mmol, 0.09 eq.), Cs ₂ CO ₃ (0.219 g, 0.67 mmol, 2.5 eq.) and BINAP (0.030 g, 0.049 mmol, 0.18 eq.) in anhydrous dioxane (7.0 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM), to yield N-[(2-aminoquino- lin-7-yl)methyl]-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- indazol-7-yl)pyridine-3-carbox- amide (Int. Q-063, 0.122 g, 0.23 mmol, 84%, white solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (dd, J = 2.2, 0.9 Hz, 1H), 8.36 (dd, J = 4.8, 1.7 Hz, 1H), 8.26 (s, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.69 (dt, J = 8.0, 2.0 Hz, 1H), 7.68 (dd, J = 8.1, 0.9 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.15 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.12 (dd, J = 8.2, 1.7 Hz, 1H), 6.86 (dd, J = 8.0, 7.4 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.62 (dd, J = 7.4, 1.0 Hz, 1H), 6.41 (s, 2H), 5.92 (d, J = 14.6 Hz, 1H), 5.87 (d, J = 1.7 Hz, 2H), 4.51 (d, J = 14.5 Hz, 1H), 3.70 – 3.57 (m, 2H), 0.90 – 0.72 (m, 2H), -0.04 (s, 9H). m/z (ESI): 525.4 [M+H] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-(1H-indazol-7-yl)pyridine -3-carboxamide (Example E- 048) TFA (0.5 mL, 6.65 mmol, 50 eq.) was added to a solution of N-[(2-aminoquinolin-7-yl)me- thyl]-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-7-y l)pyridine-3-carboxamide (Int. Q-063, 0.072 g, 0.13 mmol, 1.0 eq.) in DCM (2.0 mL) and the RM was stirred overnight at RT. It was then evaporated under reduced pressure and the residue was partitioned be- tween DCM and sat. aq. NaHCO ₃ . The aqueous layer was extracted with DCM (2x) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by preparative HPLC to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(1H-indazol-7-yl)pyridine -3-carboxamide (Ex- ample E-048, 0.008 g, 0.02 mmol, 15%, white solid, UPLC long elution purity: 99.15%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.57 (s, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.33 (dd, J = 4.9, 1.4 Hz, Ryvu Therapeutics S.A. RVU305 565 R10107WO 1H), 8.08 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.66 (dt, J = 8.3, 1.8 Hz, 1H), 7.56 (dd, J = 4.9, 4.1 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.17 – 7.10 (m, 2H), 6.82 – 6.78 (m, 2H), 6.69 (d, J = 8.9 Hz, 1H), 6.38 (s, 2H), 5.74 (d, J = 14.9 Hz, 1H), 4.72 (d, J = 14.9 Hz, 1H). m/z (ESI): 395.16 [M+H] ⁺ . Examples prepared according to General Procedure 36: ¹ Purity: UPLC long elution purity Example H-001: N-[(2-aminoquinolin-7-yl)methyl]-N-(3-hydroxy-2,3-dihydro-1H -inden-4- yl)pyridine-3-carboxamide A mixture of Cs ₂ CO ₃ (0.671 g, 2.06 mmol, 2.8 eq.), tert-butyl carbamate (0.258 g, 2.21 mmol, 3.0 eq.) and 7-{N-[(2-chloroquinolin-7-yl)methyl]pyridine-3-amido}-2,3-di hydro-1H-inden- 1-yl acetate (Int. N-051, 0.365 g, 0.73 mmol, 1.0 eq.) in anhydrous dioxane (5.0 mL) was sparged with nitrogen for 15 minutes. XPhos Pd G3 (0.062 g, 0.07 mmol, 0.1 eq.) was added and the RM was heated under microwave irradiation at 100 °C for 3.5 h. After coming back to RT, the RM was diluted with EtOAc and filtered through a pad of Celite ^® . Water was added to the filtrate and the organic phase was separated. The aqueous layer was extracted with EtOAc (1x). The combined organic layers were washed with brine, dried over anhy- drous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material dis- solved in a mixture of DCM (3 mL) and TFA (1.5 mL) and the mixture was stirred for 7 h at RT. The RM was basified to pH ≈ 10 with sat. aq. NaHCO ₃ and the mixture was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 8% Ryvu Therapeutics S.A. RVU305 566 R10107WO MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(3-hydroxy-2,3-dihy- dro-1H-inden-4-yl)pyridine-3-carboxamide (Example H-001, 0.121 g, 0.295 mmol, 40%, off- white solid, UPLC long elution purity: 99.78%). 6/4 mixture of two distinguishable "diastere- oisomer-like" components resulting from the racemic 2,3-dihydro-1H-inden-1-yl acetate and a 6/4 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ : Major component: NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (m, 2H), 7.90 (dt, J = 8.0, 1.9 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.27 (s, 1H), 7.26 – 7.17 (m, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.41 (s, 2H), 6.34 (d, J = 7.8 Hz, 1H), 5.72 (d, J = 15.0 Hz, 1H), 5.66 (d, J = 5.6 Hz, 1H), 5.55 – 5.45 (m, 1H), 4.59 (d, J = 15.1 Hz, 1H), 3.05 – 2.92 (m, 1H), 2.78 – 2.69 (m, 1H), 2.41 (m, 1H), 1.99 – 1.81 (m, 1H). Minor component: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (d, J = 1.7 Hz, 1H), 8.47 – 8.35 (m, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.67 (dt, J = 7.9, 1.8 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.36 (s, 1H), 7.26 – 7.17 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 6.41 (s, 2H), 5.81 (d, J = 14.9 Hz, 1H), 5.33 (d, J = 6.6 Hz, 1H), 4.99 – 4.88 (m, 1H), 4.64 (d, J = 15.2 Hz, 1H), 2.99 (dq, J = 12.5, 6.1 Hz, 1H), 2.64 – 2.54 (m, 1H), 2.05 (dq, J = 14.1, 7.2 Hz, 1H), 1.99 – 1.83 (m, 1H). m/z (ESI): 411.17 [M+H] ⁺ . Example H-002: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin- 3-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridi n-3-yl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide (Int. R-001) The title compound was prepared according to General Procedure 22, using N-(2-me- thanesulfonylpyridin-3-yl)-2-(trifluoromethyl)pyrimidine-5-c arboxamide (Int. K-011, 0.785 g, 2.22 mmol, 1.0 eq.), 1-bromo-4-(bromomethyl)-2-nitrobenzene (0.983 g, 3.33 mmol, 1.5 eq.) and Cs ₂ CO ₃ (0.870 g, 2.67 mmol, 1.2 eq.) in anhydrous MeCN (11.0 mL). The crude material was purified by FCC (50 to 100% EtOAc gradient in hexane) to yield N-[(4-bromo-3-nitro- Ryvu Therapeutics S.A. RVU305 567 R10107WO phenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-(trifluor omethyl)pyrimidine-5-carbox- amide (Int. R-001, 0.835 g, 1.49 mmol, 58%, white solid, UPLC purity: 87%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 2H), 8.69 (dd, J = 4.6, 1.4 Hz, 1H), 8.08 (dd, J = 8.1, 1.4 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.78 (dd, J = 8.2, 4.6 Hz, 1H), 7.62 (dd, J = 8.2, 2.1 Hz, 1H), 5.58 (d, J = 15.3 Hz, 1H), 4.77 (d, J = 15.3 Hz, 1H), 3.36 (s, 3H). m/z (ESI): 560.0 [M+H] ⁺ . N-[(4-ethenyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyri din-3-yl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide (Int. R-002) The title compound was prepared according to General Procedure 28, using N-[(4-bromo-3- nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-(tri fluoromethyl)pyrimidine-5-car- boxamide (Int. R-001, 0.83 g, 1.29 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-diox- aborolane (0.400 g, 2.60 mmol, 2.0 eq.), Cs ₂ CO ₃ (1.26 g, 3.87 mmol, 3.0 eq.) and bis(tri- phenylphosphine)palladium(II)chloride (0.091 g, 0.13 mmol, 0.101 eq.) in a mixture of diox- ane (15.0 mL) and water (6.0 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-[(4-ethenyl-3-nitrophenyl)methyl]-N-(2-methanesul- fonylpyridin-3-yl)-2-(trifluoromethyl)pyrimidine-5-carboxami de (Int. R-002, 0.621 g, 1.22 mmol, 44%, orange oil, UPLC purity: 46%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 2H), 8.68 (dd, J = 4.7, 1.4 Hz, 1H), 8.04 (dd, J = 8.1, 1.4 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.2, 4.6 Hz, 1H), 7.70 (dd, J = 8.1, 1.3 Hz, 1H), 6.96 (dd, J = 11.0, 4.4 Hz, 1H), 5.93 (d, J = 17.8 Hz, 1H), 5.63 (d, J = 15.1 Hz, 1H), 5.53 (d, J = 17.0 Hz, 1H), 4.78 (d, J = 15.1 Hz, 1H), 3.36 (s, 3H). m/z (ESI): 508.1 [M+H] ⁺ . N-[(4-formyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide (Int. R-003) The title compound was prepared according to General Procedure 29, using N-[(4-ethenyl- 3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-(t rifluoromethyl)pyrimidine-5- carboxamide (Int. R-002, 0.621 g, 0.56 mmol, 1.0 eq.), sodium periodate (0.963 g, 4.50 mmol, 8.0 eq.) and 4% aq. OsO ₄ (0.716 mL, 0.113 mmol, 0.2 eq.) in a mixture of dioxane (16 mL) and water (3 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-[(4-formyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide (Int. R-003, 0.350 g, 0.687 mmol, 55%, yellow solid, UPLC purity: 51%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.23 (s, 1H), 8.98 (s, 2H), 8.69 (dd, J = 4.6, 1.4 Hz, 1H), 8.17 (d, J = 1.5 Hz, 1H), 8.10 (dd, J = 8.2, 1.4 Hz, 1H), 7.91 (m, 2H), 7.77 (dd, J = 8.1, 4.6 Hz, 1H), 5.67 (d, J = 15.5 Hz, 1H), 4.90 (d, J = 15.5 Hz, 1H), 3.36 (s, 3H). m/z (ESI): 510.2 [M+H] ⁺ . N-[(3-amino-4-formylphenyl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide (Int. R-004) The title compound was prepared according to General Procedure 30, using N-[(4-formyl-3- nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-(tri fluoromethyl)pyrimidine-5-car- boxamide (Int. R-003, 0.350 g, 0.31mmol, 1.0 eq.), iron powder (0.173 g, 3.10 mmol, 10.0 eq.) and aq. conc. HCl (0.167 mL, 0.062 mmol, 0.20 eq.) in EtOH (3 mL). The crude material was purified by FCC (0 to 100% EtOAc in hexane) to yield N-[(3-amino-4-formylphenyl)methyl]- N-(2-methanesulfonylpyridin-3-yl)-2-(trifluoromethyl)pyrimid ine-5-carboxamide (Int. R-004, Ryvu Therapeutics S.A. RVU305 568 R10107WO 0.166 g, 0.35 mmol, 55%, orange solid, UPLC purity: 49%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 8.99 (s, 2H), 8.66 (dd, J = 4.6, 1.4 Hz, 1H), 7.96 (dd, J = 8.2, 1.5 Hz, 1H), 7.73 (dd, J = 8.1, 4.6 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.14 (s, 2H), 6.74 (s, 1H), 6.64 (dd, J = 8.1, 1.6 Hz, 1H), 5.59 (d, J = 15.3 Hz, 1H), 4.50 (d, J = 15.3 Hz, 1H), 3.40 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.30. m/z (ESI): 480.2 [M+H] ⁺ . N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-2-(trifluoro- methyl)pyrimidine-5-carboxamide (Example H-002) The title compound was prepared according to General Procedure 32 using N-[(3-amino-4- formylphenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-(tr ifluoromethyl)pyrimidine-5- carboxamide (Int. R-004, 0.16 g, 0.16 mmol, 1.0 eq.), NaH (60% in mineral oil, 0.019 g, 0.50 mmol, 3.0 eq.) and diethyl [chloro(cyano)methyl]phosphonate (Int. Q-021, 0.077 g, 0.33 mmol, 2.0 eq.) in anhydrous THF (6 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)-2-(trifluoromethyl)pyrimidine-5-c arboxamide (Example H-002, 0.082 g, 0.15 mmol, 92%, white solid, UPLC long elution purity: 98.73%). 8/2 mixture of re- stricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 2H), 8.59 (dd, J = 4.8, 1.4 Hz, 1H), 8.19 (s, 1H), 7.84 (dd, J = 8.1, 1.4 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.2, 4.7 Hz, 1H), 7.36 (s, 1H), 7.24 (dd, J = 8.3, 1.7 Hz, 1H), 6.76 (s, 2H), 5.75 (d, J = 14.6 Hz, 1H), 4.75 (d, J = 14.6 Hz, 1H), 3.34 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.29. Minor rotamer: 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 2H), 8.71 – 8.65 (m, 1H), 8.16 (s, 1H), 7.73 – 7.67 (m, 2H), 7.63 – 7.57 (m, 1H), 7.28 – 7.21 (m, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.76 (s, 2H), 5.26 (d, J = 15.4 Hz, 1H), 4.90 (d, J = 15.3 Hz, 1H), 3.38 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.15. _m/z (ESI): 537.07 [M+H] ⁺ . Example H-003: N-[(2-aminoquinolin-7-yl)methyl]-N-(3-fluoro-1,1-dioxo-2,3-d ihydro-1λ⁶- benzothiophen-7-yl)acetamide tert-Butyl N-(7-{[N-(3-hydroxy-1,1-dioxo-2,3-dihydro-1λ⁶-benzothioph en-7-yl)acetam- ido]methyl}quinolin-2-yl)carbamate (Int. R-005) The title compound was prepared according the General Procedure 22, using N-(3-hydroxy- 1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)acetamide (Int. M-109, 0.081 g, 0.33 mmol, 1.0 eq.), tert-butyl N-[7-(bromomethyl)quinolin-2-yl]carbamate (Int. A-010, 0.139 g, 0.39 mmol, 1.2 eq.) and Cs ₂ CO ₃ (0.214 g, 0.66 mmol, 2.0 eq.) in anhydrous MeCN (4 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield tert-butyl Ryvu Therapeutics S.A. RVU305 569 R10107WO N-(7-{[N-(3-hydroxy-1,1-dioxo-2,3-dihydro-1λ⁶-benzothioph en-7-yl)acetamido]me- thyl}quinolin-2-yl)carbamate (Int. R-005, 0.066 g, 0.13 mmol, 37%, beige solid, UPLC purity: 91%). 5/4 Mixture of two distinguishable “diastereoisomer-like” components in DMSO-d ₆ at RT due to the concomitant presence of amide bond rotamers and the chiral carbon bearing the hydroxy substituent: Major component: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 4.9 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.66 (dd, J = 7.7, 3.6 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.42 (s, 1H), 7.35 (dd, J = 8.2, 1.5 Hz, 1H), 6.91 (dd, J = 19.6, 7.5 Hz, 1H), 6.44 (d, J = 6.3 Hz, 1H), 5.83 (d, J = 14.9 Hz, 1H), 5.43 (t, J = 6.5 Hz, 1H), 4.22 (d, J = 15.0 Hz, 1H), 4.14 (dd, J = 13.9, 7.2 Hz, 1H), 3.49 (dd, J = 9.2, 4.5 Hz, 1H), 1.83 (s, 3H), 1.49 (s, 9H). Minor component: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 8.27 (d, J = 5.4 Hz, 1H), 7.98 (d, J = 4.9 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.66 (dd, J = 7.7, 3.6 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.45 (s, 1H), 7.33 (dd, J = 8.4, 1.6 Hz, 1H), 6.91 (dd, J = 19.6, 7.5 Hz, 1H), 6.42 (d, J = 6.0 Hz, 1H), 5.83 (d, J = 14.9 Hz, 1H), 5.46 (t, J = 6.3 Hz, 1H), 4.22 (d, J = 15.0 Hz, 1H), 4.10 (dd, J = 14.1, 7.1 Hz, 1H), 3.45 (dd, J = 8.5, 4.1 Hz, 1H), 1.80 (s, 3H), 1.49 (s, 9H). m/z (ESI): 498.4 [M+H] ⁺ . tert-Butyl N-(7-{[N-(3-fluoro-1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophe n-7-yl)acetam- ido]methyl}quinolin-2-yl)carbamate (Int. R-006) DAST (0.033 g, 0.20 mmol, 2.0 eq.) was added dropwise to a solution of tert-butyl N-(7- {[N-(3-hydroxy-1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7- yl)acetamido]methyl}quinolin- 2-yl)carbamate (Int. R-005, 0.056 g, 0.10 mmol, 1.0 eq.) in anhydrous DCM (4.0 mL) at 0 °C. The mixture was stirred at RT under nitrogen for 3 h. The RM was then partitioned be- tween ice-cold water and DCM. The organic layer was washed with sat. aq. Na ₂ CO ₃ , dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 4% MeOH gradient in DCM) to yield tert-butyl N-(7-{[N-(3-fluoro- 1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)acetamido]me thyl}quinolin-2-yl)carbamate (Int. R-006, 0.034 g, 0.07 mmol, 65%, white solid, UPLC purity: 98%). 5/4 Mixture of two dis- tinguishable “diastereoisomer-like” components in DMSO-d ₆ at RT due to the concomitant presence of amide bond rotamers and the chiral carbon bearing the fluoro substituent: Ma- jor component: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 8.26 (d, J = 9.1 Hz, 1H), 8.00 (dd, J = 9.2, 2.3 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.69 (t, J = 7.9 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.42 (ddd, J = 52.4, 13.9, 5.7 Hz, 1H), 5.84 (d, J = 14.9 Hz, 1H), 4.20 (d, J = 14.5 Hz, 1H), 4.37 – 3.96 (m, 2H), 1.83 (s, 3H), 1.49 (s, 9H). Minor com- ponent: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 8.26 (d, J = 9.1 Hz, 1H), 8.03 – 7.94 (m, 1H), 7.87 – 7.80 (m, 2H), 7.69 (t, J = 7.9 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.42 (ddd, J = 52.6, 14.0, 5.5 Hz, 1H), 5.84 (d, J = 14.8 Hz, 1H), 4.20 (d, J = 14.6 Hz, 1H), 4.32 – 4.05 (m, 2H), 1.81 (s, 3H), 1.49 (s, 9H). m/z (ESI): 500.4 [M+H] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-(3-fluoro-1,1-dioxo-2,3-d ihydro-1λ⁶-benzothiophen- 7-yl)acetamide (Example H-003) A solution of tert-butyl N-(7-{[N-(3-fluoro-1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophe n-7- yl)acetamido]methyl}quinolin-2-yl)carbamate (Int. R-006, 0.034 g, 0.07 mmol, 1.0 eq.) in a mixture of DCM (4.0 mL) and TFA (0.1 mL) was stirred at RT for 3 h. The RM was parti- tioned between CHCl ₃ /iPrOH 3:1 v/v and sat. aq. NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified Ryvu Therapeutics S.A. RVU305 570 R10107WO via FCC (0 to 10% MeOH gradient in DCM) followed by preparative HPLC (FA buffer) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(3-fluoro-1,1-dioxo-2,3-d ihydro-1λ⁶-benzothio- phen-7-yl)acetamide (Example H-003, 0.005 g, 0.01 mmol, 16%, white solid, UPLC long elu- tion purity: 94.73%) as its formate salt.5/4 Mixture of two distinguishable “diastereoisomer- like” compounds in DMSO-d ₆ at RT due to the concomitant presence of amide bond rota- mers and the chiral carbon bearing the fluoro substituent: Major component: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.16 (s, 1H), 7.88 – 7.81 (m, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.5 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.42 (ddd, J = 52.0, 14.0, 5.6 Hz, 1H), 6.41 (s, 2H), 5.80 (d, J = 14.8 Hz, 1H), 4.31 – 4.04 (m, 2H), 4.14 (d, J = 14.2 Hz, 1H), 1.80 (s, 3H). Minor component: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.16 (s, 1H), 7.89 – 7.80 (m, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.42 (ddd, J = 52.0, 14.2, 5.3 Hz, 1H), 6.41 (s, 2H), 5.79 (d, J = 14.6 Hz, 1H), 4.31 – 4.05 (m, 2H), 4.14 (d, J = 14.4 Hz, 1H), 1.82 (s, 3H). m/z (ESI): 400.16 [M+H] ⁺ . Example H-004: N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(1,1-di oxo-2,3-dihy- dro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide 2-Bromo-5-(bromomethyl)-1-fluoro-3-nitrobenzene (Int. R-007) The title compound was prepared according to General Procedure 04, using 2-bromo-1- fluoro-5-methyl-3-nitrobenzene (0.765 g, 3.2 mmol, 1.0 eq.), (BzO) ₂ (0.075 g, 0.31 mmol, 0.095 eq.) and NBS (0.69 g, 3.88 mmol, 1.19 eq.) in CCl ₄ (13 mL), followed by diethyl phos- phite (0.42 mL, 3.2 mmol, 1.0 eq.) and DIPEA (0.57 mL, 3.2 mmol, 1.0 eq.) in THF (50 mL). The crude material was purified by FCC (0 to 10% DCM gradient in hexane) to yield 2- bromo-5-(bromomethyl)-1-fluoro-3-nitrobenzene (Int. R-007, 0.425 g, 1.36 mmol, 39%, yel- low oil, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (t, J = 1.7 Hz, 1H), 7.89 (dd, J = 9.1, 1.9 Hz, 1H), 4.76 (s, 2H). N-[(4-bromo-3-fluoro-5-nitrophenyl)methyl]-N-(1,1-dioxo-2,3- dihydro-1λ⁶-benzothiophen- 7-yl)pyridine-3-carboxamide (Int. R-008) Ryvu Therapeutics S.A. RVU305 571 R10107WO The title compound was prepared according to General Procedure 22, using N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide (Int. C-004, 0.7 g, 2.40 mmol, 1.0 eq.), 2-bromo-5-(bromomethyl)-1-fluoro-3-nitrobenzene (Int. R-007, 0.685 g, 2.0 mmol, 0.83 eq.) and Cs ₂ CO ₃ (0.865 g, 2.66 mmol, 1.10 eq.) in anhydrous MeCN (12 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-[(4-bromo-3- fluoro-5-nitrophenyl)methyl]-N-(1,1-dioxo-2,3-dihydro-1λ⁶ -benzothiophen-7-yl)pyridine-3- carboxamide (Int. R-008, 0.455 g, 0.87 mmol, 33%, beige solid, UPLC purity: 91%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 1.2 Hz, 1H), 8.46 (d, J = 4.8 Hz, 1H), 7.87 (s, 1H), 7.82 (dt, J = 8.1, 1.8 Hz, 1H), 7.70 (dd, J = 9.2, 1.9 Hz, 1H), 7.50 – 7.38 (m, 2H), 7.28 (dd, J = 7.5, 5.1 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 5.62 (d, J = 15.6 Hz, 1H), 4.76 (d, J = 15.6 Hz, 1H), 3.79 – 3.63 (m, 2H), 3.38 – 3.34 (m, 2H). m/z (ESI): 521.6 [M+H] ⁺ . N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(4-et henyl-3-fluoro-5-nitro- phenyl)methyl]pyridine-3-carboxamide (Int. R-009) The title compound was prepared according to General Procedure 28, using N-[(4-bromo-3- fluoro-5-nitrophenyl)methyl]-N-(1,1-dioxo-2,3-dihydro-1λ⁶ -benzothiophen-7-yl)pyridine-3- carboxamide (Int. R-008, 0.455 g, 0.80 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.25 g, 1.62 mmol, 2.0 eq.), Cs ₂ CO ₃ (0.78 g, 2.39 mmol, 3.0 eq.) and bis(tri- phenylphosphine)palladium(II)chloride (0.056 g, 0.08 mmol, 0.1 eq.) in a mixture of dioxane (8 mL) and water (2.7 mL). The crude material was purified by FCC (0 to 3% MeOH gradi- ent) to yield N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(4-et henyl-3-fluoro-5- nitrophenyl)methyl]pyridine-3-carboxamide (Int. R-009, 0.39 g, 0.83 mmol, 94%, beige solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (s, 1H), 8.46 (d, J = 4.8 Hz, 1H), 7.83 (dt, J = 7.9, 1.9 Hz, 1H), 7.77 (s, 1H), 7.60 (dd, J = 11.1, 1.7 Hz, 1H), 7.47 – 7.39 (m, 2H), 7.28 (dd, J = 7.4, 5.1 Hz, 1H), 7.13 (dd, J = 6.7, 1.6 Hz, 1H), 6.65 (dd, J = 17.8, 11.7 Hz, 1H), 5.76 (d, J = 18.3 Hz, 1H), 5.72 (d, J = 11.8 Hz, 1H), 5.66 (d, J = 15.5 Hz, 1H), 4.76 (d, J = 15.5 Hz, 1H), 3.82 – 3.63 (m, 2H), 3.41 – 3.33 (m, 2H). _m/z (ESI): 468.8 [M+H] ⁺ . N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(3-fl uoro-4-formyl-5-nitro- phenyl)methyl]pyridine-3-carboxamide (Int. R-010) The title compound was prepared according to General Procedure 29, using N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(4-ethenyl-3-fluor o-5-nitrophenyl)methyl]pyri- dine-3-carboxamide (Int. R-009, 0.385 g, 0.74 mmol, 1.0 eq.), NaIO ₄ (0.645 g, 3.02 mmol, 4.1 eq.) and 4% aq. OsO ₄ (0.48 mL, 0.08 mmol, 0.10 eq.) in a mixture of dioxane (7.5 mL) and water (1.5 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(3-fl uoro-4-formyl-5-nitro- phenyl)methyl]pyridine-3-carboxamide (Int. R-010, 0.325 g, 0.69 mmol, 84%, white foam, UPLC purity: 91%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.16 (s, 1H), 8.63 (s, 1H), 8.47 (d, J = 4.8 Hz, 1H), 7.96 (s, 1H), 7.83 (dt, J = 7.8, 1.7 Hz, 1H), 7.79 (d, J = 10.2 Hz, 1H), 7.50 – 7.39 (m, 2H), 7.29 (dd, J = 7.6, 4.7 Hz, 1H), 7.22 (d, J = 7.1 Hz, 1H), 5.65 (d, J = 15.9 Hz, 1H), 4.86 (d, J = 15.9 Hz, 1H), 3.81 – 3.64 (m, 2H), 3.37 (t, J = 7.0 Hz, 2H). _m/z (ESI): 470.7 [M+H] ⁺ . N-[(3-amino-5-fluoro-4-formylphenyl)methyl]-N-(1,1-dioxo-2,3 -dihydro-1λ⁶-benzothio- phen-7-yl)pyridine-3-carboxamide (Int. R-011) Ryvu Therapeutics S.A. RVU305 572 R10107WO The title compound was prepared according to General Procedure 30, using N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(3-fluoro-4-formyl -5-nitrophenyl)methyl]pyridine- 3-carboxamide (Int. R-010, 0.325 g, 0.623 mmol, 1.0 eq.), iron powder (0.35 g, 6.27 mmol, 10.1 eq.) and aq.1 M HCl (0.125 mL, 0.125 mmol, 0.20 eq.) in a mixture of EtOH (6.5 mL) and water (1.1 mL). The crude N-[(3-amino-5-fluoro-4-formylphenyl)methyl]-N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide (Int. R-011, 0.23 g, 0.52 mmol, 76%, brown solid, UPLC purity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 8.63 (d, J = 1.6 Hz, 2H), 8.47 (d, J = 4.9 Hz, 1H), 7.81 (dt, J = 8.1, 1.6 Hz, 1H), 7.55 (s, 1H), 7.42 (d, J = 7.3 Hz, 2H), 7.28 (dd, J = 8.0, 5.4 Hz, 1H), 7.02 (d, J = 6.9 Hz, 1H), 6.55 (s, 1H), 6.31 (d, J = 11.8 Hz, 1H), 5.65 (d, J = 15.7 Hz, 1H), 4.48 (d, J = 15.8 Hz, 1H), 3.83 – 3.65 (m, 2H), 3.37 (t, J = 7.2 Hz, 2H). m/z (ESI): 440.8 [M+H] ⁺ . ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -123.14 (d, J = 12.2 Hz). N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(1,1-di oxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)pyridine-3-carboxamide (Example H-004) The title compound was prepared according the General Procedure 32, using diethyl [chloro(cyano)methyl]phosphonate (Int. Q-021, 0.086 g, 0.366 mmol, 1.62 eq.), NaH (60% in mineral oil, 0.014 g, 0.365 mmol, 1.62 eq.) and N-[(3-amino-5-fluoro-4-formylphenyl)me- thyl]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyr idine-3-carboxamide (Int. R- 011, 0.11 g, 0.225 mmol, 1.0 eq.) in anhydrous THF (1.5 mL). The crude material was puri- fied by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(2-amino-3-chloro-5-fluoroquino- lin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothioph en-7-yl)pyridine-3-carboxamide (Example H-004, 0.056 g, 0.113 mmol, 50%, yellow solid, UPLC long elution purity: 99.58%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (s, 1H), 8.49 – 8.42 (m, 1H), 8.18 (d, J = 0.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.33 – 7.24 (m, 2H), 7.10 (s, 1H), 7.04 (m, 3H), 6.78 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 14.9 Hz, 1H), 4.72 (d, J = 14.9 Hz, 1H), 3.85 – 3.65 (m, 2H), 3.42 – 3.34 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -122.34 (d, J = 10.6 Hz). _m/z (ESI): 497.07 [M+H] ⁺ . Example H-005: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin- Ryvu Therapeutics S.A. RVU305 573 R10107WO N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridi n-3-yl)propanamide (Int. R- 012) The title compound was prepared according to General Procedure 22, using N-(2-me- thanesulfonylpyridin-3-yl)propanamide (Int. F-002, 0.7 g, 2.852 mmol, 1.0 eq.), 1-bromo-4- (bromomethyl)-2-nitrobenzene (1.262 g, 4.28 mmol, 1.5 eq.) and Cs ₂ CO ₃ (1.115 g, 3.42 mmol, 1.2 eq.) in anhydrous MeCN (14 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in cyclohexane) to yield N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)propanamide (Int. R-012, 0.962 g, 2.175 mmol, 66%, white solid, UPLC purity: 87%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (dd, J = 4.1, 2.0 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.76 – 7.73 (m, 2H), 7.48 (dd, J = 8.3, 2.1 Hz, 1H), 5.48 (d, J = 15.4 Hz, 1H), 4.24 (d, J = 15.5 Hz, 1H), 3.48 (s, 3H), 1.98 (q, J = 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H). m/z (ESI): 442.0 [M+H] ⁺ . N-[(4-ethenyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyri din-3-yl)propanamide (Int. R-013) The title compound was prepared according to General Procedure 28, using N-[(4-bromo-3- nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)propana mide (Int. R-012, 0.96 g, 1.89 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.582 g, 3.78 mmol, 2.0 eq.), Cs ₂ CO ₃ (1.846 g, 5.66 mmol, 3.0 eq.) and bis(triphenylphosphine)palladium(II)chloride (0.133 g, 0.19 mmol, 0.1 eq.) in a mixture of dioxane (22 mL) and water (6 mL). The crude material was purified by FCC (0 to 50% EtOAc in cyclohexane) to yield N-[(4-ethenyl-3-ni- trophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)propanami de (Int. R-013, 0.75 g, 1.93 mmol, 95%, off-white solid, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (dd, J = 4.6, 1.5 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.73 (dd, J = 8.2, 4.6 Hz, 1H), 7.67 (dd, J = 8.1, 1.5 Hz, 1H), 7.56 (dd, J = 8.0, 1.8 Hz, 1H), 6.98 (dd, J = 17.4, 11.0 Hz, 1H), 5.90 (dd, J = 17.3, 1.0 Hz, 1H), 5.55 (d, J = 15.8 Hz, 1H), 5.51 (d, J = 10.7 Hz, 1H), 4.23 (d, J = 15.3 Hz, 1H), 3.48 (s, 3H), 1.99 (q, J = 6.9 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). m/z (ESI): 390.2 [M+H] ⁺ . N-[(4-formyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)propanamide (Int. R- 014) The title compound was prepared according the General Procedure 29, using N-[(4-ethenyl- 3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)propa namide (Int. R-013, 0.5 g, 1.19 mmol, 1.0 eq.), NaIO ₄ (1.022 g, 4.78 mmol, 4.0 eq.) and 4% aq. OsO ₄ (0.030 mL, 0.12 mmol, 0.1 eq.) in a mixture of dioxane (10 mL) and water (3 mL). The crude material was purified by FCC (0 to 66% EtOAc gradient in cyclohexane) to yield N-[(4-formyl-3-nitro- phenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)propanamide (Int. R-014, 0.343 g, 0.88 mmol, 62%, brown solid, UPLC purity: 84%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 8.74 (dd, J = 4.0, 2.2 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.78 (dd, J = 7.7, 1.7 Hz, 1H), 7.76 – 7.74 (m, 2H), 5.57 (d, J = 15.7 Hz, 1H), 4.37 (d, J = 15.7 Hz, 1H), 3.49 (s, 3H), 2.01 (q, J = 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). _m/z (ESI): 414.3 [M+Na] ⁺ . N-[(3-amino-4-formylphenyl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)propanamide (Int. R-015) Ryvu Therapeutics S.A. RVU305 574 R10107WO The title compound was prepared according to General Procedure 30, using N-[(4-formyl-3- nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)propana mide (Int. R-014, 0.340 g, 0.73 mmol, 1.0 eq.), iron powder (0.407 g, 7.30 mmol, 10.0 eq.) and aq. 1 M HCl (0.15 mL, 0.15 mmol, 0.2 eq.) in a mixture of EtOH (5 mL) and water (1 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-[(3-amino-4- formylphenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)propan amide (Int. R-015, 0.277 g, 0.72 mmol, 99%, off-white solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 8.72 (dd, J = 4.6, 1.5 Hz, 1H), 7.74 (dd, J = 8.0, 4.6 Hz, 1H), 7.61 (dd, J = 8.1, 1.5 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.10 (s, 2H), 6.59 (s, 1H), 6.48 (dd, J = 8.0, 1.5 Hz, 1H), 5.55 (d, J = 15.3 Hz, 1H), 3.96 (d, J = 15.3 Hz, 1H), 3.49 (s, 3H), 1.99 (q, J = 7.2 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). m/z (ESI): 362.3 [M+H] ⁺ . N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)propanamide (Example H-005) The title compound was prepared according to General Procedure 32, using diethyl [chloro(cyano)methyl]phosphonate (Int. Q-021, 0.110 g, 0.47 mmol, 2.0 eq.), NaH (60% in mineral oil, 0.027 g, 0.70 mmol, 3.0 eq.) and N-[(3-amino-4-formylphenyl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)propanamide (Int. R-015, 0.09 g, 0.23 mmol, 1.0 eq.) in anhydrous THF (3 mL). The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)pro- panamide (Example H-005, 0.05 g, 0.12 mmol, 50%, yellow solid, UPLC long elution purity: 99.28%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (dd, J = 4.7, 1.5 Hz, 1H), 8.18 (s, 1H), 7.65 – 7.59 (m, 2H), 7.42 (dd, J = 8.1, 1.5 Hz, 1H), 7.23 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 6.74 (s, 2H), 5.72 (d, J = 14.9 Hz, 1H), 4.17 (d, J = 14.9 Hz, 1H), 3.49 (s, 3H), 1.99 (q, J = 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). m/z (ESI): 419.16 [M+H] ⁺ . Example H-006: N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3- yl)-6-methylpyridine-3-carboxamide N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridi n-3-yl)-6-methylpyridine-3- carboxamide (Int. R-016) Ryvu Therapeutics S.A. RVU305 575 R10107WO The title compound was prepared according to General Procedure 22, using N-(2-me- thanesulfonylpyridin-3-yl)-6-methylpyridine-3-carboxamide (Int. K-015, 0.65 g, 2.19 mmol, 1.0 eq.), 1-bromo-4-(bromomethyl)-2-nitrobenzene (0.968 g, 3.28 mmol, 1.5 eq.) and Cs ₂ CO ₃ (0.855 g, 2.62 mmol, 1.2 eq.) in anhydrous MeCN (11 mL). The crude material was purified by two consecutive FCCs (first: 0 to 3% MeOH gradient in DCM; second: 70 to 100% EtOAc gradient in hexane) to yield N-[(4-bromo-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyri- din-3-yl)-6-methylpyridine-3-carboxamide (Int. R-016, 0.879 g, 1.74 mmol, 70%, yellow foam, UPLC purity: 88%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 4.6 Hz, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.67 (dd, J = 8.1, 4.6 Hz, 1H), 7.59 (m, 2H), 7.13 (d, J = 8.1 Hz, 1H), 5.56 (d, J = 15.4 Hz, 1H), 4.70 (d, J = 15.5 Hz, 1H), 3.31 (s, 3H), 2.37 (s, 3H). m/z (ESI): 506.5 [M+H] ⁺ . N-[(4-ethenyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyri din-3-yl)-6-methylpyridine- 3-carboxamide (Int. R-017) The title compound was prepared according the General Procedure 28, using N-[(4-bromo- 3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-6-me thylpyridine-3-carboxamide (Int. R-016, 0.769 g, 1.34 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.413 g, 2.68 mmol, 2.0 eq.), Cs ₂ CO ₃ (1.310 g, 4.02 mmol, 3.0 eq.) and bis(tri- phenylphosphine)palladium(II)chloride (0.095 g, 0.14 mmol, 0.1 eq.) in a mixture of dioxane (14 mL) and water (4 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(4-ethenyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyri din-3-yl)-6- methylpyridine-3-carboxamide (Int. R-017, 0.64 g, 1.29 mmol, 97%, orange solid, UPLC pu- rity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J = 4.5 Hz, 1H), 8.39 (s, 1H), 7.93 (s, 1H), 7.85 (dd, J = 8.1, 1.5 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.70 – 7.48 (m, 3H), 7.13 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 17.3, 11.0 Hz, 1H), 5.91 (d, J = 17.3 Hz, 1H), 5.62 (d, J = 15.2 Hz, 1H), 5.52 (d, J = 11.1 Hz, 1H), 4.72 (d, J = 15.2 Hz, 1H), 3.31 (s, 3H), 2.37 (s, 3H). m/z (ESI): 453.9 [M+H] ⁺ . N-[(4-formyl-3-nitrophenyl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)-6-methylpyridine-3- carboxamide (Int. R-018) The title compound was prepared according to General Procedure 29, using N-[(4-ethenyl- 3-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-6-me thylpyridine-3-carboxamide (Int. R-017, 0.61 g, 1.24 mmol, 1.0 eq.), 4% aq. OsO ₄ (0.79 mL, 0.12 mmol, 0.1 eq.) and NaIO ₄ (1.065 g, 4.98 mmol, 4.01 eq.) in a mixture of dioxane (15 mL) and water (2.5 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(4-formyl-3-ni- trophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-6-methyl pyridine-3-carboxamide (Int. R-018, 0.485 g, 1.07 mmol, 70%, orange solid, UPLC purity: 81%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 8.62 (d, J = 4.6 Hz, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 7.93 (dd, J = 8.2, 1.5 Hz, 1H), 7.89 (s, 2H), 7.70 – 7.53 (m, 2H), 7.14 (d, J = 8.1 Hz, 1H), 5.64 (d, J = 15.6 Hz, 1H), 4.83 (d, J = 15.6 Hz, 1H), 3.31 (s, 3H), 2.37 (s, 3H). m/z (ESI): 455.8 [M+H] ⁺ . N-[(3-amino-4-formylphenyl)methyl]-N-(2-methanesulfonylpyrid in-3-yl)-6-methylpyridine- 3-carboxamide (Int. R-019) The title compound was prepared according to General Procedure 30, using N-[(4-formyl-3- nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-6-meth ylpyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 576 R10107WO (Int. R-018, 0.485 g, 0.87 mmol, 1.0 eq.), iron powder (0.484 g, 8.67 mmol, 10.03 eq.) and aq. 1 M HCl (0.22 mL, 0.22 mmol, 0.25 eq.) in a mixture of EtOH (8.6 mL) and water (1.5 mL). The obtained crude N-[(3-amino-4-formylphenyl)methyl]-N-(2-methanesulfonylpyrid in-3- yl)-6-methylpyridine-3-carboxamide (Int. R-019, 0.39 g, 0.92 mmol, 98%, yellow oil, UPLC purity: 92%) was used in the next step without further purification. ¹ H NMR (400 MHz, ^{DMSO-d6) δ 9.78 (s, 1H), 8.59 (d, J = 4.6 Hz, 1H), 8.42 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.66} _{– 7.56 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.15 (s, 3H), 6.74 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H),} 5.62 (d, J = 15.5 Hz, 1H), 4.43 (d, J = 15.5 Hz, 1H), 3.37 (s, 3H), 2.38 (s, 3H). m/z (ESI): 425.8 [M+H] ⁺ . N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3-yl)-6-methylpyr- idine-3-carboxamide (Example H-006) The title compound was prepared according to General Procedure 34, using N-[(3-amino-4- formylphenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-6-met hylpyridine-3-carboxamide (Int. R-019, 0.36 g, 0.78 mmol, 1.0 eq.), diethyl [cyano(fluoro)methyl]phosphonate (Int. Q- 033, 0.16 g, 0.82 mmol, 1.05 eq.) and EtONa (21% solution in EtOH, 0.274 mL, 1.17 mmol, 1.50 eq.) in absolute EtOH (7.8 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) followed by preparative HPLC (formic acid buffer) and aqueous Na ₂ CO ₃ free-basing to yield N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyri- din-3-yl)-6-methylpyridine-3-carboxamide (Example H-006, 0.075 g, 0.16 mmol, 20%, white powder, UPLC long elution purity: 99.23%). 8/2 mixture of restricted C-N amide rotation iso- mers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (d, J = 3.6 Hz, 1H), 8.39 (s, 1H), 7.79 (d, J = 11.7 Hz, 1H), 7.68 – 7.57 (m, 2H), 7.56 – 7.45 (m, 2H), 7.32 (s, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.80 (s, 2H), 5.79 (d, J = 14.7 Hz, 1H), 4.66 (d, J = 14.7 Hz, 1H), 3.34 (s, 3H), 2.36 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -134.78 (d, J = 11.8 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.77 (m, 1H), 8.64 (m, 1H), 8.08 – 7.91 (m, 1H), 7.85 – 7.73 (m, 1H), 7.69 – 7.39 (m, 4H), 7.27 – 7.16 (m, 1H), 7.12 (m, 1H), 6.81 (s, 2H), 5.17 (d, J = 15.9 Hz, 1H), 4.81 (d, J = 15.0 Hz, 1H), 3.38 (s, 3H), 2.54 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -134.38 – -134.65 (m). m/z (ESI): 466.17 [M+H] ⁺ . Example H-007: N-[(2-aminoquinolin-7-yl)methyl]-N-[(8R)-5,6,7,8-tetrahydroq uinolin-8- yl]pyridine-3-carboxamide and Example H-008: N-[(2-aminoquinolin-7-yl)methyl]-N-[(8S)- 5,6,7,8-tetrahydroquinolin-8-yl]pyridine-3-carboxamide The title compounds were obtained from rac-N-[(2-aminoquinolin-7-yl)methyl]-N-(5,6,7,8- tetrahydroquinolin-8-yl)pyridine-3-carboxamide (Example B-037) by HPLC chiral separation (column: CHIRAL MIF; mobile phase: isocratic hexane/EtOH 88:12; flow rate: 19 mL/min.; elution time: 350 min.). R configuration was attributed arbitrarily to the most active com- pound in the biochemical assay (Example H-007). Ryvu Therapeutics S.A. RVU305 577 R10107WO N-[(2-aminoquinolin-7-yl)methyl]-N-[(8R)-5,6,7,8-tetrahydroq uinolin-8-yl]pyridine-3-car- boxamide (Example H-007, 6 mg, white solid, UPLC long elution purity: 98.79%, chiral purity: 100%).8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rota- mer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (d, J = 2.2 Hz, 1H), 8.65 (dd, J = 4.9, 1.6 Hz, 1H), 8.51 (dd, J = 4.7, 1.6 Hz, 1H), 8.04 (dt, J = 7.8, 2.0 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.51 (dd, J = 7.9, 5.0 Hz, 1H), 7.39 (s, 1H), 7.25 (dd, J = 7.7, 4.7 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.54 (s, 2H), 5.02 – 4.96 (m, 1H), 4.94 (d, J = 16.1 Hz, 1H), 3.78 (d, J = 16.3 Hz, 1H), 2.79 – 2.72 (m, 1H), 2.71 – 2.64 (m, 1H), 2.26 – 2.16 (m, 1H), 1.98 – 1.77 (m, 2H), 1.65 – 1.50 (m, 1H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (dd, J = 3.5, 1.8 Hz, 1H), 8.52 – 8.50 (m, 1H), 8.49 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.74 (dt, J = 7.9, 1.7 Hz, 1H), 7.62 – 7.48 (m, 1H), 7.37 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 4.4 Hz, 1H), 7.33 (s, 1H), 7.21 (dd, J = 7.9, 4.6 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 9.2 Hz, 1H), 6.54 (s, 2H), 5.34 – 5.21 (m, 1H), 4.62 (d, J = 17.3 Hz, 1H), 4.44 (d, J = 17.4 Hz, 1H), 2.85 – 2.79 (m, 1H), 2.64 – 2.59 (m, 1H), 2.17 – 2.09 (m, 1H), 1.98 – 1.79 (m, 2H), 1.78 – 1.65 (m, 1H). m/z (ESI): 410.26 [M+H] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-[(8S)-5,6,7,8-tetrahydroq uinolin-8-yl]pyridine-3-car- boxamide (Example H-008, 10 mg, white solid, UPLC long elution purity: 100%, chiral purity: 96.90%). 8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major ro- tamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (d, J = 2.1 Hz, 1H), 8.65 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (dd, J = 4.7, 1.6 Hz, 1H), 8.04 (dt, J = 7.8, 2.0 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.51 (dd, J = 7.9, 4.8 Hz, 1H), 7.39 (s, 1H), 7.25 (dd, J = 7.7, 4.7 Hz, 1H), 7.14 (dd, J = 8.2, 1.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.50 (s, 2H), 5.02 – 4.96 (m, 1H), 4.94 (d, J = 16.0 Hz, 1H), 3.78 (d, J = 16.2 Hz, 1H), 2.77 (m, 1H), 2.71 – 2.64 (m, 1H), 2.26 – 2.16 (m, 1H), 1.98 – 1.77 (m, 2H), 1.65 – 1.50 (m, 1H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (dd, J = 3.5, 1.8 Hz, 1H), 8.52 – 8.50 (m, 1H), 8.49 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 9.7 Hz, 1H), 7.74 (dt, J = 7.9, 1.7 Hz, 1H), 7.61 – 7.47 (m, 1H), 7.37 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 4.4 Hz, 1H), 7.33 (s, 1H), 7.21 (dd, J = 7.9, 4.6 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.50 (s, 2H), 5.34 – 5.21 (m, 1H), 4.62 (d, J = 17.4 Hz, 1H), 4.44 (d, J = 17.4 Hz, 1H), 2.85 – 2.79 (m, 1H), 2.64 – 2.59 (m, 1H), 2.17 – 2.09 (m, 1H), 1.98 – 1.79 (m, 2H), 1.78 – 1.65 (m, 1H). m/z (ESI): 410.27 [M+H] ⁺ . Example H-009: N-[(2-aminoquinolin-7-yl)(²H₂)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4-dihy- dro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide Ryvu Therapeutics S.A. RVU305 578 R10107WO N-[(2-chloroquinolin-7-yl)(²H₂)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)pyridine-3-carboxamide (Int. R-020) The title compound was prepared according to General Procedure 33, using N-(4,4-difluoro- 1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine -3-carboxamide (Int. M-044, 0.21 g, 0.366 mmol, 1.0 eq.), (2-chloroquinolin-7-yl)(²H₂)methanol (Int. A-015, 0.080 g, 0.40 mmol, 1.1 eq.), triphenylphosphine (0.125 g, 0.48 mmol, 1.3 eq.) and DIAD (0.096 g, 0.48 mmol, 1.3 eq.) in anhydrous THF (1.5 mL). The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-chloroquinolin-7-yl)(²H₂)methyl]-N-(4,4- difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl )pyridine-3-carboxamide (Int. R-020, 0.04 g, 0.08 mmol, 21%, off-white solid, UPLC purity: 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 8.46 (m, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.81 – 7.72 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 8.5 Hz, 1H), 7.26 (dd, J = 7.8, 5.1 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.11 – 3.93 (m, 2H), 3.03 (s, 2H). m/z (ESI): 517.3 [M+H] ⁺ . N-[(2-aminoquinolin-7-yl)(²H₂)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)pyridine-3-carboxamide (Example H-009) The title compound was prepared according to General Procedure 25, using N-[(2-chloro- quinolin-7-yl)(²H₂)methyl]-N-(4,4-difluoro-1,1-dioxo-3,4- dihydro-2H-1λ⁶-benzothiopyran- 8-yl)pyridine-3-carboxamide (Int. R-020, 0.04 g, 0.075 mmol, 1.0 eq.), Cs ₂ CO ₃ (0.037 g, 0.11 mmol, 1.5 eq.), XPhos (0.004 g, 0.01 mmol, 0.1 eq.) and Pd(OAc) ₂ (0.001 g, 0.002 mmol, 0.05 eq.) in anhydrous dioxane (5 mL), followed by treatment in a mixture of DCM (1 mL) and TFA (0.02 mL). The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)(²H₂)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4-dihydro-2H- 1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide (Example H-009, 0.005 g, 0.01 mmol, 15% yield, white solid, UPLC long elution purity: 98.09%). 75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.44 (d, J = 4.7 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.77 – 7.70 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.52 (t, J = 8.2 Hz, 1H), 7.26 (s, 1H), 7.24 (dd, J = 8.3, 5.0 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.44 (s, 2H), 4.07 – 3.87 (m, 2H), 3.16 – 2.84 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -80.44 (ddd, J = 273.4, 22.9, 12.0 Hz), -85.09 (ddd, J = 275.2, 12.3, 8.9 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (m, 1H), 8.78 – 8.66 (m, 1H), 8.19 – 8.05 (m, 1H), 7.92 – 7.80 (m, 2H), 7.78 – 7.64 (m, 1H), 7.65 – 7.46 (m, 2H), 7.19 – 7.08 (m, 1H), 7.07 – 6.99 (m, 1H), 6.93 – 6.85 (m, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.47 (s, 2H), 4.08 – 3.88 (m, 2H), 3.03 (s, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -83.04 (ddd, J = 271.4, 21.6, 11.3 Hz), -85.30 (d, J = 273.3 Hz). m/z (ESI): 497.15 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 579 R10107WO Example H-010: rac- N-[(2-aminoquinolin-7-yl)methyl]-N-(5,6,7,8-tetrahydroquinox alin-5- yl)pyridine-3-carboxamide 5,6,7,8-tetrahydroquinoxalin-1-ium-1-olate (Int. R-021) 5,6,7,8-Tetrahydroquinoxaline (2.5 g, 18.63 mmol, 1.0 eq.) was dissolved in DCM (34.0 mL). The solution was placed under nitrogen, cooled to 3 °C and mCPBA (3.86 g, 22.37 mmol, 1.20 eq.) was added in small portions over a time period of 60 min. During addition the reac- tion mixture was kept below 5 °C. After addition completion, the resulting turbid white slurry was allowed to slowly reach RT overnight. Aqueous 10% Na ₂ S ₂ O ₃ was added dropwise to the stirring RM over 20 min., sat. aq. NaHCO ₃ was added and the mixture was stirred until no more gas evolved (about for 15 min.). The organic layer was separated and washed with aq. sat. NaHCO ₃ . The combined aqueous were extracted with DCM (3x). The combined or- ganic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield 5,6,7,8-tetrahydro- quinoxalin-1-ium-1-olate (Int. R-021, 2.02 g, 13.45 mmol, 69%, white solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J = 4.1 Hz, 1H), 8.21 (d, J = 4.0 Hz, 1H), 2.84 (t, J = 5.9 Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 1.90 – 1.72 (m, 4H). m/z (ESI): 151.3 [M+H] ⁺ . Rac-5,6,7,8-tetrahydroquinoxalin-5-ol (Int. R-022) TFAA (8.055 g, 38.35 mmol, 3.0 eq.) was added dropwise to a solution of 5,6,7,8-tetrahydro- quinoxalin-1-ium-1-olate (Int. R-021, 2.02 g, 12.78 mmol, 1.0 eq.) in anhydrous DCM (22.0 mL) at 0 °C under nitrogen over a period of 30 min. The RM was stirred for 17 h, being al- lowed to slowly reach RT, before being concentrated in vacuo. The residue was taken up in DCM (15 mL), aq.2 N LiOH (13 mL) was added dropwise, and the RM was rapidly stirred at RT for 1 h. The RM was partitioned between brine and DCM and the aqueous layer was ex- tracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane followed by 0 to 10% MeOH gradient in EtOAc) to yield rac-5,6,7,8-tetra- hydroquinoxalin-5-ol (Int. R-022, 0.41 g, 2.73 mmol, 19%, black solid, UPLC purity: 93%). ¹ H ^{NMR (400 MHz, DMSO-d6) δ 8.49 – 8.43 (m, 2H), 5.37 (s, 1H), 4.64 (t, J = 4.7 Hz, 1H), 2.97} _{– 2.73 (m, 2H), 2.07 – 1.94 (m, 1H), 1.94 – 1.83 (m, 2H), 1.82 – 1.72 (m, 1H). m/z (ESI): 151.1} [M+H] ⁺ . 5,6,7,8-tetrahydroquinoxalin-5-one (Int. R-023) Ryvu Therapeutics S.A. RVU305 580 R10107WO Dess-Martin periodinane (1.2 g, 2.83 mmol, 1.15 eq.) was added portionwise over 15 min. to a solution of rac-5,6,7,8-tetrahydroquinoxalin-5-ol (Int. R-022, 0.41 g, 2.46 mmol, 1.0 eq.) in anhydrous DCM (8.5 mL) at 5 °C. The RM was stirred overnight under nitrogen, being al- lowed to slowly reach RT. The reaction was quenched by addition of sat. aq. Na ₂ S ₂ O ₃ (10 mL) followed by aq. sat. NaHCO ₃ (10 mL) and the mixture was stirred at RT for 5 min. The phases were separated and the aqueous layer was extracted with DCM (3x) and CHCl ₃ /iPrOH 3:1 v/v (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield 5,6,7,8-tetrahydroquinoxalin-5-one (Int. R- 023, 0.38 g, 2.56 mmol, 94%, brown oil, UPLC purity: 80%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (d, J = 2.3 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 3.16 (t, J = 6.2 Hz, 2H), 2.76 (dd, J = 7.4, 5.8 Hz, 2H), 2.15 (p, J = 6.4 Hz, 2H). m/z (ESI): 149.1 [M+H] ⁺ . Rac-N-[(2-chloroquinolin-7-yl)methyl]-5,6,7,8-tetrahydroquin oxalin-5-amine (Int. R-024) A mixture of 5,6,7,8-tetrahydroquinoxalin-5-one (Int. R-023, 0.18 g, 1.09 mmol, 1.0 eq.), 1- (2-chloroquinolin-7-yl)methanamine (Int. A-073, 0.305 g, 1.20 mmol, 1.1 eq.), acetic acid (0.085 mL, 1.49 mmol, 1.36 eq.) and MeOH (11.0 mL) was stirred at 60 °C for 3 h. NaBH ₃ CN (0.1 g, 1.67 mmol, 1.53 eq.) was added and the mixture was stirred at RT for 16 h. The RM was concentrated in vacuo and the crude material was purified by FCC (NH ₂ func- tionalized silica, 0 to 100% EtOAc gradient in hexane followed by 0 to 20% MeOH gradient in EtOAc) to afford rac-N-[(2-chloroquinolin-7-yl)methyl]-5,6,7,8-tetrahydroquin oxalin-5- amine (Int. R-024, 0.27 g, 0.75 mmol, 68%, beige oil, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 2.5 Hz, 1H), 8.45 (d, J = 2.6 Hz, 1H), 8.42 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 1.1 Hz, 1H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 4.17 – 4.02 (m, 2H), 3.80 (t, J = 5.4 Hz, 1H), 3.07 – 2.98 (m, 1H), 2.98 – 2.79 (m, 2H), 2.12 – 1.98 (m, 2H), 1.95 – 1.67 (m, 2H). m/z (ESI): 325.3 [M+H] ⁺ . N-[(2-chloroquinolin-7-yl)methyl]-N-(5,6,7,8-tetrahydroquino xalin-5-yl)pyridine-3-carbox- amide (Int. R-025) The title compound was prepared according to General Procedure 09, using rac-N-[(2-chlo- roquinolin-7-yl)methyl]-5,6,7,8-tetrahydroquinoxalin-5-amine (Int. R-024, 0.27 g, 0.75 mmol, 1.0 eq.), nicotinoyl chloride hydrochloride (0.27 g, 1.52 mmol, 2.03 eq.) and DMAP (0.025 g, 0.21 mmol, 0.27 eq.) in anhydrous pyridine (4.0 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield rac-N-[(2-chloroquinolin-7-yl)methyl]-N-(5,6,7,8- tetrahydroquinoxalin-5-yl)pyridine-3-carboxamide (Int. R-025, 0.198 g, 0.46 mmol, 60%, beige semi oil, UPLC purity: 97%).8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.86 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 4.9, 1.6 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.43 (d, J = 8.6 Hz, 1H), 8.08 (dt, J = 8.0, 2.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.65 (dd, J = 8.3, 1.7 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.51 (dd, J = 7.8, 4.8 Hz, 1H), 5.13 (dd, J = 11.3, 5.9 Hz, 1H), 4.97 (d, J = 16.5 Hz, 1H), 4.12 (d, J = 16.5 Hz, 1H), 2.99 – 2.91 (m, 1H), 2.76 (m, 1H), 2.32 – 2.24 (m, 1H), 2.01 (m, 1H), 1.98 – 1.85 (m, 1H), 1.80 – 1.67 (m, 1H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 – 8.51 (m, 2H), 8.43 (m, 2H), 8.03 – 7.96 (m, 1H), 7.76 (dt, J = 7.8, 1.6 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J = 8.7 Hz, 3H), 7.36 (dd, J = 7.8, 5.2 Hz, 1H), 5.32 – 5.17 (m, 1H), 4.80 (d, J = 17.7 Hz, 1H), 4.72 (d, J = 17.5 Hz, 1H), 2.99 (dd, J = 12.5, 5.4 Hz, Ryvu Therapeutics S.A. RVU305 581 R10107WO 1H), 2.92 – 2.82 (m, 1H), 2.26 – 2.14 (m, 1H), 2.08 – 1.97 (m, 1H), 1.92 (m, 1H), 1.75 (t, J = 13.1 Hz, 1H). m/z (ESI): 431.5 [M+H] ⁺ . rac-N-[(2-aminoquinolin-7-yl)methyl]-N-(5,6,7,8-tetrahydroqu inoxalin-5-yl)pyridine-3-car- boxamide (Example H-010) The title compound was prepared according to General Procedure 24, using N-[(2-chloro- quinolin-7-yl)methyl]-N-(5,6,7,8-tetrahydroquinoxalin-5-yl)p yridine-3-carboxamide (Int. R- 025, 0.19 g, 0.43 mmol, 1.0 eq.), tert-butyl carbamate (0.11 g, 0.939 mmol, 2.19 eq.), Cs ₂ CO ₃ (0.22 g, 0.67 mmol, 1.58 eq.), XPhos (0.022 g, 0.05 mmol, 0.11 eq.) and XPhos Pd G3 (0.04 g, 0.047 mmol, 0.11 eq.) in anhydrous dioxane (4.5 mL), followed by treatment with 33% TFA in DCM (5 mL). The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield rac-N-[(2-aminoquinolin-7-yl)methyl]-N-(5,6,7,8-tetrahydroqu inoxalin-5-yl)pyridine-3- carboxamide (Example H-010, 0.124 g, 0.30 mmol, 70%, white solid, UPLC long elution pu- rity: 99.73%). 7/3 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (d, J = 2.1 Hz, 1H), 8.66 (dd, J = 4.9, 1.7 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 2.5 Hz, 1H), 8.01 (dt, J = 7.9, 2.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.51 (dd, J = 7.8, 4.9 Hz, 1H), 7.37 (s, 1H), 7.12 (dd, J = 8.1, 1.7 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.40 (s, 2H), 5.09 (dd, J = 11.3, 5.9 Hz, 1H), 4.92 (d, J = 16.2 Hz, 1H), 3.88 (d, J = 16.2 Hz, 1H), 2.93 (dd, J = 12.1, 5.3 Hz, 1H), 2.75 (dd, J = 17.3, 3.8 Hz, 1H), 2.28 – 2.19 (m, 1H), 2.05 – 1.95 (m, 1H), 1.95 – 1.86 (m, 1H), 1.78 – 1.63 (m, 1H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 – 8.53 (m, 2H), 8.52 (d, J = 2.5 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.76 (dt, J = 8.0, 1.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.42 – 7.36 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.46 (s, 2H), 5.16 (s, 1H), 4.67 (d, J = 17.2 Hz, 1H), 4.60 (d, J = 17.5 Hz, 1H), 2.97 (dd, J = 12.1, 5.6 Hz, 1H), 2.90 – 2.80 (m, 1H), 2.25 (m, 1H), 2.18 – 2.08 (m, 1H), 2.06 – 1.95 (m, 1H), 1.84 – 1.74 (m, 1H). m/z (ESI): 412.40 [M+H] ⁺ . Example H-011: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4- dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide N-[(4-bromo-3-nitrophenyl)methyl]-N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)pyridine-3-carboxamide (Int. R-026) The title compound was prepared according to General Procedure 22, using 1-bromo-4- (bromomethyl)-2-nitrobenzene (0.388 g, 1.32 mmol, 1.5 eq.), N-(4,4-difluoro-1,1-dioxo-3,4- Ryvu Therapeutics S.A. RVU305 582 R10107WO dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide (Int. M-044, 0.3 g, 0.88 mmol, 1.0 eq.) and Cs ₂ CO ₃ (0.429 g, 1.32 mmol, 1.5 eq.) in anhydrous MeCN (7 mL). The crude ma- terial was purified by FCC (0 to 3% MeOH gradient in DCM) to yield N-[(4-bromo-3-nitro- phenyl)methyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ� ��-benzothiopyran-8-yl)pyri- dine-3-carboxamide (Int. R-026, 0.31 g, 0.561 mmol, 60%, yellow solid, UPLC purity: 94%). 9/1 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (s, 1H), 8.45 (d, J = 4.3 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.58 (dd, J = 8.7, 1.9 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.26 (dd, J = 8.0, 4.8 Hz, 1H), 5.68 (d, J = 15.4 Hz, 1H), 4.61 (d, J = 15.4 Hz, 1H), 3.96 (dd, J = 7.6, 4.7 Hz, 2H), 3.12 – 2.88 (m, 2H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 – 8.81 (m, 1H), 8.76 – 8.65 (m, 1H), 8.12 – 8.03 (m, 1H), 7.94 – 7.84 (m, 2H), 7.84 – 7.73 (m, 2H), 7.62 – 7.50 (m, 1H), 7.44 – 7.32 (m, 2H), 5.13 (d, J = 14.3 Hz, 1H), 4.82 (d, J = 15.1 Hz, 1H), 3.99 – 3.92 (m, 2H), 3.14 – 2.88 (m, 2H). m/z (ESI): 552.2 [M+H] ⁺ . N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyr an-8-yl)-N-[(4-ethenyl-3-nitro- phenyl)methyl]pyridine-3-carboxamide (Int. R-027) The title compound was prepared according to General Procedure 28, using N-[(4-bromo-3- nitrophenyl)methyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H -1λ⁶-benzothiopyran-8- yl)pyridine-3-carboxamide (Int. R-026, 0.25 g, 0.43 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5-tetra- methyl-1,3,2-dioxaborolane (0.131 g, 0.85 mmol, 2.0 eq.), Cs ₂ CO ₃ (0.416 g, 1.28 mmol, 3.0 eq.) and bis(triphenylphosphine)palladium(II)chloride (0.030 g, 0.04 mmol, 0.1 eq.) in a mix- ture of dioxane (3 mL) and water (1 mL). The crude material was purified by FCC (0 to 3% MeOH gradient in DCM) to yield N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothi- opyran-8-yl)-N-[(4-ethenyl-3-nitrophenyl)methyl]pyridine-3-c arboxamide (Int. R-027, 0.2 g, 0.4 mmol, 85%, yellow solid, UPLC purity: 91%). 8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (s, 1H), 8.45 (d, J = 3.6 Hz, 1H), 7.93 (s, 1H), 7.83 – 7.74 (m, 3H), 7.70 – 7.60 (m, 2H), 7.38 (d, J = 7.9 Hz, 1H), 7.26 (dd, J = 7.1, 4.2 Hz, 1H), 6.99 (dd, J = 17.3, 11.0 Hz, 1H), 5.91 (d, J = 17.3 Hz, 1H), 5.75 (d, J = 15.1 Hz, 1H), 5.52 (d, J = 11.1 Hz, 1H), 4.62 (d, J = 15.3 Hz, 1H), 4.00 – 3.89 (m, 2H), 3.13 – 2.90 (m, 2H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.94 – 8.80 (m, 1H), 8.77 – 8.64 (m, 1H), 8.14 – 8.01 (m, 1H), 7.71 – 7.60 (m, 2H), 7.63 – 7.42 (m, 5H), 7.41 – 7.29 (m, 1H), 5.91 (d, J = 17.3 Hz, 1H), 5.52 (d, J = 11.1 Hz, 1H), 5.16 (d, J = 16.6 Hz, 1H), 4.83 (d, J = 15.8 Hz, 1H), 4.01 – 3.88 (m, 2H), 3.15 – 2.87 (m, 2H). m/z (ESI): 500.8 [M+H] ⁺ . N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyr an-8-yl)-N-[(4-formyl-3-nitro- phenyl)methyl]pyridine-3-carboxamide (Int. R-028) The title compound was prepared according to General Procedure 29, using N-(4,4-difluoro- 1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-N-[(4-e thenyl-3-nitrophenyl)me- thyl]pyridine-3-carboxamide (Int. R-027, 0.2 g, 0.36 mmol, 1.0 eq.), 4% aq. OsO ₄ (0.229 mL, 0.04 mmol, 0.1 eq) and NaIO ₄ (0.308 g, 1.44 mmol, 4.0 eq) in a mixture of dioxane (5 mL) and water (1 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyr an-8-yl)-N-[(4-formyl-3- nitrophenyl)methyl]pyridine-3-carboxamide (Int. R-028, 0.15 g, 0.27 mmol, 75%, yellow solid, UPLC purity: 81%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.23 (s, 1H), 8.60 (s, 1H), 8.46 (d, J = Ryvu Therapeutics S.A. RVU305 583 R10107WO 3.9 Hz, 1H), 8.14 (s, 1H), 7.89 (s, 2H), 7.85 – 7.74 (m, 2H), 7.70 – 7.58 (m, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.27 (dd, J = 7.4, 4.6 Hz, 1H), 5.75 (d, J = 15.6 Hz, 1H), 4.75 (d, J = 15.8 Hz, 1H), 4.01 – 3.93 (m, 2H), 3.13 – 2.90 (m, 2H). m/z (ESI): 502.9 [M+H] ⁺ . N-[(3-amino-4-formylphenyl)methyl]-N-(4,4-difluoro-1,1-dioxo -3,4-dihydro-2H-1λ⁶-ben- zothiopyran-8-yl)pyridine-3-carboxamide (Int. R-029) The title compound was prepared according to General Procedure 30, using N-(4,4-difluoro- 1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-N-[(4-f ormyl-3-nitrophenyl)me- thyl]pyridine-3-carboxamide (Int. R-028, 0.15 g, 0.27 mmol, 1.0 eq.), iron powder (0.150 g, 2.69 mmol, 10.0 eq) and aq.1M HCl (0.054 mL, 0.054 mmol, 0.20 eq.) in a mixture of EtOH (5 mL) and water (1 mL). The crude material was purified by FCC (0 to 100% EtOAc gradi- ent in hexane) to yield N-[(3-amino-4-formylphenyl)methyl]-N-(4,4-difluoro-1,1-dioxo -3,4- dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide (Int. R-029, 0.09 g, 0.18 mmol, 68%, yellow solid, UPLC purity: 96%).75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.46 (dd, J = 5.2, 1.5 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.76 (dt, J = 8.1, 1.5 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.26 (dd, J = 8.0, 4.8 Hz, 1H), 7.17 (s, 2H), 6.76 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.73 (d, J = 15.6 Hz, 1H), 4.39 (d, J = 15.6 Hz, 1H), 4.00 – 3.89 (m, 2H), 3.15 – 2.90 (m, 2H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.76 (s, 1H), 8.91 (s, 1H), 8.71 (d, J = 3.6 Hz, 1H), 8.09 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.69 – 7.54 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 7.3 Hz, 1H), 7.17 (s, 2H), 6.65 (s, 1H), 6.39 (d, J = 7.7 Hz, 1H), 5.01 (d, J = 16.9 Hz, 1H), 4.57 (d, J = 16.8 Hz, 1H), 3.96 (d, J = 5.1 Hz, 2H), 3.14 – 2.90 (m, 2H). _m/z (ESI): 472.9 [M+H] ⁺ . N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4,4-difluoro-1, 1-dioxo-3,4-dihydro-2H-1λ⁶- benzothiopyran-8-yl)pyridine-3-carboxamide (Example H-011) The title compound was prepared according to General Procedure 32, using diethyl [chloro(cyano)methyl]phosphonate (Int. Q-021, 0.086 g, 0.37 mmol, 2.0 eq.), N-[(3-amino-4- formylphenyl)methyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2 H-1λ⁶-benzothiopyran-8- yl)pyridine-3-carboxamide (Int. R-029, 0.09 g, 0.18 mmol, 1.0 eq.) and NaH (60% in mineral oil, 0.021mg, 0.55 mmol, 3.0 eq.) in anhydrous THF (6 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(2-amino-3-chloroquinolin-7-yl)me- thyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzot hiopyran-8-yl)pyridine-3-carbox- amide (Example H-011, 0.057 g, 0.11 mmol, 58%, beige solid, UPLC long elution purity: 99.87%). 75/25 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 8.44 (d, J = 4.8 Hz, 1H), 8.20 (s, 1H), 7.79 – 7.71 (m, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.28 – 7.18 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.76 (s, 2H), 5.93 (d, J = 14.9 Hz, 1H), 4.59 (d, J = 14.9 Hz, 1H), 4.06 – 3.89 (m, 2H), 3.15 – 2.87 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -80.52 (ddd, J = 273.9, 22.4, 11.9 Hz), -85.07 (ddd, J = 273.6, 10.9, 7.6 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 – 8.86 (m, 1H), 8.78 – 8.65 (m, 1H), 8.20 (s, 1H), 8.16 – 8.03 (m, 1H), 7.92 – 7.81 (m, 1H), 7.80 – 7.68 (m, 1H), 7.65 (m, 2H), 7.16 – 7.06 (m, 2H), 7.05 – 6.95 (m, 1H), 6.76 (s, 2H), 5.19 (d, J = 15.9 Hz, 1H), 4.79 (d, J = 15.9 Hz, 1H), 4.07 – 3.89 (m, 2H), 3.16 Ryvu Therapeutics S.A. RVU305 584 R10107WO – 2.86 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -83.07 (d, J = 280.7 Hz), -85.27 (d, J = 270.0 Hz). m/z (ESI): 529.09 [M+H] ⁺ . Example H-012: N-[(6-amino-7-chloro-1,5-naphthyridin-3-yl)methyl]-N-(1,1-di oxo-2,3-di- hydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide 2-bromo-5-(bromomethyl)-3-nitropyridine (Int. R-030) A mixture of 2-bromo-5-methyl-3-nitropyridine (2.0 g, 9.22 mmol, 1.0 eq.), AIBN (0.303 g, 1.84 mmol, 0.2 eq.) and NBS (1.968 g, 11.06 mmol, 1.2 eq.) in DMC (18.5 mL) was stirred at reflux for 21 h. After coming back to RT, the RM was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (x2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 20% EtOAc gradient in hexane) to yield 2-bromo-5-(bromomethyl)-3-nitropyridine (Int. R-030, 2.15 g, 5.60 mmol, 61%, pale yellow oil, UPLC purity: 77%). ¹ H NMR (400 MHz, Chloroform-d) δ 8.62 (d, J = 2.3 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 4.50 (d, J = 0.5 Hz, 2H). m/z (ESI): 296.8 [M+H] ⁺ . N-[(6-bromo-5-nitropyridin-3-yl)methyl]-N-(1,1-dioxo-2,3-dih ydro-1λ⁶-benzothiophen-7- yl)pyridine-3-carboxamide (Int. R-031) The title compound was prepared according to General Procedure 22, using N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide (Int. C-004, 0.866 g, 2.97 mmol, 1.0 eq.), 2-bromo-5-(bromomethyl)-3-nitropyridine (Int. R-030, 1.979 g, 5.15 mmol, 1.73 eq.) and Cs ₂ CO ₃ (1.162 g, 3.57 mmol, 1.2 eq.) in anhydrous MeCN (15.0 mL). The crude material was purified by FCC (0 to 100% EtOAc in hexane/DCM 95:5 v/v) to yield N-[(6- bromo-5-nitropyridin-3-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1 λ⁶-benzothiophen-7-yl)pyri- dine-3-carboxamide (Int. R-031, 1.16 g, 2.17 mmol, 73%, beige foam, UPLC purity: 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (m, 2H), 8.49 – 8.43 (m, 2H), 7.81 (dt, J = 8.1, 1.7 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.44 (dd, J = 7.6, 1.0 Hz, 1H), 7.27 (dd, J = 7.9, 5.0 Hz, 1H), 7.19 (dd, J = 7.2, 1.5 Hz, 1H), 5.60 (d, J = 15.4 Hz, 1H), 4.82 (d, J = 15.4 Hz, 1H), 3.80 – 3.61 (m, 2H), 3.36 (t, J = 7.1 Hz, 2H). m/z (ESI): 504.5 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 585 R10107WO N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(6-et henyl-5-nitropyridin-3-yl)me- thyl]pyridine-3-carboxamide (Int. R-032) The title compound was prepared according to General Procedure 28, using N-[(6-bromo-5- nitropyridin-3-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-be nzothiophen-7-yl)pyridine-3-car- boxamide (Int. R-031, 1.16 g, 2.17 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-diox- aborolane (0.667 g, 4.33 mmol, 2.0 eq.), bis(triphenylphosphine)palladium(II)chloride (0.152 g, 0.22 mmol, 0.1 eq.), Cs ₂ CO ₃ (2.118 g, 6.50 mmol, 3.0 eq.) in a mixture of dioxane (24.0 mL) and water (8.0 mL). The crude material was purified by FCC (silica 15 ^m, 0 to 3% MeOH gradient in DCM) to yield N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(6-et h- enyl-5-nitropyridin-3-yl)methyl]pyridine-3-carboxamide (Int. R-032, 0.644 g, 1.43 mmol, 63%, beige solid, UPLC purity: 96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J = 1.6 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 4.8 Hz, 1H), 8.32 (d, J = 1.7 Hz, 1H), 7.82 (dt, J = 7.9, 1.8 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.27 (dd, J = 7.5, 5.1 Hz, 1H), 7.15 (dd, J = 16.7, 10.6 Hz, 1H), 7.12 – 7.09 (m, 1H), 6.52 (dd, J = 16.8, 2.1 Hz, 1H), 5.74 (dd, J = 10.6, 2.1 Hz, 1H), 5.67 (d, J = 15.3 Hz, 1H), 4.82 (d, J = 15.3 Hz, 1H), 3.82 – 3.65 (m, 2H), 3.37 (t, J = 7.0 Hz, 2H). m/z (ESI): 451.8 [M+H] ⁺ . N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(6-fo rmyl-5-nitropyridin-3-yl)me- thyl]pyridine-3-carboxamide (Int. R-033) The title compound was prepared according to General Procedure 29, using N-(1,1-dioxo- 2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(6-ethenyl-5-nitro pyridin-3-yl)methyl]pyridine-3- carboxamide (Int. R-032, 0.59 g, 1.26 mmol, 1.0 eq.), aq.4% OsO4 (0.552 mL, 0.09 mmol, 0.07 eq.) and of NaIO ₄ (1.076 g, 5.03 mmol, 4.0 eq.) in a mixture of dioxane (12 mL) and wa- ter (2 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(6-fo rmyl-5-nitropyridin-3- yl)methyl]pyridine-3-carboxamide (Int. R-033, 0.25 g, 0.48 mmol, 38%, white solid, UPLC purity: 86%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 8.96 (d, J = 1.7 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.47 (d, J = 4.7 Hz, 1H), 7.83 (dt, J = 7.9, 1.6 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 8.0, 4.8 Hz, 1H), 7.23 (dd, J = 7.1, 1.4 Hz, 1H), 5.68 (d, J = 15.7 Hz, 1H), 4.95 (d, J = 15.8 Hz, 1H), 3.81 – 3.64 (m, 2H), 3.37 (t, J = 7.0 Hz, 2H). m/z (ESI): 453.6 [M+H] ⁺ . N-[(5-amino-6-formylpyridin-3-yl)methyl]-N-(1,1-dioxo-2,3-di hydro-1λ⁶-benzothiophen-7- yl)pyridine-3-carboxamide (Int. R-034) The title compound was prepared according to General Procedure 30, using N-(1,1-dioxo-2,3-dihydro-1λ⁶-benzothiophen-7-yl)-N-[(6-fo rmyl-5-nitropyridin-3-yl)me- thyl]pyridine-3-carboxamide (Int. R-033, 0.25 g, 0.47 mmol, 1.0 eq.), iron powder (0.26 g, 4.66 mmol, 9.8 eq.) and 1 M HCl (0.1 mL, 0.1 mmol, 0.2 eq.) in a mixture of EtOH (5 mL) and water (1 mL). The crude material was purified by FCC (0 to 7% MeOH gradient in DCM) to afford N-[(5-amino-6-formylpyridin-3-yl)methyl]-N-(1,1-dioxo-2,3-di hydro-1λ⁶-benzothio- phen-7-yl)pyridine-3-carboxamide (Int. R-034, 0.077 g, 0.17 mmol, 36%, yellow solid, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 8.62 (s, 1H), 8.46 (s, 2H), 7.81 (dt, J = 8.0, 1.9 Hz, 1H), 7.41 (m, 2H), 7.28 (dd, J = 7.5, 4.5 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.17 (s, 2H), 7.00 – 6.89 (m, 1H), 5.70 (d, J = 15.6 Hz, 1H), 4.60 (d, J = 15.6 Hz, 1H), 3.84 – 3.64 (m, 2H), 3.38 (t, J = 7.1 Hz, 2H). m/z (ESI): 423.8 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 586 R10107WO N-[(6-amino-7-chloro-1,5-naphthyridin-3-yl)methyl]-N-(1,1-di oxo-2,3-dihydro-1λ⁶-ben- zothiophen-7-yl)pyridine-3-carboxamide (Example H-012) The title compound was prepared according to General Procedure 32, using diethyl [chloro(cyano)methyl]phosphonate (Int. Q-021, 0.057 g, 0.24 mmol, 1.42 eq.), NaH (0.01 g, 0.26 mmol, 1.52 eq.) and N-[(5-amino-6-formylpyridin-3-yl)methyl]-N-(1,1-dioxo-2,3-di hy- dro-1λ⁶-benzothiophen-7-yl)pyridine-3-carboxamide (Int. R-034, 0.077 g, 0.17 mmol, 1.0 eq.) in anhydrous THF (2 mL). The crude material was purified by two consecutive FCCs (first: silica, 0 to 10% MeOH gradient in DCM; second: C18 grafted silica, 10% to 100% MeCN gradient in water) to yield, after lyophilization of the relevant pure fractions, N-[(6- amino-7-chloro-1,5-naphthyridin-3-yl)methyl]-N-(1,1-dioxo-2, 3-dihydro-1λ⁶-benzothio- phen-7-yl)pyridine-3-carboxamide (Example H-012, 0.013 g, 0.03 mmol, 16%, white solid, UPLC long elution purity: 99.55%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 4.7 Hz, 1H), 8.18 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.67 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.27 (dd, J = 7.3, 4.8 Hz, 1H), 7.06 (s, 2H), 6.78 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 14.9 Hz, 1H), 4.80 (d, J = 14.9 Hz, 1H), 3.86 – 3.68 (m, 2H), 3.40 (t, J = 7.1 Hz, 2H). m/z (ESI): 480.10 [M+H] ⁺ . Example H-013: N-[(2-aminoquinolin-7-yl)methyl]-N-[(5R)-5,6,7,8-tetrahydroq uinoxalin-5- yl]pyridine-3-carboxamide and Example H-014: N-[(2-aminoquinolin-7-yl)methyl]-N-[(5S)- 5,6,7,8-tetrahydroquinoxalin-5-yl]pyridine-3-carboxamide N-[(2-aminoquinolin-7-yl)methyl]-N-[(5R)-5,6,7,8-tetrahydroq uinoxalin-5-yl]pyridine-3-car- boxamide (Example H-013) and N-[(2-aminoquinolin-7-yl)methyl]-N-[(5S)-5,6,7,8-tetrahy- droquinoxalin-5-yl]pyridine-3-carboxamide (Example H-014) were obtained from rac-N-[(2- aminoquinolin-7-yl)methyl]-N-(5,6,7,8-tetrahydroquinoxalin-5 -yl)pyridine-3-carboxamide (Example H-010) by purification by chiral HPLC (column: ReproSil ^® CHIRAL MIF; mobile phase: isocratic hexane/EtOH 88:12 v/v (+0.1% n-butylamine); flow rate: 19 mL/min.; elu- tion time: 180 min.). R and S configurations were attributed arbitrarily. N-[(2-aminoquinolin-7-yl)methyl]-N-[(5R)-5,6,7,8-tetrahydroq uinoxalin-5-yl]pyridine-3-car- boxamide (Example H-013, 17 mg, white solid, UPLC long elution purity: 99.88%, chiral HPLC purity: 100%).7/3 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (dd, J = 2.2, 0.9 Hz, 1H), 8.67 (dd, J = 4.9, 1.7 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.48 (dd, J = 2.6, 0.9 Hz, 1H), 8.01 (dt, J = 7.9, 1.9 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.51 (dd, J = 7.8, 4.8, 0.9 Hz, 1H), 7.38 (s, 1H), 7.13 (dd, J = 8.3, 1.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.48 (s, 2H), 5.09 (dd, J = 11.3, 5.9 Hz, 1H), 4.92 (d, J = 16.2 Hz, 1H), 3.89 (d, J = 16.2 Hz, 1H), 2.94 (dt, J = 12.0, 5.5 Hz, 1H), 2.76 (d, J = 17.6 Hz, 1H), 2.28 – 2.19 (m, 1H), 2.04 – 1.96 (m, 1H), 1.94 – 1.87 (m, 1H), 1.78 – 1.66 (m, 1H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 – Ryvu Therapeutics S.A. RVU305 587 R10107WO 8.53 (m, 2H), 8.52 (d, J = 2.5 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.76 (dt, J = 8.0, 1.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.42 – 7.36 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.46 (s, 2H), 5.16 (s, 1H), 4.67 (d, J = 17.2 Hz, 1H), 4.60 (d, J = 17.5 Hz, 1H), 2.97 (dd, J = 12.1, 5.6 Hz, 1H), 2.90 – 2.80 (m, 1H), 2.25 (m, 1H), 2.18 – 2.08 (m, 1H), 2.06 – 1.95 (m, 1H), 1.84 – 1.74 (m, 1H). m/z (ESI): 411.19 [M+H] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-[(5S)-5,6,7,8-tetrahydroq uinoxalin-5-yl]pyridine-3-car- boxamide (Example H-014, 20 mg, beige solid, UPLC long elution purity: 99.26%, chiral HPLC purity: 95.27%).7/3 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (dd, J = 2.2, 0.9 Hz, 1H), 8.66 (dd, J = 4.8, 1.7 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.48 (dd, J = 2.5, 0.9 Hz, 1H), 8.01 (dt, J = 7.8, 2.0 Hz, 1H), 7.89 – 7.82 (m, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.51 (dd, J = 7.8, 4.9, 0.9 Hz, 1H), 7.38 (s, 1H), 7.15 – 7.11 (m, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.48 (s, 2H), 5.09 (dd, J = 11.3, 5.9 Hz, 1H), 4.92 (d, J = 16.2 Hz, 1H), 3.89 (d, J = 16.2 Hz, 1H), 2.94 (dt, J = 12.0, 5.5 Hz, 1H), 2.80 – 2.72 (m, 1H), 2.27 – 2.19 (m, 1H), 2.04 – 1.96 (m, 1H), 1.95 – 1.87 (m, 1H), 1.77 – 1.65 (m, 1H). Minor rotamer: 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 – 8.53 (m, 2H), 8.52 (d, J = 2.5 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.76 (dt, J = 8.0, 1.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.42 – 7.36 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.46 (s, 2H), 5.16 (s, 1H), 4.67 (d, J = 17.2 Hz, 1H), 4.60 (d, J = 17.5 Hz, 1H), 2.97 (dd, J = 12.1, 5.6 Hz, 1H), 2.90 – 2.80 (m, 1H), 2.25 (m, 1H), 2.18 – 2.08 (m, 1H), 2.06 – 1.95 (m, 1H), 1.84 – 1.74 (m, 1H). m/z (ESI): 411.19 [M+H] ⁺ . Example H-015: N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2- {[1-(trifluoromethyl)cyclopropyl]amino}acetamide N-[(2-chloroquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridi n-3-yl)-2-{[1-(trifluorome- thyl)cyclopropyl]amino}acetamide (Int. R-035) The title compound was prepared according the General Procedure 29, using N-[(2-chloro- quinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin-3-yl)prop- 2-enamide (Int. O-148, 0.03 g, 0.07 mmol, 1.0 eq.), OsO ₄ (4% wt. solution in water, 0.043 mL, 0.007 mmol, 0.10 eq.) and NaIO ₄ (0.058 g, 0.27 mmol, 4.04 eq.) in a mixture of water (0.3 mL) and dioxane (1.5 mL). The crude material was stirred with 1-(trifluoromethyl)cyclopropan-1-amine (0.012 g, 0.10 mmol, 1.4 eq.) in anhydrous DCE (0.8 mL) for 2 h at RT. NaBH ₃ CN (0.008 g, 0.14 mmol, 2.0 eq.) was added and the RM was stirred overnight at RT. The RM was partitioned between DCM and aq. sat. NaHCO ₃ and the aqueous layer was extracted with DCM (x2). The com- bined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under re- duced pressure. The crude material was purified by FCC (0 to 50% EtOAc gradient in hex- ane) to yield N-[(2-chloroquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridi n-3-yl)-2-{[1- (trifluoromethyl)cyclopropyl]amino}acetamide (Int. R-035, 0.012 g, 0.02 mmol, 28%, off- white solid, UPLC purity: 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (dd, J = 4.6, 1.5 Hz, 1H), 8.45 (dd, J = 8.7, 0.8 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.66 (dd, J = 8.1, 4.6 Ryvu Therapeutics S.A. RVU305 588 R10107WO Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 7.9, 1.6 Hz, 1H), 7.56 (dd, J = 8.5, 1.7 Hz, 1H), 5.75 (d, J = 15.2 Hz, 1H), 4.35 (d, J = 15.3 Hz, 1H), 3.52 (s, 3H), 3.24 (d, J = 5.7 Hz, 2H), 2.89 (t, J = 5.7 Hz, 1H), 0.91 – 0.81 (m, 4H). m/z (ESI): 513.3 [M+H] ⁺ . N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin -3-yl)-2-{[1-(trifluorome- thyl)cyclopropyl]amino}acetamide (Example H-015) The title compound was prepared according the General Procedure 25, using N-[(2-chloro- quinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-{[ 1-(trifluoromethyl)cyclopro- pyl]amino}acetamide (Int. R-035, 0.044 g, 0.08 mmol, 1.0 eq.), tert-butyl carbamate (0.084 g, 0.72 mmol, 9.0 eq.), Cs ₂ CO ₃ (0.032 g, 0.10 mmol, 1.25 eq.), XPhos (0.011 g, 0.02 mmol, 0.25 eq.) and Pd(OAc) ₂ (0.003 g, 0.01 mmol, 0.13 eq.) in anhydrous dioxane (3 mL), followed by treatment in a mixture of DCM (2.4 mL) and TFA (0.6 mL). The crude material was purified by FCC (0 to 7% MeOH gradient in DCM) to yield N-[(2-aminoquinolin-7-yl)methyl]-N-(2- methanesulfonylpyridin-3-yl)-2-{[1-(trifluoromethyl)cyclopro pyl]amino}acetamide (Example H-015, 0.015 g, 0.03 mmol, 50%, white foam, UPLC long elution purity: 99.50%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.63 (dd, J = 8.1, 4.7 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.41 (s, 2H), 5.70 (d, J = 14.6 Hz, 1H), 4.16 (d, J = 14.7 Hz, 1H), 3.50 (s, 3H), 3.19 (m, 2H), 2.87 (t, J = 5.4 Hz, 1H), 0.93 – 0.80 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -71.64. m/z (ESI): 494.14 [M+H] ⁺ . Example H-016: N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4- dihydro-2H-1λ⁶-benzothiopyran-8-yl)pyridine-3-carboxamide The title compound was prepared according to General Procedure 32, using N-[(3-amino-4- formylphenyl)methyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2 H-1λ⁶-benzothiopyran-8- yl)pyridine-3-carboxamide (Int. R-029, 0.015 g, 0.03 mmol, 1.0 eq.), diethyl [bromo(cy- ano)methyl]phosphonate (Int. Q-053, 0.012 g, 0.04 mmol, 1.4 eq.) and NaH (60% in mineral oil, 0.002 g, 0.05 mmol, 1.5 eq.) in anhydrous THF (0.5 mL). The crude material was purified by Preparative HPLC (formic acid buffer) to yield N-[(2-amino-3-bromoquinolin-7-yl)me- thyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ⁶-benzot hiopyran-8-yl)pyridine-3-carbox- amide (Example H-016: 0.002 g, 0.003 mmol, 10%). 9/1 mixture of restricted C-N amide ro- tation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 – 8.53 (m, 1H), 8.48 – 8.41 (m, 1H), 8.38 (s, 1H), 7.79 – 7.71 (m, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.28 – 7.19 (m, 2H), 7.07 (d, J = 8.2 Hz, 1H), 6.68 (s, 2H), 5.92 (d, J = 14.9 Hz, 1H), 4.59 (d, J = 14.8 Hz, 1H), 3.98 (m, 2H), 3.16 – 2.89 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -80.53 (ddd, J = 273.7, 23.5, 12.7 Hz), -85.07 (ddd, J = 274.0, 13.9, 7.1 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 – 8.85 (m, 1H), 8.76 – Ryvu Therapeutics S.A. RVU305 589 R10107WO 8.65 (m, 1H), 8.40 – 8.36 (m, 1H), 8.12 – 8.04 (m, 1H), 7.91 – 7.81 (m, 1H), 7.79 – 7.56 (m, 3H), 7.17 – 6.94 (m, 3H), 6.68 (s, 2H), 5.18 (d, J = 15.1 Hz, 1H), 4.78 (d, J = 15.1 Hz, 1H), 4.06 – 3.89 (m, 2H), 3.15 – 2.94 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -83.08 (d, J = 266.9 Hz), -85.28 (d, J = 269.5 Hz). m/z (ESI): 574.04[M+H] ⁺ . Example H-017: N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(2-meth anesul- fonylpyridin-3-yl)-2-(trifluoromethyl)pyrimidine-5-carboxami de N-[(4-bromo-3-fluoro-5-nitrophenyl)methyl]-N-(2-methanesulfo nylpyridin-3-yl)-2-(trifluo- romethyl)pyrimidine-5-carboxamide (Int. R-036) The title compound was prepared according the General Procedure 22, using N-(2-me- thanesulfonylpyridin-3-yl)-2-(trifluoromethyl)pyrimidine-5-c arboxamide (Int. K-011, 0.6 g, 1.70 mmol, 1.0 eq.), 2-bromo-5-(bromomethyl)-1-fluoro-3-nitrobenzene (Int. R-007, 0.64 g, 1.88 mmol, 1.11 eq.) and cesium carbonate (0.83 g, 2.55 mmol, 1.5 eq.) in anhydrous MeCN (17.0 mL). The crude material was purified by FCC (0 to 60% EtOAc gradient in hexane) to yield N-[(4-bromo-3-fluoro-5-nitrophenyl)methyl]-N-(2-methanesulfo nylpyridin-3-yl)-2-(tri- fluoromethyl)pyrimidine-5-carboxamide (Int. R-036, 0.82 g, 1.42 mmol, 76%, brownish oil, UPLC purity: 91%).9/1 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 2H), 8.70 (dd, J = 4.6, 1.4 Hz, 1H), 8.17 (dd, J = 8.2, 1.5 Hz, 1H), 7.95 (t, J = 1.6 Hz, 1H), 7.83 (dd, J = 9.1, 2.0 Hz, 1H), 7.82 (dd, J = 8.1, 4.7 Hz, 1H), 5.55 (d, J = 15.5 Hz, 1H), 4.78 (d, J = 15.5 Hz, 1H), 3.36 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.30, -102.35 (d, J = 9.3 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 2H), 8.77 (d, J = 3.7 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.85 (s, 2H), 7.73 (d, J = 8.8 Hz, 1H), 5.25 (d, J = 16.4 Hz, 1H), 4.91 (d, J = 15.9 Hz, 1H), 3.40 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.18, -101.88 (d, J = 9.4 Hz). m/z (ESI): 578.1 [M+H] ⁺ . N-[(4-ethenyl-3-fluoro-5-nitrophenyl)methyl]-N-(2-methanesul fonylpyridin-3-yl)-2-(trifluo- romethyl)pyrimidine-5-carboxamide (Int. R-037) Ryvu Therapeutics S.A. RVU305 590 R10107WO The title compound was prepared according to General Procedure 28, using N-[(4-bromo-3- fluoro-5-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-y l)-2-(trifluoromethyl)pyrimi- dine-5-carboxamide (Int. R-036, 0.78 g, 1.23 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (0.39 g, 2.53 mmol, 2.06 eq.), Pd(PPh ₃ )Cl ₂ (0.09 g, 0.13 mmol, 0.10 eq.) and Cs ₂ CO ₃ (1.25 g, 3.84 mmol, 3.13 eq.) in a mixture of dioxane (13 mL) and water (4.5 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to yield N-[(4-ethenyl-3-fluoro-5-nitrophenyl)methyl]-N-(2-methanesul fonylpyridin-3-yl)-2-(trifluo- romethyl)pyrimidine-5-carboxamide (Int. R-037, 0.7 g, 1.33 mmol, 87%, yellowish oil, NMR purity: 80%).9/1 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 2H), 8.70 (dd, J = 4.7, 1.4 Hz, 1H), 8.15 (dd, J = 8.2, 1.4 Hz, 1H), 7.85 (s, 1H), 7.80 (dd, J = 8.2, 4.6 Hz, 1H), 7.73 (dd, J = 11.1, 1.5 Hz, 1H), 6.68 (dd, J = 17.8, 11.6 Hz, 1H), 5.79 (d, J = 19.4 Hz, 1H), 5.74 (d, J = 11.7 Hz, 1H), 5.58 (d, J = 15.4 Hz, 1H), 4.78 (d, J = 15.4 Hz, 1H), 3.36 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.30, -112.18 (d, J = 10.7 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 2H), 8.77 (d, J = 4.0 Hz, 1H), 7.93 (d, J = 6.3 Hz, 1H), 7.88 – 7.78 (m, 1H), 7.75 (s, 1H), 7.64 (d, J = 11.0 Hz, 1H), 6.60 (dd, J = 17.5, 11.8 Hz, 1H), 5.83 – 5.67 (m, 2H), 5.26 (d, J = 16.3 Hz, 1H), 4.94 (d, J = 16.1 Hz, 1H), 3.40 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.18, -111.75 (d, J = 10.9 Hz). m/z (ESI): 526.2 [M+H] ⁺ . N-[(3-fluoro-4-formyl-5-nitrophenyl)methyl]-N-(2-methanesulf onylpyridin-3-yl)-2-(trifluo- romethyl)pyrimidine-5-carboxamide (Int. R-038) The title compound was prepared according to General Procedure 29, using N-[(4-ethenyl- 3-fluoro-5-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3 -yl)-2-(trifluoromethyl)pyrim- idine-5-carboxamide (Int. R-037, 0.7 g, 1.07 mmol, 1.0 eq.), OsO ₄ (4 wt. % in H ₂ O; 0.68 mL, 0.11 mmol, 0.1 eq.) and sodium periodate (0.915 g, 4.28 mmol, 4.01 eq.) in a mixture of diox- ane (13.0 mL) and water (4.5 mL). The crude material was purified by FCC (0 to 50% EtOAc gradient in hexane) to obtain N-[(3-fluoro-4-formyl-5-nitrophenyl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)-2-(trifluoromethyl)pyrimidine-5-c arboxamide (Int. R-038, 0.46 g, 0.87 mmol, 81%, beige solid, UPLC purity: 99%).9/1 mixture of restricted C-N amide rota- tion isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 8.98 (s, 2H), 8.71 (dd, J = 4.6, 1.4 Hz, 1H), 8.21 (dd, J = 8.2, 1.4 Hz, 1H), 8.04 (d, J = 1.3 Hz, 1H), 7.92 (dd, J = 10.4, 1.2 Hz, 1H), 7.82 (dd, J = 8.2, 4.6 Hz, 1H), 5.60 (d, J = 15.8 Hz, 1H), 4.89 (d, J = 15.8 Hz, 1H), 3.36 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.30, -115.50 (d, J = 10.4 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 9.28 (s, 2H), 8.77 (d, J = 4.1 Hz, 1H), 7.98 – 7.89 (m, 2H), 7.87 – 7.79 (m, 2H), 5.35 (d, J = 16.2 Hz, 1H), 5.03 (d, J = 16.3 Hz, 1H), 3.41 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.17, -114.96 (d, J = 12.1 Hz). m/z (ESI): 528.1 [M+H] ⁺ . N-[(3-amino-5-fluoro-4-formylphenyl)methyl]-N-(2-methanesulf onylpyridin-3-yl)-2-(trifluo- romethyl)pyrimidine-5-carboxamide (Int. R-039) The title compound was prepared according to General Procedure 30, using N-[(3-fluoro-4- formyl-5-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-y l)-2-(trifluoromethyl)pyrimi- dine-5-carboxamide (Int. R-038, 0.46 g, 0.86 mmol, 1.0 eq.), iron powder (0.485 g, 8.68 mmol, 10.06 eq.) and 1 M aq. HCl (0.175 mL, 0.17 mmol, 0.20 eq.) in a mixture of EtOH (8.5 Ryvu Therapeutics S.A. RVU305 591 R10107WO mL) and water (1.5 mL). The crude N-[(3-amino-5-fluoro-4-formylphenyl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)-2-(trifluoromethyl)pyrimidine-5-c arboxamide (Int. R-039, 0.43 g, 0.86 mmol, 93%, beige foam, UPLC purity: 93%) was used in the next step without further purification. 8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 9.00 (s, 2H), 8.68 (dd, J = 4.7, 1.4 Hz, 1H), 8.07 (dd, J = 8.2, 1.4 Hz, 1H), 7.78 (dd, J = 8.2, 4.6 Hz, 1H), 7.53 (s, 2H), 6.56 (s, 1H), 6.43 (dd, J = 12.2, 1.5 Hz, 1H), 5.53 (d, J = 15.5 Hz, 1H), 4.48 (d, J = 15.6 Hz, 1H), 3.40 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.31, -122.94 (d, J = 12.2 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.08 (s, 1H), 9.27 (s, 2H), 8.77 (d, J = 4.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.85 (dd, J = 8.0, 4.7 Hz, 1H), 7.53 (s, 2H), 6.52 (s, 1H), 6.35 (d, J = 12.0 Hz, 1H), 5.08 (d, J = 16.5 Hz, 1H), 4.65 (d, J = 16.6 Hz, 1H), 3.43 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -69.19, -122.58 (d, J = 12.1 Hz). m/z (ESI): 498.5 [M+H] ⁺ . N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(2-meth anesulfonylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide (Example H-017) The title compound was prepared according to General Procedure 32, using N-[(3-amino-5- fluoro-4-formylphenyl)methyl]-N-(2-methanesulfonylpyridin-3- yl)-2-(trifluoromethyl)pyrimi- dine-5-carboxamide (Int. R-039, 0.15 g, 0.28 mmol, 1.0 eq.), diethyl [chloro(cyano)me- thyl]phosphonate (Int. Q-021, 0.1 g, 0.42 mmol, 1.52 eq.) and NaH (60% in mineral oil, 0.018 g, 0.47 mmol, 1.68 eq.) in anhydrous THF (4 mL). The crude material was purified by two consecutive FCCs (first: NH ₂ functionalized silica, 0 to 2% MeOH gradient in DCM; second: silica, 0 to 10% MeOH gradient in DCM) to yield N-[(2-amino-3-chloro-5-fluoroquinolin-7- yl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-(trifluoromet hyl)pyrimidine-5-carboxamide (Example H-017, 0.074 g, 0.133 mmol, 47%, white solid, UPLC long elution purity: 99.66%). 8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 2H), 8.62 (dd, J = 4.6, 1.4 Hz, 1H), 8.20 (s, 1H), 7.94 (dd, J = 8.2, 1.5 Hz, 1H), 7.66 (dd, J = 8.1, 4.6 Hz, 1H), 7.19 (s, 1H), 7.11 (dd, J = 10.6, 1.4 Hz, 1H), 7.02 (s, 2H), 5.69 (d, J = 14.8 Hz, 1H), 4.74 (d, J = 14.8 Hz, 1H), 3.35 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.29, -122.24 (d, J = 10.5 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 2H), 8.69 (d, J = 4.5 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.72 (dd, J = 8.0, 4.1 Hz, 1H), 7.07 (s, 2H), 7.10 – 7.02 (m, 2H), 5.24 (d, J = 15.3 Hz, 1H), 4.91 (d, J = 15.3 Hz, 1H), 3.39 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.16, -121.92 (d, J = 10.3 Hz). m/z (ESI): 555.06 [M+H] ⁺ . N-[(2-amino-5-fluoro-3-methylquinolin-7-yl)methyl]-N-(2-meth anesulfonylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide (Example H-018) Ryvu Therapeutics S.A. RVU305 592 R10107WO The title compound was prepared according to General Procedure 32, using diethyl (1-cy- anoethyl)phosphonate (0.027 g, 0.14 mmol, 1.26 eq.), NaH (60% in mineral oil, 0.007 g, 0.18 mmol, 1.63 eq.), N-[(3-amino-5-fluoro-4-formylphenyl)methyl]-N-(2-methanesulf onylpyri- din-3-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide (Int. R-039, 0.06 g, 0.11 mmol, 1.0 eq.) in anhydrous THF (2.0 mL).The crude material was purified by two consecutive FCCs (first: silica, 0 to 10% MeOH gradient in DCM; second: NH ₂ functionalized silica, 0 to 2% MeOH gradient in DCM) to yield N-[(2-amino-5-fluoro-3-methylquinolin-7-yl)methyl]-N-(2- methanesulfonylpyridin-3-yl)-2-(trifluoromethyl)pyrimidine-5 -carboxamide (Example H-018, 0.011 g, 0.021 mmol, 19%, white solid, UPLC long elution purity: 99.61%).8/2 mixture of re- stricted C-N amide rotation isomers in DMSO-d ₆ at RT: Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 3H), 8.60 (dd, J = 4.6, 1.4 Hz, 1H), 7.89 (dd, J = 8.1, 1.5 Hz, 1H), 7.82 (s, 1H), 7.63 (dd, J = 8.1, 4.6 Hz, 1H), 7.12 (s, 1H), 6.99 (dd, J = 10.8, 1.5 Hz, 1H), 6.51 (s, 2H), 5.70 (d, J = 14.6 Hz, 1H), 4.71 (d, J = 14.6 Hz, 1H), 3.35 (s, 3H), 2.22 (s, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -69.28, -123.74 (d, J = 10.6 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 2H), 8.68 (d, J = 4.0 Hz, 1H), 7.78 (s, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.71 (dd, J = 7.8, 4.4 Hz, 1H), 7.02 (s, 1H), 6.92 (d, J = 10.5 Hz, 1H), 6.51 (s, 2H), 5.21 (d, J = 15.1 ^{Hz, 1H), 4.88 (d, J = 15.2 Hz, 1H), 3.39 (s, 3H), 2.20 (s, 3H). 19F NMR (376 MHz, DMSO-d6} + ⁾ _{δ -69.15, -123.49 (d, J = 10.8 Hz). m/z (ESI): 535.11 [M+H] .} Example H-019: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesul- fonylphenyl)-2-methylpyrimidine-5-carboxamide The title compound was prepared according to General Procedure 33, using N-(4-fluoro-2- methanesulfonylphenyl)-2-methylpyrimidine-5-carboxamide (Int. K-016, 0.12 g, 0.37 mmol, 1.0 eq.), PPh ₃ (0.242 g, 0.92 mmol, 2.5 eq.), (2-amino-3-chloroquinolin-7-yl)methanol (Int. A-119, 0.091 g, 0.41 mmol, 1.12 eq.) and DIAD (0.186 g, 0.92 mmol, 2.5 eq.) in anhydrous THF (3 mL). The crude material was purified by two consecutive FCCs (first: 0 to 100% EtOAc gradient in hexane; second: 0 to 5% MeOH gradient in DCM) to yield N-[(2-amino-3- chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfonylphe nyl)-2-methylpyrimidine-5- carboxamide (Example H-019, 0.01 g, 0.02 mmol, 5%, white solid, UPLC long elution purity: 99.10%). 8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major ro- tamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 2H), 8.28 (s, 1H), 7.85 (dd, J = 8.3, 3.0 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.53 (ddd, J = 10.5, 7.8, 3.0 Hz, 1H), 7.47 (s, 1H), 7.43 (dd, J = 8.9, 5.0 Hz, 1H), 7.32 (dd, J = 8.2, 1.6 Hz, 1H), 6.98 (s, 2H), 5.66 (d, J = 14.8 Hz, 1H), 4.68 (d, J = 14.9 Hz, 1H), 3.24 (s, 3H), 2.54 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -108.86 (d, J = 5.8 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 2H), 8.24 (s, 1H), 7.93 (dd, J = 8.2, 3.0 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.58 (td, J = 8.5, 3.1 Hz, 1H), 7.29 – 7.22 (m, Ryvu Therapeutics S.A. RVU305 593 R10107WO 2H), 7.15 (d, J = 8.2 Hz, 1H), 6.98 (s, 2H), 5.21 (d, J = 16.0 Hz, 1H), 4.77 (d, J = 16.0 Hz, 1H), 3.32 (s, 3H), 2.70 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -110.34 (d, J = 6.2 Hz). m/z (ESI): 500.08 [M+H] ⁺ . Example H-020: N-[(2-amino-3-bromoquinolin-7-yl)methyl]-N-(4,4-difluoro-1,1 -dioxo-3,4- dihydro-2H-1λ⁶-benzothiopyran-8-yl)-2-methylpyrimidine-5- carboxamide Step 1 was performed according to General Procedure 22, using 1-bromo-4-(bromomethyl)- 2-nitrobenzene (0.77 g, 2.61 mmol, 1.52 eq.), 4,4-difluoro-N-(2-methylpyrimidin-5-yl)-1,1- dioxo-3,4-dihydro-2H-1λ⁶-benzothiopyran-8-carboxamide (Int. K-027, 0.606 g, 1.71 mmol, 1.0 eq.) and Cs ₂ CO ₃ (0.845 g, 2.59 mmol, 1.51 eq.) in MeCN (9 mL). The crude material was purified by FCC (0 to 70% EtOAc gradient in hexane) to yield N-[(4-bromo-3-nitro- phenyl)methyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ� ��-benzothiopyran-8-yl)-2- methylpyrimidine-5-carboxamide (Int. R-040, 0.691 g, 1.22 mmol, 70%, yellow solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (s, 2H), 8.01 (d, J = 2.0 Hz, 1H), 7.89 – 7.85 (m, 2H), 7.75 (t, J = 8.0 Hz, 1H), 7.60 – 7.51 (m, 2H), 5.67 (d, J = 15.4 Hz, 1H), 4.58 (d, J = 15.4 Hz, 1H), 4.04 – 3.89 (m, 2H), 3.10 – 2.90 (m, 2H), 2.53 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -82.14 (ddd, J = 273.3, 19.3, 13.1 Hz), -84.63 (ddd, J = 273.4, 12.9, 10.4 Hz). m/z (ESI): 568.2 [M+H] ⁺ . Step 2: Step 2 was carried out according to General Procedure 28, using N-[(4-bromo-3-nitro- phenyl)methyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1λ� ��-benzothiopyran-8-yl)-2- methylpyrimidine-5-carboxamide (Int. R-040, 0.690 g, 1.20 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.371 g, 2.41 mmol, 2.0 eq.), Cs ₂ CO ₃ (1.18 g, 3.62 mmol, 3.0 eq.) and Pd(PPh ₃ )Cl ₂ (0.085 g, 0.12 mmol, 0.1 eq.) in a mixture of dioxane (8 mL) and water (3 mL). 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-benzothiopyr an-8-yl)-N-[(4-ethenyl- 3-nitrophenyl)methyl]-2-methylpyrimidine-5-carboxamide (Int. R-041, 0.534 g, 1.04 mmol, 85%, yellow solid, UPLC purity: 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (s, 2H), 7.93 (s, Ryvu Therapeutics S.A. RVU305 594 R10107WO 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 6.99 (dd, J = 17.7, 11.6 Hz, 1H), 5.92 (d, J = 17.3 Hz, 1H), 5.73 (d, J = 15.2 Hz, 1H), 5.53 (d, J = 11.1 Hz, 1H), 4.58 (d, J = 15.3 Hz, 1H), 4.13 – 3.84 (m, 2H), 3.15 – 2.85 (m, 2H), 2.52 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -82.05 (ddd, J = 275.0, 18.7, 10.9 Hz), -84.61 (ddd, J = 272.8, 13.9, 8.4 Hz). m/z (ESI): 515.5 [M+H] ⁺ . Step 3: Step 3 was carried out according to General Procedure 29, using N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-N-[(4-ethenyl-3-n itrophenyl)methyl]-2- methylpyrimidine-5-carboxamide (Int. R-041, 0.534 g, 1.03 mmol, 1.0 eq.), OsO ₄ (4 wt. % in H ₂ O, 0.654 mL, 0.10 mmol, 0.1 eq.), and NaIO ₄ (0.880 g, 4.11 mmol, 4.0 eq.) in a mixture of dioxane (15 mL) and water (3 mL). 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-benzothiopyr an- 8-yl)-N-[(4-formyl-3-nitrophenyl)methyl]-2-methylpyrimidine- 5-carboxamide (Int. R-042, 0.428 g, 0.83 mmol, 77%, black solid, UPLC purity: 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 8.63 (s, 2H), 8.13 (s, 1H), 7.93 – 7.84 (m, 3H), 7.75 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 5.75 (d, J = 15.6 Hz, 1H), 4.71 (d, J = 15.6 Hz, 1H), 4.06 – 3.89 (m, 2H), 3.11 – 2.89 (m, 2H), 2.54 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -82.19 (ddd, J = 273.6, 19.4, 13.7 Hz), -84.62 (ddd, J = 273.1, 13.0, 9.9 Hz). m/z (ESI): 517.5 [M+H] ⁺ . Step 4: Step 4 was carried out according to General Procedure 30, using N-(4,4-difluoro-1,1-dioxo- 3,4-dihydro-2H-1λ⁶-benzothiopyran-8-yl)-N-[(4-formyl-3-ni trophenyl)methyl]-2-methylpy- rimidine-5-carboxamide (Int. R-042, 0.428 g, 0.79 mmol, 1.0 eq.), iron powder (0.46 g, 8.24 mmol, 10.46 eq.) and conc. HCl (0.157 mL, 1.88 mmol, 2.4 eq.) in a mixture of EtOH (8 mL) and water (1.5 mL). The crude material was purified by FCC (0 to 70% EtOAc gradient in hexane) to yield N-[(3-amino-4-formylphenyl)methyl]-N-(4,4-difluoro-1,1-dioxo -3,4-dihy- dro-2H-1λ⁶-benzothiopyran-8-yl)-2-methylpyrimidine-5-carb oxamide (Int. R-043, 0.297 g, 0.61 mmol, 66%, yellow solid, UPLC purity: 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 8.63 (s, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.15 (s, 2H), 6.75 (s, 1H), 6.60 (dd, J = 8.0, 1.2 Hz, 1H), 5.70 (d, J = 15.6 Hz, 1H), 4.36 (d, J = 15.6 Hz, 1H), 4.06 – 3.91 (m, 2H), 3.16 – 2.84 (m, 2H), 2.54 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -81.66 (ddd, J = 273.5, 20.6, 12.2 Hz), -84.74 (ddd, J = 273.5, 13.3, 8.9 Hz). m/z (ESI): 487.5 [M+H] ⁺ . Step 5: Step 5 was carried out according to General Procedure 32, using N-[(3-amino-4- formylphenyl)methyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2 H-1λ⁶-benzothiopyran-8-yl)- 2-methylpyrimidine-5-carboxamide (Int. R-043, 0.244 g, 0.43 mmol, 1.0 eq.), diethyl [bromo(cyano)methyl]phosphonate (Int. Q-053, 0.182 g, 0.64 mmol, 1.5 eq.) and NaH (60% in mineral oil, 0.055 g, 1.43 mmol, 3.37 eq.) in anhydrous THF (6 mL). The crude material was purified by preparative HPLC (formic acid buffer) to yield N-[(2-amino-3-bromoquino- lin-7-yl)methyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1� �⁶-benzothiopyran-8-yl)-2- methylpyrimidine-5-carboxamide (Example H-020, 0.081 g, 0.138 mmol, 32%, white solid, UPLC long elution purity: 98.76%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (s, 2H), 8.40 (s, Ryvu Therapeutics S.A. RVU305 595 R10107WO 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.33 (s, 1H), 7.24 (m, 2H), 6.69 (s, 2H), 5.91 (d, J = 14.8 Hz, 1H), 4.58 (d, J = 14.9 Hz, 1H), 4.01 (m, 2H), 3.18 – 2.88 (m, 2H), 2.54 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -81.34 (ddd, J = 274.0, 21.8, 12.0 Hz), -84.62 (ddd, J = 273.4, 13.4, 9.1 Hz). m/z (ESI): 589.95 [M+H] ⁺ . Example H-021: N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(2-meth anesul- fonylpyridin-3-yl)-2-methylpyrimidine-5-carboxamide Step 1 was performed according to General Procedure 22, using N-(2-methanesulfonylpyri- din-3-yl)-2-methylpyrimidine-5-carboxamide (Int. K-055, 0.185 g, 0.59 mmol, 1.0 eq.), 2- bromo-5-(bromomethyl)-1-fluoro-3-nitrobenzene (Int. R-007, 0.2 g, 0.61 mmol, 1.03 eq.) and cesium carbonate (0.285 g, 0.87 mmol, 1.47 eq.) in MeCN (6.0 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-[(4-bromo-3-fluoro-5-ni- trophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-methyl pyrimidine-5-carboxamide (Int. R-044, 0.204 g, 0.41 mmol, 75%, yellow oil, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (dd, J = 4.6, 1.4 Hz, 1H), 8.61 (s, 2H), 8.15 (dd, J = 8.1, 1.4 Hz, 1H), 7.97 – 7.92 (m, 1H), 7.81 (dd, J = 9.1, 1.9 Hz, 1H), 7.80 (dd, J = 8.1, 4.7 Hz, 1H), 5.54 (d, J = 15.6 Hz, 1H), 4.74 (d, J = 15.6 Hz, 1H), 3.35 (s, 3H), 2.55 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 102.40 (d, J = 9.1 Hz). m/z (ESI): 526.2 [M+H] ⁺ . Step 2: Step 2 was carried out according to General Procedure 28, using N-[(4-bromo-3-fluoro-5- nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-meth ylpyrimidine-5-carboxamide (Int. R-044, 0.41 g, 0.72 mmol, 1.0 eq.), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.225 g, 1.46 mmol, 2.03 eq.), Cs ₂ CO ₃ (0.705 g, 2.16 mmol, 3.01 eq.) and PdCl ₂ (PPh ₃ ) ₂ (0.051 g, 0.07 mmol, 0.10 eq.) in a mixture of dioxane (7.5 mL) and water (2.5 mL). The crude ma- terial was purified by FCC (0 to 100% EtOAc gradient in hexane) to give N-[(4-ethenyl-3- fluoro-5-nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-y l)-2-methylpyrimidine-5-car- boxamide (Int. R-045, 0.315 g, 0.67 mmol, 85%, beige foam, UPLC purity: 92%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (dd, J = 4.7, 1.4 Hz, 1H), 8.61 (s, 2H), 8.12 (dd, J = 8.2, 1.3 Hz, 1H), Ryvu Therapeutics S.A. RVU305 596 R10107WO 7.85 (s, 1H), 7.78 (dd, J = 8.2, 4.6 Hz, 1H), 7.71 (dd, J = 11.1, 1.2 Hz, 1H), 6.68 (dd, J = 17.8, 11.7 Hz, 1H), 5.79 (d, J = 19.4 Hz, 1H), 5.75 (d, J = 11.8 Hz, 1H), 5.57 (d, J = 15.5 Hz, 1H), 4.74 (d, J = 15.5 Hz, 1H), 3.34 (s, 3H), 2.55 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -112.24 (d, J = 11.1 Hz). m/z (ESI): 472.6 [M+H] ⁺ . Step 3: Step 3 was carried out according to General Procedure 29, using N-[(4-ethenyl-3-fluoro-5- nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-meth ylpyrimidine-5-carboxamide (Int. R-045, 0.315 g, 0.61 mmol, 1.0 eq.), OsO ₄ (4 wt. % in H ₂ O, 0.4 mL, 0.063 mmol, 0.10 eq.) and sodium periodate (0.55 g, 2.57 mmol, 4.18 eq.) in a mixture of dioxane (8.0 mL) and wa- ter (2.6 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N-[(3-fluoro-4-formyl-5-nitrophenyl)methyl]-N-(2-methanesulf onylpyridin-3-yl)-2- methylpyrimidine-5-carboxamide (Int. R-046, 0.295 g, 0.62 mmol, 95%, white foam, UPLC purity: 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 (s, 1H), 8.70 (dd, J = 4.6, 1.4 Hz, 1H), 8.62 (s, 2H), 8.18 (dd, J = 8.2, 1.4 Hz, 1H), 8.04 (s, 1H), 7.90 (d, J = 10.3 Hz, 1H), 7.80 (dd, J = 8.1, 4.6 Hz, 1H), 5.59 (d, J = 15.8 Hz, 1H), 4.85 (d, J = 15.8 Hz, 1H), 3.35 (s, 3H), 2.55 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -115.51 (dd, J = 9.8, 4.0 Hz). m/z (ESI): 474.5 [M+H] ⁺ . Step 4: Step 4 was carried out according to General Procedure 30, using N-[(3-fluoro-4-formyl-5- nitrophenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-meth ylpyrimidine-5-carboxamide (Int. R-046, 0.295 g, 0.59 mmol, 1.0 eq.), iron powder (0.325 g, 5.82 mmol, 9.94 eq.) and conc. HCl (0.12 mL, 1.44 mmol, 2.4 eq.) in a mixture of EtOH (6.0 mL) and water (1.0 mL). The obtained crude N-[(3-amino-5-fluoro-4-formylphenyl)methyl]-N-(2-methanesul- fonylpyridin-3-yl)-2-methylpyrimidine-5-carboxamide (Int. R-047, 0.28 g, 0.63 mmol, 96%, dark beige foam, UPLC purity: 89%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 8.68 (dd, J = 4.7, 1.4 Hz, 1H), 8.63 (s, 2H), 8.02 (dd, J = 8.1, 1.5 Hz, 1H), 7.76 (dd, J = 8.1, 4.6 Hz, 1H), 7.55 (s, 2H), 6.59 (s, 1H), 6.40 (d, J = 12.1 Hz, 1H), 5.53 (d, J = 15.7 Hz, 1H), 4.44 (d, J = 15.7 Hz, 1H), 3.40 (s, 3H), 2.56 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -123.03 (d, J = 12.2 Hz). m/z (ESI): 444.6 [M+H] ⁺ . Step 5: Step 5 was carried out according to General Procedure 32, using diethyl [chloro(cyano)me- thyl]phosphonate (Int. Q-021, 0.085 g, 0.36 mmol, 1.50 eq.) N-[(3-amino-5-fluoro-4- formylphenyl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-met hylpyrimidine-5-carbox- amide (Int. R-047, 0.12 g, 0.24 mmol, 1.0 eq.) and NaH (60% in mineral oil, 0.015 g, 0.39 mmol, 1.63 eq.) in anhydrous THF (3.1 mL). The crude material was purified by FCC (silica, 0 to 10% MeOH gradient in DCM) to yield N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)me- thyl]-N-(2-methanesulfonylpyridin-3-yl)-2-methylpyrimidine-5 -carboxamide (Example H- 021, 0.076 g, 0.152 mmol, 63%, light beige solid, UPLC long elution purity: 99.78%). 9/1 mix- ture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 – 8.62 (m, 1H), 8.62 (s, 2H), 8.22 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.65 (dd, J = 8.1, 4.6 Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 10.6 Hz, 1H), 7.04 (s, 2H), 5.71 (d, J = 14.8 Hz, 1H), 4.71 (d, J = 14.8 Hz, 1H), 3.36 (s, 3H), 2.55 (s, 3H). ¹⁹ F NMR (376 MHz, Ryvu Therapeutics S.A. RVU305 597 R10107WO DMSO-d ₆ ) δ -122.26 (d, J = 10.7 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 2H), 8.72 – 8.66 (m, 1H), 8.22 (s, 1H), 7.86 – 7.78 (m, 1H), 7.73 (s, 1H), 7.15 – 7.07 (m, 2H), 7.04 (s, 2H), 5.21 (d, J = 14.8 Hz, 1H), 4.91 (d, J = 15.3 Hz, 1H), 3.41 (s, 3H), 2.71 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -121.78 – -121.92 (m). m/z (ESI): 501.08 [M+H] ⁺ . Example H-022: N-[(2-amino-5-fluoro-3-methylquinolin-7-yl)methyl]-N-(2-meth anesul- fonylpyridin-3-yl)-2-methylpyrimidine-5-carboxamide The title compound was prepared according to General Procedure 32, using N-[(3-amino-5- fluoro-4-formylphenyl)methyl]-N-(2-methanesulfonylpyridin-3- yl)-2-methylpyrimidine-5- carboxamide (Int. R-047, 0.075 g, 0.15 mmol, 1.0 eq.), diethyl (1-cyanoethyl)phosphonate (0.035 g, 0.18 mmol, 1.22 eq.) and NaH (60% in mineral oil, 0.01 g, 0.26 mmol, 1.73 eq.) in anhydrous THF (2.5 mL). The crude material was purified by FCC (silica, 0 to 10% MeOH gradient in DCM) to yield N-[(2-amino-5-fluoro-3-methylquinolin-7-yl)methyl]-N-(2-me- thanesulfonylpyridin-3-yl)-2-methylpyrimidine-5-carboxamide (Example H-022, 0.015 g, 0.03 mmol, 20%, white solid, UPLC long elution purity: 96.10%).9/1 mixture of restricted C- ^{N amide rotation isomers in DMSO-d6 at RT: Major rotamer: 1H NMR (400 MHz, DMSO-d6)} _{δ 8.61 (s, 2H), 8.60 (d, J = 4.8 Hz, 1H), 7.84 (s, 1H), 7.82 (dd, J = 8.5, 1.5 Hz, 1H), 7.62 (dd, J} = 8.2, 4.6 Hz, 1H), 7.12 (s, 1H), 6.99 (d, J = 10.7 Hz, 1H), 6.54 (s, 2H), 5.71 (d, J = 14.7 Hz, 1H), 4.68 (d, J = 14.7 Hz, 1H), 3.35 (s, 3H), 2.54 (s, 3H), 2.24 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -123.75 (d, J = 10.6 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 2H), 8.68 (s, 1H), 7.84 – 7.75 (m, 2H), 7.74 – 7.65 (m, 1H), 7.03 (s, 1H), 6.91 (m, 1H), 6.54 (s, 2H), 5.19 (d, J = 14.1 Hz, 1H), 4.88 (d, J = 14.5 Hz, 1H), 3.40 (s, 3H), 2.73 (s, 3H), 2.24 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -123.41 (d, J = 9.1 Hz). m/z (ESI): 481.13 [M+H] ⁺ . Example I-001: N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin-3- yl)-2-(trifluoromethyl)-1,3-thiazole-4-carboxamide, General Procedure 37 Ryvu Therapeutics S.A. RVU305 598 R10107WO N-[(2-chloro-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfo nylpyridin-3-yl)-2-(trifluoro- methyl)-1,3-thiazole-4-carboxamide (Int. O-124, 0.18 g, 0.27 mmol, 1.0 eq.) and 1-(2,4-di- methoxyphenyl)methanamine (0.14 g, 0.84 mmol, 3.13 eq.) were stirred in DMSO (2.0 mL) for 7 h at 100 °C. After coming back to RT, the RM was diluted with EtOAc and the solution was washed with brine (3x). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was stirred in a mixture of TFA (1.1 mL) and DCM (2.5 mL) at RT for 16 h, and the volatiles were evaporated under reduced pressure. The residue was taken up in MeOH and the solution was passed down a SCX col- umn, washing with MeOH and eluting with 2 M ammonia in MeOH. The fraction containing the title compound were evaporated under reduced pressure and the crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(2-amino-3-fluoroquinolin-7- yl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2-(trifluoromet hyl)-1,3-thiazole-4-carbox- amide (Example I-001, 0.12 g, 0.23 mmol, 85%, white solid, UPLC long elution purity: 99.39%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.65 (dd, J = 4.6, 1.5 Hz, 1H), 7.82 (d, J = 11.7 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.57 (dd, J = 8.1, 4.6 Hz, 1H), 7.40 (dd, J = 8.1, 1.5 Hz, 1H), 7.37 (s, 1H), 7.23 (dd, J = 8.2, 1.1 Hz, 1H), 6.82 (s, 2H), 5.86 (d, J = 14.9 Hz, 1H), 4.52 (d, J = 14.9 Hz, 1H), 3.27 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -60.61, -134.75 (d, J = 11.8 Hz). m/z (ESI): 526.11 [M+H] ⁺ . Examples prepared according to General Procedure 37: Ryvu Therapeutics S.A. RVU305 599 R10107WO Ryvu Therapeutics S.A. RVU305 600 R10107WO Ryvu Therapeutics S.A. RVU305 601 R10107WO Ryvu Therapeutics S.A. RVU305 602 R10107WO Ryvu Therapeutics S.A. RVU305 603 R10107WO Ryvu Therapeutics S.A. RVU305 604 R10107WO Ryvu Therapeutics S.A. RVU305 605 R10107WO Ryvu Therapeutics S.A. RVU305 606 R10107WO Ryvu Therapeutics S.A. RVU305 607 R10107WO Ryvu Therapeutics S.A. RVU305 608 R10107WO Ryvu Therapeutics S.A. RVU305 609 R10107WO Ryvu Therapeutics S.A. RVU305 610 R10107WO Ryvu Therapeutics S.A. RVU305 611 R10107WO Ryvu Therapeutics S.A. RVU305 612 R10107WO Ryvu Therapeutics S.A. RVU305 613 R10107WO Ryvu Therapeutics S.A. RVU305 614 R10107WO Ryvu Therapeutics S.A. RVU305 615 R10107WO Ryvu Therapeutics S.A. RVU305 616 R10107WO Ryvu Therapeutics S.A. RVU305 617 R10107WO Ryvu Therapeutics S.A. RVU305 618 R10107WO Ryvu Therapeutics S.A. RVU305 619 R10107WO Ryvu Therapeutics S.A. RVU305 620 R10107WO ¹ Purity: UPLC long elution purity Example J-001: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyclopropyl-N-(2 -methanesul- fonylpyridin-3-yl)pyridine-3-carboxamide, General Procedure 38a A mixture of 6-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyridine-3-ca rboxamide (Int. K-037, 0.125 g, 0.37 mmol, 1.0 eq.), 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-7-(iodome- thyl)quinolin-2-amine (Int. A-100, 0.203 g, 0.41 mmol, 1.1 eq.), and cesium carbonate (0.183 g, 0.56 mmol, 1.5 eq.) in MeCN (10.0 mL) was stirred at 65 °C for 1 h. After coming back to RT, the RM was filtered on a pad of Celite ^® , rinsing the filter cake with MeCN and the fil- trate was evaporated under vacuum. The residue was taken up in a mixture of TFA (0.87 mL) and DCM (5 mL) and the mixture was stirred overnight at RT. The RM was evaporated Ryvu Therapeutics S.A. RVU305 621 R10107WO under vacuum and the residue was partitioned between DCM and sat. aq. Na ₂ CO ₃ . The aqueous phase was extracted with DCM and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under vacuum. The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-amino-3-chloroquinolin-7-yl)me- thyl]-6-cyclopropyl-N-(2-methanesulfonylpyridin-3-yl)pyridin e-3-carboxamide (Example J- 001, 0.118 g, 0.23 mmol, 63%, white solid, UPLC long elution purity: 99.90%). 65/35 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.61 – 7.49 (m, 3H), 7.33 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.77 (s, 2H), 5.79 (d, J = 14.8 Hz, 1H), 4.69 (d, J = 14.8 Hz, 1H), 3.35 (s, 3H), 2.08 – 1.96 (m, 1H), 0.97 – 0.79 (m, 4H). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (s, 1H), 8.64 (s, 1H), 8.03 – 7.89 (m, 1H), 7.70 – 7.60 (m, 3H), 7.59 – 7.47 (m, 2H), 7.27 – 7.19 (m, 1H), 7.17 – 7.04 (m, 1H), 6.77 (s, 2H), 5.21 (d, J = 14.2 Hz, 1H), 4.85 (d, J = 14.1 Hz, 1H), 3.39 (s, 3H), 2.27 – 2.11 (m, 1H), 1.10 – 0.88 (m, 4H). m/z (ESI): 508.12 [M+H] ⁺ . Examples prepared according to General Procedure 38a: Ryvu Therapeutics S.A. RVU305 622 R10107WO Ryvu Therapeutics S.A. RVU305 623 R10107WO Ryvu Therapeutics S.A. RVU305 624 R10107WO Ryvu Therapeutics S.A. RVU305 625 R10107WO Ryvu Therapeutics S.A. RVU305 626 R10107WO Ryvu Therapeutics S.A. RVU305 627 R10107WO Ryvu Therapeutics S.A. RVU305 628 R10107WO Ryvu Therapeutics S.A. RVU305 629 R10107WO Ryvu Therapeutics S.A. RVU305 630 R10107WO Ryvu Therapeutics S.A. RVU305 631 R10107WO Ryvu Therapeutics S.A. RVU305 632 R10107WO Ryvu Therapeutics S.A. RVU305 633 R10107WO Ryvu Therapeutics S.A. RVU305 634 R10107WO Ryvu Therapeutics S.A. RVU305 635 R10107WO Ryvu Therapeutics S.A. RVU305 636 R10107WO Ryvu Therapeutics S.A. RVU305 637 R10107WO Ryvu Therapeutics S.A. RVU305 638 R10107WO Ryvu Therapeutics S.A. RVU305 639 R10107WO Ryvu Therapeutics S.A. RVU305 640 R10107WO Ryvu Therapeutics S.A. RVU305 641 R10107WO ¹ Purity: UPLC long elution purity Example K-001: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(2-methanesulfon ylpyridin- 3-yl)-6-methyl-5-(trifluoromethyl)pyridine-3-carboxamide, General Procedure 38b A mixture of N-(2-methanesulfonylpyridin-3-yl)-6-methyl-5-(trifluoromethy l)pyridine-3-car- boxamide (Int. M-143, 0.067 g, 0.18 mmol, 1.0 eq.), 3-chloro-N-[(2,4-dimethoxyphenyl)me- thyl]-7-(iodomethyl)quinolin-2-amine (Int. A-100, 0.119 g, 0.18 mmol, 1.0 eq.) and Cs ₂ CO ₃ (0.071 g, 0.22 mmol, 1.2 eq.) in anhydrous MeCN (4.0 mL) was stirred at 65 °C for 1 h. Af- ter coming back to RT, the mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (2x) and the combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by FCC (0 to 33% EtOAc gradient in hexane) to yield N-[(3-chloro-2- {[(2,4-dimethoxyphenyl)methyl]amino}quinolin-7-yl)methyl]-N- (2-methanesulfonylpyridin- 3-yl)-6-methyl-5-(trifluoromethyl)pyridine-3-carboxamide (m/z (ESI): 700.5 [M+H] ⁺ ). This intermediate was stirred with PTSA hydrate (0.125 g, 0.66 mmol, 3.6 eq.) in toluene at reflux for 1 h. After coming back to RT, the RM was partitioned between 1 M aq. NaOH and DCM. The aqueous layer was extracted with DCM (2x) and the combined organic extracts were washed with brine and dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by two consecutive FCCs (first: NH ₂ functional- ized silica, 0 to 5% MeOH gradient in DCM; second: C18 functionalized silica, 5% to 95% MeCN gradient in water) to yield, after lyophilization, N-[(2-amino-3-chloroquinolin-7- yl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-6-methyl-5-(tri fluoromethyl)pyridine-3-car- boxamide (Example K-001, 0.038 g, 0.07 mmol, 38%, white solid, UPLC long elution purity: 99.86%). 8/2 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major ro- tamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (s, 1H), 8.56 (d, J = 4.6 Hz, 1H), 8.19 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.1, 4.6 Hz, 1H), 7.35 (s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 6.75 (s, 2H), 5.74 (d, J = 14.7 Hz, 1H), 4.74 (d, J = 14.7 Hz, 1H), 3.31 (s, 3H), 2.54 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -61.36. Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 – 8.97 (m, 1H), 8.71 – 8.63 (m, 1H), 8.32 – 8.23 (m, Ryvu Therapeutics S.A. RVU305 642 R10107WO 1H), 8.21 – 8.15 (m, 1H), 7.76 – 7.67 (m, 2H), 7.67 – 7.59 (m, 1H), 7.21 – 7.10 (m, 2H), 6.75 (s, 2H), 5.23 – 5.08 (m, 1H), 4.91 – 4.80 (m, 1H), 3.39 (s, 3H), 2.70 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -61.36. m/z (ESI): 550.13 [M+H] ⁺ . Examples prepared according to General Procedure 38b: Ryvu Therapeutics S.A. RVU305 643 R10107WO Ryvu Therapeutics S.A. RVU305 644 R10107WO ¹ Purity: UPLC long elution purity Example L-001: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-{1,1-dioxo-2H,3H -1λ⁶- thieno[3,2-b]pyridin-7-yl}-6-(trifluoromethyl)pyridine-3-car boxamide, General Procedure 41 Ryvu Therapeutics S.A. RVU305 645 R10107WO g, 1.16 mmol, 1 eq.), (3-chloro-2-{[(2,4-dimethoxyphenyl)methyl]amino}quinolin-7-y l)meth- anol (Int. A-099, 0.548 g, 1.51 mmol, 1.3 eq.) and PPh ₃ (0.450 g, 1.72 mmol, 1.47 eq.) in an- hydrous toluene (17 mL). The RM was stirred under nitrogen at RT for 1 h and was evapo- rated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gra- dient in DCM) to yield N-[(3-chloro-2-{[(2,4-dimethoxyphenyl)methyl]amino}quinolin- 7- yl)methyl]-N-{1,1-dioxo-2H,3H-1λ⁶-thieno[3,2-b]pyridin-7- yl}-6-(trifluoromethyl)pyridine- 3-carboxamide (Int. V-001, 0.420 g, 0.53 mmol, 45%, yellow solid, UPLC purity: 88%). m/z (ESI): 698.7 [M+H] ⁺ . Step 2: A mixture of N-[(3-chloro-2-{[(2,4-dimethoxyphenyl)methyl]amino}quinolin- 7-yl)methyl]-N- {1,1-dioxo-2H,3H-1λ⁶-thieno[3,2-b]pyridin-7-yl}-6-(triflu oromethyl)pyridine-3-carboxamide (Int. V-001, 0.42 g, 0.53 mmol, 1.0 eq.) and PTSA monohydrate (0.504 g, 2.65 mmol, 5.0 eq.) in toluene (5.0 mL) was refluxed for 90 min. After coming back to RT, the RM was basified by addition of aq.2 M NaOH and the phases were separated. The aqueous phase was ex- tracted with DCM (3x) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH in DCM) followed by trituration in absolute EtOH to yield N-[(2-amino-3-chlo- roquinolin-7-yl)methyl]-N-{1,1-dioxo-2H,3H-1λ⁶-thieno[3,2 -b]pyridin-7-yl}-6-(trifluorome- thyl)pyridine-3-carboxamide (Example K-001, 0.19 g, 0.35 mmol, 65%, white solid, UPLC long elution purity: 99.75%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.17 (s, 1H), 8.14 (dd, J = 8.2, 1.5 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.22 (dd, J = 8.2, 1.7 Hz, 1H), 6.98 (d, J = 5.3 Hz, 1H), 6.76 (s, 2H), 6.07 – 5.56 (m, 1H), 5.10 – 4.73 (m, 1H), 3.94 (t, J = 7.0 Hz, 2H), 3.61 – 3.41 (m, 2H). m/z (ESI): 550.13 [M+H] ⁺ . Examples prepared according to General Procedure 41: Ryvu Therapeutics S.A. RVU305 646 R10107WO Ryvu Therapeutics S.A. RVU305 647 R10107WO ¹ Purity: UPLC long elution purity Example M-001: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesul- fonylphenyl)-6-(3-oxopiperazin-1-yl)pyridine-3-carboxamide Step 1: Step 1 was performed according to General Procedure 38a, using 6-bromo-N-(4-fluoro-2- methanesulfonylphenyl)pyridine-3-carboxamide (Int. K-082, 0.67 g, 1.76 mmol, 1.0 eq.), 3- chloro-N-[(2,4-dimethoxyphenyl)methyl]-7-(iodomethyl)quinoli n-2-amine (Int. A-100, 1.9 g, 2.29 mmol, 1.3 eq.) and Cs ₂ CO ₃ (1.5 g, 4.75 mmol, 2.7 eq.) in a mixture of anhydrous MeCN (38 mL) and anhydrous DMF (2 mL), followed by treatment with 25% TFA in DCM (12 mL). The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane) to yield N- [(2-amino-3-chloroquinolin-7-yl)methyl]-6-bromo-N-(4-fluoro- 2-methanesul- fonylphenyl)pyridine-3-carboxamide (Int. V-002, 0.74 g, 1.18 mmol, 67%, white foam, UPLC purity: 90%).7/3 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J = 2.4 Hz, 1H), 8.20 (s, 1H), 7.83 (dd, J = 8.3, 3.0 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.62 (dd, J = 8.4, 2.3 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.48 (td, J = 8.2, 2.9 Hz, 1H), 7.39 (s, 1H), 7.33 (dd, J = 8.9, 4.9 Hz, 1H), 7.27 (dd, J = 8.2, 1.7 Hz, 1H), 6.76 (s, 2H), 5.65 (d, J = 14.8 Hz, 1H), 4.64 (d, J = 14.8 Hz, 1H), 3.22 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -109.05 (td, J = 8.0, 5.0 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 8.03 (dd, J = 8.3, 2.4 Hz, 1H), 7.90 (dd, J = 8.3, 3.1 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.61 – 7.58 (m, 1H), 7.57 – 7.51 (m, 1H), 7.21 (dd, J = 9.0, 4.6 Hz, 1H), 7.19 (d, J = 4.3 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.79 (s, 2H), 5.14 (d, J = 15.9 Hz, 1H), 4.70 (d, J = 15.8 Hz, 1H), 3.31 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -110.38 (td, J = 8.1, 5.3 Hz). m/z (ESI): 565.5 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 648 R10107WO Step 2: A Biotage ^TM microwave vial was charged with N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6- bromo-N-(4-fluoro-2-methanesulfonylphenyl)pyridine-3-carboxa mide (Int. V-002, 0.16 g, 0.255 mmol, 1.0 eq.), piperazin-2-one (0.077 g, 0.77 mmol, 4.0 eq.) and TEA (0.21 mL, 1.53 mmol, 6.0 eq.) and anhydrous NMP (4.0 mL). The atmosphere was replaced by argon, the vial was sealed and the RM was stirred at 140 °C for 5.5 h and at RT overnight. The RM was then partitioned between sat. aq. Na ₂ CO ₃ and DCM, and the aqueous layer was ex- tracted with DCM (3x). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 100% EtOAc gradient in hexane followed by 0 to 10% MeOH gradient in EtOAc) to yield N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2- methanesulfonylphenyl)-6-(3-oxopiperazin-1-yl)pyridine-3-car boxamide (Example M-001, 0.105 g, 0.18 mmol, 70%, white solid, UPLC long elution purity: 99.76%). 7/3 mixture of re- stricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (s, 1H), 8.13 – 8.08 (m, 1H), 8.02 (s, 1H), 7.86 (dd, J = 8.4, 3.0 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.52 – 7.40 (m, 2H), 7.36 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.21 – 7.15 (m, 1H), 6.75 (s, 2H), 6.62 (d, J = 9.0 Hz, 1H), 5.70 (d, J = 15.1 Hz, 1H), 4.54 (d, J = 15.0 Hz, 1H), 3.98 – 3.93 (m, 2H), 3.72 – 3.65 (m, 2H), 3.23 (m, 2H), 3.20 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -109.99 – -110.10 (m). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 – 8.47 (m, 1H), 8.19 (s, 1H), 8.16 – 8.08 (m, 1H), 7.94 – 7.81 (m, 2H), 7.67 – 7.58 (m, 1H), 7.52 – 7.40 (m, 1H), 7.21 (d, J = 22.9 Hz, 1H), 7.13 – 7.03 (m, 2H), 6.97 – 6.87 (m, 1H), 6.79 (s, 2H), 5.35 (d, J = 15.0 Hz, 1H), 4.72 (d, J = 15.0 Hz, 1H), 4.11 – 4.03 (m, 2H), 3.83 – 3.76 (m, 2H), 3.34 – 3.34 (m, 5H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -110.93 – -111.15 (m). _m/z (ESI): 583.13 [M+H] ⁺ . Example M-002: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesul- fonylphenyl)-6-(4-methyl-3-oxopiperazin-1-yl)pyridine-3-carb oxamide The title compound was prepared in the same manner as for Example M-001, using N-[(2- amino-3-chloroquinolin-7-yl)methyl]-6-bromo-N-(4-fluoro-2-me thanesulfonylphenyl)pyri- dine-3-carboxamide (Int. V-002, 0.16 g, 0.26 mmol, 1.0 eq.), 1-methylpiperazin-2-one (0.087 g, 0.762 mmol, 3.0 eq.) and TEA (0.21 mL, 1.50 mmol, 5.9 eq.) in anhydrous NMP (4 mL). The crude material was purified by FCC (0 to 5% MeOH gradient in EtOAc) to yield N-[(2- amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesul fonylphenyl)-6-(4-methyl-3- Ryvu Therapeutics S.A. RVU305 649 R10107WO oxopiperazin-1-yl)pyridine-3-carboxamide white solid (Example M-002, 0.14 g, 0.23 mmol, 92%, white solid, UPLC long elution purity: 99.85%). 85/15 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (s, 1H), 8.04 – 8.00 (m, 1H), 7.86 (dd, J = 8.3, 3.0 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.52 – 7.41 (m, 2H), 7.36 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.21 – 7.13 (m, 1H), 6.75 (s, 2H), 6.66 (d, J = 9.2 Hz, 1H), 5.69 (d, J = 15.0 Hz, 1H), 4.54 (d, J = 15.0 Hz, 1H), 4.04 – 3.99 (m, 2H), 3.82 – 3.73 (m, 2H), 3.34 (s, 3H), 3.21 – 3.17 (m, 2H), 2.87 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -109.95 – -110.11 (m). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 8.18 (s, 1H), 7.92 – 7.82 (m, 2H), 7.68 – 7.59 (m, 1H), 7.51 – 7.41 (m, 1H), 7.28 – 7.15 (m, 1H), 7.14 – 7.04 (m, 2H), 7.00 – 6.91 (m, 1H), 6.78 (s, 2H), 5.34 (d, J = 15.7 Hz, 1H), 4.71 (d, J = 15.6 Hz, 1H), 4.14 (s, 2H), 3.89 (s, 2H), 3.34 (s, 3H), 3.27 – 3.22 (m, 2H), 2.89 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -110.89 – -111.15 (m). m/z (ESI): 597.15 [M+H] ⁺ . Example M-003: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesul- fonylphenyl)-6-(4-methylpiperazin-1-yl)pyridine-3-carboxamid e The title compound was prepared in the same manner as for Example M-001, using N-[(2- amino-3-chloroquinolin-7-yl)methyl]-6-bromo-N-(4-fluoro-2-me thanesulfonylphenyl)pyri- dine-3-carboxamide (Int. V-002, 0.16 g, 0.26 mmol, 1.0 eq.), 1-methylpiperazine (0.077 g, 0.77 mmol, 2.98 eq.) and TEA (0.22 mL, 1.58 mmol, 6.1 eq.) in anhydrous NMP (3.0 mL). The crude material was purified by FCC (0 to 10% MeOH gradient in DCM) to yield N-[(2-amino- 3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfonylp henyl)-6-(4-methylpiperazin- 1-yl)pyridine-3-carboxamide (Example M-003, 0.105 g, 0.18 mmol, 69%, beige solid, UPLC long elution purity: 99.22%).7/3 mixture of restricted C-N amide rotation isomers in DMSO- d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (s, 1H), 7.99 (s, 1H), 7.86 (dd, J = 3.0, 8.4 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.47 (td, J = 2.9, 8.2 Hz, 1H), 7.38 – 7.35 (m, 2H), 7.23 (m, 1H), 7.19 – 7.13 (m, 1H), 6.75 (s, 2H), 6.65 (d, J = 7.6 Hz, 1H), 5.69 (d, J = 15.0 Hz, 1H), 4.53 (d, J = 15.1 Hz, 1H), 3.51 – 3.43 (m, 4H), 3.19 (s, 3H), 2.35 – 2.29 (m, 4H), 2.18 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -110.02 – -110.17 (m). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 – 8.45 (m, 1H), 8.20 – 8.17 (m, 1H), 7.90 – 7.80 (m, 2H), 7.67 – 7.59 (m, 1H), 7.52 – 7.43 (m, 1H), 7.29 – 7.12 (m, 1H), 7.13 – 7.02 (m, 2H), 7.01 – 6.88 (m, 1H), 6.78 (s, 2H), 5.35 (d, J = 15.9 Hz, 1H), 4.71 (d, J = 15.9 Hz, 1H), 3.65 – 3.54 (m, 4H), 3.23 (s, 3H), 2.41 – 2.33 (m, 4H), 2.19 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -111.00 – -111.18 (m). m/z (ESI): 583.17 [M+H] ⁺ . Ryvu Therapeutics S.A. RVU305 650 R10107WO Example H-023: N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesul- fonylphenyl)-6-(1-hydroxy-2-methylpropan-2-yl)pyridine-3-car boxamide Step 1 was performed according to General Procedure 38a, using Cs ₂ CO ₃ (0.316 g, 0.97 mmol, 2.0 eq.), 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-7-(iodomethyl)quino lin-2-amine (Int. A-100, 0.290 g, 0.61 mmol, 1.25 eq.) and 2-{5-[(4-fluoro-2-methanesulfonylphenyl)car- bamoyl]pyridin-2-yl}-2-methylpropyl acetate (Int. M-207, 0.2 g, 0.48 mmol, 1.0 eq.) in MeCN (6.0 mL), followed by treatment with 20% TFA in DCM (5 mL) for 24 h at RT. The obtained crude 2-(5-{[(2-amino-3-chloroquinolin-7-yl)methyl](4-fluoro-2-met hanesul- fonylphenyl)carbamoyl}pyridin-2-yl)-2-methylpropyl acetate (Int. V-003, m/z (ESI): 600.0 [M+H] ⁺ ) was used in the next step without further purification. Step 2: A solution of K ₂ CO ₃ (0.422 g, 3.05 mmol, 5.0 eq.) in water (4.0 mL) was added to a suspen- sion of crude 2-(5-{[(2-amino-3-chloroquinolin-7-yl)methyl](4-fluoro-2-met hanesul- fonylphenyl)carbamoyl}pyridin-2-yl)-2-methylpropyl acetate (Int. V-003) in MeOH (8 mL) and the RM was stirred at RT for 1 h. The reaction was quenched by addition of sat. aq. NH ₄ Cl and the mixture was extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by FCC (0 to 5% MeOH gradient in DCM) to yield N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-meth anesulfonylphenyl)-6-(1-hy- droxy-2-methylpropan-2-yl)pyridine-3-carboxamide (Example H-023, 0.127 g, 0.23 mmol, 48% over 2 steps, white solid, UPLC long elution purity: 100%). 6/4 mixture of restricted C-N amide rotation isomers in DMSO-d ₆ at RT: Major rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J = 2.3 Hz, 1H), 8.20 (s, 1H), 7.86 (dd, J = 8.3, 2.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.63 – 7.55 (m, 2H), 7.46 (td, J = 8.5, 2.9 Hz, 1H), 7.38 (s, 1H), 7.28 – 7.21 (m, 2H), 6.76 (s, 2H), 5.72 (d, J = 14.9 Hz, 1H), 4.60 (t, J = 5.7 Hz, 1H), 4.56 (d, J = 14.9 Hz, 1H), 3.45 (d, J = 5.6 Hz, 2H), 3.19 (s, 3H), 1.15 (s, 6H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -109.55 (td, J = 7.6, 5.0 Hz). Minor rotamer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (d, J = 2.3 Hz, 1H), 8.18 (s, 1H), 8.03 (dd, J = 8.2, 2.3 Hz, 1H), 7.89 (dd, J = 7.9, 3.0 Hz, 1H), 7.62 – 7.55 (m, 1H), 7.52 (td, J = 8.4, 2.6 Hz, 1H), 7.29 – 7.20 (m, 2H), 7.15 (dd, J = 8.9, 4.9 Hz, 1H), 7.11 (dd, J = 8.2, 1.7 Hz, 1H), 6.79 (s, 2H), 5.20 (d, J = 15.9 Hz, 1H), 4.70 (d, J = 15.9 Hz, 1H), 4.66 (t, J = 5.6 Hz, 1H), 3.57 (d, J = 5.8 Hz, 2H), 3.30 (s, 3H), 1.28 (s, 3H), 1.27 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -110.61 (td, J = 8.3, 5.8 Hz). m/z (ESI): 557.38 [M+H] ⁺ . Biological assays and data Ryvu Therapeutics S.A. RVU305 651 R10107WO As stated above, the compounds of the present invention are PRMT5 modulators and are useful in treating diseases by PRMT5 activity regulation. The biological activity of the com- pounds of the present invention can be determined by any appropriate test to determine the activity of the compound as PRMT5 modulator, as well as cell lines and in vivo models, in particular in presence or absence of MTA as exemplified below. Biochemical assay for recombinant PRMT5/MEP50 complex in presence or absence of MTA Four mixes were prepared on ice: Mix 1 – containing 3x concentrated PRMT5/MEP50 enzyme (in-house production) in 1x buffer (50 mM TRIS pH 8.0, 50 mM KCl, 15 mM MgCl ₂ , 1 mM EDTA) including 3x carrier protein (BSA, final conc. 0.005%) and reducing agent (DTT, final conc. 1 mM) Mix 2 - 1x buffer including 3x carrier protein and reducing agent Mix 3 – containing 3x concentrated Histone H4 (N-terminal Peptide, Biotinylated; EpiCy- pher, #12-0029) in 1x buffer; Mix 4 – containing 3x concentrated SAM in 1x buffer. Briefly, 5 µL of Mix 4 were added on a plate with 1% of DMSO or MTA at 0.8 µM (dispensed with Tecan D300e or Echo acoustic dispenser). Then using a MultiFlo FX dispenser, 5 µL of Mix 1 and Mix 2 were added to the appropriate wells and the plate was pre-incubated for 20 minutes at RT. After that, the tested compounds at 10 concentrations, each one in duplicate, were added and normalized to 3% of DMSO (using a Tecan D300e or an Echo acoustic dispenser) and incubated again for 20 minutes at RT. Then, 5 µL of Mix 3 were added to all the wells except the low control wells (buffer 1x was added instead to the low control wells). The plate was incubated at RT for 60 min. After 60 min, 5 µL of TFA were added to all wells using DragonFly Discovery liquid dispenser and the plate was incubated at RT for 5 minutes. After 5 minutes, 5 µL of MTase-Glo Reagent (Promega #V7601 or #V7602) 1X was added using a MultiFlo FX dispenser and the plate was incubated at RT for 30 min. Next, 15 µL of MTaseGlo Detection Solution was added to all wells and the plate was incubated at RT for 30 min. Afterwards, the luminescence signal was recorded using plate reader. The data were analyzed in GraphPad Prism ^® . IC ₅₀ , Hill slope and efficacy parameters were determined by fitting a variable slope sigmoidal function. HCT116 MTAP Knockout model The HCT116 cell line was purchased from PHE ECACC (Acc No: 91091005). The HCT116 MTAP KO cell line was generated using a CRISPR/Cas9 system and sgRNA targeting the MTAP gene. HCT116 cell line was co-transfected with MTAP CRISPR/Cas9 KO and MTAP HDR plasmids (Santa Cruz Biotechnology, sc-406223, and sc-406223-HDR, respectively), followed by puromycin selection. Knockout of the MTAP gene after clonal selection was val- idated using western blotting (Antibody Cell Sig., 4158). HCT116 WT and HCT116 MTAP Ryvu Therapeutics S.A. RVU305 652 R10107WO knockout cells were propagated in RPMI 1640 medium supplemented with 10% FBS and 1 mM sodium pyruvate in a humidified 5% CO ₂ tissue culture incubator. SDMA ELISA assay: On Day 0, HCT116 parental and HCT116 MTAP KO cells were seeded in 96-well plate in RPMI 1640 medium containing 10% FBS and 1% sodium pyruvate and incubated overnight in a humidified, 5% CO ₂ tissue culture incubator. On Day 1, the cells were treated with DMSO vehicle control or a dose response of test com- pounds dispensed to wells at defined concentration using a Tecan D300e digital dispenser (n=2) normalized with DMSO. On Day 4, 10 µl of alamarBlue reagent (amount equal to 5% of the well volume) were added to each well and the cells were incubated at 37 °C in a 5% CO ₂ incubator for 5 h. The fluo- rescence intensity was measured with a plate reader at 540 nm excitation wavelength and 590 nm emission wavelength. The culture medium was removed and the cells were washed with PBS. Then the PBS was completely removed. 50 µL of Lysis Buffer (PathScan ^® Sand- wich ELISA Lysis Buffer diluted 2x in PBS including Halt Protease & Phosphatase Inhibitor Cocktail (100x), ThermoScientific) was added to each well and the plate was incubated on ice for 15 minutes followed by freezing of the plate at -80 °C. On Day 5, the lysates were thawed, diluted, 100 µl was transferred to an ELISA plate (Thermo Scientific, 442404) and incubated for 2 h at RT. Next, the lysate was removed and each well was washed three times with 200 µL of the Wash Buffer (PBS with 0.05% Tween 20). 100 µL of the Blocking Buffer (PBS with 0.05% Tween 20 and 5% BSA) were added to each well and incubated for 2 h at RT at 250 rpm. Next the wells were washed three times with Wash Buffer and 40 µL of the SDMA antibody (Cell Signaling #13222S; 1:1000, Wash Buffer with 1% BSA) were added to each well. The plate was sealed and incubated on the rocking platform overnight at 4 °C. On Day 6 antibodies were removed and each well was washed five times with 200 µL of the Wash Buffer.40 µL of HRP-linked anti-rabbit IgG antibody (Cell Signaling #7074S; 1:2000, Wash Buffer with 1% BSA) were added to each well and the plate was incubated for 2 h at RT protected from light. Next, antibodies were removed and each well was washed five times with 200 µL of the Wash Buffer. 100 µL of Substrate Solution (Invitrogen 00-4201-56) were added to each well and plate was incubated for 10 min. at RT. Then, 50 µL of Stop So- lution (aq.1 M H ₂ SO ₄ ) were added and the plate was mixed gently. The absorbance at 450 nm was measured. For data analysis, dose-response curves were determined and the relevant parameters were calculated (EC ₅₀ , HillSlope, efficacy and %effect for the 2 highest tested compound concentrations) by fitting a variable-slope sigmoidal function [EC ₅₀ inhibition; normalization: 0% POS CTL, 100% VEH CTL] using the GraphPad Prism ^® software. Outliers were excluded from the graphs. Biochemical (with and without MTA) and cellular potency (in HCT116-WT and MTAP KO cell lines) Compounds are classified according to their IC ₅₀ /EC ₅₀ values in the assays described above in three groups: Ryvu Therapeutics S.A. RVU305 653 R10107WO A = IC ₅₀ /EC ₅₀ ≤ 0.1 ^M; B = 0.1 ^M < IC ₅₀ /EC ₅₀ ≤ 1 ^M; C = 30 ^M ≥ IC ₅₀ /EC ₅₀ > 1 ^M Ryvu Therapeutics S.A. RVU305 654 R10107WO Ryvu Therapeutics S.A. RVU305 655 R10107WO Ryvu Therapeutics S.A. RVU305 656 R10107WO Ryvu Therapeutics S.A. RVU305 657 R10107WO Ryvu Therapeutics S.A. RVU305 658 R10107WO Ryvu Therapeutics S.A. RVU305 659 R10107WO Ryvu Therapeutics S.A. RVU305 660 R10107WO Ryvu Therapeutics S.A. RVU305 661 R10107WO Ryvu Therapeutics S.A. RVU305 662 R10107WO Ryvu Therapeutics S.A. RVU305 663 R10107WO Ryvu Therapeutics S.A. RVU305 664 R10107WO Ryvu Therapeutics S.A. RVU305 665 R10107WO Ryvu Therapeutics S.A. RVU305 666 R10107WO Ryvu Therapeutics S.A. 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