WO2024074611A1 - Inhibiteurs de prmt5 - Google Patents

Inhibiteurs de prmt5 Download PDF

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Publication number
WO2024074611A1
WO2024074611A1 PCT/EP2023/077562 EP2023077562W WO2024074611A1 WO 2024074611 A1 WO2024074611 A1 WO 2024074611A1 EP 2023077562 W EP2023077562 W EP 2023077562W WO 2024074611 A1 WO2024074611 A1 WO 2024074611A1
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Prior art keywords
methyl
carboxamide
amino
pyridine
aminoquinolin
Prior art date
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PCT/EP2023/077562
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English (en)
Inventor
Adam RADZIMIERSKI
Aneta BOBOWSKA
Oleksandr LEVENETS
Aleksandra Julia WIECKOWSKA
Nicolas Felix Pierre BOUTARD
Iana LEVENETS
Martin Edward Swarbrick
Marcin Tomasz NOWOGRODZKI
Marta Katarzyna SOWINSKA
Julia Krzywik
Karol ZUCHOWICZ
Didier Pez
Karolina Maria GLUZA
Sujit SASMAL
Szymon PALUCH
Marianna GIRARDI
Joanna Agnieszka SZEREMETA-SPISAK
John King-Underwood
Mateusz Piotr SWIRSKI
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Ryvu Therapeutics S.A.
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Publication of WO2024074611A1 publication Critical patent/WO2024074611A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • 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.
  • 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.
  • SAM S-adenosylmethionine
  • PRMT5 Protein methyltransferase 5
  • MMA omega-N monomethylarginine
  • SDMA symmetrical dime- thylarginine
  • 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.
  • p16/CDKN2a cyclin dependent kinase inhibitor 2A
  • Metabolic gene MTAP (methylthioadenosine phosphorylase) is localized at the 9p21 chromosome in the close proximity to p16/CDKN2A tumor-suppressor locus. Co-deletion of MTAP may be observed in 80-90% of all tumors harboring homozygous deletion of CDKN2A, which 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).
  • MTA methylthioadenosine
  • RVU305 2 R10107WO whole proteome R10107WO whole proteome
  • 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.
  • 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.
  • 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.
  • 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-oul 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-oul 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/
  • 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.
  • 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 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;
  • R X3 is halogen.
  • 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- sti
  • each sub- stigool comprise one or more, same or different heteroatoms
  • 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 .
  • a 1 is phenyl, pyridinyl, pyrazolyl, or thiophenyl;
  • a 2 is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl.
  • Ryvu Therapeutics S.A is another preferred embodiment.
  • RVU305 7 R10107WO B is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocy-rod 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 .
  • B is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocy-rod 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
  • 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.
  • A is a moiety selected from the group consisting of Ryvu Therapeutics S.A. RVU305 8 R10107WO
  • 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-methanesulfonylpyridin-3-yl)acet- amide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1 ⁇ 6-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N- ⁇ 1,1-dioxo-2H,3H-1 ⁇ 6-thieno[3,2-b]pyridin- 7-yl ⁇ acetamide, N-[(2-amino-5-fluoroquinolin-7-yl
  • 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-(trifluoromethyl)phenyl]pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylquinolin-3-yl)acetamide, N- ⁇ [2-amino-3-(hydroxymethyl)quinolin-7-yl]methyl ⁇ -N-(2-methanesulfonylphenyl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2,3-dihydro-1-benzofuran-7-yl)acet
  • 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-methanesulfonylphenyl)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-methanesulfonylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(ethanesulfonyl)phenyl]pyridine-3-carboxamide,
  • 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-methanesulfonylpyridin-3-yl)cyclobu- tane-1-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-5-chloro-N-(2-methanesulfonylpyridin-3-yl)pyridine-3- carboxamide, 4- ⁇ N-[(2-aminoquinolin-7-yl)methyl]-3-(pyridin-2-yl)propanamido ⁇ -1-methyl-1H-pyrazole- 3-carboxamide, N-[(2-amino-5-fluoroquinolin-7
  • 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-methanesulfonylphenyl)oxolane-2-carboxa- mide, 4- ⁇ N-[(2-aminoquinolin-7-yl)methyl]acetamido ⁇ -1-
  • 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-dihydro-1 ⁇ 6,2-benzothiazol-7- yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzoxazol-4-yl)pyridine-3-carboxamide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-(5,6,7,8-tetrahydroquinolin-8-yl)pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]pyridine-3-carbox- amide, rac-N-[(2-aminoquinolin-7-yl)methyl]
  • 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-methanesulfonyl-5-methylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyano-N-(2-methanesulfonylphenyl)pyridine- 3-carboxamide, N-[(6-amino-1,5-naphthyridin-3-yl)methyl]-N-(4,4-difluoro-1,1-dioxo-3,4-dihydro-2H-1 ⁇ 6-
  • RVU305 19 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(4-fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide, and N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyano-N-(2-methanesulfonylpyridin-3-yl)pyri- dine-3-carboxamide.
  • the compound of formula (I) is selected from the group consisting of: N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(difluoromethoxy)phenyl]pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonyl-5-methylpyridin-3-yl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonylphenyl)-2-(trifluoromethyl)py- rimidine-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(5-chloro-2-methanesulfonylphenyl)pyrazolo[1,5- a]pyridine-3-carboxamide, N-[(2-aminoquinol
  • RVU305 21 R10107WO N-[(3-amino-2-methylquinoxalin-6-yl)methyl]-N-(2-methanesulfonylphenyl)-2-(trifluorome- thyl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1 ⁇ 6-benzothiophen- 7-yl)-2,6-dimethylpyridine-3-carboxamide, N-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin-3-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide, N-[(2-amino-5-fluoro-3-methylquinolin-7-yl)methyl]-N-(2-methanesulfonylpyri
  • RVU305 22 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(2-methanesulfonylphenyl)-2,6-dimethylpyri- dine-4-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(5-chloro-2-methanesulfonylpyridin-3-yl)pyri- dine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1 ⁇ 6-benzothiophen- 7-yl)-5-(trifluoromethyl)pyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-5-cyano-N-(2-methanesulfonylphenyl)pyridine- 3-car
  • RVU305 23 R10107WO N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-chloro-2-methanesulfonylphenyl)-6- methylpyridine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfonylphenyl)-2-(pro- pan-2-yl)pyrimidine-5-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfonylphenyl)-6- methylpyridazine-3-carboxamide, N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-cyano-N-(4-fluoro-2-methanesul- fonylphenyl)pyridine-4-
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ).
  • 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.
  • 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.
  • X 4 is CH or CR X4 .
  • X 5 is CH or CR X5 .
  • 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 .
  • 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • formula (Ia*) preferably none of X 2 and X 3 is N.
  • the compound of formula (I) is a compound of formula (Ia*), wherein preferably none of X 2 and X 3 is N.
  • formula (Ib*) preferably none of X 1 and X 3 is N.
  • 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.
  • 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.
  • 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;
  • 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:
  • the compound of formula (I) is a compound of formula (I*-0), (I*-1), (I*-2), (I*-3), (Ib*-0), and (Ic*-0).
  • 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).
  • RVU305 30 R10107WO
  • 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.
  • R X1 , R X2 , R X3 , R X4 , and R X5 is pre- sent.
  • R X5 is absent so that X 5 is N or CH, preferably CH.
  • R X4 is absent so that X 4 is N or CH, prefera- bly CH.
  • R X4 and R X5 are absent s that X 4 and X 5 are N or CH, preferably CH.
  • R X1 is halogen, CD 3 , C 1 -alkyl, C 1 -haloalkyl, or C 1 -hydroxyalkyl.
  • R X2 is NH 2 .
  • 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.
  • R 10107WO 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/
  • 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
  • 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.
  • 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-
  • 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
  • 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.
  • 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 un
  • 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.
  • 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 .
  • R 1 is CH 3 .
  • R 1 is unsubstituted pyridinyl.
  • R 1 is pyridinyl substituted with one substituent selected from Cl, F, CH 3 , or CF 3 .
  • 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.
  • 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*),
  • 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.
  • a 1 is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocy-hack 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 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 .
  • 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 .
  • a 1 is phenyl, pyridinyl, pyrazolyl, or thiophenyl.
  • a 1 is phenyl, pyridinyl, or pyrazolyl.
  • 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
  • a 1 is unsubstituted.
  • 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.
  • 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 .
  • 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 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.
  • Ryvu Therapeutics S.A 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-
  • 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.
  • 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.
  • R A1 is halogen.
  • R A1 is F.
  • 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.
  • 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.
  • 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.
  • a 1 is selected from the group consisting of Ryvu Therapeutics S.A.
  • 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.
  • a 2 is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocy-hack 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 .
  • 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 .
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • B is a 5- to 7-membered saturated, partially or fully unsaturated, or aromatic carbocy-hack 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 .
  • B is a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocy-rod 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 .
  • 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-mann 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.
  • (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).
  • 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
  • B is unsubstituted.
  • B 1 is unsubstituted.
  • B 1 is unsubstituted.
  • B 1 is unsubstituted.
  • B 1 is unsubstituted.
  • 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.
  • R A2 is halogen, CN, OH, C 1 -C 4 -alkyl, or C 1 -C 4 -haloalkyl.
  • R A2 is halogen, CN, C 1 -C 2 -alkyl, or C 1 -C 2 -haloalkyl.
  • R A2 is halogen or C 1 -C 2 -alkyl.
  • R A2 is Cl, F, or C 1 -alkyl.
  • 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 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.
  • R B is halogen or C 1 -C 2 -alkyl; or two R B attached to the same atom form an oxo group.
  • 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.
  • R B1 is halogen, CN, OH, C 1 -C 4 -alkyl, or C 1 -C 4 -haloalkyl.
  • R B1 is halogen, CN, C 1 -C 2 -alkyl, or C 1 -C 2 -haloalkyl.
  • R B1 is halogen or C 1 -C 2 -alkyl.
  • R B1 is F or C 1 -alkyl.
  • 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 .
  • 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
  • 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 .
  • the moiety A is not unsubsti- tuted naphthyl or naphthyl substituted with cyano.
  • 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.
  • the compound of formula (I) according to the present invention is not: .
  • 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-methanesulfonylpyridin-3-yl)acet- amide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1 ⁇ 6-benzothiophen- 7-yl)pyridine-3-carboxamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N- ⁇ 1,1-dioxo-2H,3H-1 ⁇ 6-thieno[3,2-b]pyridin- 7-yl ⁇ acetamide, N-[(2-amino-5-fluoroquinolin-7-yl)methyl]-N-(1,1-dioxo-2,3-dihydro-1 ⁇ 6-benzothiophen- 7-yl)acetamide, N
  • RVU305 51 R10107WO N-[(2-amino-3-methylquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-amino-5-fluoroquinolin-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-amino-5-bromoquinolin-7-yl)methyl]-N-(2-methanesulfonylpyridin-3-yl)pyridine-3- carboxamide, N- ⁇ [2-amino-4-(hydroxymethyl)quinolin-7-yl]methyl ⁇ -N-(2-methanesulfonylphenyl)pyri- dine-3-carboxamide, N-[(2-amino
  • 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-(trifluoromethyl)phenyl]pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonylquinolin-3-yl)acetamide N- ⁇ [2-amino-3-(hydroxymethyl)quinolin-7-yl]methyl ⁇ -N-(2-methanesulfonylphenyl)pyri- dine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2,3-dihydro-1-benzofuran-7-yl)acetamide
  • 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-methanesulfonylphenyl)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-methanesulfonylpyridin-3-yl)pyridine-3- carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(ethanesulfonyl)phenyl]pyridine-3-carboxamide,
  • 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-methanesulfonylpyridin-3-yl)cyclobu- tane-1-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-5-chloro-N-(2-methanesulfonylpyridin-3-yl)pyridine-3- carboxamide, 4- ⁇ N-[(2-aminoquinolin-7-yl)methyl]-3-(pyridin-2-yl)propanamido ⁇ -1-methyl-1H-pyrazole- 3-carboxamide, N-[(2-amino-5-fluoroquinolin-7
  • 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-methanesulfonylphenyl)oxolane-2-carboxa- mide, 4- ⁇ N-[(2-aminoquinolin-7-yl)methyl]acetamido ⁇ -1-
  • 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-dihydro-1 ⁇ 6,2-benzothiazol-7- yl)pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(1,3-benzoxazol-4-yl)pyridine-3-carboxamide, rac-N-[(2-aminoquinolin-7-yl)methyl]-N-[5,6,7,8-tetrahydroquinolin-8-yl]pyridine-3-carbox- amide, N-[(2-aminoquinolin-7-yl)methyl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]pyridine-3-carbox- amide, rac-N-[(2-aminoquinolin-7-yl)
  • RVU305 60 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-cyano-N-(4-fluoro-2-methanesul- fonylphenyl)pyridine-3-carboxamide, and N-[(2-amino-3-fluoroquinolin-7-yl)methyl]-6-cyano-N-(2-methanesulfonylpyridin-3-yl)pyri- dine-3-carboxamide.
  • the compound of formula (I) is selected from the group consisting of: N-[(2-aminoquinolin-7-yl)methyl]-N-[2-(difluoromethoxy)phenyl]pyridine-3-carboxamide, N-[(2-aminoquinolin-7-yl)methyl]-N-(2-methanesulfonyl-5-methylpyridin-3-yl)-5-(trifluoro- methyl)pyridine-3-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(2-methanesulfonylphenyl)-2-(trifluoromethyl)py- rimidine-5-carboxamide, N-[(3-aminoquinoxalin-6-yl)methyl]-N-(5-chloro-2-methanesulfonylphenyl)pyrazolo[1,5- a]pyridine-3-carboxamide, N-[((2-aminoquino
  • RVU305 65 R10107WO N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-(1-cyanocyclopropyl)-N-(4-fluoro-2-me- thanesulfonylphenyl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-N-(4-fluoro-2-methanesulfonylphenyl)-6-(ox- etan-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-6-(3,3-difluoropyrrolidin-1-yl)-N-(2-me- thanesulfonylpyridin-3-yl)pyridine-3-carboxamide, N-[(2-amino-3-chloroquinolin-7-yl)methyl]-5-chloro-6-cyano-
  • 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.
  • 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.
  • conformers conformational stere- oisomers
  • 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.
  • rotational isomers as used herein also includes atropiso- mers.
  • Rotational isomers 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.
  • the absolute configuration is assigned P or ⁇ for clockwise and M or ⁇ for counterclockwise.
  • all four groups can be ranked by Cahn–Ingold–Prelog priority rules, with overall priority given to the 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.
  • 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.
  • 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.
  • the rotational isomers (rotamers) of the com- pounds according to the invention can be separated and isolated and can thus be termed atropisomers.
  • the barrier to rotation about the C-N bond between the tertiary amide nitrogen 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.
  • 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.
  • dia- stereoisomer-like mixture 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.
  • 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.
  • 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).
  • restricted bond rotation e.g., the restricted rotation about the C-N amide bond
  • 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.
  • class 2 and class 3 atropisomers are separable.
  • 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.
  • 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.
  • 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.
  • 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.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the disclosure includes compounds of formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Deuterium labeled or substituted 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.
  • concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • H hydrogen
  • hydrophilicity factor hydrogen
  • D deuterium
  • substituted means that a hydrogen atom bonded to a desig- nated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected.
  • substituted when used in reference to a designated atom, means that at- tached to the atom is a hydrogen, which can be replaced with a suitable substituent.
  • the term “one or more” is intended to cover at least one substituent, e.g.1 to 10 substituents, preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most preferably 1, or 2 substituents.
  • substituents e.g.1 to 10 substituents, preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most preferably 1, or 2 substituents.
  • Cn-Cm indicates in each case the possible number of carbon atoms in the group.
  • halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine, or bromine.
  • alkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably 1 to 5 or 1 to 4 carbon atoms, more preferably 1 to 3 or 1 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.
  • haloalkyl 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.
  • alkoxy denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom to the remainder of the molecule and has usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom.
  • alkoxy group examples are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-bu- tyloxy, iso-butyloxy, tert.-butyloxy, and the like.
  • alkoxyalkyl refers to an alkoxy group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, which is bonded via an alkyl group as defined herein having usually from 1 to 4 car- bon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, to the remainder of the molecule.
  • alkyl group which is bonded via oxygen to a further al- kyl group, which is then bonded to the remainder of the molecule.
  • alkoxy- alkyl group examples are methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and the like.
  • haloalkoxy denotes in each case a straight-chain or branched alkoxy group having from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more 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.
  • hydroxyalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms, and being further substituted with 1 to 5, preferably with 1 to 2 hydroxy groups, in particular with 1 hydroxy group, wherein a hydroxy group is a OH group.
  • the one hydroxy group is terminating the straight-chain or branched alkyl group so that the hydroxy group is bonded to an alkyl bridge, which is bonded to the remainder of the molecule.
  • hydroxyalkyl group examples include 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.
  • aminoalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms, and being further substituted with 1 to 5, preferably with 1 to 2 amino groups, in particular with 1 amino group, wherein an amino group is a NH 2 group.
  • the one amino group is terminating the straight-chain or branched alkyl group so that the amino group is bonded to an alkyl bridge, which is bonded to the 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.
  • cycloalkyl denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclo- butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopro- pyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl, cyclobutyl, cyclopentyl, and cyclo- hexyl are preferred.
  • carrier 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.
  • aryls are covered by the term “carbocycles”.
  • the term “aryl” or “aromatic carbocycle” refers to aromatic carbocyclic rings based on carbon atoms as ring members, preferably 6-membered aromatic carbocyclic rings based on carbon atoms as ring members. A preferred example is phenyl.
  • aryl further covers “aromatic carbobicycles” as defined herein.
  • the term “carbocyclic” or “carbo- cyclyl” covers phenyl and cycloalkyl, for example phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • carbobicycle 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.
  • the term “aromatic” in connection with the carbobicyclic ring means that both rings of the bicylic moiety are aromatic, so that, e.g., 8 ⁇ electrons are present in case of a 10-membered aromatic carbobicyclic ring.
  • the term “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]
  • the carbobicycle is a fused car- bobicycle, which is preferably aromatic, for example naphthalene.
  • 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.
  • carbocyclylalkyl examples include benzyl (i.e. phenylmethyl), phenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylme- thyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl.
  • carbocyclyloxy 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.
  • carbocyclyloxyalkyl denotes in each case a carbocyclyloxy group, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom.
  • 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.
  • 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.
  • the heterocycle is an aromatic heterocycle, preferably a 5- or 6-membered aromatic heterocycle comprising one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2.
  • aromatic heterocycles are provided below in connection with the definition of “hetaryl”. “Hetaryls” or “heteroaryls” are covered by the term “heterocycles”.
  • the saturated or 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 .
  • 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.
  • heterocyclic 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.
  • 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.
  • 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.
  • heteroaryl or “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” includes monocyclic 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO 2 .
  • 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.
  • heteroaryl further covers “aromatic heterobicycles” as defined above.
  • heterocyclylalkyl refers to a heterocyclyl as defined herein, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom.
  • heterocyclylalkyl include pyridinyl- methyl, pyrimidinylmethyl, pyrazolylmethyl, and piperidinylmethyl.
  • heterocyclyloxy denotes in each case a heterocyclyl as defined herein, which is bonded via an oxygen atom to the remainder of the molecule.
  • a carbon atom of the heterocyclyl is bonded to the oxygen atom.
  • heterocyclyloxy in- clude pyridinyloxy, pyrimidinyloxy, pyrazolyloxy, and piperidinyloxy.
  • heteroaryloxy referring to the corresponding group, which is bonded to the remain- der of the molecule via an oxygen atom.
  • heterocyclyloxyalkyl denotes in each case a heterocyclyloxy group, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom.
  • 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.
  • bicyclic moiety can refer to any bicyclic groups, which are present in the com- pounds of formula (I), and which are defined above.
  • the singular forms of “a” and “an” also include the corresponding plurals unless the context clearly dictates otherwise. The same applies for plural forms used herein, which also include the singular forms unless the context clearly dictates otherwise.
  • 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%.
  • the term “comprising” is not limiting.
  • the term “consisting of” is considered to be a preferred embodiment of the term “comprising of”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group which preferably consists of these embodiments only.
  • pharmaceutically acceptable excipient 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.
  • 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”.
  • 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.
  • administration is by subcutaneous, intra-tumoral or peri-tumoral routes, in particular in the treatment of cancer.
  • Particularly preferred is intra- tumoral administration.
  • 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.
  • HFA hydrofluoroalkane
  • 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.
  • 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.
  • 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 a
  • the compounds of the present invention are administered in a pharmaceuti- cal composition
  • 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.
  • 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.
  • carrier also covers an antibody that delivers the compound of formula (I).
  • 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
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoro- methane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • 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.
  • compositions 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).
  • 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, hydroxypropyl
  • 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.
  • 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.
  • 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.
  • a carrier which constitutes one or more accessory ingredients.
  • 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.
  • 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 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.
  • said pharmaceutical composition comprises said compound as the only pharma- ceutically active agent.
  • 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.
  • 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.
  • 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.
  • a proliferative disorder such as cancer or pre-cancerous syndromes associated with MTAP deficiency and/or MTA accumulation.
  • the compound of the present invention or a pharmaceutical composition comprising the same is for use in the treatment of a disease selected from the group consisting of cancer or pre-cancerous syndromes.
  • 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.
  • 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
  • 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 Aden
  • 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.
  • 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, Blad
  • 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.
  • 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.
  • 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).
  • chemotherapeutic agents such as STING pathway modulating com- pounds, TLR agonists and checkpoint inhibitors.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound of the present invention is administered prior to administra- tion of the distinct cancer treatment.
  • the distinct cancer treatment is administered prior to administration of the compound of the present invention.
  • the present invention is further illustrated by the following examples. Examples The following abbreviations are used herein: 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.
  • 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).
  • 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 ® 5 ⁇ m NX-C18110 ⁇ (00G-4454-P0-AX LC Column 250 x 21.2 mm, AX) column.
  • 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).
  • a base for example NaH or Cs 2 CO 3
  • 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).
  • 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).
  • 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.
  • a base such as NaH or Cs 2 CO 3
  • 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).
  • 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.
  • mCPBA 33.9 g, 196.44 mmol, 1.2 eq.
  • 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.
  • 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%).
  • 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 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.
  • 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.
  • 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).
  • 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%).
  • 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).
  • 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.
  • the obtained crude methyl 2-oxo-1,2-dihydroquinoline-7-carboxylate Int. A-013, 0.803 g, 3.95 mmol, 95%, UPLC purity: 99%
  • UPLC purity 99%
  • 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.
  • DIBAL-D 0.7 M in toluene, 10.6 mL, 7.42 mmol, 2.1 eq.
  • 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.
  • 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).
  • 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.).
  • 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).
  • 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.
  • 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.
  • Step 4 was performed according to General Procedure 03b, using 5 ⁇ chloro ⁇ 7 ⁇ methyl ⁇ 1,2 ⁇ dihydroquinolin ⁇ 2 ⁇ one (Int.
  • 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.
  • 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.
  • 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.
  • Step 4 was performed according to General Procedure 03b, using 5-bromo-7-methyl-1,2- dihydroquinolin-2-one (Int.
  • Step 5 Step 5 was performed according to General Procedure 04, using 5-bromo-2-chloro-7- methylquinoline (Int.
  • 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.
  • 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).
  • 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.
  • 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%
  • 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.
  • 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%).
  • Step 3 was performed according to General Procedure 02, using 6 ⁇ methoxy ⁇ 7 ⁇ methylquinolin ⁇ 1 ⁇ ium ⁇ 1 ⁇ olate (Int.
  • Step 5 was performed according to General Procedure 04, using 2 ⁇ chloro ⁇ 6 ⁇ methoxy ⁇ 7 ⁇ methylquinoline (Int.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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%).
  • 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).
  • 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.).
  • 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-ist in hexane) to yield 2,8-dichloro-7-methylquinoline (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).
  • 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.
  • 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.
  • 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, 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.
  • 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.
  • 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.
  • Step 2 was performed according to General Procedure 03b, using methyl 7-methyl-2-oxo- 1,2-dihydroquinoline-4-carboxylate (Int.
  • Step 3 was performed according to General Procedure 04, using 2-chloro-7-methylquino- line-4-carboxylate (Int.
  • 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%).
  • 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- Jerusalem pressure. The obtained crude (2-chloro-7-methylquinolin-3-yl)methanol (Int.
  • 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.
  • (2-chloro-7- methylquinolin-3-yl)methanol Int. A-066, 0.49 g, 2.28 mmol, 1.0 eq.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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- Jerusalem 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.
  • 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).
  • 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.
  • 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.
  • Step 4 was performed according to General Procedure 04, using 2-chloro-7-methylquinazo- line (Int.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%).
  • 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.
  • 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-carboxylate (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.
  • 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)methanol (Int.
  • 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.
  • 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%).
  • 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.
  • 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-naphthyridine-3-carboxylate (Int.
  • 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-naphthyridin-3-yl)methanol (Int.
  • 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.
  • 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).
  • 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.
  • AIBN 0.0
  • 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.
  • 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.
  • 2-chloro-4-(methoxymethyl)quinoline-7-carbonitrile Int. A-111, 0.187 g, 0.80 mmol, 1.0 eq.
  • 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%).
  • 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%).
  • 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.
  • 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).
  • DIBAL-H 1.0 M in THF, 21.93 mL, 21.93 mmol, 10.0 eq.
  • Step 3 A solution of methyl 4-amino-5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyridine-2-carboxylate (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 ⁇ carboxylate (Int. A-122, 0.425 g, 2.01 mmol, 65%, white solid, UPLC purity: 98%).
  • 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 ⁇ carboxylate (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.
  • 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.
  • 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%).
  • 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.
  • 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.
  • 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-carboxylate (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-yl)methanol (Int.
  • 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.
  • 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.
  • 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)methanol (Int.
  • 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).
  • 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.
  • 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%).
  • 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%).
  • RVU305 149 R10107WO Ryvu Therapeutics S.A. RVU305 150 R10107WO 2-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(2-methanesulfonylphenyl)acetamide (Int.
  • 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%).
  • 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-1 ⁇ 6-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 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%).
  • 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.
  • 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 quizzed 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%).
  • 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 .
  • 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-1 ⁇ 6- 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.
  • 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.
  • 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).
  • N-(5-methanesulfonyl-1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide (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 DryS
  • 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.
  • N-(2-methanesulfonylpyridin-3-yl)-4-methylpyridine-3-carboxamide (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.
  • Step 2 was performed according to General Procedure 08 using 5-fluoro-2-methanesul- fonylaniline (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 ⁇ L, 1.90 g, 9.41 mmol, 1.3 eq.) was added and the RM was stirred for 1 hour at RT.
  • 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.
  • 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.
  • 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).
  • Step 2 General Procedure 19 A Biotage TM microwave vial was charged with 7-bromo-1 ⁇ 6-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.
  • RVU305 200 R10107WO N- ⁇ 2-[(4-methoxyphenyl)methyl]-3-methyl-1,1-dioxo-2H-1 ⁇ 6,2,4-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.
  • 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 ® .
  • Step 5 A mixture of 2-amino-6-bromo-N-[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (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.
  • Step 6 The title compound was prepared according to General Procedure 19, using 8-bromo-2-[(4- methoxyphenyl)methyl]-3-methyl-2H-1 ⁇ 6,2,4-benzothiadiazine-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).
  • 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.
  • Step 5 A Biotage TM microwave vial was charged with 8-bromo-4,4-difluoro-3,4-dihydro-2H-1 ⁇ 6- 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.
  • 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%).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • Step 2 was performed according to General Procedure 20, using N-[2-chloro-5-(trifluorome- thyl)pyridin-3-yl]pyridine-3-carboxamide (Int.
  • 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).
  • 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).
  • 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.
  • Step 2 was performed according to General Procedure 20, using N-(2-bromo-5-fluoro- pyridin-3-yl)acetamide (Int.
  • 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%).
  • N-(4-methyl-1,1-dioxo-2,3-dihydro-1 ⁇ 6-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-1 ⁇ 6- 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.
  • 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-1 ⁇ 6-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.
  • 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-1 ⁇ 6-benzothiophen-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).
  • 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%).
  • 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.
  • 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.
  • 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
  • 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%).
  • 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.
  • 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.
  • 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.
  • Step 2 was performed according to General Procedure 14, using 2-cyclopropoxyacetic acid (Int.
  • 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 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-ist 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%).
  • 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).
  • 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%).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 1-(5-fluoro-2-nitrophenyl)-1H-pyrazole Int. M-091, 1.355 g, 4.91 mmol, 1.0 eq.
  • 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).
  • 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).
  • 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.
  • 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).
  • 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).
  • 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).
  • 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).
  • 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-1 ⁇ 6,2-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.
  • Step 6 was performed according the General Procedure 09, using 7-amino-2-tert-butyl-2,3- dihydro-1 ⁇ 6,2-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.
  • 7-amino-2-tert-butyl-2,3- dihydro-1 ⁇ 6,2-benzothiazole-1,1-dione Int. M-103, 0.435 g, 1.74 mmol, 1.0 eq.
  • DMAP 0.043 g, 0.35 mmol,
  • 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.
  • Step 5 was performed according to General Procedure 19, using 7-bromo-3-hydroxy-2,3- dihydro-1 ⁇ 6-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).
  • 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).
  • 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-carboxamide (Int.
  • 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).
  • Step 1 A pressure vessel was charged with 8-bromo-4,4-difluoro-3,4-dihydro-2H-1 ⁇ 6-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.
  • 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-1 ⁇ 6-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).
  • 2-(propan-2-yloxy)acetic acid 0.2 g, 1.69 mmol, 1.1 eq.
  • 8-amino-4,4-difluoro-3,4-dihydro-2H-1 ⁇ 6-benzothiopyran- 1,1-dione Int. M-113, 0.35 g, 1.5 mmol,
  • 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.
  • 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).
  • Step 2 was performed according the General Procedure 20, using N-(2-chloro-5-methylpyri- din-3-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide (Int.
  • Step 1 A solution of N- ⁇ 1,1-dioxo-2H,3H-1 ⁇ 6-thieno[3,2-b]pyridin-7-yl ⁇ acetamide (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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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
  • 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.
  • 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.
  • oxane-4-carboximidamide hydrochloride Int. M-128, 0.434 g, 2.45 mmol, 1.0 eq.
  • 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.
  • 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).
  • 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.
  • 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.

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Abstract

La présente invention concerne des composés de formule (I) et des sels, des stéréoisomères, des atropoisomères, des rotamères, des tautomères ou des N-oxydes de ceux-ci qui sont utiles en tant qu'inhibiteurs de PRMT5. La présente invention concerne en outre les composés de formule (I) destinés à être utilisés en tant que médicament et des compositions pharmaceutiques comprenant lesdits composés.
PCT/EP2023/077562 2022-10-05 2023-10-05 Inhibiteurs de prmt5 WO2024074611A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020205660A1 (fr) * 2019-03-29 2020-10-08 University Of Florida Research Foundation, Incorporated Composés inhibiteurs de la prmt5
WO2021111322A1 (fr) * 2019-12-03 2021-06-10 Lupin Limited Analogues nucléosidiques substitués en tant qu'inhibiteurs de prmt5
WO2021163344A1 (fr) * 2020-02-12 2021-08-19 Amgen Inc. Nouveaux inhibiteurs de prmt5
WO2023278564A1 (fr) * 2021-07-02 2023-01-05 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 à coopération avec la mta à base d'aminopyridine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020205660A1 (fr) * 2019-03-29 2020-10-08 University Of Florida Research Foundation, Incorporated Composés inhibiteurs de la prmt5
WO2021111322A1 (fr) * 2019-12-03 2021-06-10 Lupin Limited Analogues nucléosidiques substitués en tant qu'inhibiteurs de prmt5
WO2021163344A1 (fr) * 2020-02-12 2021-08-19 Amgen Inc. Nouveaux inhibiteurs de prmt5
WO2023278564A1 (fr) * 2021-07-02 2023-01-05 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 à coopération avec la mta à base d'aminopyridine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Cancer Principles and Practice of Oncology", 15 February 2001, LIPPINCOTT WILLIAMS & WILKINS PUBLISHERS

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