[go: up one dir, main page]

WO2025125665A1 - Nouveaux imidazoles substitués utilisés en tant qu'inhibiteurs de nav1.8 - Google Patents

Nouveaux imidazoles substitués utilisés en tant qu'inhibiteurs de nav1.8 Download PDF

Info

Publication number
WO2025125665A1
WO2025125665A1 PCT/EP2024/086446 EP2024086446W WO2025125665A1 WO 2025125665 A1 WO2025125665 A1 WO 2025125665A1 EP 2024086446 W EP2024086446 W EP 2024086446W WO 2025125665 A1 WO2025125665 A1 WO 2025125665A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
chloro
fluorophenyl
imidazol
methylsulfonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/086446
Other languages
English (en)
Inventor
Mauro Marigo
Marcel MÜLBAIER
Sebastian Krüger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of WO2025125665A1 publication Critical patent/WO2025125665A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/84—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • Navi .8 was first found predominantly in peripheral sensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia (TG), it was originally termed SNS (sensory neuron specific) (Akopian A.N. et al Nature (1996) Vol 379 pp 257-261) or PN3 (peripheral nerve 3) (Sangameswaran L. et al J. Biol. Chem. (1996) Vol 271 pp 5953-5956).
  • SNS sensor neuron specific
  • PN3 peripheral nerve 3
  • Navi.8 is localized at free nerve endings, where pain signaling is initiated in the skin (Persson A.K. et al Mol. Pain. (2010) 6:84) and is diffusely localized along the entire length of non-myelinated axons of sciatic nerve (Rush A.M. et al. Eur. J.Neurosci (2005) Vol 22 pp 39-49).
  • the invention relates to a compound according to general formula (I) wherein
  • Li represents O, C(R 7 ) 2 -O, O-C(R 7 ) 2 , N(R 7 ), C(R 7 ) 2 -N(R 7 ), N(R 7 )-C(R 7 ) 2 , S, C(R 7 ) 2 -S, S-C(R 7 ) 2 , C(R 7 ) 2 , or C(R 7 ) 2 C(R 7 ) 2 ;
  • a and B independently from one another represent phenyl, 5- to 10-membered heteroaryl, Ci-6-alkyl, Cs-io-cyclo- alkyl, or 4- to 10-membered heterocycloalkyl;
  • R 2 and R 2 independently from one another represent F, Cl, Br, CN, Ci-6-alkyl, C>, -e-cycloalky I.
  • SF 5 , phenyl or C e-cycloalkyk x and y independently from one another represent 0, 1, 2, 3, or 4;
  • R4 represents H, Cl, CN, Ci-e-alkyl, or Ce-e-cycloalkyk
  • L 2 represents bond, Ci-3-alkylene, or Ci- 2 -alkylene-N(H);
  • Re represents Ci. 6 -alkyl
  • R 7 represents H, or Ci. 4 -alkyl; wherein Ci-e-alkyl, Ci-4-alkyl, Ci-4-alkylene, Ci-3-alkylene and Ci- 2 -alkylene in each case independently from one another is linear or branched, saturated or unsaturated; wherein Ci-e-alkyl, Ci-4-alkyl, Ci-4-alkylene, Ci-3-alkylene, Ci- 2 -alkylene, C iu-cycloalkyl.
  • the compound according to the invention is present in form of a physiologically acceptable salt.
  • physiologically acceptable salt preferably refers to a salt obtained from a compound according to the invention and a physiologically acceptable acid or base.
  • the compound according to the invention may be present in any possible form including solvates, cocrystals and polymorphs.
  • solvate preferably refers to an adduct of (i) a compound according to the invention and/or a physiologically acceptable salt thereof with (ii) distinct molecular equivalents of one or more solvents.
  • the compound according to the invention may be present in form of the racemate, enantiomers, diastereomers, tautomers or any mixtures thereof.
  • imidazoles show annular tautomerism.
  • the compounds according to the invention may have one or more stereocenter.
  • the person skilled in art knows by looking at a chemical structure whether the depicted compound has one or more stereocenters or not.
  • the chemical structure includes bold bonds and/or hashed bonds to indicate the relative structural orientation of those substituents connected by the bold bonds and/or hashed bonds to the superior structure. If the bold bonds and/or hashed bonds are depicted in form of a wedge, the absolute stereochemical configuration of the compound is known and thereby indicated. If the bold bonds and/or hashed bonds are depicted as a straight bond (i.e. no wedge), the absolute stereochemical configuration of the compound has not been determined. In that case, the bold bonds and/or hashed bonds merely serve to indicate that this particular compound is present as one enantiomer or one diastereomer (e.g.
  • the invention also includes isotopic isomers of a compound of the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound.
  • Preferred isotopes are 2 H (deuterium), 3 H (tritium), 13 C and 14 C.
  • Isotopic isomers of a compound of the invention can generally be prepared by conventional procedures known to a person skilled in the art.
  • Ci-4-alkyl and Ci-e-alkyl preferably mean acyclic and preferably saturated hydrocarbon residues, which can be linear (i.e. unbranched) or branched and which can be unsubstituted or mono- or polysubstituted (e.g. di- or trisubstituted), and which contain 1 to 4 (i.e. 1, 2, 3 or 4) or 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) carbon atoms, respectively.
  • Ci-4-alkyl and Ci-e-alkyl are saturated.
  • Ci-4-alkyl and Ci-e-alkyl are unsaturated and are selected from C2-4-alkenyl, C2-e-alkenyl, C2-4-alkynyl and C2-6-alkynyl.
  • Preferred Ci-4-alkyl groups are selected from the group consisting of methyl, ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • Ci-e-alkyl groups are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec -butyl, tert-butyl, n-pentyl, 2-pentyl, 3 -pentyl, 2- methylbutyl, 3 -methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl and n-hexyl.
  • Preferred C 2.4 - alkenyl groups are selected from the group consisting of ethenyl, propenyl and butenyl.
  • Preferred C2-6-alkenyl groups are selected from C2-4-alkenyl.
  • Preferred C2-4-alkynyl groups are selected from the group consisting of ethynyl, propynyl, and butynyl, more preferably propynyl, most preferably prop-l-ynyl.
  • Preferred C2-6-alkynyl groups are selected from C2-4-alkynyl.
  • A represents phenyl, 5- or 6-membered heteroaryl, or C 3 _- -cycloalkyl, more preferably phenyl or 5- or 6-membered heteroaryl.
  • A represents phenyl, thiophenyl, pyridyl, cyclohexyl or cyclobutyl; more preferably phenyl or thiophenyl.
  • B represents phenyl, 5- to 10-membered heteroaryl, Ci-6-alkyl, C 3 .io-cyclo- alkyl, or 4- to 10-membered heterocycloalkyl.
  • B represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[2.5]octyl, spiro [2.3] hexyl, spiro[3.3]heptyl, bicyclo [3.1.1] heptyl, bicyclo[2.2.1]heptyl, bicy- clo[3.2.0]heptyl, bicyclo[2.2.2]octyl, bicyclo[4.1.0]heptyl, 2,3-dihydro-lH-indenyl, bicylo[l.
  • Li represents O, C(R-) 2 -O. O-C(R-) 2 .
  • Li represents O, O-C(R 7 ) 2 , N(R 7 ), S, or C(R 7 ) 2 . More preferably, Li represents O, O- CH(CH 3 ), O-CH 2 , NH, or N(CH 3 ).
  • B when Li represents NH, B preferably represents 5 to 10-membered heteroaryl, more preferably 5 or 6-membered heteroaryl, wherein said heteroaryl preferably contains at least one nitrogen.
  • B when Li represents O or O-C(R 7 ) 2 , B preferably represents Cs-io-cycloalkyl or phenyl.
  • R 7 represents H, or Ci. 4 -alkyl. In a preferred embodiment, R 7 represents H or methyl.
  • R 2 and R3 independently from one another represent F, Cl, Br, CN, Ci-6-alkyl, C3-6- cycloalkyl, NH 2 , N(H)Ci-4-alkyl, N(Ci-4-alkyl) 2 , OH, O-Ci-4-alkyl, O-C e-cycloalkyl.
  • SF 5 phenyl or CVe-cycloal- kyl.
  • R 2 represents F, Cl, CN, Ci-6-alkyl, or O-Ci-4-alkyl; preferably wherein Ci-e-alkyl and Ci-4-alkyl can in each case independently be unsubstituted, mono-, di- or trisubstituted with F.
  • x and y are 2, 3 or 4; the 2, 3 or 4 entities of R 2 and the 2, 3 or 4 entities of R3 are not identical.
  • x represents 2
  • one R 2 will represent F and one R 2 will represent Cl, or both R 2 will represent F, or both R 2 will represent Cl.
  • y represents 2
  • one R3 will represent F and one R3 will represent Cl.
  • x and y independently from one another represent 0, 1, 2, 3, or 4.
  • x and y independently from one another represent 0, 1, 2 or 3; more preferably 0, 1 or 2, most preferably 1 or 2.
  • x represents 2.
  • R 4 represents H, Cl, CN, Ci-6-alkyl, or C e-cycloalkyl: preferably H or Ci-6-alkyl; more preferably H, CH 3 , CH 2 OH, CH 2 OCH 3 , CH 2 N(CH 3 ) 2 or propynyl. In a particularly preferred embodiment, R4 represents H or CH 3 .
  • L 2 represents bond, Ci-3-alkylene, or Ci. 2 -alkylene-N(H).
  • L 2 represents bond or Ci. 3 -alkylene; more preferably bond, methylene, or ethylene. In a particularly preferred embodiment, L 2 represents bond.
  • R 6 represents Ci-6-alkyl; more preferably methyl or 2-propyl; most preferably methyl.
  • the compound accoridng to the invention is preferably selected from the group consisting of
  • IH-imidazole -59 2-(((4-chloro-3-fluorobenzyl)oxy)(3-chloro-4-fluorophenyl)methyl)-5-methyl-4-(methylsul- fonyl)-
  • IH-imidazole -61 2-((3-chloro-4-fluorophenyl)((2,5-difluorobenzyl)oxy)methyl)-5-methyl-4-(methylsulfonyl)-
  • the compound according to the invention is an inhibitor of Na v 1.8.
  • the term "inhibitor of Na v 1.8" preferably means that the respective compound exhibits in a patch clamp assay an IC50 value on Navi.8 of at most 10 pM (10-10 -6 mol/L); more preferably at most 1 pM; still more preferably at most 500 nM (IO -9 mol/L); even more preferably at most 100 nM; and most preferably at most 10 nM.
  • the compound according to the invention is a selective inhibitor of Nav 1.8.
  • selective inhibitor of Nav 1.8 preferably means that the respective compound preferably does not exhibit any inhibitory activity on Navi.1, Navl.2, Navi.4, Navi.5 and Navl.6.
  • the skilled artisan knows suitable ways to determine whether a compound exhibits inhibitory effects on any of Na v l. l, Na v E2, Na v E4, Na v 1.5 and Na v 1.6.
  • the invention therefore relates to a compound according to the invention for use in the inhibition of Nav 1.8.
  • another aspect of the invention relates to a compound according to the invention for use in the treatment of pain. Still another aspect of the invention relates to a method of treatment of pain; comprising the administration of a therapeutically effective amount of a compound according to the invention to a subject in need thereof, preferably a human.
  • a further aspect of the invention relates to a compound according to the invention as medicament.
  • the pharmaceutical dosage form comprises a compound according to the invention and one or more pharmaceutical excipients such as physiologically acceptable carriers, additives and/or auxiliary substances; and optionally one or more further pharmacologically active ingredient.
  • suitable physiologically acceptable carriers, additives and/or auxiliary substances are fdlers, solvents, diluents, colorings and/or binders. These substances are known to the person skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre, Editio Cantor Aulendoff).
  • the pharmaceutical dosage form according to the invention is preferably for systemic, topical or local administration, preferably for oral administration. Therefore, the pharmaceutical dosage form can be in form of a liquid, semisolid or solid, e.g. in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, fdms, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, if appropriate pressed into tablets, decanted in capsules or suspended in a liquid, and can also be administered as such.
  • a liquid, semisolid or solid e.g. in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, fdms, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosol
  • the pharmaceutical dosage form according to the invention is preferably prepared with the aid of conventional means, devices, methods and processes known in the art.
  • the amount of the compound according to the invention to be administered to the patient may vary and is e.g. dependent on the patient's weight or age and also on the type of administration, the indication and the severity of the disorder.
  • Preferably 0.001 to 100 mg/kg, more preferably 0.05 to 75 mg/kg, most preferably 0.05 to 50 mg of a compound according to the invention are administered per kg of the patient's body weight.
  • another aspect of the invention relates to the pharmaceutical dosage form according to the invention for use in the treatment of pain. Still another aspect of the invention relates to a method of treatment of pain; comprising the administration of a pharmaceutical dosage form according to the invention to a subject in need thereof, preferably a human.
  • the desired L 2 -R 5 moieties can be obtained also, but not exclusively, by functional group interconversion (FGI) known to the person skilled in the art.
  • FGI functional group interconversion
  • transformations include but are not limited to the conversion of iodinated or brominated intermediates to e.g. sulfones using sulfinate salts (Synthesis, 2016, 48, 1939-1973) or multi-step procedures to yield intermediate thioethers under transition metal catalysis followed by oxidation to yield sulfoxides (Chem. Rev. 2022, 122, 16110-16293) or sulfoximines (Chem. Eur. J. 2021, 27, 17293-17321).
  • transformations include but are not limited to conversion of intermediate thioethers into sulfonyl chlorides and further to sulfonamides.
  • Suitable protecting groups, protecting and deprotecting protocols might be used to enable such functional group interconversion (FGI).
  • FGI functional group interconversion
  • Suitable protecting groups and relative reactivities are known in the literature and include e.g. SEM, benzyl, Boc, esters groups and TMS among others (T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley -Interscience, 2007, 4 th edition, 872-893).
  • compounds of the general formula (A) or (B) after deprotonation can be added to aldehydes of the general formula (C) to yield alcohols of the general formula (D).
  • preferred bases include LDA
  • halogenation after the metal-organic addition step is performed.
  • Preferred reagents include NIS.
  • Compounds of the general formula (E) can be prepared from compounds of the general formula (D) by functional group interconversion (FGI) known to the person skilled in the art.
  • Compounds of the general formula (E) can be deprotected to yield compounds of general formula (H).
  • Compounds of the general formula (F) can be prepared by oxidation of compounds of general formula (D) using oxidizing agents such MnO 2 .
  • Compounds of the general formula (G) can be prepared from compounds of the general formula (F) by functional group interconversion (FGI) known to the person skilled in the art.
  • Scheme 1 A, R 2 , R4, Rs, L 2 , and x are as defined in claim 1.
  • PG protecting group
  • Hal I, Br.
  • compounds of the general formula (I-a) can be prepared from compounds of the general formula (H) using amines of general formula (J) under acid catalysis. Suitable acids include e.g. pTSA.
  • Compounds of the general formula (I-b) can be prepared from compounds of the general formula (H) by treatment with alcohols (K) under acid catalysis. Suitable acids include e.g. pTSA.
  • compounds of the general formula (I-b) can be alternatively obtained by treatment of compounds of the general formula (E) with the corresponding alkyl halides (L) followed by deprotection.
  • Compounds of the general formula (I-c) can be alternatively obtained from (E) and (K) using Mitsonobu conditions followed by deprotection. Suitable reagents for the Mitsonubu reaction include DIAD and PPh 3 .
  • compounds of the general formula (I-d) can be prepared by reaction of metal-organic compounds of the general formula (M) with compounds of the general formula (G), subsequent elimination of the intermediate alcohol and concomitant deprotection using acidic conditions (for example in the presence of an acid such as pTSA and heating) followed by hydrogenation of the intermediate double bond.
  • Compounds of the general formula (I-a) can be prepared from compounds of the general formula (G) using a sequence of reductive amination with amines of the general formula (J) followed by deprotection. Reductive amination employs reagents and conditions known to the person skilled in the art.
  • Scheme 4: A, B, R 2 , R3, R4, Rs, R7, L 2 , n 0 or 1, x and y are as defined in claim 1.
  • PG protecting group.
  • compounds of the general formula (B) can be converted to intermediates of the general formula (P), using reagents of the general formula (O) under conditions employing Pd 2 (dba) 3 , Xanthphos and heat in a sealed tube.
  • compounds of the general formula (R-l), (R-2), (R-3) and (R-4) can be obtained from the corresponding compounds of the general formula (A), (B), (P) or (N) in the presence of reagents of the general formula (Q) and aldehydes of the general formula (C) in presence of a base such as sodium carbonate.
  • compounds of general formula (R-3-a) can be obtained from compounds of the general formula (R-2) using reagents of the general formula (0-1) under conditions such as the presence of Pd 2 (dba) 3 , Xanthphos and heat in a sealed tube.
  • Compounds of general formula (R-3-a) can be converted to compounds of the general formula (R-4-a) in the presence of reagents such as diacetoxyiodobenzene and ammonium carbonate.
  • reagents such as diacetoxyiodobenzene and ammonium carbonate.
  • Compounds of general formula (R-3-a) can be converted to compounds of the general formula (R-4-b) by oxidation in the presence of reagents such as meta-chloroperbenzoic acid in dichloromethane.
  • (R-4-a) and (R-4-b) fall in the general definition of (R-4).
  • intermediates of the general formula (U) can be prepared from aldehydes of the general formula (C) and primary amines of general formula (J-l).
  • An acid catalyst as pTSA, drying agents such as MgSC>4 and heating can be used to perform such transformation.
  • Deprotonation of compounds of general formula (A), (B), (P) or (N) in the presence of bases such as LDA followed by the addition of intermediates of the general formula (U) yield compounds of the general formula (V-l), (V-2), (V-3) and (V-4). Deprotection of these compounds yields compounds of the general formula (W-l), (W-2), (W-3) and (I-e).
  • compounds of the general formula (S-1) can be converted to compounds of the general formula (S-2).
  • Preferred reagents include NIS.
  • Compounds of the general formula (S-3) can be obtained from compounds of the general formula (S-2) by reaction with reagent of general formula (O) under conditions such as the presence of Pd 2 (dba) 3 , Xantphos and heat in a sealed tube.
  • compounds of general formula (S-4-a) can be obtained from compounds of the general formula (S-3) in the presence of reagents such as diacetoxyiodobenzene and ammonium carbonate.
  • Compounds of the general formula (S-3), where RI 2 is a protecting group such as PMB or Bn can be converted into compounds of the general formula (X) using reagents as for example NCS and acetic acid. Addition of ammonia to compounds of the general formula (X) leads to the formation of compounds of general formula (S-4-c).
  • Compounds of general formula (S-4-a) and (S-4-c) are included in compounds of general formula (S-4).
  • ABPR automated back pressure regulation
  • ACN acetonitrile
  • BINAP 2,2'-bis(diphenylphosphino)-l,l'- binaphthalin
  • Boc 2 O di-tert-butyl dicarbonate
  • DAST diethylaminosulfur trifluoride
  • dba dibenzylideneacetone
  • DCE 1,2-dichloroethane
  • DCM dichloromethane
  • DIAD diisopropyl azodicarboxylate
  • DIBAL-H diisobutylaluminium hydride
  • DIPEA V.
  • reaction progress was monitored by TLC and LCMS.
  • the reaction mixture was quenched by ice cold water (100 mL), extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous NaiSO i and solvent was evaporated under reduced pressure and it was purified by chromatography to afford the title compound (0.5 g, 14%).
  • Step-3 To a stirred solution of the product of Step-2 (4.3 g, 7.28 mmol, 1.0 equiv.) in dioxane (50 mL) was degassed with argon for 10 min followed by the addition of NaSMe (0.8 g, 10.91 mmol, 1.5 equiv.), Xantphos (0.6 g, 1.09 mmol, 0.15 equiv.) andPd 2 (dba) 3 (0.7 g, 0.73 mmol, 0.1 equiv.) at room temperature. The reaction mixture was heated at 110 °C for 16 h in a sealed tube. Reaction mixture was cooled to room temperature and diluted with ice water.
  • Preparative chiral SFC column: (R, R)-Whelk-O-1 (21.1 x 250 mm) 5 pm; co-solvent: of 0.3% iPrNFF in n-hexane/MeOH/iPrOH (60:30: 10), flow: 70 mL/min; % of co-solvent: 10%; ABPR: lOObr; T: 35 °C.
  • Step-1 To a starred solution of lH-imidazol-4-ylmethanol hydrochloride (5 g, 37.15 mmol, 1.0 equiv.) in dimethylformamide (50 mL) was cold to 0°C, added DIPEA (17 mL, 94.0 mmol, 2.53 equiv.) followed by SEM-C1 (7.3 mL, 40.87 mmol, 1.1 equiv.) and the reaction mixture was starred at rt for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2x50 mL).
  • Step-2 to a stirred solution of the product of Step-1 (7 g, 30.5 mmol, 1.0 equiv.) in THF (100 mL) at 0°C, NaH (60% in oil) (2.5 g, 61.04 mmol, 2.0 equiv.) was added portion wise and stirred at same temperature for 30 min. Mel (2.85 mL, 45.78 mmol, 1.5 equiv.) was added to the reaction mass and stirred at rt for 16h. The reaction mixture was quenched with sat. NH 4 C1 solution (50 mL) and extracted with ethyl acetate (2 x 50 mL).
  • Step-1 To a stirred solution of 4-chloro-3-fluorophenol (10.0 g, 68.23 mmol, 1.0 equiv.) was added TFA (65.0 mL) at 0 °C and was added 1,3,5,7-tetraazaadamantane (11.5 g, 81.88 mmol, 1.2 equiv.) in small portions. The mixture was then refluxed overnight at 80 °C, then cooling it at 0 °C followed by addition of cone. H 2 SO 4 (0.433 mL) and water (65.0 mL), the reaction was stirred at room temperature for 1 hr. The completion of the reaction was monitored by TLC.
  • Step-2 To a stirred solution of 5-chloro-4-fluoro-2-hydroxybenzaldehyde (2.43 g, 13.921 mmol, 1.0 equiv.) in dimethylformamide (20.0 mL) were added potassium carbonate (3.848 g, 27.842 mmol, 2.0 equiv.) and methyl iodide (1.7 mL, 27.8 mmol, 2.0 equiv.) at 0 °C and the reaction was stirred at RT for 16h. The completion of the reaction was monitored by LCMS and TLC ⁇ 20% EtOAc- hexane; Rf 0.4 ⁇ .
  • the intermediates were prepared from the corrspoding aldehydes in analogous method to the preparation of intermediate 19.
  • the intermediates were prepared from the corrspoding aldehydes in analogous method to the preparation of intermediate 20.
  • Step-1 To a stirred solution of l-chloranyl-2-methylsulfanyl-ethane (5.0 g, 36.16 mmol, 1.0 equiv.) was added Mel (11.3 mL, 180.82 mmol, 5.0 equiv.) at RT and was stirred at RT for 36 h. The reaction mixture was concentrated under reduced pressure to afford to crude product which was stirred in a diethyl ether (50 mL) for 30 min. Solid precipitated was filtered, washed with diethyl ether (20 mL), acetone (20 mL) and dried under reduced pressure to afford 2-chloroethyl-di(methyl) sulfonium iodide.
  • Step-2 To a stirred of solution of potassium tert-butoxide (1.9 g, 17.15 mmol, 2.0 equiv.) intBuOH (100 mL) was added 4,4-difluorocyclohexan-l-one (1.0 g, 7.45 mmol, 1.0 equiv.) and stirred at RT for 30 min. To the reaction mixture was added (2-chloroethyl)dimethylsulfanium iodide (1.5 g, 5.96 mmol, 0.8 equiv.) portion wise and stirred for 16 h at RT.
  • reaction mixture was filtered, the filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). the combined organic layers were washed with water (200 mL), brine solution (200 mL), dried over sodium sulphate and concentrated under reduced pressure to get crude product which was used in next step without further purification.
  • Step-3 To a solution of 7,7-difluorospiro[2.5]octan-4-one (500 mg , 3.12 mmol, 1.0 equiv.) in MeOH (10 mL) was added NaBH 4 (237 mg, 6.24 mmol, 2.0 equiv.) at 0 °C and stirred at RT for Ih. Reaction mixture was quenched with water (50 mL) and extracted with DCM (100 mL). Organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to get crude product which was used without further purification.
  • Intermediate 89 To a solution of 7,7-difluorospiro[2.5]octan-4-one (500 mg , 3.12 mmol, 1.0 equiv.) in MeOH (10 mL) was added NaBH 4 (237 mg, 6.24 mmol, 2.0 equiv.) at 0 °C and stirred at RT for Ih. Reaction mixture
  • Step 1 To a stirred solution of 6-bromo-3 -chloropicolinic acid (l g, 4.229 mmol) in THF (15 mL) was added diisobutylaluminium hydride (IM solution in toluene, 10.5 mL) at -78 °C and the mixture was stirred at - 78 °C for 3 h. The reaction mixture was quenched with saturated NH 4 C1 solution (50 mL) and extracted with ethyl acetate (2 x200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaiSO i. filtered and concentrated under reduced pressure to get the crude compound, which upon purification by flash chromatography afforded 500 mg (53%) of 6-bromo-3-chloropicolinaldehyde.
  • IM solution in toluene 10.5 mL
  • Step 2 To a stirred solution of 6-bromo-3-chloropicolinaldehyde (500 mg, 2.268 mmol) in DCM (10 mL) was added diethylaminosulfur trifluoride (1.65 mL) at -78 °C and the reaction mixture was then stirred at ambient temperature for 3 h. The reaction mixture was quenched with saturated NaHCO 3 solution (20 mL) and extracted with ethyl acetate (2x100 mL).
  • Step 3 To a stirred solution of 6-bromo-3-chloro-2-(difluoromethyl)pyridine (200 mg, 0.825 mmol) in 1,4-diox- ane (5 mL) at ambient temperature were added tert-Butyl carbamate (386.5 mg) and cesium carbonate (806 mg). The mixture was degassed with argon for 5 min, prior to the addition of xantphos (47 mg) and Pd 3 (dba) 3 (37 mg). The mixture was heated to 100 °C for 16 h. The reaction mixture was filtered through a celite pad and the filtrate was diluted with water (10 mL) and extracted with ethyl acetate (2x50 mL).
  • Step 4 To a stirred solution of tert-butyl (5-chloro-6-(difluoromethyl)pyridin-2-yl)carbamate (180 mg) in 1,4 dioxane (2 mL) was added 4 M HC1 in 1,4-dioxane (2 mL) at 0 °C and the reaction mixture was allowed to stirr at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether (2x20 mL), decanted and dried to obtain 120 mg the title compound as the HC1 salt.
  • Step-1 To a solution of 3,5-difluoropyridine-2,6-diamine (10 g, 68.91 mmol, 1.0 equiv.) in acetic acid (100 mL) was added isobenzofuran- 1,3 -dione (11.3 g, 75.81 mmol, 1.0 equiv.) and stirred at 100 °C for 3 h.
  • reaction mixture was quenched with water (200 mL), the precipitated solid was filtered, washed with water (100 mL) and dried under reduced pressure to get 2-(6-amino-3,5-difluoropyridin-2-yl)-2,3-dihydro-lH-isoindole-l, 3-dione.
  • Step-2 To a stirred solution of 2-(6-amino-3,5-difluoropyridin-2-yl)-2,3-dihydro-lH-isoindole-l, 3-dione (16 g, 58.14 mmol, 1.0 equiv.) in acetonitrile (100 mL) were added CuBr (16.68 g, 2.0 equiv.) and tert-butyl nitrite (14 mL, 2.0 equiv.) at 0 °C and was stirred at 80 °C for 6 h.
  • Step-3 A mixture of 2-(6-bromo-3,5-difluoropyridin-2-yl)-2,3-dihydro-lH-isoindole-l, 3-dione (15 g, 44.23 mmol, 1.0 equiv.) and 7 M NH3 in MeOH (50 mL) was stirred at RT for 2 h. Reaction mixture was concentrated under reduced pressure to get crude product which was purified by column chromatography afford 6-bromo-3,5- difluoropyridin-2-amine. Yield: 86% (8.0 g, 38.46 mmol).
  • Step-4 A mixture of 6-bromo-3,5-difluoropyridin-2-amine (4.0 g, 1.0 equiv.), methyl boronic acid (5.8 g, 5.0 equiv.) and K2CO3 (8.0 g, 3.0 equiv.) in 1,4-dioxane (30 mL) was degassed with argon for 5 min followed by addition of Pd(PPh 3 )4 (1.10 g, 0.05 equiv.), and was stirred at 100 °C for 16 h. Reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (150 mL), washed with water (100 mL) and brine (100 mL).
  • Step-1 To a stirred solution of 6-bromo-5-fluoropyridin-2-amine (1.7 g, 8.9 mmol, 1.0 equiv.) inDCM (30.0 mL) were added triethylamine (1.86 mL, 13.35 mmol, 1.5 equiv.), 4-dimethylaminopyridine (0.109 g, 0.89 mmol, 0.1 equiv.) and Boc 2 O (2.5 equiv.) at 0°C and the reaction mixture was stirred at RT for 16 h.
  • Step-2 A mixture of ⁇ 2-[(6-bromo-5-fluoropyridin-2-yl)[2-(formyloxy)-2-methylpropan-2-yl]amino]-2- methylpropan-2-yl ⁇ formate (2.0 g, 5.08 mmol, 1.0 equiv.) in dioxane (4.0 mL) and water (1.0 mL), was degassed with argon for 10 min.
  • Step-3 To a stirred solution of tert-butyl [tert-butyl(formyl)- ⁇ 3 ⁇ -oxidanyl](5-fluoro-6-methylpyridin-2-yl)amino formate (0.75 g, 2.26 mmol, 1.0 equiv.) in DCM (10.0 mL) was added TFA (2.0 mL ) at 0°C and the reaction mixture was stirred at RT for 4 h. After reaction was, the reaction mixture was evaporated under reduced pressure and quenched by using NaHCCh solution (10.0 mL), diluted with ethyl acetate (20 mL) and washed with H 2 O (2 x 10 mL) and brine (2 x 10 mL).
  • Step-1 To a stirred solution of l-(6-bromo-3-fluoropyridin-2-yl)ethan-l-one (2.5 g, 11.47 mmol, 1.0 equiv.) in DCM (30 mL) was drop-wise added Diethylaminosulfur Trifluoride (15 mL, 114.67 mmol, 10.0 equiv.) at 0 °C and stirred at RT for 16 h. The reaction mixture was quenched with NaHCOs, solution at 0 °C and diluted with DCM (50 mL). The organic layer was separated, washed with water (20 mL) and brine (20 mL).
  • Step-2 A solution of 6-bromo-2-(l,l-difluoroethyl)-3-fluoropyridine (400 mg, 1.67 mmol, 1.0 equiv.) in dioxane (10 mL) was degassed with Argon for 10 min followed by the addition of diphenylmethanimine (604 mg, 3.53 mmol, 2.0 equiv.), Cs 2 COs (1.1 g, 3.33 mmol, 2.0 equiv.), BINAP (104 mg, 0.17 mmol, 0.1 equiv.), Pd(OAc) 2 (37 mg, 0.17 mmol, 0.1 equiv.) and was stirred at 100 °C for 16 h in a sealed tube.
  • diphenylmethanimine 604 mg, 3.53 mmol, 2.0 equiv.
  • Cs 2 COs 1.1 g, 3.33 mmol, 2.0 equiv.
  • BINAP 104 mg, 0.17 mmol
  • Step-3 To a solution of N-(6-(l,l-difluoroethyl)-5-fluoropyridin-2-yl)-l,l-diphenylmethanimine (800 mg, 2.35 mmol, 1.0 equiv.) in THF (10 mL) was added 1(N) HO (10 mL) at 0 °C and stirred at RT for 3 h. The reaction mixture was diluted with water (25 mL), neutralized with sat. NaHCOs solution to pH ⁇ 7 and extracted with [M+H]+ (2x 200 mL).
  • Step-1 To a solution of 6-chloro-3-fluoropyridine-2-carbaldehyde (3 g, 18.8 mmol, 1.0 equiv.) in DCM (50 mL) was drop-wise added Diethylaminosulfur Trifluoride (4.47 mL, 33.84 mmol, 1.8 equiv.) at -30 °C and was gradually warmed to RT over 4 h. The reaction mixture was quenched with NaHCCL solution (100 mL) at 0 °C, diluted with DCM (200 mL), layers were separated, and organic layer was washed with water (100 mL) and brine (100 mL).
  • Step-2 A mixture of 6-chloro-2-(difluoromethyl)-3-fluoropyridine (3 g, 16.52 mmol, 1.0 equiv.), diphenylme- thanimine (5.5 mL, 33.05 mmol, 2.0 equiv.) and Cs2CO3 (10.8 g, 33.05 mmol, 2.0 equiv.) in 1,4-dioxane (60 mL) was degassed with Argon gas for 15 min followed by the addition of BINAP (1029 mg, 1.65 mmol, 0.1 equiv.), Pd(OAc)2 (371 mg, 1.65 mmol, 0.1 equiv.) and stirred at 100 °C for 16 h.
  • BINAP 1029 mg, 1.65 mmol, 0.1 equiv.
  • Pd(OAc)2 371 mg, 1.65 mmol, 0.1 equiv.
  • Step-3 To a solution of 6-(difluoromethyl)-N-(diphenylmethylidene)-5-fluoropyridin-2 -amine (4.2 g, 12.87 mmol, 1.0 equiv.) in THF (60 mL) was added IN HC1 (60 mL) at 0 °C and stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to get a residue which was basified with saturated NaHC'CL solution to pH ⁇ 8 and extracted with ethyl acetate (2 x 100 mL).
  • Step-1 To a stirred solution of 6-bromo-5-fluoropyridin-2 -amine (1 g, 5.236 mmol, 1 equiv.) in l,4-dioxane:water (15 ml) was added CS2CO3 (5.12 g, 15.707 mmol, 3 equiv.) and degassed with Argon for 5 mins. Cyclopropyl- boronic acid (2.25 g, 26.178 mmol, 5 equiv.) and Pd(dppf)Cl 2 (0.383 g, 0.524 mmol, 0.1 equiv.) were added and the reaction mixture was stiired at 100°C for 16h.
  • Step-1 To a stirred solution of 6-bromo-5-fluoropyridin-2 -amine (1 g, 5.236 mmol, 1 equiv.) in l,4-dioxane:water (15 ml) was added K3PO4 (3.33 g, 15.707 mmol, 3 equiv.) and degassed with Argon for 5 mins. Ethylboronic acid (1.93 g, 26.178 mmol, 5 equiv.) and Pd(dppf)C12.DCM(0.428 g, 0.524 mmol, 0.1 equiv.) were added and the reaction mixture was stiired at 100°C for 16h.
  • Step-1 A solution of 2-chloro-4-methoxy-5-methylpyrimidine (600 mg, 3.78 mmol,l equiv.) in dioxane (8 mL) was degassed with argon for 10 min followed by the addition of diphenylmethanimine (1.4 g, 7.57 mmol, 2.0 equiv.), CS2CO3 (2.4 g, 7.57 mmol, 2.0 equiv.), BINAP (0.23 g, 0.38 mmol, 0.1 equiv.) and Pd(OAc) 2 (0.085 g, 0.38 mmol, 0.1 equiv.). and stirred at 100 °C for 16 h.
  • Step 1 A mixture of 4-iodo-lH-imidazole (20 g, 103.11 mmol), sodium acetate (14.4 g, 176.31 mmol), acetic acid (8.8 mL, 154.66 mmol) and 37% HCHO (72 mL) was refluxed for 30 h. The reaction mixture was cooled and extracted with ethylacetate (3 x 150 mL).
  • Step 2 To a solution of (4-iodo-lH-imidazol-5-yl)methanol (8 g, 35.71 mmol) in dimethylformamide (70 mL) was added sodium hydride (60% in mineral oil, 1.4 g, 35.71 mmol) at 0 °C and the mixture was stirred for 30 min, followed by the addition of SEM-C1 (6.3 mL, 35.71 mmol). The reaction mixture was stirred at room temperature for 16 h and was then quenched with cold NH 4 C1 solution (50 mL) and extracted with EtOAc (2 x 150 mL).
  • Step 3 To a solution of (4-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-5-yl)methanol and the corresponding N-SEM regioisomer (5.5 g, 15.48 mmol) in dimethylformamide (60 mL) were added imidazole (4.2 g, 61.92 mmol) and 4-dimethylaminopyridine (0.38 g, 3.1 mmol) followed by tert-butyl(chlor)diphenylsilan (16.1 mL, 61.92 mmol) at 0 °C and the mixture was stirred at room temperature for 16 h.
  • Step 4 To a solution of 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazole and the corresponding SEM regioisomer (3.5 g, 5.9 mmol) and (4-methoxyphenyl)methanethiol (0.9 mL, 6.49 mmol) in 1,4-dioxane (40 mL) were added Xantphos (0.51 g, 0.88 mmol) and DIPEA (2.3 mL, 12.97 mmol) followed by purging with argon for 15 min.
  • the intermediates were prepared from the corrspoding aldehydes in analogous method to the preparation of intermediate 104.
  • Step 1 To a stirred solution of lH-imidazol-4-ylmethanol hydrochloride (5 g, 37.15 mmol) in dimethylformamide (50 mL) at
  • Step 2 To a stirred solution of (l-((2-(trimethylsilyl) ethoxy) methyl)- lH-imidazol-4-yl) methanol and the corresponding N-SEM regioisomer (7 g, 30.5 mmol) in THF (100 mL) at 0 °C was added NaH (60% in mineral oil, 2.5 g, 61.04 mmol) portionwise. The mixture was then stirred at 0 °C for 30 minutes. Mel (2.85 mL, 45.78 mmol) was added, stirring was continued at room temperature for 16 h. The reaction mixture was quenched with sat.
  • Step 3 To a solution of 4-(methoxymethyl)-l -((2 -(trimethylsilyl) ethoxy) methyl)-lH-imidazole and the corresponding SEM regioisomer (3 g, 12.38 mmol) in acetonitrile (35 mL) were added 3-chloro-4-fluorobenzaldehyde (2 g, 12.38 mmol) and diisopropylcarbamic chloride (2 g, 12.38 mmol) followed by DIPEA (6.5 mL, 37.13 mmol) at room temperature and the resulting reaction mixture was heated to 80 °C for 16 h. The reaction mixture was concentrated.
  • Step 4 To a stirred solution of (3-chloro-4-fluorophenyl)(4-(methoxymethyl)-l-((2-(trimethylsilyl)ethoxy)me- thyl)-lH-imidazol-2-yl)methyl diisopropylcarbamate and the corresponding SEM regioisomer (3 g, 5.67 mmol) in ACN (50 mL) was added NIS (5.1 g, 22.68 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 6 h followed by stirring at room temperature for 16 h.
  • Step 5 A stirred solution of (3-chloro-4-fluorophenyl)(5-iodo-4-(methoxymethyl)-l-((2-(trimethylsilyl)eth- oxy)methyl)-lH-imidazol-2-yl)methyl diisopropylcarbamate and the corresponding SEM regioisomer (5 g, 7.633 mmol) in 1,4-dioxane (75 mL) was degassed with argon for 10 minutes followed by the addition of benzyl mer- captan (1.8 mL, 15.266 mmol), DIPEA (4.0 mL, 22.90 mmol), Xantphos (0.670 g, 1.145 mmol) andPd2(dba)s (0.7 g, 0.763 mmol) at room temperature.
  • Step-1 To a solution of (5-methyl-lH-imidazol-4-yl)methanol(10 g, 89.18 mmol, 1.0 equiv.) in dimethylforma- mide (50 mL) were added DIPEA (46.6 mL, 267.55 mmol, 3.0 equiv.) and SEM-C1 (17.7 mL, 133.77 mmol, 1.5 equiv.) at 0 °C and stirred at RT for 6 h. Reaction mixture was concentrated, diluted with water (150 mL), extracted with ethyl acetate (300 mL).
  • Step-2 To a solution of (5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)methanol (3 g, 12.38 mmol, 1.0 equiv.) in DCM (50 mL) was added SOCk (4.5 mL, 61.88 mmol, 5.0 equiv.) at 0 °C and stirred at RT for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (200 mL).
  • Step 1 To a stirred solution of intermediate 5 (0.200 g, 0.460 mmol) and phenol (0.064 g, 0.690 mmol) in THF (10 mL) at 0 °C were added diethyl azodicarboxylate (0.108 mL, 0.690 mmol) and triphenylphosphine (0.180 g, 0.690 mmol). The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure to yield the crude product, which was purified by flash chromatography (SiCK 20-30% EtOAc/PE) to yield the product (0.140 g, 60%).
  • Step 2 The product from step 1 (0.120 g, 0.235 mmol) was dissolved in HO (4N) in 1,4-dioxane (2.0 mL) at rt and the mixture was stirred for 4 h. The reaction mixture was then basified with aqueous NaHC'CL and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiCL. 50% EtOAc/PE) to afford the title compound (0.030 g, 34%).
  • Step 1 To a stirred solution of intermediate 5 (300 mg, 0.690 mmol, 1.0 equiv.) and 4-fluoro-2-methoxyphenol (0.12 mL, 1.5 equiv.) in Toluene (10 mL) at 0 °C were added l,l'-( Azodicarbonyl) dipiperidine, 97% (522 mg, 2.1 mmol.) and tributylphosphine (0.5 mL) sequentially under argon. Resulting reaction mixture was stirred at rt for 16 h. The progress of reaction was monitored by LC-MS. Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SC>4 and concentrated under vacuum. The crude product was purified by Normal phase column chromatography.
  • Step 2 The product from step 1 was dissolved in HC1 (4N) in 1,4-dioxane (10 mL) at 0 °C. Resulting reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated under vacuum, basified with NaHCO, solution (pH ⁇ 9) at 0 °C and extracted with ethyl acetate (3 x15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by prep-HPLC to afford racemic compound (0.030 g, 34%) followed by chiral SFC to yield the title compound as individual enantiomers.
  • reaction mixture was monitored by LCMS.
  • the successful reaction mixtures were quenched with water and extracted with ethyl acetate (50 mL). Organic layer was washed with water (10 mL), brine (10 mL) and dried over Na2SO4. Solvent was concentrated under reduced pressure to get crude product which was purified by flash column chromatography on silica gel.
  • the reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with ice water (100 mL) and adjusted to pH 7.0 with sodium bicarbonate solution, followed by extraction with ethyl acetate (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to get the crude product, which upon purification by GRACE flash chromatography [C18, 12 g, RP column] using acetonitrile and water as an eluent afforded 100 mg of the title compound. The title compound was then separated into individual enantiomers using chiral SFC.
  • Step 1 To a solution of Intermediate 27 (0.2 g, 0.347 mmol, 1.0 equiv.) and 1-methylcyclohexan-l-ol (10.0 equiv.) in THF (2.0 mL) at rt under N 2 gas was added boron trifluoride diethyl etherate (0.5 mmol, 1.5 equiv.) and followed by trifluoroacetic acid (0.12 mL, 1.562 mmol, 4.5 equiv.). The resulting reaction mixture was maintained under stirring at 90 °C for 30 min. The reaction was monitored by LC-MS.
  • the reaction mixture was diluted with ice water (25 mL) and adjusted the pH-8.0 with NaHCCh solution and extracted with dichloromethane (2 ⁇ 50 mL). The combined extracts were washed with brine (25 mL), dried over anhydrous Na 2 SO i and filtered, the filtrate was concentrated under reduced pressure to get 0.28 g of cmde product.
  • Step 2 (0.19 g, 0.349 mmol, 1.0 equiv.) and tetra-n-butylammonium fluoride, IM soln, in THF (1.75 mL) in THF (1.9 mL) was stirred at 90 °C for 1 h.
  • the reaction mixture was diluted with ice water (50 mL) and extracted with dichloromethane (2x50 mL). The combined extracts were washed with brine (25 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to get the crude product.
  • the crude product was purified by prep-HPLC to give 85 mg (58%) and followed by chiral SFC to yield the title compound as individual enantiomers.
  • Step-1 To a solution of Intermediate 27 (300 mg, 0.521 mmol, 1.0 equiv.), 1-methylcyclobutan-l-ol (180 mg, 2.083 mmol, 4 equiv.) in THF (10 mL) was added boron trifluoride etherate (0.1 mL, 0.781 mmol, 1.5 equiv.) followed by trifluoroacetic acid (0.18 mL, 2.343 mmol, 4.5 equiv.) and was stirred at 60 °C (pre-heated oil bath) for 2 h in a sealed tube. The reaction mixture was diluted with ethyl acetate (50 mL), washed with sat.
  • Step-2 To a solution of the profuct of Step-1 in THF (10 mL) was added 1 M TBAF in THF (6 mL, 5.80 mmol, 10 equiv.) and stirred at 80 °C for 16 h. The reaction mixture was quenched with sat. NH 4 C1 solution (30 mL) and extracted with ethyl acetate (2 x 100 mL).
  • Step-1 To a stirred solution of (Intermediate 27 (500 mg, 0.87 mmol, 1 equiv.) and cyclohexanol (0.45 mL, 4.34 mmol, 5 equiv.) inTHF (10 mL) was added Boron trifluoride etherate (48%) (0.32 mL, 1.30 mmol, 1.5 equiv.) followed by TFA (0.3 mL, 3.91 mmol, 4.5 equiv.) at room temperature. Resulting solution was stirred at 60 °C for 30 min in sealed tube.
  • Step-2 To a stirred solution of the product from Step-1 (380 mg, 0.72 mmol, 1 equiv.) in DCM (1 mL) was added TFA (6 mL) at 0C. Resulting solution was stirred at 800C for 6h. After completion of starting material (monitored by LCMS) reaction mixture was concentrated. Obtained residue was quenched by sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with water followed by brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to afford crude product.
  • Step-1 To a solution of Intermediate 27 (250 mg, 0.43 mmol, 1.0 equiv.) and 2-fluorophenyl)methanol (0.1 mL, 0.86 mmol, 2.0 equiv.) in THF (15 mL) were added boron trifluoride etherate (0.08 mL, 0.65 mmol, 1.5 equiv.) and TFA (0.15 mL, 1.95 mmol, 4.5 equiv.) at 0 °C. Reaction mixture was stirred at 60 °C for 1 h in a sealed tube. Reaction mixture was concentrated under reduced pressure, diluted with ice-cold water (20 mL) and neutralised with sat. NaHCCL solution.
  • Step-2 A mixture of crude product from Step-1 and TFA (4 mL) was stirred at 80 °C for 1 h. Reaction mixture was concentrated under reduced pressure, diluted with MeOH (15 mL), Amberlyst A21 resin (100 mg) was added and stirred at RT for 2 h. After filtration, the filtrate was concentrated under reduced pressure to get the crude product which was purified by RP-prep-HPLC to get the racemic final product (80 mg, 0.187 mmol). folio wed by chiral SFC to yield the title compound as individual enantiomers.
  • Example 51 -methyl-4-(methylsulfonyl)-l H-imidazol-2-yl)methoxy)methyl)pyridine
  • Step-1 To a solution of Intermediate 27 (200 mg, 0.346 mmol, 1.0 equiv.), pyridin-2-ylmethanol (0.34 mL, 3.465 mmol, 10.0 equiv.) in DCM (4.0 mL) was added boron trifluoride etherate (0.17 mL, 1.386 mmol, 4 equiv.) followed by trifluoroacetic acid (0.26 mL, 3.465 mmol, 10.0 equiv.) and was stirred at 60 °C in pre-heated oil bath for 3 h. The reaction mixture was quenched with aq. NaHCO 3 and extracted with ethyl acetate (2 x 50 mL).
  • Step-2 A mixture of crude product from Step-1 and TFA (1.0 mL) was stirred at 60 °C for 20 min. The reaction mixture was concentrated under reduced pressure to get the residue, which was dissolved in MeOH (10 mL), Amberlyst-A21 ion exchange resin (500 mg) was added and stirred for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to get the crude product which was purified by RP-Prep HPLC purification to yield racemic 2-(((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-lH-imidazol-2-yl)meth- oxy)methyl)pyridine.
  • Step-1 To a solution of Intermediate 27 250 mg, 0.43 mmol, 1.0 equiv.), (5-methyl-l,3-thiazol-2-yl)metha- nol (280 mg, 2.16 mmol, 5.0 equiv.), in THF (6 mL) was added boron trifluoride etherate (0.1 mL, 0.78 mmol, 1.5 equiv.) followed by trifluoroacetic acid (0.18 mL, 2.34 mmol, 4.5 equiv.) and was heated 60 °C for 90 min in a sealed tube. The reaction mixture was quenched with aq. NaHCCL and extracted with ethyl acetate (2 x 50 mL).
  • Step-2 A mixture of crude product from Step- in TFA (3 mL) was stirred at 80 °C for 15 min in a pre-heated oil bath. The reaction mixture was concentrated under reduced pressure, diluted with MeOH (10 mL), Amberlyst- A21 ion exchange resin (500 mg) was added and stirred for 2 h. After filtration, the filtrate was concentrated under reduced pressure to get the crude product which was purified by RP-prep-HPLC to get racemic compound, followed by chiral SFC to yield the title compound as individual enantiomers.
  • Example 213, 214 The title compounds were prepared from the appropriate intermediates and reagents using an analogous method to that described for Example 196. Chiral compounds can be separated after synthesis using chiral SFC or chiral HPLC. Example 213, 214
  • Step 1 To a solution of Intermediate 9 (0.5 g, 1.157 mmol) inDCM (20.0 mL) were added 4, 4-difluorocyclohexan- 1-amine hydrochloride (0.3 g, 1.736 mmol), triethylamine (0.3 mL, 1.736 mmol) and TiC'l i (IM in DCM; 1.75 mL, 0.173 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. To this mixture were then added MeOH (10.0 mL) and NaCNBH 3 (0.15 g, 2.315 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h.
  • Step 2 To a stirred solution of the crude product from step 1 (0.5 g, 0.906 mmol, 1.0 eq.) in DCM (5.0 mL) was added 4(M) HC1 in dioxane (15.0 mL) at 0 °C. The reaction was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to obtain a residue which was neutralized with NaHCO 3 solution and extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting crude product was purified by CombiFlash column chromatography followed by chiral SFC to yield the title compound as individual enantiomers.
  • reaction mixture was neutralized with NaHCO;, solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over Na 2 SO4 and concentrated under reduced pressure. The residue was purified by CombiFlash column chromatography (SiO 2 . 0-60% EtOAc/Hex) followed by SFC to yield the title compound as individual enantiomers.
  • Step-1 To a solution of intermediate 9 (0.6 g, 1.386 mmol, 1.0 equiv.) inDCM (20.0 mL) were added 4-fluoroan- iline 4-fluoroaniline (0.231 g, 2.079 mmol, 1.0 equiv.), triethylamine (0.3 mL, 2.079 mmol, 1.5 equiv.) and TiCL (IM in DCM; 2.1 mL 2.079 mmol, 1.5 equiv.) at dropwise at 0° C. Reaction mixture was stirred at 0 °C for 3 h.
  • Step-2 The product from Step-1 (0.25 g, 0.473 mmol, 1.0 equiv.) in methanol (12.0 mL) were added acetic acid (1.5 mL), formaldehyde (37%, 5.0 mL) and sodium cyanoborohydride (0.12 g, 1.894 mmol, 3.0 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Reaction was diluted with ice water and neutralized with NaHCO 3 solution. Aqueous layer was extracted with ethyl acetate (2 x 100 mL).
  • Step-3 To a stirred solution of the crude product from Step-2 in DCM (5.0 mL) was added 4(M) HO in dioxane (15.0 mL) at 0 °C. Reaction was stirred at room temperature for 4 h. Reaction mixture was concentrated under reduced pressure to get residue which was neutralized with NaHCO 3 solution and extracted with ethyl acetate (2x 100 mL). Combined organic layer was washed with brine, dried over Na 3 SO i and concentrated under reduced pressure to get crude product. Resulting crude was purified by combiflash column chromatography to yield the title compound. Yield (over 2 steps): 57% (0.11 g, 0.267 mmol).
  • step 3 The title compounds were prepared from the appropriate intermediates and reagents using an analogous method to that described for Example 221 for step 1 and step 2 but with step 3 follows: to a stirred solution of the product of step 2 (0.6 g, 1 equiv.) in dimethylformamide (15.0 mL) was added CsF (0.66 g, 4.0 equiv.) at room temperature. Reaction was stirred at 80 °C for 16 h. Reaction mixture was diluted with ice water and extracted with ethyl acetate (2 x 100 mL). Combined organic layer was washed with brine, dried over sodium sulphate, and concentrated under reduced pressure to get cmde product. Resulting crude was purified by RP prep HPLC to yield the titlae compound.
  • Step 1 To a solution of Intermediate 27 (0.300 g, 0.521 mmol) in THF (15 mL) was added 5-chloro-3-methoxy- pyridin-2-amine (0.413 g, 2.603 mmol) followed by boron trifluoride etherate (0.111 g, 0.781 mmol) and trifluoroacetic acid (0.267 g, 2.343 mmol) at ambient temperature. The resulting mixture was heated to 80 °C for 1 h. The mixture was concentrated under reduced pressure to get the crudecresidue, which was diluted with sat. NaHCO 3 solution (20 mL) and extracted with ethyl acetate (2 ⁇ 20 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na2SO i. filtered, concentrated under reduced pressure and purified by flash chromatography.
  • Step 2 The product from Step 1 (0.230 g, 0.390 mmol) in THF (11.5 mL), was added tetra butyl ammonium fluoride (IM solution in THF, 1.951 mL, 1.951 mmol) at ambient temperature. The resulting mixture was heated to 90 °C for 1 h. The mixture was concentrated under reduced pressure to obtain a residue, which was diluted with sat. NaHCO 3 solution (20 mL) and extracted with ethyl acetate (2x20 mL).
  • IM solution in THF 1.951 mL, 1.951 mmol
  • Step 1 To a stirred solution of Intermediate 27 (300 mg, 0.521 mmol) in THF (10 mL) was added pyridin-2 -amine (245.013 mg, 2.603 mmol) followed by boron trifluoride etherate (0.097 mL, 0.781 mmol) and trifluoroacetic acid (0.191 mL, 2.343 mmol), The reaction mixture was heated to 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was neutralized with saturated NaHC'CL solution (10 mL) and extracted with ethyl acetate (2 ⁇ 50 mL). The combined organic layers were dried over anhydrous Na SO i. filtered and concentrated under reduced pressure to obtain the crude compound, which upon purification by flash chromatography (C18, 24 g cartridge, eluted with 0.1% formic acid and acetonitrile), afforded 150 mg (55%) of the desired intermediate.
  • pyridin-2 -amine 245.013 mg, 2.6
  • Step 2 To a stirred solution of the isolated intermediate in 1,4-dioxane (5 mL) was added 4M HO in 1,4-dioxane (2 mL) at 0 °C and the mixture was stirred at ambient temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether (20 mL), decanted and dried. The obtained material was purifyed by prep-HPLC to yield 60 mg (53%) of the title compound. The title compound was then separated into individual enantiomers using chiral SFC.
  • Step 1 To a stirred solution of Interemediate 27 (250 mg, 0.434 mmol, 1.0 equiv.) and 5-chloropyrimidin-2 -amine (281 mg, 2.17 mmol, 5.0 equiv.) in DCM (20.0 mL) were added boron trifluoride etherate (0.08 mL, 0.65 mmol, 1.5 equiv.) and TFA (0.149 mL, 1.952 mmol, 4.5 equiv.) and was stirred at rt for Ih min. Reaction mixture was diluted with ice-cold water (50 mL) and extracted with DCM (2 x 50 mL). Combined organic layers were washed with sat.
  • Step 2 To a stirred solution of the product of Stepl, in TFA (4.5 mL) was heated at 60 °C for 20 min. Reaction mixture concentrated under reduce pressure to get crude product which was diluted with MeOH (15.0 mL), Am- berlyst A21 (500 mg) resin was added to and stirred at RT for 2 h. Reaction mixture was filtered, washed with MeOH (10.0 mL) and the filtrate was concentrated under reduced pressure to get crude product which was purified by reverse phase prep HPLC to afford racemif title compound. The title compound was then separated into individual enantiomers using chiral SFC.
  • Preparative chiral SFC column: I Cellulose C (21.1 mmx250 mm), 5p; co-solvent: MeOH, flow: 70 mL/min; % of co-solvent: 35%; ABPR: 100 bar; T: 35 °C; 240 (Yield: 17 mg): first eluting enantiomer. 241 (Yield: 17 mg): second eluting enantiomer.
  • Preparateive chiral SFC column: ((21.1 mm x 250mm ), 5p; co-solvent: 0.2% (7N ammonia in methanol) in isopropanol, flow: 60 mL/min; % of co-solvent: 20%; ABPR: 120bar T: 35°C; 292 (Yield: 31 mg) first eluting enantiomer. 293 (Yield: 27 mg): second eluting enantiomer.
  • Step 1 To a stirred solution of Intermediate 27 (1 g, 1.736 mmol) in THF (10 mL) were added thiazol-2-amine (868.99 mg, 8.678 mmol), BF3-Et2O (367.06 mg, 2.603 mmol) and trifluoroacetic acid (890.47 mg, 7.810 mmol) and the reaction mixture was heated to 100 °C for 1 h. The mixture was concentrated under reduced pressure and the residue was neutralized with saturated NaHCCh solution (50 mL), then extracted with ethyl acetate (2x200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaiSO i.
  • Step 2 To a stirred solution of N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-l-((2-(trimethylsi- lyl)ethoxy)methyl)-lH-imidazol-2-yl)methyl)thiazol-2-amine (150 mg, 0.282 mmol) in dimethylformamide (3 mL) was added N-bromosuccinimide (50.2 mg, 0.28 mmol) at ambient temperature and the mixture was stirred for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2x100 mL).
  • Step 3 To a stirred solution of 5-bromo-N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-l-((2-(trime- thylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)methyl)thiazol-2 -amine (100 mg, 0.164 mmol) in 1,4-dioxane (2 mL) was added 4 M HO in 1,4-dioxane (2 mL) at 0 °C and the reaction mixture was stirred at ambient temperature for 16 h.
  • Step 1 To a mixture of Intermediate 27 (0.3 g, 0.521 mmol) and 3-chloro-5-fluoropyridin-2-amine (0.153 g, 1.04 mmol) in THF (6.0 mL) at 0 °C was added boron trifluoride etherate (0.1 mL, 0.8 mmol) followed by trifluoroacetic acid (0.18 mL, 2.3 mmol). The resulting mixture was heated to 90 °C for 2 h in a sealed tube. The mixture was concentrated under reduced pressure to get the residue. The residue was diluted with ice water (50 mL) and adjusted the pH to 7.0 with sodium bicarbonate solution and extracted with ethyl acetate (2x100 mL).
  • Step 2 To a stirred solution of 3-chloro-N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-l-((2-(trime- thylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)methyl)-5-fluoropyridin-2 -amine (0.05 g, 0.087 mmol) in a mixture of toluene: water (9:1) (2 mL) was added potassium phosphate (0.055 g, 0.260 mmol) ar ambient temperature.
  • the miyture was degassed with argon for 5 minutes prior to the addition of cyclopropylboronic acid (0.007 g, 0.087 mmol), palladium(II) acetate (0.002 g, 0.009 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.007 g, 0.017 mmol).
  • cyclopropylboronic acid 0.007 g, 0.087 mmol
  • palladium(II) acetate 0.002 g, 0.009 mmol
  • 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl 0.007 g, 0.017 mmol
  • Step 3 To a solution of N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-lH-imidazol-2-yl)methyl)-3- cyclopropyl-5-fluoropyridin-2 -amine (0.1 g, 0.17 mmol) in THF (2.0 mL) at 0 °C was added tetrabutylammonium fluoride (IM solution in THF, 0.662 mL, 0.662 mmol). The resulting reaction mixture was heated to 80 °C for 2 h. The mixture was concentrated under reduced pressure to get the crude residue.
  • IM solution in THF 0.662 mL, 0.662 mmol
  • Step 1 Mg (0.12 g, 5.07 mmol) was taken up in a two-neck flasked equipped with a reflux condenser and was dried under an argon atmosphere. Et 2 O (8.0 mL) was added, followed by the addition of a catalytic amount of I 2 . Then, a solution of l-(bromomethyl)-4-fluorobenzene (0.8 g, 4.23 mmol) in Et 2 O (3 mL) was added dropwise to the mixture at rt. The reaction mixture was stirred at rt for 1 h. To the freshly prepared Grignard reagent was then added a solution of intermediate 9a (0.3 g, 0.6 mmol) in Et 2 O (3 mL) at rt.
  • Step 2 To a solution of l-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-l-(5-methanesulfonyl-l- ⁇ [2-(trimethylsi- lyl) ethoxy] methyl ⁇ -lH-imidazol-2-yl) ethan-l-ol (0.2 g, 0.37 mmol) were added toluene (100.0 mL) and pTSA (0.06 g, 0.37 mmol) at rt. The reaction mixture was heated to 100 °C for 16 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was neutralized with sat.
  • Step 3 A solution of 2-[(E)-l-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl) ethenyl]-5-methanesulfonyl-lH-im- idazole (0.23 g, 0.57 mmol) in MeOH (20.0 mL) was degassed with N 2 for 15 minutes followed by the addition of PtO 2 (0.15 g) at rt. The reaction mixture was stirred at 80 °C in an autoclave vessel under 10.3 bar H 2 gas pressure for 16 h. The reaction mixture was cooled to rt and filtered through celite. The filtrate was concentrated under reduced pressure to get the crude product, which was purified by reverse phase prep. HPLC and chiral HPLC to get the title compound as individual enantiomers.
  • Step-1 To a stirred solution of Intermediate 34a (1.8 g, 3.52 mmol, 1.0 equiv.) in MeOH (80 mL) were added diacetoxyiodobenzene (211.3 g, 35.22 mmol, 10.0 equiv.) and ammonium carbonate (3.4 g, 35.22 mmol, 10.0 equiv.) at room temperature. Reaction mixture was stirred at room temperature for 2 h. Reaction mixture was washed with water and extracted with ethyl acetate (3 x 200 mL). Combined organic part was washed with cold brine and dried over Na 2 SC>4. Organic layer was concentrated under reduced pressure to get cmde.
  • Step-2 To a stirred solution of the product of Step-1 (0.2 g, 0.37 mmol, 1.0 equiv.) in AcOH (10 mL) and H 2 O (2 mL) was heated at 70 °C for 2 h. Reaction mixture was cooled to room temperature and evaporated under reduced pressure to get crude. Crude was basified with saturated NaHC'CL. Aqueous part was extracted with ethyl acetate (3 x 80 mL) and washed with brine. Combined organic layer was dried over Na 2 SO i. filtered and evaporated under reduced pressure to get the cmde product. The crude was purified through combi flash column chromatography (0-20% MeOH in EtOAc as eluent) to obtain racemic title compound, followed by normal phase chiral separation.
  • Preparative first chiral SFC column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5p; co-solvent: isopropanol, flow: 70 mL/min; % of co-solvent: 35%; ABPR: 100 bar; T: 35 °C.
  • Preparative second chiral SFC column: I Cellulose Z (30 mm x 250mm), 5p; co-solvent: 0.2% (7N ammonia in methanol) in acetonitrile-isopropanol (1:1), flow: 100 mL/min; % of co-solvent: 20%; ABPR: 100 bar; T: 35 °C. First eluting: 355, second eluting: 356. 355: Yield: 8% (33 mg, 0.07 mmol).
  • Preparative first chiral SFC column: Chiralpak IG (30 mm x 250 mm), 5p; co-solvent: 0.2% (7N ammonia in methanol) in isopropanol, flow: 100 mL/min; % of co-solvent: 35%; ABPR: 100 bar; T: 35 °C.
  • First eluting mixture of 359 and 360, second eluting: mixture of 361 and 362.
  • Preparative second chiral SFC column:! Cellulose Z (30 mm x 250mm), 5p; co-solvent: 0.2% (7N ammonia in methanol) in acetonitrile-isopropanol (1:1), flow: 100 mL/min; % of co-solvent: 35%; ABPR: 100 bar; T: 35 °C. First eluting: 359, second eluting: 360.
  • Preparative first chiral SFC column: I Cellulose Z (30 mm x 250mm), 5p; co-solvent: 0.2% (7N ammonia in methanol) in acetonitrile-isopropanol (1:1), flow: 100 mL/min; % of co-solvent: 30%; ABPR: 100 bar; T: 35 °C.
  • Preparative second chiral SFC column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5p; co-solvent: isopropanol, flow: 100 mL/min; % of co-solvent: 40%; ABPR: 100 bar; T: 35 °C. First eluting: 364, second eluting: 365.
  • Preparative first chiral SFC column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5p; co-solvent: 0.2% (7N ammonia in methanol) in acetonitrile-isopropanol (1:1), flow: 90 mL/min; % of co-solvent: 30%; ABPR: 100 bar; T: 35 °C.
  • Preparative second chiral SFC column: I Cellulose Z (30 mm x 250mm), 5p; co-solvent: 0.2% (7N ammonia in methanol) in acetonitrile-isopropanol (1:1), flow: 70 mL/min; % of co-solvent: 35%; ABPR: 100 bar; T: 35 °C. First eluting: 367, second eluting: 368.
  • Preparative first chiral SFC column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5p; co-solvent: isopropanol, flow: 100 mL/min; % of co-solvent: 30%; ABPR: 100 bar; T: 35 °C.
  • Preparative second chiral SFC column: Chiralpak IC (30 mm x 250mm), 5p; co-solvent: 0.2% (7N ammonia in methanol) in acetonitrile-isopropanol (1:1), flow: 70 mL/min; % of co-solvent: 35%; ABPR: 100 bar; T: 35 °C. First eluting: 371, second eluting: 372.
  • Preparative first chiral SFC column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5p; co-solvent 0.2% (7N ammonia in methanol) in isopropanol, flow: 100 mL/min; % of co-solvent: 20%; ABPR: 100 bar; T: 35 °C.
  • Preparative second chiral SFC column: I Cellulose C (21.1 mm> ⁇ 250 mm), 5p; co-solvent: 0.2% (7N ammonia in methanol) in isopropanol, flow: 60 mL/min; % of co-solvent: 20%; ABPR: 100 bar; T: 35 °C. First eluting: 375, second eluting: 376.
  • Preparative chiral SFC column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5p; co-solvent 0.2% (7N Ammonia in MeOH) in isopropanol, flow: 100 mL/min; % of co-solvent: 20%; ABPR: 100 bar; T: 35 °C.
  • Analytical Chiral HPLC condition Chiral SFC: column: (R, R) WHELK-01 (4.6 x 150 mm), 3.5 pm, mobile phase 0.3 % iPrNH 2 in isopropanol; flow: 3 mL/min; % of co-solvent: 20%; ABPR: 1000 psi; T: 35 °C.
  • Preparative first chiral SFC column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5p; co-solvent 0.2% (7N ammonia in methanol) in isopropanol, flow: 70 mL/min; % of co-solvent: 35%; ABPR: 100 bar; T : 35 °C.
  • Preparative second chiral SFC column CHIRALPAK IC (30 mm x 250mm), 5p; co-solvent: 0.2% (7N ammonia in methanol) in isopropanol, flow: 70 mL/min; % of co-solvent: 30%; ABPR: 100 bar; T: 35 °C. First eluting: 383, second eluting: 384.
  • Preparative first chiral SFC column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5p; co-solvent 0.2% (7N ammonia in methanol) in isopropanol, flow: 120 mL/min; % of co-solvent: 20%; ABPR: 100 bar; T: 35 °C.
  • Preparative second chiral SFC column I Cellulose C (21.1 mm> ⁇ 250 mm ), 5p; co-solvent: 0.2% (7N ammonia in methanol) in isopropanol, flow: 70 mL/min; % of co-solvent: 25%; ABPR: 100 bar; T: 35 °C. First eluting: 387, second eluting: 388.

Landscapes

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

Abstract

L'invention concerne des composés selon la formule générale (I) qui agissent en tant qu'inhibiteurs de Nav1.8 et peuvent être utilisés dans le traitement de la douleur.
PCT/EP2024/086446 2023-12-15 2024-12-16 Nouveaux imidazoles substitués utilisés en tant qu'inhibiteurs de nav1.8 Pending WO2025125665A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23217130.6 2023-12-15
EP23217130 2023-12-15

Publications (1)

Publication Number Publication Date
WO2025125665A1 true WO2025125665A1 (fr) 2025-06-19

Family

ID=89222965

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/086446 Pending WO2025125665A1 (fr) 2023-12-15 2024-12-16 Nouveaux imidazoles substitués utilisés en tant qu'inhibiteurs de nav1.8

Country Status (1)

Country Link
WO (1) WO2025125665A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022263498A1 (fr) * 2021-06-15 2022-12-22 Grünenthal GmbH Amides de pyrazole substitués

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022263498A1 (fr) * 2021-06-15 2022-12-22 Grünenthal GmbH Amides de pyrazole substitués

Non-Patent Citations (34)

* Cited by examiner, † Cited by third party
Title
AKOPIAN A.N ET AL., NAT. NEUROSCI, vol. 2, 1999, pages 541 - 548
AKOPIAN A.N. ET AL., NATURE, vol. 379, 1996, pages 257 - 261
BENNETT D.L. ET AL., PHYSIOL REV, vol. 99, no. 99, 2019, pages 1079 - 1151
BLAIR N.T. ET AL., J. NEUROSCI, vol. 23, 2003, pages 10338 - 10350
CATTERALL W.A, TRENDS PHARMACOL. SCI, vol. 8, 1987, pages 57 - 65
CHEM. EUR. J., vol. 27, 2021, pages 17293 - 17321
CHEM. REV., vol. 122, 2022, pages 16110 - 16293
CHOI J.S., J. NEUROPHYSIOL, vol. 106, 2011, pages 3173 - 3184
CRAWFORDCATERINA, TOXICOLOGIC PATHOLOGY, vol. 48, no. 1, 2020, pages 174
EIJKENBOOM I. ET AL., J. NEUROL NEUROSURG PSYCHIATRY, vol. 90, no. 3, 2019, pages 342 - 352
FABER C.G. ET AL., ANN. NEUROL, vol. 71, 2012, pages 26 - 39
GOODWIN GMCMAHON S.B, NATURE REVIEWS NEUROSCIENCE, vol. 22, 2021, pages 263 - 274
HAN C ET AL., J. NEUROL NEUROSURG PSYCHIATRY, vol. 85, 2014, pages 499 - 505
HILLE, B., J. GEN. PHYSIOL., vol. 69, 1977, pages 497 - 515
HILLE. B: "Ion Channels of Excitable Membranes", 1992, SINAUER ASSOCIATES, INC, pages: 391 - 421
HONDEGHEM L.MKATZUNG B.G, ANNU. REV. PHARMACOL. TOXICOL, vol. 24, pages 387 - 423
J. NEUROSCI, vol. 22, pages 8352 - 8356
JARVIS M.F, ALPROC NATL ACAD SCI USA, vol. 104, 2007, pages 8520 - 8525
JOSHI S.K. ET AL., PAIN, vol. 123, 2006, pages 75 - 82
KIST A.M. ET AL., PLOS ONE, vol. 11, 2016, pages 0161789
KORT M.E. ET AL., BIOORG MED CHEM LETT, vol. 20, 2010, pages 6812 - 6815
LAIRD J.M. ET AL., J. NEUROSCI, 2002
LUMPKINCATERINA, NATURE, vol. 445, 2007, pages 858 - 865
NOVAKOVIC S.D. ET AL., J. NEUROSCI, vol. 18, 1998, pages 2174 - 2187
PAYNE C.E. ET AL., BR J PHARMACOL, vol. 172, 2015, pages 2654 - 2670
PERSSON A.K. ET AL., MOL. PAIN, vol. 6, 2010, pages 84
RENGANATHAN MET, J. NEUROPHYSIOL, vol. 86, 2001, pages 629 - 640
ROZA C. ET AL., J PHYSIOL, vol. 550, 2003, pages 921 - 926
RUSH A.M. ET AL., J.NEUROSCI, vol. 22, 2005, pages 39 - 49
SANGAMESWARAN L. ET AL., J. BIOL. CHEM., vol. 271, 1996, pages 5953 - 5956
SCANIO M.J. ET AL., BIOORG MED CHEM, vol. 18, 2010, pages 7816 - 7825
SYNTHESIS, vol. 48, 2016, pages 1939 - 1973
T. W. GREENP. G. M. WUTS: "Protective Groups in Organic Synthesis", 2007, WILEY-INTERSCIENCE, pages: 872 - 893
TAN Z.Y. ET AL., J. NEUROSCI, vol. 34, 2014, pages 7190 - 7197

Similar Documents

Publication Publication Date Title
TWI826471B (zh) 化合物
EP2280945B1 (fr) Pyrazoles trisubstitués en tant que modulateurs des récepteurs de l'acétylcholine
EP2210880B1 (fr) Dérivés de benzoxazinone
JP4388997B2 (ja) イミダゾール誘導体
EP2758389B1 (fr) Carboxamides de pyrazole comme inhibiteurs de la janus kinase
JP3930560B2 (ja) 炎症の処置のための１，２−置換イミダゾリル化合物
TWI664181B (zh) 做為ｐｄｅ２抑制劑之經取代的［１，２，４］三唑并［１，５－ａ］嘧啶－７－基化合物
EP2704573A1 (fr) Dérivés d'aminométhyl-biaryl-benzotriazole
JP6412102B2 (ja) ヤヌスキナーゼ阻害剤としてのシクロアルキルニトリルピラゾロピリドン
WO2007085540A1 (fr) Derives 1h-indaz0l-4-yl-2,4-pyrimidinediamine
JP6305510B2 (ja) ヤヌスキナーゼ阻害剤としての非環式シアノエチルピラゾロピリドン
AU2014234907B2 (en) Geminally substituted cyanoethylpyrazolo pyridones as Janus kinase inhibitors
ES2976515T3 (es) Compuestos y composiciones para tratar afecciones asociadas con la actividad del receptor APJ
JPWO2003026661A1 (ja) インスリン分泌促進剤及び新規なピリミジン誘導体
CN108349935B (zh) 吡咯烷衍生物
CA3180803A1 (fr) Hydropyrroles substitues condenses en tant qu'antagonistes du recepteur muscarinique m4 de l'acetylcholine
WO2015012400A1 (fr) Inhibiteur du transporteur de la glycine
AU2012323038B2 (en) 2-oxo-piperidinyl derivatives
WO2025125665A1 (fr) Nouveaux imidazoles substitués utilisés en tant qu'inhibiteurs de nav1.8
WO2013147183A1 (fr) Composé triazinone et inhibiteur des canaux calciques de type t
TW202542116A (zh) 作為Ｎａｖ１．８的抑制劑之進一步經取代的咪唑
US10689354B2 (en) Aminoazole derivative
CA3009485C (fr) Compose de phenylimidazole
TW201609718A (zh) 唑啶以及噁嗪烷衍生物
WO2025125666A1 (fr) Imidazoles substitués utilisés en tant qu'inhibiteurs de nav1.8

Legal Events

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

Ref document number: 24829114

Country of ref document: EP

Kind code of ref document: A1