WO2024133292A1 - Nouveaux antagonistes de ccr8 - Google Patents

Nouveaux antagonistes de ccr8 Download PDF

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WO2024133292A1
WO2024133292A1 PCT/EP2023/086683 EP2023086683W WO2024133292A1 WO 2024133292 A1 WO2024133292 A1 WO 2024133292A1 EP 2023086683 W EP2023086683 W EP 2023086683W WO 2024133292 A1 WO2024133292 A1 WO 2024133292A1
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ethyl
carboxylate
piperidine
naphthalene
sulfonamido
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Wim DEHAEN
Steven De Jonghe
Tom VAN LOY
Dominique Schols
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Katholieke Universiteit Leuven
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • 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
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings

Definitions

  • the invention relates to naphthalene sulfonamide compounds and their medical use.
  • the human CC chemokine receptor 8 (CCR8) is G protein-coupled receptor (GPCR) for which the CC chemokine ligand 1 (CCL1) is the best established endogenous agonist.
  • CCR8 is expressed mainly on T-helper type 2 cells (Th2 cells) cells, which play a crucial role in adaptive immunity. Because recruitment of Th2 cells from the circulation to the site of inflammation is important for orchestrating inflammatory responses, there has been much interest in CCR8 inhibition as a therapeutic strategy.
  • preclinical animal studies clearly demonstrated the involvement of CCR8 in various inflammatory diseases, including atopic dermatitis, allergic enteritis and asthma, although the data were controversial and sometimes inconclusive.
  • CCR8 expression is enriched on tumor-infiltrating CD4 + Foxp3 + regulatory T cells (Tregs), compared to peripheral Tregs.
  • Tregs tumor-infiltrating CD4 + Foxp3 + regulatory T cells
  • These tumorresident CCR8+ Tregs are endowed with a highly immunosuppressive phenotype and hamper effective antitumor immunity, which was demonstrated for several types of cancer (breast, lung, colon and liver).
  • high CCR8+ Treg numbers correlated with more advanced disease stages and poor prognosis.
  • tumor-resident Tregs are targeted by various monoclonal antibodies and nanobodies, that both showed significant tumor growth inhibition and prolonged survival when evaluated in preclinical animal models, either as monotherapy or in combination with anti-PD-1 agents. Their antitumoral effect is ascribed to their ability to selectively deplete the immuno-suppressive tumorinfiltrating Treg cells.
  • CCR8 small molecule CCR8 antagonists
  • the number of chemotypes that are known to act as CCR8 antagonists is rather limited, and include oxazolidinone-based and naphthalene-sulfonamide-based analogues.
  • SB-649701 is an oxazolidinone analogue reported by researchers from GSK [Jin etal. (2007) Bioorg Med Chem Lett 17, 1722-1725]. This compound showed low nM activity, when evaluated in a human CCR8 calcium mobilization assay, although it lacked antagonistic activity against the mouse, rat and guinea pig CCR8.
  • this compound behaves as a functional human CCR8 antagonist when evaluated in various chemotaxis assays.
  • SB-649701 lacked activity against other GPCRs (including various other chemokine receptors) and showed acceptable ADMET properties.
  • the naphthalene sulfonamide series were reported by Jenkins et al. (2007) J Med Chem 50, 566-584 and Rummel etal. (2012) BrJ Pharmacol, 167, 1206-1217].
  • This series of compounds, exemplified by NS-15 showed at least 300-fold selectivity versus other GPCRs, did not significantly inhibit P450 isozymes, and lacked significant hERG binding.
  • -Ri is selected from substituents II III, or IV, wherein X, Y, Z are each independently selected from N or CH, wherein A is NH, O or S, wherein R3 is an aryl or heteroaryl group, both groups optionally substituted with a group selected from halogen, Cl-5 alkyl, Cl-5 alkoxy, cyano, haloalkyl and nitro, -R2 is
  • Ri is substituent II or III
  • D is S or P
  • B is NH or O
  • Ri is substituent IV
  • D is P and B is NH
  • R 4 is selected from the group consisting of a substituted or unsubstituted aliphatic, substituted or unsubstituted cycloaliphatic substituted unsubstituted heterocycloaliphatic, substituted or unsubstituted aryl and substituted or unsubstituted hetero(aryl) group, or wherein
  • -Ri is selected from the group of substituents II, III or IV wherein X, Y, Z are each independently selected from N or CH, wherein A is NH, O or S, wherein R3 is an aryl or heteroaryl group, optionally substituted with a group selected from halogen, Cl-5alkyl, Cl-5 alkoxy, cyano, haloalkyl, nitro,
  • -R2 is wherein D is S or P, wherein B is NH or O, wherein R 4 is selected from a substituted or unsubstituted aliphatic, substituted or unsubstituted cycloaliphatic, substituted or unsubstituted heterocycloaliphatic, substituted or unsubstituted aryl or substituted or unsubstituted hetero(aryl) group, 2.
  • a compound according to any one of the statements 1 to 8, for use a medicament for use a medicament.
  • CCR.8 mediated disease is selected from the group consisting of asthma, atopic dermatitis, allergic rhinitis, dermatitis, eczema, urticaria, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple scelerosis, diabetes and cancer.
  • a pharmaceutical composition comprising a compound according to any one of the statements 1 to 6, and a pharmaceutically acceptable carrier.
  • -Ri is selected from substituents II or III wherein X, Y, Z are each independently selected from N or CH, wherein A is NH, O or S , wherein R3 is an aryl or heteroaryl group, both groups optionally substituted with a group selected from halogen, Cl-5 alkyl, Cl-5 alkoxy, cyano, haloalkyl and nitro,
  • -R1 is selected from the group of substituents II, III or IV wherein X, Y, Z are each independently selected from N or CH, wherein A is NH, O or S, wherein R3 is an aryl or heteroaryl group, optionally substituted with a group selected from halogen, Cl-5alkyl, Cl-5 alkoxy, cyano, haloalkyl, nitro,
  • -R2 is wherein D is S or P, wherein B is NH or O, wherein R4 is selected from a substituted or unsubstituted aliphatic, cycloaliphatic, heterocycloaliphatic, aryl or hetero(aryl) group,
  • Reference compounds 4 and 6 were both prepared according to a previously reported procedure (Scheme 1) [Verhaegen et al. (2021) Bioorg Chem 107, 104560]. Briefly, sulfonylation of 1-bromo-naphthalene 1 afforded sulfonylchloride 2, which was subsequently reacted with ethyl 4-amino-l-piperidinecarboxylate or 4- methoxyaniline, yielding intermediates 3 and 5, respectively. Introduction of the o- toluamide moiety was achieved via a Buchwald-Hartwig amidation reaction, yielding reference compounds 4 and 6.
  • Reagents and conditions (a) HSO3CI, chloroform, 0 °C; (b) amine, EtsN, DCM, rt ; (c) Pd(OAc)2, Xantphos, CS2CO3, o-toluamide, Ar, dioxane, 100 °C.
  • Compound 3 was selected as a key intermediate from which easily structural variety can be introduced.
  • Various /V-linked heteroaromatics were introduced on compound 3 by a typical Ullmann coupling using an appropriate azole, including an imidazole, a pyrazole and various triazoles (Scheme 2) [Zhang et al. (2015) Journal of Organic Chemistry 80, 705-710] .
  • the desired target compound was isolated as the sole product.
  • 4-phenyl-l,2,3-triazole and benzotriazole a mixture of the 1,4- and 2,4-disubstituted 1,2,3-triazoles (compounds 7d-e and 7f- g, respectively) was obtained.
  • Reagents and conditions (a) Cui, L-proline, K2CO3, azole, Ar, DMSO, 120 °C.
  • Reagents and conditions (a) Cui, DMEDA, sodium ascorbate, HzO/ethanol 3/7, 100 °C. A number of sulfur and oxygen-containing heteroaromatics (thiazole, oxazole, thiadiazole and oxadiazole) were appended the naphthalene scaffold via a carbon linkage (Scheme 4). Since the halogen-substituted heterocycles were much more readily available, when compared to the boronate containing equivalents, the bromide of key intermediate 3 was transformed into the pinacol boronate 10 using a Suzuki-Miyaura borylation with bis(pinacolato)diboron. [Seifert et al.
  • Reagents and conditions (a) PdCl2(dppf), KOAc, bis(pinacolato)diboron, Ar, dioxane, 80 °C; (b) Pd(PPh 3 ) 4 , K 2 CO 3 , aromatic bromide, THF/H 2 O 4: 1, 100 °C.
  • the bromide containing key intermediate 3 was first transformed into the cyano congener 12, using potassium ferrocyanide (K 4 [Fe(CN)e]) as a safe cyanide source, by palladium- catalyzed chemistry [Ren et al. (2009) Org Process Res Dev 13, 2002489] Cyclocondensation of 12 with benzhydrazide furnished the desired analogue 13 [Yeung et al. (2005) Tetrahedron 46, 3429-3432] (Scheme 5).
  • K 4 [Fe(CN)e] potassium ferrocyanide
  • Reagents and conditions (a) Pd(OAc) 2 , NazCCh, K 4 [Fe(CN)e], NMP, 140 °C; (b) K2CO3, benzhydrazide, n-butanol, 150 °C.
  • the synthesis of the inverted sulfonamide 18 started with the coupling of 1-amino- 4-bromonaphthalene 14 with 4-methoxybenzenesulfonylchloride, yielding sulfonamide 15 (Scheme 6). Buchwald amidation of 15 with o-toluamide turned out to be cumbersome as nearly all starting material was recovered after the reaction, most probably due to poisoning of the palladium catalyst.
  • Reagents and conditions (a) 4-methoxybenzene sulfonylchloride, pyridine, rt ; (b) TBAI, NaH, 4-methoxybenzylbromide, Ar, DMF, rt ; (c) Pd(OAc)2, Xantphos, CS2CO3, o-toluamide, Ar, dioxane, 100 °C; (d) TFA, DCM, rt.
  • Reagents and conditions (a) 4-methoxybenzenesulfonamide, DMAP, EtsN, Mukaiyama's reagent, DCM, rt ; (b) DMAP, pyridine, BoczO, THF, 60 °C ; (c) Pd(OAc)2, Xantphos, CS2CO3, o-toluamide, Ar, dioxane, 100 °C.
  • TBDPS tert-butyldiphenylsilyl Reagents and conditions: (a) NH 4 0H, Et20, acetone, 0 °C; (b) TBDPS-CI, EtsN, Ar, THF, 50 °C; (c) PPhsCl2, EtsN, Ar, Chloroform, 0 °C; (d) ethyl 4-aminopiperidine-l- carboxylate; (e) Pd(OAc)2, Xantphos, CS2CO3, o-toluamide, Ar, dioxane, 100 °C; (f) TBAF, THF, 40 °C.
  • the synthesis of the phosphonoamidate analogue 32 was achieved via a different strategy (Scheme 9).
  • the phosphonate moiety was introduced on the naphthalene scaffold via palladium-catalyzed chemistry using diethyl phosphite and starting from l-amino-4-bromonaphthalene 14 [Bessmertnykh et al. (2009) Chem Lett 38, 738- 739]
  • the exocyclic amino group was then converted to the amide 30 by reaction with o-toluoyl chloride [Jenkins et al. cited above].
  • Reagents and conditions (a) Pd2(OAc)2, PPhs, diethylphosphite, EtsN, Ar, ethanol, 80 °C; (b) o-toluoyl chloride, pyridine, 100 °C; (c) NaOH, H2O, dioxane, 100 °C; (d) 2,2'-dithiopyridine, PPF13, EtsN, ethyl 4-aminopiperidine-l-carboxylate, pyridine, 60 °C.
  • Isoquinoline analog 38 was synthesized starting from 5-bromoisoquinoline 34. (Scheme 10).
  • the sulfonic acid moiety was introduced using fuming sulfuric acid affording compound 35, which was isolated by precipitation from water [WO2013178362A1].
  • the sulfonic acid 35 was then transformed into the sulfonamide 37 via a one pot reaction using the sulfonyl chloride as an in situ prepared intermediate [Jenkins et al. cited above].
  • the amide moiety was introduced via Buchwald coupling yielding target compound 38 [Ruiz-Castello & Buchwald, cited above].
  • Reagents and conditions (a) fuming sulfuric acid, 100°C; (b) thionyl chloride, DMF, 75°C; (c) DMAP, EtsN, ethyl 4-aminopiperidine-l-carboxylate, DCM, rt.; (d) Pd(OAc)2, Xantphos, CS2CO3, o-toluamide, Ar, dioxane, 100 °C.
  • the basic principle of the calcium mobilization assay is to load cells with a calcium-sensitive dye, which fluoresces when bound to calcium; therefore, an increased fluorescence signal is indicative of activation of CCR8. Hence, inhibition of CCL1 induced calcium mobilization by various compounds is indicative for their CCR8 antagonistic activity.
  • the pyrazole (compound 7a), the imidazole (compound 7b), the 1,2,4-triazole (compound 7c) and the 2,4- disubstituted 1,2,3-triazole analogue (compound 7e) showed potent inhibition of labeled CCL1 binding, with IC50 values in the range of 18-42 nM.
  • the same analogues were also endowed with excellent activity in the functional CCR8 calcium mobilization assay (IC50 values between 0.089 and 3.2 pM), although a 5- to 76-fold loss in activity in the calcium assay is observed, when compared to the binding assay.
  • the 1,4-disubstituted 1,2,3-triazole (compound 7d) was the most potent analogue within this series.
  • IC50 5 nM
  • This potency of compound 7d is not that surprising, since the triazole moiety has gained widespread use, as an excellent non-classical bioisoster of the trans amide bond [Kumari et al. (2020) J. Med. Chem 63, 12290- 12358].
  • the potent CCR8 antagonistic activity of triazole 7d prompted us to probe the SAR around the phenyl ring (Table 2). Fusing the phenyl moiety with the triazole ring afforded the regioisomeric benzotriazole derivatives 7f and 7g. Both regioisomers are 40-fold less active in the binding assay, when compared to the phenyl-substituted triazole analogue 7d. Their decreased activity as CCR8 antagonists is more pronounced in the calcium mobilization assay, as evident from their IC50 values in the low pM range.
  • the sulfur-containing heteroaromatics such as the 1,3,4-thiadiazole Ila, the 5-phenylthiazole 11b and the 2- phenylthiazole 11c do show activities in the binding assay with IC50 values of 10 nM or less, but loose quite some activity (40- to 120-fold) upon evaluation in the calcium assay.
  • Table 3. CCL1 competition binding and CCR8 calcium mobilization data of compounds lla-e and 13 a ICso : the compound concentration inhibiting CCL1 AF647 binding by 50%.
  • b ICso the compound concentration that inhibits CCL1 induced intracellular calcium flux by 50%.
  • NMR spectra were acquired on commercial instruments (Bruker Avance 300 MHz, Bruker AMX 400 MHz or Bruker Avance 11+ 600 MHz) and chemical shifts (6) are reported in parts per million (ppm) referenced to tetramethylsilane ( 1 H), or the internal (NMR) solvent signal ( 13 C).
  • High resolution mass spectra were acquired on a quadrupole orthogonal acceleration time-of-flight mass spectrometer (Synapt G2 HDMS, Waters, Milford, MA, USA). Samples were infused at 3 pL/min and spectra were obtained in positive mode with a resolution of 15 000 (FWHM) using leucine enkephalin as lock mass.
  • This compound was prepared according to the general procedure using 3- phenylpyrazole (36.0 mg, 0.25 mmol, 2.5 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (13.3 mg, 26% yield).
  • This compound was prepared according to the general procedure using 4- phenylimidazole (36.0 mg, 0.25 mmol, 2.5 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (21.3 mg, 41% yield).
  • This compound was prepared according to the general procedure using 3-phenyl- 1,2,4-triazole (36.3 mg, 0.25 mmol, 2.5 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (31.3 mg, 62% yield).
  • Both compounds were prepared according to the general procedure on a doubled scale using 4-phenyl-l,2,3-triazole (72.5 mg, 0.5 mmol, 2.5 eq.).
  • the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding title compound 7d as a solid (28.0 mg, 27% yield) and title compound 7e as a solid (29.1 mg, 28% yield).
  • Both compounds were prepared according to the general procedure on a doubled scale using lH-benzo[d][l,2,3]triazole (59.6 mg, 0.5 mmol, 2.5 eq.).
  • the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding title compound 7f as a solid (13.8 mg, 14% yield) and title compound 7g as a solid (20.9 mg, 22% yield).
  • This compound was prepared according to the general procedure using 2- methoxyphenyl acetylene (31 pl, 0.24 mmol, 1.2 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (54.8 mg, 51% yield).
  • This compound was prepared according to the general procedure using 3- methoxyphenyl acetylene (30 pl, 0.24 mmol, 1.2 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (30.1 mg, 28% yield). 1
  • This compound was prepared according to the general procedure using 4- methoxyphenyl acetylene (26 pl, 0.24 mmol, 1.2 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (71.8 mg, 67% yield).
  • This compound was prepared according to the general procedure using 2- methoxyphenyl acetylene (30 pl, 0.24 mmol, 1.2 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (47.9 mg, 46% yield).
  • This compound was prepared according to the general procedure using 2- methoxyphenyl acetylene (31 pl, 0.24 mmol, 1.2 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (31.4 mg, 30% yield).
  • This compound was prepared according to the general procedure using 2- methoxyphenyl acetylene (30 pl, 0.24 mmol, 1.2 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (36.9 mg, 36% yield).
  • This compound was prepared according to the general procedure using 2- methoxyphenyl acetylene (28 pl, 0.24 mmol, 1.2 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (31.2 mg, 30% yield).
  • This compound was prepared according to the general procedure using 2- methoxyphenyl acetylene (28 pl, 0.24 mmol, 1.2 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (26.6 mg, 25% yield).
  • This compound was prepared according to the general procedure using 2- methoxyphenyl acetylene (35 pl, 0.24 mmol, 1.2 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (31.8 mg, 28% yield).
  • This compound was prepared according to the general procedure using 2- methoxyphenyl acetylene (39 pl, 0.24 mmol, 1.2 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (23.7 mg, 21% yield).
  • the reaction tube was evacuated and backfilled with argon three times before dissolving the solids in anhydrous dioxane which was degassed using 5 freeze pump thaw cycles (20 ml).
  • the reaction was allowed to stir 20h at 80 °C, after which the mixture was filtered over celite, washed with DCM and concentrated in vacuo.
  • the crude residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (8/2) as the mobile phase yielding the title compound as a solid (462.2 mg, quantitative yield).
  • This compound was prepared according to the general procedure using 2-bromo-5- phenyl-l,3,4-thiadiazole (36.2mg, 0.15 mmol, 1.5 eq.).
  • the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (37.3 mg, 71%).
  • This compound was prepared according to the general procedure using 2-bromo-5- phenylthiazole (36.0 mg, 0.15 mmol, 1.5 eq.). The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (39.3 mg, 75%).
  • This compound was prepared according to the general procedure using 5-bromo-2- phenylthiazole (36.0 mg, 0.15 mmol, 1.5 eq.).
  • the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (36.5 mg, 70%).
  • This compound was prepared according to the general procedure using 2-bromo-5- phenyl-l,3,4-oxadiazole (33.8 mg, 0.15 mmol, 1.5 eq.).
  • the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (29.8 mg, 59%).
  • This compound was prepared according to the general procedure using 5-bromo-2- phenyloxazole (33.6 mg, 0.15 mmol, 1.5 eq.).
  • the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of petroleum ether/ethyl acetate (6/4), yielding the title compound as a solid (32.9 mg, 65%).
  • benzhydrazide (27.2 mg, 0.2 mmol, 2 eq.), ethyl-4-((4-cyanonaphthalene)-l- sulfonylamino)-piperidine-l-carboxylate 11 (38.7 mg, 0.1 mmol, 1 eq.), K2CO3 (27.6 mg, 0.2 mmol, 2 eq.) and n-butanol (0.5ml) were added and allowed to stir for 5h at 150 °C. The mixture was quenched with water and extracted three times with dichloromethane.
  • N-(4- bromonaphthalen-l-yl)-4-methoxybenzenesulfonamide (15) (392.3 mg, 1 mmol, 1 eq.), TBAI (96.7 mg, 0.3 mmol, 0.3 eq.), NaH (72.0 mg, 3 mmol, 3 eq.) were added.
  • the round bottom flask was evacuated and backfilled with argon three times before dissolving the solids in anhydrous DMF (10 ml). The mixture was allowed to stir for 10 minutes at 0 °C before adding 4-methoxybenzylbromide (216 pl, 1.5 mmol, 1.5 eq.).
  • the reaction tube was evacuated and backfilled with argon three times. Anhydrous dioxane (0.8 ml) was added and the reaction was allowed to stir for 16h at 100 °C. The mixture was diluted with DCM (8 ml) and filtered. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (6/4) as the mobile phase yielding the title compound as a solid (367.5 mg, 81% yield).
  • the reaction tube was evacuated and backfilled with argon three times. Anhydrous dioxane (0.4 ml) was added and the reaction was allowed to stir for 16h at 100 °C. The mixture was diluted with DCM (4 ml) and filtered. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (6/4) as the mobile phase yielding the title compound as a solid (152.4 mg, 80% yield).
  • triphenylphosphine dichloride (249.9 mg, 0.75 mmol, 1.5 eq.) was added.
  • the round bottom flask was evacuated and backfilled with argon three times.
  • Chloroform (1.67 ml) was added followed by the dropwise addition of triethylamine (111 pl, 0.8 mmol, 1.6 eq.).
  • the reaction mixture was allowed to stir for 20 minutes before cooling it down to 0 °C.
  • the reaction tube was evacuated and backfilled with argon three times. Anhydrous dioxane (0.2 ml) was added and the reaction was allowed to stir for 16h at 100 °C. The mixture was diluted with DCM (4 ml) and filtered. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (6/4) as the mobile phase yielding the title compound as a solid (90.7 mg, 62% yield). The product was used in the next step without further purification.
  • 4-bromonaphthalen-l-amine 14 (1.111 g, 5 mmol, 1 eq.), Pd(OAc)2 (22.5 mg, 0.1 mmol, 0.02 eq.) and triphenylphosphine (78.7 mg, 0.3 mmol, 0.06 eq.) were added.
  • the reaction tube was evacuated and backfilled with argon three times and ethanol (10 ml), diethyl phosphite (0.78 ml, 12 mmol, 1.2 eq.) and triethylamine (1.05 ml, 7.5 mmol, 1.5 eq.) were added.
  • diethyl (4- aminonaphthalen-l-yl)phosphonate 29 (1.1 g, 3.7 mmol, 1 eq.), DCM (40 ml) and 2-methylbenzoylchloride (0.724 ml, 5.55 mmol, 1.5 eq.) were added.
  • the mixture was allowed to stir for 5 minutes at room temperature before addition of triethylamine (4ml).
  • the reaction mixture was allowed to stir for 15h at room temperature and washed two times with HCI (IM) and water.
  • the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.
  • Silica gel column chromatography of the crude product using DCM/MeOH (95/5) as the mobile phase provided the title compound as a solid (1.294 g, 88% yield). The product was used in the next step without further purification.
  • the hCCLl AF647 binding inhibition assay was performed and analyzed as described in [Liu et al. (2021) Biochem Pharmacol. 188, 114565]. Briefly, 50 pL/well of serial compound dilutions and 50 pL/well of hCCLl AF647 (2 nM final concentration) were mixed in a U-bottom 96-well plate. Then 100 pL/well of 1 x 10 5 Jurkat.hCCR8 cells, resuspended in the assay buffer, was added. After mixing samples were and incubated for 30 min at room temperature (RT) protected from light.
  • RT room temperature
  • MFI mean fluorescence intensity
  • Human glioblastoma U87 cells stably expressing CD4 and CCR8 (U87.CD4.CCR8) were seeded at 20,000 cells per well in gelatin-coated black-walled polystyrene 96- well plates and incubated overnight at 37°C and 5% CO2. The next day, cell culture medium was replaced with 80pL/well of Calcium 6 Assay Kit loading medium (Molecular Devices), which was prepared according the manufacturer's instructions. After incubating the cells for 2h at 37°C and 5% CO2 they were transferred to the FLIPR Tetra device (Molecular Devices). Serial dilutions of compounds were added to the cells first and incubated for lOmin.
  • hCCLl a fixed concentration of hCCLl (5.88nM final concentration) was added to induce a CCR8-mediated intracellular Ca 2+ release.
  • All responses were normalized by dividing through a baseline determined just before the time of hCCLl addition and also background corrected by subtracting the averaged normalized response from untreated (i.e., no compound) and unstimulated (i.e., no hCCLl) cells. The percentage (%) inhibition induced by the compounds was then calculated relative to positive control samples (i.e., no compound, only hCCLl stimulation). Based on the dose-dependent % inhibition, IC50 values were calculated using non-linear curve fitting in Graphpad Prism 9.0.0.

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Abstract

L'invention concerne de nouveaux antagonistes de CCR8, basés sur NS-15 en tant que structure de conducteur, qui ont été conçus et synthétisés. Pour maintenir le potentiel de liaison hydrogène, la mise au point est effectuée sur les remplacements isostériques de la liaison amide. De plus, des isosters de la fraction sulfonamide, ainsi que de l'échafaudage naphtalène sont divulgués.
PCT/EP2023/086683 2022-12-19 2023-12-19 Nouveaux antagonistes de ccr8 WO2024133292A1 (fr)

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EP22214497.4 2022-12-19
EP22214497 2022-12-19

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